From: Subject: Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: The CINDERELLA trial Date: Wed, 3 Nov 2010 11:07:05 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CB7B47.3FB6CC30" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5994 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CB7B47.3FB6CC30 Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958944/ =EF=BB=BF Randomised phase I/II = study to evaluate carbon ion radiotherapy versus fractionated = stereotactic radiotherapy in patients with recurrent or progressive = gliomas: The CINDERELLA trial
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BMC Cancer. 2010; 10: 533.=20
Published online 2010 = October 6.=20 doi: 10.1186/1471-2407-= 10-533.
PMCID:=20 = PMC2958944
Copyright=20 =C2=A92010 Combs et al; licensee BioMed Central Ltd.
Randomised phase I/II study to evaluate=20 carbon ion = radiotherapy=20 versus fractionated stereotactic radiotherapy in = patients with recurrent or progressive gliomas: = The=20 CINDERELLA trial
Stephanie E Combs,3D"corresponding1=20 Iris Burkholder,2 Lutz Edler,2 Stefan=20 Rieken,1 Daniel Habermehl,1 Oliver=20 J=C3=A4kel,3 Thomas Haberer,3 Renate=20 Haselmann,1 Andreas Unterberg,4 Wolfgang=20 Wick,5 and J=C3=BCrgen Debus1
1Department of Radiation Oncology, = University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120=20 Heidelberg, Germany
2Institute of Medical Biometry and = Informatics, University of Heidelberg, Im Neuenheimer Feld 305, = 69120=20 Heidelberg, Germany
3Heidelberger Ionenstrahl = Therapiezentrum=20 (HIT), Im Neuenheimer Feld 450, 69120 Heidelberg, Germany
4Department of Neurooncology, = University=20 Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, = Germany
5Department of Neurosurgery, = University=20 Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, = Germany
3D"correspondingCorresponding=20 author.
Stephanie E Combs:=20 stephanie.combs/at/med.uni-heidelberg.de ; Iris Burkholder: = StaBiL/at/Burkholder.de ; Lutz Edler: l.edler/at/dkfz.de ; Stefan Rieken: stefan.rieken/at/med.uni-heidelberg.de ; Daniel Habermehl: = daniel.habermehl/at/med.uni-heidelberg.de ; Oliver J=C3=A4kel: = oliver.jaekel/at/med.uni-heidelberg.de ; Thomas Haberer: Thomas.haberer/at/med.uni-heidelberg.de ; Renate Haselmann: = renate.haselmann/at/med.uni-heidelberg.de ; Andreas Unterberg: = andreas.unterberg/at/med.uni-heidelberg.de ; Wolfgang Wick: wolfgang.wick/at/med.uni-heidelberg.de ; J=C3=BCrgen Debus: = juergen.debus/at/med.uni-heidelberg.de
Received July 22, 2010; Accepted October = 6,=20 2010.
This is an Open Access article = distributed under=20 the terms of the Creative Commons Attribution License (http://creativecommons.org/lice= nses/by/2.0),=20 which permits unrestricted use, distribution, and reproduction in = any=20 medium, provided the original work is properly cited.
Abstract
Background
Treatment of patients = with=20 recurrent glioma includes neurosurgical resection, chemotherapy, = or=20 radiation therapy. In most cases, a full course of radiotherapy = has been=20 applied after primary diagnosis, therefore application of = re-irradiation=20 has to be applied cauteously. With modern precision photon = techniques such=20 as fractionated stereotactic radiotherapy (FSRT), a second course = of=20 radiotherapy is safe and effective and leads to survival times of = 22, 16=20 and 8 months for recurrent WHO grade II, III and IV gliomas.
Carbon ions offer physical and = biological=20 characteristics. Due to their inverted dose profile and the high = local=20 dose deposition within the Bragg peak precise dose application and = sparing=20 of normal tissue is possible. Moreover, in comparison to photons, = carbon=20 ions offer an increased relative biological effectiveness (RBE), = which can=20 be calculated between 2 and 5 depending on the GBM cell line as = well as=20 the endpoint analyzed. Protons, however, offer an RBE which is = comparable=20 to photons.
First Japanese Data on = the=20 evaluation of carbon ion radiation therapy for the treatment of = primary=20 high-grade gliomas showed promising results in a small and = heterogeneous=20 patient collective.
Methods Design
In the current Phase=20 I/II-CINDERELLA-trial re-irradiation using carbon ions will be = compared to=20 FSRT applied to the area of contrast enhancement representing = high-grade=20 tumor areas in patients with recurrent gliomas. Within the Phase I = Part of=20 the trial, the Recommended Dose (RD) of carbon ion radiotherapy = will be=20 determined in a dose escalation scheme. In the subsequent = randomized Phase=20 II part, the RD will be evaluated in the experimental arm, = compared to the=20 standard arm, FSRT with a total dose of 36 Gy in single doses of 2 = Gy.
Primary endpoint of the = Phase I part=20 is toxicity. Primary endpoint of the randomized part II is = survival after=20 re-irradiation at 12 months, secondary endpoint is = progression-free=20 survival.
Discussion
The Cinderella = trial is the=20 first study to evaluate carbon ion radiotherapy for recurrent = gliomas, and=20 to compare this treatment to photon FSRT in a randomized setting = using an=20 ion beam delivered by intensity modulated = rasterscanning.
Trial Registration
NCT01166308
Background
Recurrent gliomas = remain a major=20 challenge in radiation oncology. In the past, second courses of=20 radiotherapy have only been applied reluctantly, in fear of=20 treatment-related side effects. However, modern radiation = techniques have=20 enabled the radiation oncologist to deliver high local doses as an = effective salvage treatment with low rates of side effects.
Especially for GBM, with = unsatisfactory=20 outcomes even after extensive research over the past centuries, = effective=20 treatment at tumor recurrence are needed urgently. With surgery = and=20 supportive care alone, overall survival is about 3-5 months. = Postoperative=20 RT can increase overall survival to 9-12 months [1]. A number of studies have shown that an = additional=20 treatment with chemotherapy can increase overall survival. This = benefit,=20 however, is commonly associated with a high risk of = treatment-related side=20 effects, especially with combination treatments, such as PCV, and = with=20 BCNU. Only recently, significant increase in overall survival = could be=20 achieved by adding TMZ, an orally applicable alkylating substance, = to=20 postoperative radiotherapy. In a prospective randomized Phase III = study=20 performed by the EORTC radiochemotherapy with TMZ was compared to=20 postoperative radiation alone. Overall survival could be increased = from=20 12.1 months to 14.6 months, with acceptable toxicity. TMZ was = applied in a=20 dose of 75 mg/m2/die during radiotherapy, followed by 6 = cycles=20 of adjuvant TMZ [2]. Therefore, standard treatment of patients with = GBM is=20 currently considered to be postoperative radiochemotherapy with = TMZ,=20 followed by 6 cycles or adjuvant TMZ.
However, with an overall survival = of about 15=20 months, treatment outcome still remains insufficient, and patients = develop=20 tumor recurrences soon after primary diagnosis.
