From: Subject: Malignant Gliomas: MR Imaging Spectrum of Radiation Therapy- and Chemotherapy-induced Necrosis of the Brain after Treatment -- Kumar et al. 217 (2): 377 -- Radiology Date: Thu, 11 Sep 2008 10:45:51 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_00A8_01C913FB.8F2EFC70" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_00A8_01C913FB.8F2EFC70 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://radiology.rsnajnls.org/cgi/content/full/217/2/377?ijkey=cd8cf14266f3c09b31b0c5a037ff3558cbf3908e Malignant Gliomas: MR Imaging Spectrum of Radiation = Therapy- and Chemotherapy-induced Necrosis of the Brain after Treatment = -- Kumar et al. 217 (2): 377 -- Radiology
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(Radiology. 2000;217:377-384.)
=A9 RSNA, 2000 =

Neuroradiology

Malignant Gliomas: MR Imaging Spectrum of Radiation Therapy- and=20 Chemotherapy-induced Necrosis of the Brain after Treatment1=20

Ashok J. Kumar, MD, Norman E. Leeds, = MD,=20 Gregory N. Fuller, MD, PhD, Pamela Van Tassel, MD 2,=20 Moshe H. Maor, MD, Raymond E. Sawaya, MD and Victor A. = Levin,=20 MD

1 From the Division of Diagnostic Imaging = (A.J.K.,=20 N.E.L., P.V.T.), and the Departments of Pathology (G.N.F.), Radiation = Oncology=20 (M.H.M.), Neurosurgery (R.E.S.), and Neuro-Oncology (V.A.L.), University = of=20 Texas M.D. Anderson Cancer Center, Box 57, 1515 Holcombe Blvd, Houston, = TX=20 77030. From the 1995 RSNA scientific assembly. Received October 20, = 1999;=20 revision requested November 19; final revision received March 17, 2000; = accepted=20 April 24. V.A.L. and G.N.F. supported in part by NIH grant CA 55261. = Address=20 correspondence to A.J.K. (e-mail: akumar@mdanderson.org). =


3D"   =20 ABSTRACT
TOP
3D"ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
<= B>PURPOSE:=20 To describe both the common and less frequently encountered = magnetic=20 resonance (MR) imaging features of radiation therapy=96 and=20 chemotherapy-induced brain injury, with particular emphasis = on=20 radiation necrosis.

MATERIALS AND METHODS: A cohort of 148 adult patients = underwent=20 surgical resection of malignant brain (glial) tumors and were = subsequently entered into a research protocol that consisted = of=20 accelerated radiation therapy with carboplatin followed by=20 chemotherapy with procarbazine, lomustine, and vincristine.=20 Patients typically underwent sequential MR imaging at = 6=968-week=20 intervals during the 1st year and at 3=966-month intervals = during=20 subsequent years. In all patients, histopathologic confirmation = of=20 lesion composition was performed by board-certified = neuropathologists.=20

RESULTS: The patients exhibited different types of MR=20 imaging=96detected abnormalities of the brain: pure radiation = necrosis=20 in 20 patients, a mixture of predominantly radiation necrosis = with=20 limited recurrent and/or residual tumor (less than 20% of = resected=20 tissue) in 16 patients, radiation necrosis of the cranial = nerves=20 and/or their pathways in two patients, radiation-induced=20 enhancement of the white matter in 52 patients, and = radiation-induced=20 enhancement of the cortex in nine patients.

CONCLUSION: The frequent diagnostic dilemma of recurrent = neoplasm=20 versus radiation necrosis is addressed in this study through = a=20 description of the varying spatial and temporal patterns of = radiation=20 necrosis at MR imaging.

Index terms: Brain, necrosis, 13.47 =95 Brain = neoplasms,=20 13.363 =95 Brain neoplasms, MR, 13.121411, 13.121415, 13.12143 =95 Brain = neoplasms,=20 therapeutic radiology =95 Radiations, injurious effects, complications = of=20 therapeutic radiology, 13.47


3D"   =20 INTRODUCTION
TOP
ABSTRACT
3D"INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
D= uring the=20 past decade, the treatment of malignant gliomas has = benefitted from=20 several advances, including early detection of tumors by = using=20 magnetic resonance (MR) imaging, improvements in = neurosurgical=20 instrumentation that have facilitated more precise radical = resection=20 of neoplasms, advances in the delivery of radiation doses to = tumors,=20 and new chemotherapeutic protocols. However, the sequential = MR images=20 obtained in these patients have demonstrated a variety of = radiation=20 therapy=96 and chemotherapy-induced changes in the brain. = Radiation=20 necrosis is the most substantial and most severe form of=20 radiation-induced injury with therapeutic implications. The = diagnosis=20 of radiation necrosis at imaging has been challenging, = primarily=20 because the pattern of abnormal enhancement closely mimics = that of=20 recurrent brain tumor. The purpose of this retrospective = study was=20 to review our experience with the MR imaging spectrum of=20 radiation necrosis.