For anaplastic gliomas, overall = survival=20 after standard treatment following primary diagnosis, including=20 neurosurgical resection and postoperative radiotherapy, lies = between 18=20 and 50 months [3]. However, also these patients develop tumor = recurrences=20 after primary diagnosis, and effective salvage treatments are=20 required.
Treatment of low grade gliomas = has been=20 discussed controversially over the last years with respect to = optimal=20 radiation dose and time point of radiotherapy. It has been shown, = that=20 doses of 45-54 Gy are sufficient for long-term local tumor = control, and=20 that early application of radiotherapy can increase = progression-free=20 survival significantly, without altering overall survival as = compared to=20 treatment applied for tumor progression [4]. During follow-up, patients develop not only low = grade=20 tumor progression, but also high-grade malignant tumor = lesions.
In the past, a second course of = radiotherapy=20 has been applied reluctantly with conventional techniques as = treatment=20 outcome outweighs the risk of treatment-related side effects [5]. With modern high-precision stereotactic photon=20 techniques, such as Fractionated Stereotactic Radiotherapy (FSRT)=20 re-irradiation could be established as a safe and effective = treatment=20 option for recurrent gliomas [6]. Survival times of 111, 50 and 21 months for WHO = Grade II,=20 III and IV gliomas could be shown with FSRT, with very low rates = of side=20 effects. However, outcome still remains unsatisfactory [7].
Charged particles provide the = physical=20 advantage of an inverted dose profile which enables steep dose = gradients.=20 Neighboring organs at risk and surrounding normal tissue can be = spared=20 from radiation doses. Additionally, heavy charged particles, such = as=20 carbon ions, as high-LET beams, are characterized by an enhanced = RBE. For=20 glioblastoma cell lines, RBE values between 2 and 5 have been = reported=20 depending on cell line and endpoint [8,9].
In general, GBM are = treatment-resistant=20 tumors. Early studies using a high-dose proton boost could show = that total=20 doses up to 90 Gy E were effective in preventing local tumor = recurrences,=20 however, such high doses were associated with high rates of side = effects=20 [10]. Therefore, in general, standard radiation = therapy is=20 applied up to a total dose of 60 Gy. Besides the physical = advantages of=20 high local dose deposition provided by protons, carbon ions are a=20 promising treatment alternative due to their biological benefits. = A=20 clinical study performed by the National Institute of Radiological = Sciences (NIRS) treated 48 patients with malignant gliomas with a = carbon=20 ion boost up to total doses of 24.8 Gy E, of which 32 were GBM [11]. In this study, no treatment related toxicity = exceeding=20 CTCAE Grade II or higher were observed. Therefore, the concept of = a carbon=20 ion radiotherapy for the treatment of recurrent gliomas with = contrast=20 enhancing lesions is a promising treatment alternative.
Carbon ion radiotherapy was = available by the=20 Department of Radiation Oncology at the Gesellschaft f=C3=BCr=20 Schwerionenforschung (GSI) in Darmstadt since 1997. Superior = treatment=20 results for a number of tumor entities, such as chordomas and=20 chondrosarcomas of the skull base, as well as ACC have been shown, = and=20 carbon ion radiotherapy is currently performed in the clinical = routine for=20 these patients [12,13]. Safety of carbon ion radiotherapy with = respect to=20 critical organs at risk, such as the brain, brainstem or spinal = chord,=20 have been shown in these studies. At the Heidelberg Ion Therapy = Center=20 (HIT), treatment of over 1300 patients per year with Proton and = Carbon ion=20 RT is possible.
In vitro data for the = treatment of=20 GBM with carbon ions have shown superior effectivity compared to = photons=20 [14]. Our own data have shown a high RBE for carbon = ion RT=20 for GBM; additionally a combination of carbon ion radiotherapy and = TMZ=20 have been evaluated and show an additive effect in GBM-cell lines = [8]. A first clinical study evaluating a carbon ion = boost in=20 patients with GBM was recently published by Mizoe et al. [15]. Median overall survival in patients with = glioblastoma=20 was 17 months; however, only small patient numbers were evaluated = and=20 standard chemotherapy with TMZ was not applied. In that study, the = carbon=20 ion boost was applied with increasing total doses up to 24.8 Gy E. = While=20 toxicity was low even in the high dose arm, the data showed that = patients=20 seem to benefit from the high dose carbon ion boost.
The promising results in primary = GBM and the=20 known physical and biological properties of carbon ion offer a = promising=20 treatment alternative that should be evaluated for the treatment = of=20 patients with recurrent gliomas.
In the present = CINDERELLA trial, the=20 impact of carbon ion radiotherapy using intensity modulated = rasterscanning=20 will be compared to FSRT which is considered the treatment = standard=20 alternative for patients with recurrent gliomas. In a first Phase = I=20 design, the RD of carbon ion radiotherapy for re-irradiation of = gliomas=20 will be determined. In the following Phase II part, the RD of = carbon ions=20 will be compared to standard photon radiotherapy delivered as=20 FSRT,
Methods and Design
Study design
The trial will be = performed as a=20 single-center two-armed randomized Phase I/II study.
Phase I: Dose Escalation
Patients fulfilling the = inclusion=20 criteria will be treated with increasing total doses of carbon ion = radiotherapy to RD of carbon ion radiotherapy for re-irradiation = of=20 recurrent gliomas.
Patients will be treated = within=20 seven increasing dose regimens starting at 10 =C3=97 3 GyE up to = 16 =C3=97 3=20 GyE.
Phase II: Randomized Part
Patients fulfilling the = inclusion=20 criteria will be randomized into two arms:
Arm A - Experimental Arm
Carbon Ion Radiation = Therapy
The total dose applied will be = the RD=20 determined in the Phase I part of the study protocol.
Arm B - Standard Arm
Fractionated Stereotactic = Radiotherapy with=20 Photons
Total Dose 36 Gy, 18 fractions, 2 = Gy single=20 dose
A flow chart of the study is = shown in Fig. =E2=80=8BFig.11.
3D"Figure
<= /DIV>
Figure 1
Flow Chart of the=20 Cinderella-Study.
Study objectives
The purpose of the = trial is to=20 compare carbon ion radiotherapy to FSRT for the treatment of = recurrent=20 gliomas delivered to the area of contrast-enhancement in = T1-weighted MRI=20 and/or Amino-Acid-PET-positive lesions.
In the Phase I study, the RD of = carbon ion=20 radiotherapy will be determined in a dose escalation scheme. The = primary=20 endpoint is toxicity.
In the randomized Phase = II part of=20 the study, carbon ion radiotherapy treated at the recommended dose = evaluated in the phase I part will be compared to standard photon=20 radiotherapy delivered as FSRT. The primary endpoint is survival = after=20 re-irradiation at 12 months.
Primary Objectives
Phase I
The primary = objective is any=20 Grade IV toxicity related to the study treatment according to = CTCAE Grade=20 IV.
Phase II
The primary = objective is=20 survival after re-irradiation at 12 months.
Secondary Objectives
Phase I
The secondary = objective in the=20 Phase I part is survival after re-irradiation
Phase II
The secondary = objectives of=20 the study are progression-free survival, toxicity and=20 safety.