3D"   =20 MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
3D"MATERIALS AND = METHODS
RESULTS
DISCUSSION
REFERENCES
 
O= ne=20 hundred forty-eight patients (82 men, 66 women; mean age, 41 = years;=20 age range, 18=9675 years) with malignant gliomas=9792 with = glioblastoma=20 multiforme, 40 with anaplastic astrocytoma, nine with = anaplastic=20 mixed glioma, and seven with anaplastic = oligodendroglioma=97were=20 entered into research protocol DM88-113 after they gave = institutional=20 review board=96approved informed consent and after undergoing = either=20 total or subtotal resection of their tumors (1).=20 After surgery, the patients received accelerated = fractionation=20 radiation therapy and concomitant carboplatin-based = chemotherapy. The=20 accelerated radiation therapy consisted of three doses of = 1.9=962.0 Gy=20 each per day, with a 4-hour interval between fractions. = Carboplatin=20 was given intravenously for 2 hours at a dose of 33 = mg/m2,=20 1.75 hours before each radiation treatment. This regimen was=20 administered with a 6-MV linear accelerator for 5 consecutive = days.=20 After a 2-week break, a second course of treatment identical = to the=20 first was given so that a total dose of 57=9660 Gy was given; = the=20 majority of patients received 57 Gy following an amendment to = the=20 protocol.

The radiation portal was generally limited to a 2=963-cm = margin=20 around the enhancing tumor and the nonenhancing abnormal = tumoral=20 signal intensity (not edema), if present, at T2-weighted = imaging. In=20 tumors that were closer to the midline=97for example, corpus = callosal=20 tumors=97partially opposing portals were used and resulted in = margins=20 wider than 3 cm in the lateral dimension. Postradiation = chemotherapy=20 consisted of procarbazine, lomustine, and vincristine, = beginning=20 within 4 weeks after the completion of radiation therapy. The = administration of procarbazine, lomustine, and vincristine = was=20 repeated at 6-week intervals for 1 year or until tumor=20 progression.

The preoperative and postoperative follow-up MR images of the=20 brain obtained in the 148 patients were reviewed by two = authors=20 (A.J.K., N.E.L.), and the findings were tabulated by means of = consensus. The information gathered from the MR images = consisted=20 of (a) the enhancing or nonenhancing features of primary=20 neoplasm, (b) the appearance and location of recurrent = enhancing lesions, single or multiple, (c) the = proximity of=20 the recurrent lesion to the primary tumor, and (d) the = interval between the end of radiation therapy and the = histopathologic=20 confirmation of radiation necrosis. The MR images of the = brain=20 consisted of standard nonenhanced and contrast = material=96enhanced=20 studies that were obtained both at our institution and at = outside=20 imaging centers.

At our institution, the MR images of the brain, which were = obtained=20 by using a 1.5-T unit (Signa Horizon 5X; GE Medical Systems,=20 Milwaukee, Wis), consisted of transverse T2-weighted=20 (2,000=963,000/80=96100 [repetition time msec/echo time = msec], one signal=20 acquired) and intermediate-weighted (2,000=963,000/20=9630, = one=20 signal acquired) images and pre- and postcontrast transverse, = T1-weighted, spin-echo images (500=96600/8=9616, two = signals=20 acquired). The postcontrast transverse and coronal T1-weighted = images=20 were obtained by administering gadopentetate dimeglumine = (Magnevist;=20 Berlex Laboratories, Wayne, NJ) intravenously at a dose of = 0.1 mmol=20 per kilogram of body weight. Occasionally, sagittal = postcontrast=20 T1-weighted images of the brain also were obtained as = needed.=20

In the patients in the DM88-113 protocol, postsurgical follow-up = MR images were obtained either within 72 hours or 2=964 = weeks=20 after surgery. Follow-up MR images were obtained within 2 = weeks after=20 completing radiation therapy and at 6=968-week intervals = during the=20 procarbazine, lomustine, and vincristine treatment period. = During=20 year 2 after treatment, follow-up MR images were obtained at = 3-month=20 intervals; during year 3, at 4-month intervals; and during = year 4, at=20 6-month intervals. If clinical deterioration occurred, MR = images were=20 obtained as needed.

Histopathologic examination of 36 surgically resected tissue=20 specimens=97nine by means of stereotactic biopsy and 27 = by means=20 of open resection=97was performed by board-certified = neuropathologists=20 (one of which was G.N.F.). The autopsy results in nine = patients also=20 were available.


3D"   =20 RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
3D"RESULTS
DISCUSSION
REFERENCES
 
T= herapy-induced=20 necrosis in the brain, which was proved at histopathologic=20 examination, was found in 22 of the 56 patients with = anaplastic=20 gliomas and in 14 of the 92 patients with glioblastomas under = protocol DM88-113. The necrosis of the brain was attributed = to=20 the combined effects of radiation therapy and chemotherapy. = Isodose=20 curves revealed that all of the radiation-induced necroses = occurred=20 within the radiation portal. Analysis of the long-T2=96weighted = images=20 was not found to be helpful in differentiating recurrent = tumor from=20 radiation necrosis.

Twenty of the 36 surgical specimens had histopathologic evidence = of radiation necrosis with no evidence of tumor, and 16 had=20 evidence of a mixture of extensive necrosis with residual = and/or=20 recurrent tumor (less than 20% of resected tissue). The = common=20 and uncommon features of radiation necrosis included = radiation=20 necrosis simulating a recurrent glioma at the site of the = surgical=20 cavity (Fig=20 1), distant to the site of the primary tumor on the = ipsilateral=20 side (Fig=20 2), or on the contralateral side (Fig=20 3), and multiple radiation-induced necrotic masses=20 simulating multiple metastases (Fig=20 4a) and/or multiple sclerosis (Fig=20 4b).



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  		Figure 1a. Radiation = necrosis=20 simulating a recurrent glioma in a 44-year-old woman who = underwent=20 resection of a nonenhancing anaplastic mixed glioma in the = left=20 anterior temporal lobe followed by accelerated radiation = therapy (60=20 Gy) and chemotherapy. (a) Postcontrast coronal = T1-weighted=20 spin-echo image (700/16) obtained 17 months after radiation = therapy=20 shows ringlike areas of abnormal enhancement (solid arrows) = have=20 developed around the surgical cavity. A left paraventricular = enhancing lesion (open arrow) characteristic of = posttreatment change=20 also is noted. (b) Histologic section reveals a=20 characteristic finding in radiation necrosis=97a blood = vessel with=20 fibrinoid necrosis of the wall (N) and a narrowed = lumen=20 (arrow). (Hematoxylin-eosin stain; original magnification, = x400.) (c) High-power=20 photomicrograph reveals radiation-induced telangiectasia = (arrows).=20 (Hematoxylin-eosin stain; original magnification, x200.) =

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  		Figure 1b. Radiation = necrosis=20 simulating a recurrent glioma in a 44-year-old woman who = underwent=20 resection of a nonenhancing anaplastic mixed glioma in the = left=20 anterior temporal lobe followed by accelerated radiation = therapy (60=20 Gy) and chemotherapy. (a) Postcontrast coronal = T1-weighted=20 spin-echo image (700/16) obtained 17 months after radiation = therapy=20 shows ringlike areas of abnormal enhancement (solid arrows) = have=20 developed around the surgical cavity. A left paraventricular = enhancing lesion (open arrow) characteristic of = posttreatment change=20 also is noted. (b) Histologic section reveals a=20 characteristic finding in radiation necrosis=97a blood = vessel with=20 fibrinoid necrosis of the wall (N) and a narrowed = lumen=20 (arrow). (Hematoxylin-eosin stain; original magnification, = x400.) (c) High-power=20 photomicrograph reveals radiation-induced telangiectasia = (arrows).=20 (Hematoxylin-eosin stain; original magnification, x200.) =

 = ;


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  		Figure 1c. Radiation = necrosis=20 simulating a recurrent glioma in a 44-year-old woman who = underwent=20 resection of a nonenhancing anaplastic mixed glioma in the = left=20 anterior temporal lobe followed by accelerated radiation = therapy (60=20 Gy) and chemotherapy. (a) Postcontrast coronal = T1-weighted=20 spin-echo image (700/16) obtained 17 months after radiation = therapy=20 shows ringlike areas of abnormal enhancement (solid arrows) = have=20 developed around the surgical cavity. A left paraventricular = enhancing lesion (open arrow) characteristic of = posttreatment change=20 also is noted. (b) Histologic section reveals a=20 characteristic finding in radiation necrosis=97a blood = vessel with=20 fibrinoid necrosis of the wall (N) and a narrowed = lumen=20 (arrow). (Hematoxylin-eosin stain; original magnification, = x400.) (c) High-power=20 photomicrograph reveals radiation-induced telangiectasia = (arrows).=20 (Hematoxylin-eosin stain; original magnification, x200.) =

 = ;