Patient selection: Inclusion=20 criteria
Patients meeting all of = the=20 following criteria will be considered for admission to the = trial:
- unifocal, supratentorial = recurrent glioma=20 (primary histologies including any WHO Grade II or III glioma or=20 glioblastoma)
- prior course of standard photon = radiotherapy
- contrast enhancement on = T1-weighted MRI=20 and/or Amino-Acid-PET-positive high-grade tumor areas
- indication re-irradiation
- age =E2=89=A5 18 years of = age
- Karnofsky Performance Score = =E2=89=A560
- For women with childbearing = potential, (and=20 men) adequate contraception.
- Ability of subject to = understand character=20 and individual consequences of the clinical trial
- Written informed = consent (must be=20 available before enrolment in the trial)
Patient selection: Exclusion=20 criteria
Patients presenting = with any of the=20 following criteria will not be included in the trial:
- Multifocal Glioma or = Gliomatosis=20 cerebri
- refusal of the patients to take = part in the=20 study
- previous re-irradiation or = prior=20 radiosurgery or prior treatment with interstitial radioactive = seeds
- time interval of < 6 months = after=20 primary radiotherapy
- Patients who have not yet = recovered from=20 acute toxicities of prior therapies
- Known carcinoma < 5 years = ago (excluding=20 Carcinoma in situ of the cervix, basal cell carcinoma, squamous = cell=20 carcinoma of the skin) requiring immediate treatment interfering = with=20 study therapy
- Pregnant or lactating = women
- Participation in = another clinical=20 study or observation period of competing trials, = respectively.
Treatment Assignment
Radiation therapy = according to the=20 protocol will be performed in patients included into the study and = after=20 assignment of the patients to the treatment arms after=20 randomization.
Patients withdrawn from = the trial=20 retain their identification codes (e.g. randomization number, if = already=20 given). New patients must always be allotted a new identification=20 code.
Treatment Planning
For FSRT and particle = therapy,=20 patients will be immobilized using an individually manufactured = head mask.=20 For treatment planning, contrast-enhanced CT as well as MR-imaging = will be=20 performed for optimal target definition.
Treatment planning for carbon ion = and FSRT is=20 to be performed about 1-2 weeks prior to the start of=20 re-irradiation.
Organs at risk such as the brain = stem, optic=20 nerves, chiasm and spinal chord will be contoured. Dose = constraints of=20 normal tissue will be respected according to Emami et al. [16].
The Treatment Volume for = Re-Irradiation will=20 be defined as the area of contrast enhancement on T1-weighted = MR-imaging=20 adding a safety margin of 5 mm.
Amino-Acid-PET or = SPECT-Examinations may be=20 used in addition to contrast-enhanced MRI for target volume = definition but=20 are not mandatory.
FSRT planning is performed using = standard=20 photon-treatment planning systems such as HELAX, Masterplan or = STP.
Carbon ion RT planning is = performed using the=20 treatment planning software PT-Planning (Siemens, Erlangen, = Germany)=20 including biologic plan optimization. Biologically effective dose=20 distributions will be calculated using the a/=CE=B2 ratio for = gliomas as well=20 as for the endpoint late toxicity to the brain.
No interruptions > 4 days = during study=20 treatment (carbon ion radiotherapy or FSRT) are allowed.
Patient positioning = prior to FSRT or=20 particle therapy will be evaluated by comparison of x-rays to the = DRRs.=20 Set up deviations >3 mm are corrected prior to=20 radiotherapy.
Dose Prescription Experimental = (Carbon)=20 Arm
The = intensity-controlled rasterscan=20 system will be used for beam application. In the Phase I Dose = Escalation=20 Part, increasing doses of carbon ion radiotherapy will be = evaluated in 7=20 steps starting at 10 =C3=97 3 Gy E up to 16 =C3=97 3 Gy E. In this = part, the RD of=20 carbon ion radiotherapy for re-irradiation of gliomas will be=20 determined.
Therafter, the RD determined will = be chosen=20 for the randomized phase II part of the study. The total dose will = be=20 prescribed to the maximum of the calculated dose distribution for = the=20 target volume. Treatment planning aims in the coverage of the = target=20 volume by the 90%-isodose line.
Dose specification is based on = biologic=20 equivalent dose because of the high RBE of carbon ions, which = differs=20 throughout the target volume due to its dependence on various = factors. RBE=20 will be calculated at each voxel throughout the target volumes and = biological optimization will be performed. The dose prescription = used is=20 related to the isoeffective dose GyE using daily fractions of 2 Gy = and a=20 weekly fractionation of 5 =C3=97 3 Gy.
A typical treatment plan is shown = in Fig. =E2=80=8BFig.22.
<= STRONG>Figure=20 1
Flow Chart=20 of the Cinderella-Study.
3D"Figure
<= /DIV>
Figure 2
Typical treatment plan = for carbon ion=20 radiotherapy for a patients with a recurrent glioblatoma. = Treatment is performed using the Siemens TPS for particle therapy, = target=20 volume delienation is based on CT- and MR-imaging with contrast=20 enhancement.
Dose Prescription Standard = (Photon)=20 Arm
Eighteen fractions = of a single=20 dose of 2 Gy up to a total dose of 36 Gy will be prescribed to the = isocenter. Treatment planning aims in the coverage of the target = volume by=20 the 90%-isodose line.
Statistical calculations for = trial sample=20 size
The statistical methods = applied for=20 this study are subject to GCP guidelines (Guidelines of the = International=20 Conference on Harmonisation (ICH) e.g.
=E2=80=A2 ICH E3: Structure and = Contents of Clinical=20 Study Reports,
=E2=80=A2 ICH E6: Good Clinical = Practice (GCP).=20 Consolidated Guideline,
=E2=80=A2 ICH E9: Note = for Guidance on=20 Statistical Principles in Clinical Trials) and will be performed = in=20 accordance with CESAR SOP 8 (Statistical Analysis/Biometry) in = their=20 versions valid at the date of the original study = protocol.
Study Hypothesis
Phase I
Phase I part of = this study is=20 conducted to choose the Recommended Dose (RD) of carbon ion = radiotherapy=20 for the phase II part between seven dose levels based on the dose=20 escalation scheme.
Phase II
The phase II part = of this=20 study is designed to demonstrate superiority in survival of carbon = ion=20 radiotherapy (experimental) to FSRT (standard) in patients with = recurrent=20 or progressive gliomas. The primary endpoints variable is overall = survival=20 time after at least 12 months of follow-up (OS_12m) defined as = time to=20 death for any reason during the follow-up period of at least 12 = months=20 starting from date of randomization.
Sample Size Calculation
Phase I
Seven DLs are included = in the dose=20 finding part. It is assumed that the probability of a DLT is 1/3. = With n =3D=20 8 patients in each DL, the power that at each DL at least one DLT = is=20 observed is greater than 95%. Therefore a maximum of 56 patients = will be=20 treated in the phase I part of this study.
Within this study, DLTs = are defined=20 as any grade IV toxicity according to CTCAE Version 4.0 associated = to=20 study treatment.
Phase II
=E2=80=A2 The size of = the phase II part of=20 this study is determined by the primary aim of testing = experimental=20 treatment for superiority over standard treatment. This endpoint = is a=20 censored failure time.