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  		Figure 2a. Evolution of = radiation=20 necrosis. Radiation necrosis with tumorlike growth arising = distant=20 (anterior and inferior) to the site of the primary tumor in = a=20 22-year-old man who had been treated with surgery, = accelerated=20 radiation therapy (57 Gy), and chemotherapy for a = nonenhancing=20 anaplastic astrocytoma in the right parietal lobe. (a)=20 Postcontrast transverse T1-weighted spin-echo image = (600/8)=20 obtained 16 months after completion of radiation therapy = shows small=20 enhancing lesions in the right superficial temporal lobe = (arrow) and=20 paraventricular region (arrowhead) of the deep temporal = lobe. (b)=20 Postcontrast transverse T1-weighted spin-echo image = (600/8)=20 obtained 2 months 15 days later demonstrates a rapid = increase in the=20 size of the lesions (solid arrows) in a, as well as = new=20 enhancing lesions (open arrows). Rapid growth of the = paraventricular=20 mass was associated with surrounding edema (E) and = mass=20 effect. Two weeks later, the patient underwent partial = excision of=20 the mass, and histopathologic analysis revealed foci of = necrosis,=20 gliosis, and scattered atypical cells but no evidence of = recurrent=20 tumor. =

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  		Figure 2b. Evolution of = radiation=20 necrosis. Radiation necrosis with tumorlike growth arising = distant=20 (anterior and inferior) to the site of the primary tumor in = a=20 22-year-old man who had been treated with surgery, = accelerated=20 radiation therapy (57 Gy), and chemotherapy for a = nonenhancing=20 anaplastic astrocytoma in the right parietal lobe. (a)=20 Postcontrast transverse T1-weighted spin-echo image = (600/8)=20 obtained 16 months after completion of radiation therapy = shows small=20 enhancing lesions in the right superficial temporal lobe = (arrow) and=20 paraventricular region (arrowhead) of the deep temporal = lobe. (b)=20 Postcontrast transverse T1-weighted spin-echo image = (600/8)=20 obtained 2 months 15 days later demonstrates a rapid = increase in the=20 size of the lesions (solid arrows) in a, as well as = new=20 enhancing lesions (open arrows). Rapid growth of the = paraventricular=20 mass was associated with surrounding edema (E) and = mass=20 effect. Two weeks later, the patient underwent partial = excision of=20 the mass, and histopathologic analysis revealed foci of = necrosis,=20 gliosis, and scattered atypical cells but no evidence of = recurrent=20 tumor. =

 = ;


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  		Figure 3. Radiation = necrosis of the=20 contralateral cerebral hemisphere simulating a multicentric = tumor=20 with corpus callosal involvement in a 30-year-old woman who=20 underwent resection of a glioblastoma in the left frontal = lobe=20 followed by accelerated radiation therapy and chemotherapy. = On the=20 postcontrast coronal T1-weighted spin-echo image (500/11), = the thin=20 black arrows point to the craniotomy site. Thirteen months = after=20 radiation therapy, the patient developed an irregularly = enhancing=20 mass in the right frontal lobe white matter (large white = arrow),=20 cortex (small white arrow), and corpus callosum (C), = with=20 surrounding edema (E) and subfalcine herniation. = Stereotactic=20 biopsy of the enhancing regions revealed radiation necrosis. = The=20 open arrows point to fingerlike contrast-enhanced white = matter=20 projections toward the arcuate fibers. =

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  		Figure 4a. Autopsy-proved = radiation=20 necrosis within both cerebral hemispheres simulating = multiple=20 metastases and/or tumefactive multiple sclerosis in a = 30-year-old=20 man who underwent subtotal resection of a multicentric, = nonenhancing=20 anaplastic astrocytoma in the right parietal lobe and left = anterior=20 temporal lobe followed by whole-brain accelerated radiation = therapy=20 (60 Gy) and chemotherapy. (a) Postcontrast transverse = T1-weighted spin-echo image (500/17) obtained 17 months = after=20 radiation therapy shows multiple enhancing masses (solid = arrows)=20 within the frontal lobe white matter simulating metastases. = Central=20 soap bubble-like areas of necrosis (open arrow) were seen = within the=20 masses. Autopsy revealed no evidence of tumor, and the=20 histopathologic findings showed extensive areas of radiation = necrosis that corresponded to the multiple enhancing lesions = identified at MR imaging. (b) Postcontrast sagittal=20 T1-weighted spin-echo image (500/17) shows multiple = periventricular=20 enhancing lesions involving the adjacent corpus callosum = (arrows)=20 and the temporal horn (arrowheads) that are distributed = along the=20 body of the lateral ventricle and simulating tumefactive = multiple=20 sclerosis. =

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  		Figure 4b. Autopsy-proved = radiation=20 necrosis within both cerebral hemispheres simulating = multiple=20 metastases and/or tumefactive multiple sclerosis in a = 30-year-old=20 man who underwent subtotal resection of a multicentric, = nonenhancing=20 anaplastic astrocytoma in the right parietal lobe and left = anterior=20 temporal lobe followed by whole-brain accelerated radiation = therapy=20 (60 Gy) and chemotherapy. (a) Postcontrast transverse = T1-weighted spin-echo image (500/17) obtained 17 months = after=20 radiation therapy shows multiple enhancing masses (solid = arrows)=20 within the frontal lobe white matter simulating metastases. = Central=20 soap bubble-like areas of necrosis (open arrow) were seen = within the=20 masses. Autopsy revealed no evidence of tumor, and the=20 histopathologic findings showed extensive areas of radiation = necrosis that corresponded to the multiple enhancing lesions = identified at MR imaging. (b) Postcontrast sagittal=20 T1-weighted spin-echo image (500/17) shows multiple = periventricular=20 enhancing lesions involving the adjacent corpus callosum = (arrows)=20 and the temporal horn (arrowheads) that are distributed = along the=20 body of the lateral ventricle and simulating tumefactive = multiple=20 sclerosis. =

 = ;
The=20 MR imaging features commonly seen in radiation necrosis are a = soap=20 bubble=96like interior (Fig=20 4a) and a Swiss cheese=96like interior (Fig=20 5). The MR imaging characteristics of radiation necrosis = in both=20 groups=97that is, in the patients with pure radiation = necrosis and in=20 those with predominantly radiation necrosis=97are outlined in = the Table.=20 In the 20 patients with pure radiation necrosis, the primary = tumor=20 was nonenhancing in 10 anaplastic gliomas and enhancing in 10 = tumors=97three anaplastic gliomas and seven glioblastomas. In = the 16=20 patients with necrosis intermingled with tumor, the primary = tumor=20 was enhancing in three anaplastic gliomas and seven=20 glioblastomas and nonenhancing in six anaplastic gliomas.=20 Infratentorial radiation-induced necrosis following radiation = therapy=20 for parietal lobe glioblastoma is illustrated in Figure=20 6. The intervals from completion of radiation therapy to=20 histopathologic confirmation of necrotic lesions in both = groups are=20 illustrated in Figure=20 7.



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  		Figure 5. Postcontrast = coronal=20 T1-weighted follow-up spin-echo image (600/16) obtained 3 = years 7=20 months after radiation therapy in a 36-year-old man who = underwent=20 surgery, accelerated radiation therapy (60 Gy), and = chemotherapy for=20 a right frontal lobe nonenhancing anaplastic astrocytoma = shows=20 radiation necrosis of the bilateral frontal lobe white = matter (white=20 arrows) with a Swiss cheese pattern of interior (straight = black=20 arrows) and secondary atrophy of the brain. Arcuate fibers = (curved=20 arrows) of the white matter also were affected. = Radiation-induced=20 necrosis was identified at computed tomography (CT) 17 = months after=20 therapy, and the diagnosis was confirmed by using serial MR = images.=20 The patient died 5 years after the initial diagnosis. =

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  = 		MR Imaging Characteristics of = Radiation=20 Necrosis of the Brain in 36 Patients=20 =
 


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  		Figure 6. Infratentorial = necrosis=20 following radiation therapy in a 21-year-old woman who = underwent=20 surgery, accelerated radiation therapy (60 Gy), and = chemotherapy for=20 a left parietal lobe glioblastoma multiforme. On the = postcontrast=20 coronal T1-weighted spin-echo image (500/11), the open arrow = points=20 to a large surgical cavity with no residual tumor 13 months = after=20 resection. The solid arrows point to solid areas of abnormal = enhancement involving the white matter in both cerebellar=20 hemispheres. This abnormal enhancement was presumed to = represent=20 radiation necrosis; however, this was not verified with=20 histopathologic analysis. Six months later, the patient died = of=20 recurrent parietoccipital lobe glioblastoma. =

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  		Figure 7. Chart (top) and = plot=20 graph (bottom) illustrate the intervals, in months, from = completion=20 of radiation therapy to histopathologic confirmation of=20 treatment-induced necrosis. = AG =3D anaplastic=20 glioma, GBM =3D glioblastoma multiforme. Top: The = data in the=20 middle and right columns are numbers of patients. Bottom: = The four=20 columns represent box plots of actual data (=B1 SD). The = median values=20 are designated by the horizontal line bisecting each box, = and the=20 ranges are designated by the upper and lower bars outside = the boxes.=20 Necrosis refers to pure radiation necrosis, and = Mix=20 refers to predominantly necrosis with limited residual = and/or=20 recurrent tumor. =

 = ;
Radiation-induced=20 enhancement in the brain without radiation necrosis was = observed in=20 the white matter (Fig=20 8) in 52 patients and in the cortex (Fig=20 9) in nine patients. Radiation-induced necrosis of the = optic=20 pathway (Fig=20 10) was seen in one patient, and radiation-induced = necrosis of=20 the auditory pathway (Fig=20 11) was seen in one other patient.