=E2=80=A2 Information on the = OSB_12mR=20 (overall survival rate after 12 months of follow-up for standard=20 treatment) is given in literature data [17].
To calculate survival data, a = population=20 distribution of GBM in 34.3%, Grade III Tumors in 24.4% and low = grade=20 gliomas in 41.3% was used [17]. Survival rates for overall survival were = taken as=20 published previously with 23% for GBM 65% for Grade III, and 77% = for=20 low-grade gliomas observed at 12 months after re-irradiation [17].
Overall OSB_12mR can = be calculated=20 as weighted mean rate. Therefore OSB_12mR is expected = to be=20 56%. The study will be designed to detect an improvement in = OS_12mR of 10%=20 (OSA_12mR =3D 66%).
The statistical error rates for = this test of=20 superiority are set as =CE=B1 =3D 0.05 and =CE=B2 =3D 0.20 (power = 80%). Sample size=20 calculation is based on an unstratified log-rank. It can be = expected that=20 including histology in a stratified log-rank test will increase = the power=20 as compared to the unstratified test.
The recruitment period will be 36 = months with=20 a minimal follow-up time of 12 months. In order to put more = patients on=20 the experimental treatment, an unbalanced randomization allocation = ratio=20 of 2:3 was chosen.
For this set of = assumptions, the=20 sample size calculation programme PASS 2008 yields the total = sample size=20 for standard treatment of n =3D 138 and n =3D 207 for experimental = treatment.=20 Allowing for failures for various reasons of 10%, a total of N =3D = 380 is=20 required for this part of the study (n =3D 152 in standard arm and = n =3D 228=20 in experimental arm). Patients will be stratified by=20 histology.
Statistical Methods
Phase I
Primary endpoint
Safety will be = assessed by the=20 type, incidence and severity (graded by the NCI CTC-AE Version = 4.0) and=20 relation to treatment. All patients treated at least once with one = of the=20 seven dose levels defined above will be described individually and = summarized by dose level. No confirmatory statistical analysis = will be=20 performed.
Secondary endpoint
Descriptive summary = tables will be=20 presented on baseline patient characteristics as well as for all = safety=20 parameters by dose level. Patients will be monitored for adverse = events=20 using NCI-CTC version 4.0.
Phase II
Primary endpoint
The primary endpoint = variable OS_12=20 m was planned to be analysed by a one sided logrank test of = stratified by=20 histology testing H0: OSA-12 m =3D = OSB-12 m=20 versus H1: OSA-12 m > OSB-12 m = at the=20 level of alpha =3D 5%. One interim analysis is planned when 50% of = the=20 number of expected events under the null-hypothesis have occurred. = In=20 order to preserve the significance level of 5% a sequential plan = with=20 alpha-spending of De-Mets and Lan with limits of O'Brien and = Fleming is=20 applied.
Overall survival will be = summarized=20 by Kaplan-Meier curves. Median estimates as well as associated 95% = confidence intervals will be reported. Further, a descriptive = analysis of=20 the primary outcome variable is performed applying a = Cox-regression=20 model.
Secondary endpoints
=E2=80=A2 = Progression-free survival will be=20 analyzed analogously to the primary endpoints. P-value of the = logrank test=20 and test within the Cox regression will be interpreted=20 descriptively.
=E2=80=A2 Safety/Toxicity will be assessed by the = type,=20 incidence, severity (graded by the NCT CTCAE Version 4.0), and = relatedness=20 of AEs to treatment and by assessment of laboratory parameters = related to=20 safety. Tolerability and dosing will be described by numbers of = patients=20 in whom treatment was given as planned, delayed or permanently = stopped.=20 All analyses will be performed separately for both treatment = groups.
A detailed SAP will be = designed=20 after initiating the study and before start of data analysis by = the=20 biometric center. It will consider all analyses necessary to = characterize=20 the study populations and to evaluate the primary and secondary=20 endpoints.
Interim Analysis
Phase I
Besides the = planned analysis=20 during and after phase I part, no further interim analysis are=20 planned.
Phase II
For the primary aim and = the primary=20 endpoint of the phase II, one interim analysis will be performed = when 40%=20 of the expected events under the null-hypothesis have occurred. = Under the=20 study hypotheses, 114 events will be occurred under the null = hypothesis=20 approximately after 26 months after start of recruitment.
Using O'Brien-Fleming approach = with one=20 scheduled interim analysis, hypothesis testing would be conducted = at an=20 interim significance level of =CE=B1 =3D 0.008. If significance is = found in=20 favour of the test treatment, the study may be stopped with = sufficient=20 statistical evidence of efficacy. If the level of significance is = not=20 reached at the interim analysis, the study continues to normal = completion=20 at which time the hypothesis testing is conducted at a = significance level=20 of =CE=B1 =3D 0.042. This stagewise procedure will have an overall = significance=20 of =CE=B1 =3D 0.05.
If for any reason no = confirmative=20 interim analysis will be performed, the final significance level = will be=20 5%.
Dose Escalation Scheme
The dose-escalation = part of this=20 study was designed to enroll successive cohorts of 8 patients, = each to be=20 started on a fixed dose of carbon ion therapy. The starting dose = was=20 specified as 10 =C3=97 3 Gy E for the first cohort. Planned dose = level for=20 subsequent cohorts were 11 =C3=97 3 Gy E, 12 =C3=97 3 Gy E, 13 = =C3=97 3 Gy E, 14 =C3=97 3 Gy=20 E, 15 =C3=97 3 Gy E and 16 =C3=97 3 Gy E.
Dose escalation was to be stopped = when the=20 maximum tolerated dose (MTD) was reached. MTD was defined as one = dose=20 level below that at which dose limiting toxicities (DLT) was = observed in=20 one-third or more of the patients meaning that at least 3 of the 8 = patients in one dose cohort experienced a DLT. If maximum 2 DLTs = were=20 observed at one dose level, the next higher dose level will be = evaluated.=20 The maximum tolerated dose corresponds to the recommended dose for = the=20 following phase II part of this trial.
Toxicities were graded = using the NCI=20 Common Toxicity Criteria Version 4.0. DLT was defined as any=20 treatment-related event qualifying as NCI grade 4.
Ethics, informed consent and = safety
A positive Ethics Vote = was obtained=20 by the Local Ethics Committee of the medical Faculty at the = University of=20 Heidelberg, Germany.
Before study = recruitment, a positive=20 vote of the Bundesamt f=C3=BCr Strahlenschutz (BfS) is = necessary.
Treatment at tumor = progression
After completion of = study treatment=20 not adjuvant treatment is conducted as part of this protocol. = Further=20 treatments may be initiated as needed clinically.
For tumor progression, = treatment=20 alternatives will be evaluated and discussed in the = interdisciplinary=20 setting considering options of neurosurgical resection, systemic = treatment=20 such as chemotherapy, a second course of radiation therapy, or=20 other.