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  		Figure 8. Spontaneous = regression of=20 radiation-induced multifocal enhancement of the white matter = that=20 gradually disappeared within 29 months. Follow-up = postcontrast=20 transverse T1-weighted spin-echo image (500/11) obtained in = a=20 41-year-old man who underwent surgery, accelerated radiation = therapy, and chemotherapy for a nonenhancing anaplastic = astrocytoma=20 involving the left parietal lobe shows multinodular foci of=20 radiation-induced enhancement (arrows) within the white = matter. =

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  		Figure 9. = Radiation-induced damage=20 to the cortex simulating subacute infarction. Postcontrast=20 transverse T1-weighted spin-echo image (500/11) obtained 17 = months=20 after therapy in a 34-year-old man who had received = accelerated=20 radiation therapy (57 Gy) and chemotherapy for an anaplastic = astrocytoma involving the left cingulate gyrus shows an = enhancing=20 area (arrow) in the right insular cortex. This enhancing = area was=20 present on the follow-up MR image (not shown) obtained 1 = year later. =

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  		Figure 10. Postcontrast = transverse=20 T1-weighted fat-suppressed spin-echo image (500/11) obtained = in a=20 26-year-old man after surgery, 9 months after accelerated = radiation=20 therapy (55.5 Gy) and chemotherapy for a frontal lobe = anaplastic=20 astrocytoma, shows radiation necrosis involving the optic = nerves=20 (open arrows), chiasm (arrowheads), and tracts (solid = arrows). The=20 necrosis was confirmed at autopsy. =

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  		Figure 11a. Radiation = necrosis of=20 the pons involving the white matter tracts, including the = region of=20 the auditory pathway lateral lemniscus, in a 44-year-old = woman who=20 had undergone resection of a left temporal lobe anaplastic=20 astrocytoma followed by accelerated radiation therapy (60 = Gy) and=20 chemotherapy. (a) Postcontrast transverse T1-weighted = spin-echo image (700/16) shows radiation-induced necrosis = involving=20 the lateral aspect of the pons (solid arrow). The open arrow = points=20 to an enhancing area posterior to the surgical cavity in the = temporal lobe that was histopathologically proved to be = radiation=20 necrosis. (b) Whole-mount histologic section of the = left pons=20 in a shows pallor of the fiber tracts and nuclei = (arrows).=20 The principal fiber tract of the auditory pathways, the = lateral=20 lemniscus, is included within the area of demyelination.=20 (Hematoxylin-eosin stain; original magnification, x4.) =

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  		Figure 11b. Radiation = necrosis of=20 the pons involving the white matter tracts, including the = region of=20 the auditory pathway lateral lemniscus, in a 44-year-old = woman who=20 had undergone resection of a left temporal lobe anaplastic=20 astrocytoma followed by accelerated radiation therapy (60 = Gy) and=20 chemotherapy. (a) Postcontrast transverse T1-weighted = spin-echo image (700/16) shows radiation-induced necrosis = involving=20 the lateral aspect of the pons (solid arrow). The open arrow = points=20 to an enhancing area posterior to the surgical cavity in the = temporal lobe that was histopathologically proved to be = radiation=20 necrosis. (b) Whole-mount histologic section of the = left pons=20 in a shows pallor of the fiber tracts and nuclei = (arrows).=20 The principal fiber tract of the auditory pathways, the = lateral=20 lemniscus, is included within the area of demyelination.=20 (Hematoxylin-eosin stain; original magnification, x4.) =

 = ;

3D"   =20 DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
3D"DISCUSSION
REFERENCES
 
<= STRONG>Pathophysiology=20 of Radiation-induced Damage to the Brain
Currently, a = complete=20 understanding of the pathophysiology of radiation therapy=96 = and=20 chemotherapy-induced injury to the central nervous system is = lacking.=20 Relevant variables include total radiation dose, radiation = field=20 size, radiation fraction size, number and frequency of = radiation=20 doses, combination of radiation therapy and chemotherapy, = duration of=20 survival, and age of the patient at treatment (2).=20 Understanding the importance of specific MR imaging findings = in this=20 patient population is aided by a familiarity with the current = concepts of the pathophysiology of radiation-induced damage = to the=20 central nervous system, which are reviewed in the following=20 text.

The postulated mechanisms that may contribute to = radiation-induced=20 neurotoxicity include (a) vascular injury, (b) glial = and=20 white matter damage, (c) effects on the fibrinolytic = enzyme=20 system, and (d) immune mechanisms.