Discussion
Treatment of recurrent = gliomas=20 still remains an interdisciplinary challenge. Re-irradiation using = high-precision photon techniques has been established as a = standard=20 treatment in this clinical situation for a subgroup of patients: = Several=20 different fractionation schemes are applied in this setting, = including=20 hypofractionated regimens or radiosurgery, however, in our = institution,=20 Fractionated Stereotactic Radiotherapy (FSRT) with an attempted = total dose=20 of 36 Gy in 2 Gy single fractions is considered standard treatment = [18-23]. Still outcome of these patients is not = satisfactory and=20 novel treatment appraoches are required.
With heavy charged particle beams = such as=20 carbon ions, the physical benefits of an ion beam in conjunction = with the=20 higher relative biological effectiveness (RBE) can be exploited = for the=20 treatment of different tumor entities. For several indications, = superior=20 clinical results as compared to photon radiotherapy have been = shown [24]. Preclinical studies have shown the RBE to be = between 3=20 and 5 for high-grade gliomas, therefore demonstrating that carbon = ions are=20 a promising treatment alternative for patients with recurrent = gliomas [8,25].
Early clincial data on carbon ion = radiotherapy in primary high-grade brain tumors have shown overall = safety=20 even with extensive dose escalation with promising results; = however, few=20 patients had been included into this study, and therefore = validation in a=20 larger patients collective is warranted [26].
Until now, no patients have been = treated with=20 carbon ion radiotherapy for recurrent gliomas. Based on the = preclinical=20 data as well as the clinical experience so far, this concept = should be=20 evaluated.
Therefore, the present = CINDERELLA=20 trial evaluates carbon ion radiotherapy performed as = re-irradiation in=20 patients with recurrent gliomas compared to FSRT with standard = dosing. In=20 a first Phase I part of the study, a dose escalation will be = performed to=20 determine the optimal dose of carbon ion radiotherapy that can be=20 prescribed in this clinical setting. Thereafter, in the Phase II = part of=20 the trial, patients will be randomized between carbon ion = radiotherapy and=20 FSRT.
Abbreviations
ACC: Adenoid = Cystic=20 Carcinomas; BCNU: Carmustine; DL: Dose level; DLT: Dose limiting = toxicity;=20 FSRT: Fractionated Stereotactic Radiotherapy; GBM: Glioblastoma; = GSI:=20 Gesellschaft f=C3=BCr Schwerionenforschung; GY E: Gray Equivalent; = HIT:=20 Heidelberger Ionenstrahl herapiezentrum; NIRS: National Institute = for=20 Radiological Sciences; RBE: Relative Biological Effectiveness; RD: = Recommended Dose; RT: Radiotherapy; TMZ: Temozolomide; WHO: World = Health=20 Organization
Competing interests
The authors = declare that they=20 have no competing interests.
Authors' contributions
SEC, JD, IB, LE = and WW have=20 developed the study concept. SEC, JD, IB and LE wrote the study = protocol=20 and obtained ethics approval. SEC, JD, WW, AU, SR and DH will = provide=20 patient care. TH and OJ will perform treatment planning and beam=20 application for carbon ion radiotherapy. SEC, WW and JD will = implement the=20 protocol and oversee collection of the data. All authors = contributed to=20 and approved the final manuscript.
Pre-publication history
The pre-publication = history for=20 this paper can be accessed here:
http://www.biomedcentral.com/1471-2407/10= /533/prepub
Acknowledgements
The research = defining the role=20 of carbon ion radiotherapy for primary brain tumors and tumors of = the=20 skull base is financed within the Klinische Forschergruppe=20 =E2=80=9ESchwerionentherapie in der Radioonkologie" KFO 214 = supoerted by the=20 Deutsche Forschungsgemeinschaft (DFG).
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  • Iwadate Y, Mizoe J, Osaka Y, = Yamaura A,=20 Tsujii H. High linear energy transfer carbon radiation = effectively kills=20 cultured glioma cells with either mutant or wild-type p53. = Int J Radiat Oncol Biol Phys. = 2001;50:803=E2=80=938. [PubMed]
  • Mizoe=20 JE, Tsujii H, Hasegawa A, Yanagi T, Takagi R, Kamada T. et al. = Phase=20 I/II clinical trial of carbon ion radiotherapy for malignant = gliomas:=20 combined X-ray radiotherapy, chemotherapy, and carbon ion = radiotherapy.=20 Int J Radiat Oncol Biol Phys.=20 2007;69:390=E2=80=936. [PubMed]
Articles from BMC=20 Cancer are provided here courtesy of
BioMed Central
<= STRONG>Figure=20 2
Typical=20 treatment plan for carbon ion radiotherapy for a patients = with a=20 recurrent glioblatoma. Treatment is performed using = the=20 Siemens TPS for particle therapy, target volume delienation = is based=20 on CT- and MR-imaging with contrast = enhancement.

PubMed articles by these = authors

  • Combs,=20 S.
  • Burkholder,=20 I.
  • Edler,=20 L.
  • Debus,=20 J.

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PADDING-TOP: 5px } .x-panel-btns-ct .x-btn { CLEAR: none; FLOAT: right } .x-panel-btns-ct .x-panel-btns TD { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = PADDING-TOP: 0px; BORDER-RIGHT-WIDTH: 0px } .x-panel-btns-ct .x-panel-btns-right TABLE { CLEAR: none; FLOAT: right } .x-panel-btns-ct .x-panel-btns-left TABLE { CLEAR: none; FLOAT: left } .x-panel-btns-ct .x-panel-btns-center { TEXT-ALIGN: center } .x-panel-btns-ct .x-panel-btns-center TABLE { MARGIN: 0px auto } .x-panel-btns-ct TABLE TD.x-panel-btn-td { PADDING-RIGHT: 3px; PADDING-LEFT: 3px; PADDING-BOTTOM: 3px; = PADDING-TOP: 3px } .x-panel-btns-ct .x-btn-focus .x-btn-left { BACKGROUND-POSITION: 0px -147px } .x-panel-btns-ct .x-btn-focus .x-btn-right { BACKGROUND-POSITION: 0px -168px } .x-panel-btns-ct .x-btn-focus .x-btn-center { BACKGROUND-POSITION: 0px -189px } .x-panel-btns-ct .x-btn-over .x-btn-left { BACKGROUND-POSITION: 0px -63px } .x-panel-btns-ct .x-btn-over .x-btn-right { BACKGROUND-POSITION: 0px -84px } .x-panel-btns-ct .x-btn-over .x-btn-center { BACKGROUND-POSITION: 0px -105px } .x-panel-btns-ct .x-btn-click .x-btn-center { BACKGROUND-POSITION: 0px -126px } .x-panel-btns-ct .x-btn-click .x-btn-right { BACKGROUND-POSITION: 0px -84px } .x-panel-btns-ct .x-btn-click .x-btn-left { BACKGROUND-POSITION: 0px -63px } ------=_NextPart_000_0000_01CB7B47.3FB6CC30 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.ncbi.nlm.nih.gov/core/ext.ncbi/1/css/themes/xtheme-oldentrez.css .x-panel { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-STYLE: solid; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-STYLE: = solid; BORDER-LEFT-STYLE: solid; BORDER-RIGHT-COLOR: #d0d0d0; = BORDER-BOTTOM-STYLE: solid } .x-panel-header { BORDER-RIGHT: #d0d0d0 1px solid; BORDER-TOP: #d0d0d0 1px solid; = BACKGROUND-IMAGE: url(../../img/oldentrez/panel/white-top-bottom.gif); = BORDER-LEFT: #d0d0d0 1px solid; COLOR: #333; BORDER-BOTTOM: #d0d0d0 1px = solid } .x-panel-body { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-bbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tbar-noheader .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-mc .x-panel-tbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-body-noheader { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-mc .x-panel-body { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tl .x-panel-header { COLOR: #333 } .x-panel-tc { BACKGROUND-IMAGE: url(../../img/oldentrez/panel/top-bottom.gif) } .x-panel-tl { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND-IMAGE: = url(../../img/oldentrez/panel/corners-sprite.gif); BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tr { BACKGROUND-IMAGE: url(../../img/oldentrez/panel/corners-sprite.gif) } .x-panel-bc { BACKGROUND-IMAGE: url(../../img/oldentrez/panel/top-bottom.gif) } .x-panel-bl { BACKGROUND-IMAGE: url(../../img/oldentrez/panel/corners-sprite.gif) } .x-panel-br { BACKGROUND-IMAGE: url(../../img/oldentrez/panel/corners-sprite.gif) } .x-panel-mc { BACKGROUND: #f1f1f1 } .x-panel-mc .x-panel-body { BORDER-RIGHT: 0px; BORDER-TOP: 0px; BACKGROUND: none transparent scroll = repeat 0% 0%; BORDER-LEFT: 0px; BORDER-BOTTOM: 0px } .x-panel-ml { BACKGROUND-IMAGE: url(../../img/oldentrez/panel/left-right.gif) } .x-panel-mr { BACKGROUND-IMAGE: url(../../img/oldentrez/panel/left-right.gif) } .x-tool { BACKGROUND-IMAGE: url(../../img/oldentrez/panel/tool-sprites.gif) } .x-panel-ghost { BACKGROUND: #e0e0e0 } .x-panel-ghost UL { BORDER-LEFT-COLOR: #b0b0b0; BORDER-BOTTOM-COLOR: #b0b0b0; = BORDER-TOP-COLOR: #b0b0b0; BORDER-RIGHT-COLOR: #b0b0b0 } .x-grid-panel .x-panel-mc .x-panel-body { BORDER-RIGHT: #d0d0d0 1px solid; BORDER-TOP: #d0d0d0 1px solid; = BORDER-LEFT: #d0d0d0 1px solid; BORDER-BOTTOM: #d0d0d0 1px solid } .x-btn-left { BACKGROUND-IMAGE: url(../../img/oldentrez/button/btn-sprite.gif) } .x-btn-right { BACKGROUND-IMAGE: url(../../img/oldentrez/button/btn-sprite.gif) } .x-btn-center { BACKGROUND-IMAGE: url(../../img/oldentrez/button/btn-sprite.gif) } .x-border-layout-ct { BACKGROUND: #f0f0f0 } .x-accordion-hd { BACKGROUND-IMAGE: url(../../img/oldentrez/panel/light-hd.gif) } .x-layout-collapsed { BORDER-LEFT-COLOR: #e0e0e0; BORDER-BOTTOM-COLOR: #e0e0e0; = BORDER-TOP-COLOR: #e0e0e0; BACKGROUND-COLOR: #eee; BORDER-RIGHT-COLOR: = #e0e0e0 } .x-layout-collapsed-over { BACKGROUND-COLOR: #fbfbfb } .x-tip .x-tip-top { BACKGROUND-IMAGE: url(../../img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-top-left { BACKGROUND-IMAGE: url(../../img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-top-right { BACKGROUND-IMAGE: url(../../img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-ft { BACKGROUND-IMAGE: url(../../img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-ft-left { BACKGROUND-IMAGE: url(../../img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-ft-right { BACKGROUND-IMAGE: url(../../img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-bd-left { BACKGROUND-IMAGE: url(../../img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-bd-right { BACKGROUND-IMAGE: url(../../img/oldentrez/qtip/tip-sprite.gif) } .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: = url(../../img/oldentrez/toolbar/bg.gif) #f0f4f5 repeat-x left top; = BORDER-BOTTOM-COLOR: #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; = BORDER-RIGHT-COLOR: #d0d0d0 } .x-toolbar BUTTON { COLOR: #444 } .x-toolbar .x-btn-menu-arrow-wrap .x-btn-center BUTTON { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/btn-arrow.gif) } .x-toolbar .x-btn-text-icon .x-btn-menu-arrow-wrap .x-btn-center BUTTON = { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/btn-arrow.gif) } .x-toolbar .x-btn-over .x-btn-left { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over .x-btn-right { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over .x-btn-center { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over BUTTON { COLOR: #111 } .x-toolbar .x-btn-click .x-btn-left { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-pressed .x-btn-left { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-menu-active .x-btn-left { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-click .x-btn-right { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-pressed .x-btn-right { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-menu-active .x-btn-right { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-click .x-btn-center { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-pressed .x-btn-center { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-menu-active .x-btn-center { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .ytb-sep { BACKGROUND-IMAGE: url(../images/default/grid/grid-split.gif) } .x-tab-panel-header { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: #eaeaea; BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-footer { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: #eaeaea; BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-header { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-footer { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } UL.x-tab-strip-top { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: = url(../../img/oldentrez/tabs/tab-strip-bg.gif) #dbdbdb repeat-x left = top; BORDER-BOTTOM-COLOR: #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; = PADDING-TOP: 2px; BORDER-RIGHT-COLOR: #d0d0d0 } UL.x-tab-strip-bottom { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND-IMAGE: = url(../../img/oldentrez/tabs/tab-strip-btm-bg.gif); BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-strip SPAN.x-tab-strip-text { COLOR: #333 } .x-tab-strip-over SPAN.x-tab-strip-text { COLOR: #111 } .x-tab-strip-active SPAN.x-tab-strip-text { COLOR: #333 } .x-tab-strip-disabled .x-tabs-text { COLOR: #aaaaaa } .x-tab-strip-top .x-tab-right { BACKGROUND-IMAGE: url(../../img/oldentrez/tabs/tabs-sprite.gif) } .x-tab-strip-top .x-tab-left { BACKGROUND-IMAGE: url(../../img/oldentrez/tabs/tabs-sprite.gif) } .x-tab-strip-top .x-tab-strip-inner { BACKGROUND-IMAGE: url(../../img/oldentrez/tabs/tabs-sprite.gif) } .x-tab-strip-bottom .x-tab-right { BACKGROUND-IMAGE: = url(../../img/oldentrez/tabs/tab-btm-inactive-right-bg.gif) } .x-tab-strip-bottom .x-tab-left { BACKGROUND-IMAGE: = url(../../img/oldentrez/tabs/tab-btm-inactive-left-bg.gif) } .x-tab-strip-bottom .x-tab-strip-active .x-tab-right { BACKGROUND-IMAGE: url(../../img/oldentrez/tabs/tab-btm-right-bg.gif) } .x-tab-strip-bottom .x-tab-strip-active .x-tab-left { BACKGROUND-IMAGE: url(../../img/oldentrez/tabs/tab-btm-left-bg.gif) } 