Vascular injury.=97In acute radiation-induced injury, = transient=20 vasodilatation occurs with variable changes in capillary = permeability=20 that sometimes manifest as vasogenic edema (3,4).=20 Changes in capillary permeability, in response to radiation = therapy=20 to the central nervous system, have been quantitated and = found=20 to entail specific molecular-size variability (5,6).=20 In chronic radiation-induced injury, vascular endothelial = damage=20 takes place (4).=20 Fike et al (7)=20 demonstrated in animal studies that vascular abnormalities = occur=20 before the development of parenchymal changes in the brain. = The=20 pathologic findings consist of endothelial damage, vascular = ectasia,=20 and telangiectasia, all of which result in increased = capillary=20 permeability at the site of vascular injury with resultant = cytotoxic=20 and vasogenic edema (4).=20 Progressive vascular changes include vessel wall thickening = caused by=20 hyalinization, with consequent thrombosis, infarction, and = necrosis=20 (4).=20 The results of these studies provide support for the concept=20 that vascular injury has a pivotal role in the development of = radiation-induced neurotoxic effects in the brain. This = hypothesis,=20 however, has not been proved and is not universally accepted. = One=20 alternative concept is that cytokine release may stimulate = new vessel=20 formation, which contributes to capillary leakage. =

Glial and white matter damage.=97It has been shown that=20 oligodendrocytes are extremely sensitive to radiation and = that=20 their destruction is associated with radiologic evidence of = the=20 demyelination that ensues (4,8).=20 Although neurons are relatively insensitive to radiation, = there is=20 sufficient loss of cellular components, primarily in white = matter, to=20 account for the observed reduction in brain volume that = accompanies=20 central nervous system radiation toxicity. Documented = metabolic=20 changes that occur in irradiated cells=97for example, reduced = glycolysis=97are associated with a decrease in glucose = consumption,=20 which correlates with the decrease in glucose and oxygen = utilization=20 observed on the positron emission tomographic scans obtained = in=20 patients with radiation-induced central nervous system = necrosis (9).=20

Effects on the fibrinolytic enzyme system.=97Sawaya (10)=20 examined necrotic brain tissue samples obtained in patients=20 with radiation-induced necrosis and found an absence of = tissue=20 plasminogen activator and an excess of urokinase plasminogen=20 activator. These enzymes are members of a complex = fibrinolytic=20 pathway that has potent variable effects on blood vessels and = brain tissue. Tissue plasminogen activator affects fibrinogen = during blood clotting, whereas urokinase plasminogen = activator=20 is active in extracellular proteolysis. An increase in = urokinase=20 plasminogen activator with a concomitant decrease in tissue=20 plasminogen activator may contribute to cytotoxic edema and=20 tissue necrosis.

Immune mechanisms.=97An intriguing concept, the validity = of=20 which is currently unknown, is the possibility of an immune = response=20 in the host secondary to tissue damage caused by radiation = and=20 chemotherapy. The potential role of autoimmune vasculitis in = the=20 response of the central nervous system to radiation-induced = damage=20 needs further investigation (8).=20

Histopathologic Features
The end point of = radiation=20 injury is necrosis that may develop months to years after the = completion of radiation therapy and is frequently = irreversible and=20 often progressive (4,11).=20 Radiation necrosis occurs most commonly around blood vessels = within=20 white matter (4,11).=20 The most common histopathologic features are fibrinoid = necrosis of=20 blood vessel walls, with surrounding perivascular parenchymal = coagulative necrosis (Fig=20 1). Extension and confluence of multiple perivascular = foci of=20 necrosis result in large serpiginous or "geographic" zones of = parenchymal necrosis (Fig=20 1), which are followed by the deposition of mineral salts = (ie,=20 dystrophic calcification). An additional vascular lesion that = is=20 often observed consists of clusters of abnormally dilated,=20 thin-walled telangiectasias (Fig=20 1c). Late vascular changes include vessel wall thickening = caused=20 by hyalinization, with resultant luminal narrowing (Fig=20 1b). White matter changes include focal and diffuse=20 demyelination.

Radiologic Findings
Several articles (12=9626)=20 on the imaging findings of adverse effects of therapeutic = radiation=20 to the brain have been published. Van Tassel et al (23)=20 described MR findings of brain injury after accelerated = fractionation=20 radiation therapy combined with carboplatin chemotherapy for = the=20 treatment of malignant gliomas. The present study is an = extension and=20 expansion of that work, with emphasis on both the common and = uncommon=20 features of radiation necrosis of the brain.