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url(../../img/oldentrez/tabs/scroll-left.gif); BORDER-BOTTOM-COLOR: = #aeaeae; BORDER-TOP-COLOR: #aeaeae; BORDER-RIGHT-COLOR: #aeaeae } .x-tab-scroller-right { BORDER-LEFT-COLOR: #aeaeae; BACKGROUND-IMAGE: = url(../../img/oldentrez/tabs/scroll-right.gif); BORDER-BOTTOM-COLOR: = #aeaeae; BORDER-TOP-COLOR: #aeaeae; BORDER-RIGHT-COLOR: #aeaeae } .x-window-proxy { BORDER-LEFT-COLOR: #b0b0b0; BACKGROUND: #e0e0e0; BORDER-BOTTOM-COLOR: = #b0b0b0; BORDER-TOP-COLOR: #b0b0b0; BORDER-RIGHT-COLOR: #b0b0b0 } .x-window-tl .x-window-header { COLOR: #555 } .x-window-tc { BACKGROUND-IMAGE: url(../../img/oldentrez/window/top-bottom.png) } .x-window-tl { BACKGROUND-IMAGE: url(../../img/oldentrez/window/left-corners.png) } .x-window-tr { BACKGROUND-IMAGE: url(../../img/oldentrez/window/right-corners.png) } .x-window-bc { BACKGROUND-IMAGE: url(../../img/oldentrez/window/top-bottom.png) } .x-window-bl { BACKGROUND-IMAGE: url(../../img/oldentrez/window/left-corners.png) } .x-window-br { BACKGROUND-IMAGE: url(../../img/oldentrez/window/right-corners.png) } .x-window-mc { BORDER-RIGHT: #d0d0d0 1px solid; BORDER-TOP: #d0d0d0 1px solid; = BACKGROUND: #e8e8e8; BORDER-LEFT: #d0d0d0 1px solid; BORDER-BOTTOM: = #d0d0d0 1px solid } .x-window-ml { BACKGROUND-IMAGE: url(../../img/oldentrez/window/left-right.png) } .x-window-mr { BACKGROUND-IMAGE: url(../../img/oldentrez/window/left-right.png) } .x-panel-ghost .x-window-tl { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-collapsed .x-window-tl { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-window-plain .x-window-mc { BORDER-RIGHT: #eee 1px solid; BORDER-TOP: #d0d0d0 1px solid; = BACKGROUND: #e8e8e8; BORDER-LEFT: #d0d0d0 1px solid; BORDER-BOTTOM: #eee = 1px solid } .x-window-plain .x-window-body { BORDER-RIGHT: #d0d0d0 1px solid; BORDER-TOP: #eee 1px solid; = BACKGROUND: none transparent scroll 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PADDING-LEFT: 0px; FONT-SIZE: 0px; = PADDING-BOTTOM: 0px; MARGIN: 0px; OVERFLOW: hidden; BORDER-LEFT: #99bbe8 = 1px solid; LINE-HEIGHT: 0; PADDING-TOP: 0px; BORDER-BOTTOM: #99bbe8 1px = solid } .x-panel-ghost * { CURSOR: move! important } .x-panel-dd-spacer { BORDER-RIGHT: #99bbe8 2px dashed; BORDER-TOP: #99bbe8 2px dashed; = BORDER-LEFT: #99bbe8 2px dashed; BORDER-BOTTOM: #99bbe8 2px dashed } .x-panel-btns-ct { PADDING-RIGHT: 5px; PADDING-LEFT: 5px; PADDING-BOTTOM: 5px; = PADDING-TOP: 5px } .x-panel-btns-ct .x-btn { CLEAR: none; FLOAT: right } .x-panel-btns-ct .x-panel-btns TD { BORDER-TOP-WIDTH: 0px; PADDING-RIGHT: 0px; PADDING-LEFT: 0px; = BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: 0px; PADDING-BOTTOM: 0px; = PADDING-TOP: 0px; BORDER-RIGHT-WIDTH: 0px } .x-panel-btns-ct .x-panel-btns-right TABLE { CLEAR: none; FLOAT: right } .x-panel-btns-ct .x-panel-btns-left TABLE { CLEAR: none; FLOAT: left } .x-panel-btns-ct .x-panel-btns-center { TEXT-ALIGN: center } .x-panel-btns-ct .x-panel-btns-center TABLE { MARGIN: 0px auto } .x-panel-btns-ct TABLE TD.x-panel-btn-td { PADDING-RIGHT: 3px; PADDING-LEFT: 3px; PADDING-BOTTOM: 3px; = PADDING-TOP: 3px } .x-panel-btns-ct .x-btn-focus .x-btn-left { BACKGROUND-POSITION: 0px -147px } .x-panel-btns-ct .x-btn-focus .x-btn-right { BACKGROUND-POSITION: 0px -168px } .x-panel-btns-ct .x-btn-focus .x-btn-center { BACKGROUND-POSITION: 0px -189px } .x-panel-btns-ct .x-btn-over .x-btn-left { BACKGROUND-POSITION: 0px -63px } .x-panel-btns-ct .x-btn-over .x-btn-right { BACKGROUND-POSITION: 0px -84px } .x-panel-btns-ct .x-btn-over .x-btn-center { BACKGROUND-POSITION: 0px -105px } .x-panel-btns-ct .x-btn-click .x-btn-center { BACKGROUND-POSITION: 0px -126px } .x-panel-btns-ct .x-btn-click .x-btn-right { BACKGROUND-POSITION: 0px -84px } .x-panel-btns-ct .x-btn-click .x-btn-left { BACKGROUND-POSITION: 0px -63px } .x-btn-menu-wrap { WIDTH: 0px! important } .x-menu { BACKGROUND: #f0f0f0 0px 0px } .x-menu-list-item IMG { DISPLAY: none } .x-menu-list-item A.x-menu-item { PADDING-LEFT: 8px } .port H1.x-panel-header-text { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FONT-SIZE: 100%; PADDING-BOTTOM: = 0px; MARGIN: 0px; PADDING-TOP: 0px } .port H2.x-panel-header-text { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FONT-SIZE: 100%; PADDING-BOTTOM: = 0px; MARGIN: 0px; PADDING-TOP: 0px } .port H3.x-panel-header-text { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FONT-SIZE: 100%; PADDING-BOTTOM: = 0px; MARGIN: 0px; PADDING-TOP: 0px } .port H4.x-panel-header-text { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FONT-SIZE: 100%; PADDING-BOTTOM: = 0px; MARGIN: 0px; PADDING-TOP: 0px } .port H5.x-panel-header-text { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FONT-SIZE: 100%; PADDING-BOTTOM: = 0px; MARGIN: 0px; PADDING-TOP: 0px } .port H6.x-panel-header-text { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FONT-SIZE: 100%; PADDING-BOTTOM: = 0px; MARGIN: 0px; PADDING-TOP: 0px } DIV.x-panel-body { PADDING-RIGHT: 5px; PADDING-LEFT: 5px; PADDING-BOTTOM: 5px; = PADDING-TOP: 5px } .port .x-panel-header { PADDING-RIGHT: 3px; PADDING-LEFT: 5px; PADDING-BOTTOM: 4px; = PADDING-TOP: 5px } .x-panel { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-STYLE: solid; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-STYLE: = solid; BORDER-LEFT-STYLE: solid; BORDER-RIGHT-COLOR: #d0d0d0; = BORDER-BOTTOM-STYLE: solid } .x-panel-header { BORDER-RIGHT: #d0d0d0 1px solid; BORDER-TOP: #d0d0d0 1px solid; = BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/white-top-bottom.gif); = BORDER-LEFT: #d0d0d0 1px solid; COLOR: #333; BORDER-BOTTOM: #d0d0d0 1px = solid } .x-panel-body { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-bbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tbar-noheader .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-mc .x-panel-tbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-body-noheader { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-mc .x-panel-body { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tl .x-panel-header { COLOR: #333 } .x-panel-tc { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/top-bottom.gif) } .x-panel-tl { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/corners-sprite.gif); = BORDER-BOTTOM-COLOR: #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; = BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tr { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/corners-sprite.gif) } .x-panel-bc { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/top-bottom.gif) } .x-panel-bl { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/corners-sprite.gif) } .x-panel-br { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/corners-sprite.gif) } .x-panel-mc { BACKGROUND: #f1f1f1 } .x-panel-mc .x-panel-body { BORDER-RIGHT: 0px; BORDER-TOP: 0px; BACKGROUND: none transparent scroll = repeat 0% 0%; BORDER-LEFT: 0px; BORDER-BOTTOM: 0px } .x-panel-ml { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/left-right.gif) } .x-panel-mr { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/left-right.gif) } .x-tool { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/tool-sprites.gif) } .x-panel-ghost { BACKGROUND: #e0e0e0 } .x-panel-ghost UL { BORDER-LEFT-COLOR: #b0b0b0; BORDER-BOTTOM-COLOR: #b0b0b0; = BORDER-TOP-COLOR: #b0b0b0; BORDER-RIGHT-COLOR: #b0b0b0 } .x-grid-panel .x-panel-mc .x-panel-body { BORDER-RIGHT: #d0d0d0 1px solid; BORDER-TOP: #d0d0d0 1px solid; = BORDER-LEFT: #d0d0d0 1px solid; BORDER-BOTTOM: #d0d0d0 1px solid } .x-btn-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/button/btn-sprite.gif) } .x-btn-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/button/btn-sprite.gif) } .x-btn-center { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/button/btn-sprite.gif) } .x-border-layout-ct { BACKGROUND: #f0f0f0 } .x-accordion-hd { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/light-hd.gif) } .x-layout-collapsed { BORDER-LEFT-COLOR: #e0e0e0; BORDER-BOTTOM-COLOR: #e0e0e0; = BORDER-TOP-COLOR: #e0e0e0; BACKGROUND-COLOR: #eee; BORDER-RIGHT-COLOR: = #e0e0e0 } .x-layout-collapsed-over { BACKGROUND-COLOR: #fbfbfb } .x-tip .x-tip-top { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-top-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-top-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-ft { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-ft-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-ft-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-bd-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-bd-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/bg.gif) #f0f4f5 repeat-x left = top; BORDER-BOTTOM-COLOR: #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; = BORDER-RIGHT-COLOR: #d0d0d0 } .x-toolbar BUTTON { COLOR: #444 } .x-toolbar .x-btn-menu-arrow-wrap .x-btn-center BUTTON { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/btn-arrow.gif) } .x-toolbar .x-btn-text-icon .x-btn-menu-arrow-wrap .x-btn-center BUTTON = { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/btn-arrow.gif) } .x-toolbar .x-btn-over .x-btn-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over .x-btn-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over .x-btn-center { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over BUTTON { COLOR: #111 } .x-toolbar .x-btn-click .x-btn-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-pressed .x-btn-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-menu-active .x-btn-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-click .x-btn-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-pressed .x-btn-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-menu-active .x-btn-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-click .x-btn-center { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-pressed .x-btn-center { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-menu-active .x-btn-center { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .ytb-sep { BACKGROUND-IMAGE: = url(/core/extjs/ext-2.1/resources/images/default/grid/grid-split.gif) } .x-tab-panel-header { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: #eaeaea; BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-footer { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: #eaeaea; BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-header { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-footer { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } UL.x-tab-strip-top { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-strip-bg.gif) #dbdbdb = repeat-x left top; BORDER-BOTTOM-COLOR: #d0d0d0; BORDER-TOP-COLOR: = #d0d0d0; PADDING-TOP: 2px; BORDER-RIGHT-COLOR: #d0d0d0 } UL.x-tab-strip-bottom { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-strip-btm-bg.gif); = BORDER-BOTTOM-COLOR: #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; = BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-strip SPAN.x-tab-strip-text { COLOR: #333 } .x-tab-strip-over SPAN.x-tab-strip-text { COLOR: #111 } .x-tab-strip-active SPAN.x-tab-strip-text { COLOR: #333 } .x-tab-strip-disabled .x-tabs-text { COLOR: #aaaaaa } .x-tab-strip-top .x-tab-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tabs-sprite.gif) } .x-tab-strip-top .x-tab-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tabs-sprite.gif) } .x-tab-strip-top .x-tab-strip-inner { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tabs-sprite.gif) } .x-tab-strip-bottom .x-tab-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-btm-inactive-right-bg.gif) } .x-tab-strip-bottom .x-tab-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-btm-inactive-left-bg.gif) } .x-tab-strip-bottom .x-tab-strip-active .x-tab-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-btm-right-bg.gif) } .x-tab-strip-bottom .x-tab-strip-active .x-tab-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-btm-left-bg.gif) } .x-tab-strip .x-tab-strip-closable A.x-tab-strip-close { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-close.gif) } .x-tab-strip .x-tab-strip-closable A.x-tab-strip-close:hover { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-close.gif) } .x-tab-panel-body { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: #fff; BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-bbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-tbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-header-plain .x-tab-strip-spacer { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: #eaeaea; BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-scroller-left { BORDER-LEFT-COLOR: #aeaeae; BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/scroll-left.gif); = BORDER-BOTTOM-COLOR: #aeaeae; BORDER-TOP-COLOR: #aeaeae; = BORDER-RIGHT-COLOR: #aeaeae } .x-tab-scroller-right { BORDER-LEFT-COLOR: #aeaeae; BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/scroll-right.gif); = BORDER-BOTTOM-COLOR: #aeaeae; BORDER-TOP-COLOR: #aeaeae; = BORDER-RIGHT-COLOR: #aeaeae } .x-window-proxy { BORDER-LEFT-COLOR: #b0b0b0; BACKGROUND: #e0e0e0; BORDER-BOTTOM-COLOR: = #b0b0b0; BORDER-TOP-COLOR: #b0b0b0; BORDER-RIGHT-COLOR: #b0b0b0 } .x-window-tl .x-window-header { COLOR: #555 } .x-window-tc { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/window/top-bottom.png) } .x-window-tl { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/window/left-corners.png) } .x-window-tr { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/window/right-corners.png) } .x-window-bc { BACKGROUND-IMAGE: = 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