Radiation-induced necrosis of the white = matter.=97Radiation-induced=20 necrosis is the end result of perivascular coagulative = necrosis=20 affecting the white matter. As expected, radiation necrosis=20 occurs most commonly at the site of maximum radiation = delivery,=20 that is, in the immediate vicinity of the tumor site and = surrounding=20 the surgical cavity of a partially or totally resected tumor=20 (Fig=20 1). Radiation necrosis can closely resemble recurrent tumor = at MR=20 imaging or CT because of the following shared characteristics:=20 (a) origin at or close to the original tumor site, = (b)=20 contrast enhancement, (c) growth over time, (d) = edema,=20 and (e) exertion of mass effect. With respect to the = MR=20 imaging characteristics of radiation necrosis, most lesions = consist=20 of an enhancing mass with a central area of necrosis. The = contrast=20 enhancement of these lesions is secondary to = radiation-induced=20 endothelial damage, which leads to the breakdown of the = blood-brain=20 barrier. The use of platinum-based chemotherapy drugs, such = as=20 cisplatin and carboplatin, combined with radiation therapy = may=20 contribute to the development of radiation-induced necrosis = (27=9630).=20 On T2-weighted images, the solid portion of the = radiation-induced=20 necrotic mass has low signal intensity, and the central = necrotic=20 component shows increased signal intensity.

In addition to the most common pattern of radiation necrosis,=20 which consists of a single lesion arising at the site of the=20 original primary tumor, other less common patterns also may = be=20 observed. Examples include (a) multiple lesions, (b) = lesions=20 in the contralateral hemisphere, (c) lesions arising = remotely=20 from a primary cerebral site=97for example, in the cerebellum = (Fig=20 6) or brain stem, and (d) subependymal lesions. Each of=20 these rarer patterns of radiation necrosis can be suggestive = of=20 a different pathologic process. For example, radiation necrosis=20 occurring at the site of the resected primary tumor can be = easily=20 mistaken for recurrent tumor (Fig=20 1). Necrosis occurring distant to the primary site of = tumor may=20 mimic multifocal glioma (Fig=20 2). In Figure=20 3, the radiation necrosis around the periventricular = white matter=20 of the contralateral hemisphere simulating multicentric = glioma has=20 tumorlike associated edema and mass effect. Marks et al (2)=20 described radiation necrosis arising contralaterally to the = primary=20 tumor site in one patient following whole-brain irradiation. = In our=20 series, we observed this finding in eight patients. =

Multiple lesions can resemble multiple metastases (Fig=20 4a). The predilection for periventricular white matter=20 involvement in radiation necrosis may, on rare occasion, = mimic=20 tumefactive multiple sclerosis (Fig=20 4b). The radiation necrosis that develops in the = periventricular=20 white matter may be explained by the fact that this = neuroanatomic=20 region has a relatively poor blood supply from long medullary = arteries that lack collateral vessels and is therefore = vulnerable to=20 ischemic effects produced by postradiation vasculopathy (31,32).=20 Therapy-induced necrotic lesions can also spread = subependymally and=20 mimic subependymal tumor spread (Fig=20 2b).

As radiation necrosis progresses with tumorlike growth, it can=20 lead to severe shrinkage of the white matter and cortex and=20 result in focal brain atrophy (Fig=20 5). The arcuate fibers in white matter are relatively = resistant=20 to radiation necrosis and are usually involved late in the = disease=20 process. An additional variant of radiation necrosis that = warrants=20 brief attention is the Swiss cheese pattern. This pattern can = be=20 visualized as a result of diffuse necrosis affecting the = white matter=20 and adjacent cortex. The Swiss cheese pattern reflects = diffuse=20 enhancements at the margins affecting the cortex and white = matter,=20 with intermixed foci of necrosis. Compared with lesions with = the soap=20 bubble pattern, Swiss cheese lesions are larger, more = variable in=20 size, and more diffuse (Fig=20 5).

The incidence of radiation necrosis after conventional therapy=20 ranges from 5% to 24%, with higher rates at autopsy (2,33).=20 In our series of 148 patients with treated malignant gliomas, = pure radiation necrosis was observed in 20 (13.5%) patients,=20 and a mixture of predominantly radiation necrosis = intermingled=20 with limited residual and/or recurrent tumor (less than 20% = of=20 resected tissue) was found in 16 (10.8%). It is important to = remember=20 that radiation-induced necrosis is a dynamic pathophysiologic = process=20 with several possible clinical outcomes. Although continued = growth=20 with attendant cytotoxic edema and mass effect is commonly = seen,=20 lethal progression is not inevitable in all cases. Some = lesions will=20 stabilize, and others will regress in size. Surgery may be = required=20 to reduce the mass effect and edema, and despite advancements = in=20 special imaging techniques, surgery may be needed to = establish an=20 accurate histopathologic diagnosis. Finally, despite the use = of total=20 gross resection, which includes removal of the necrotic = tissue,=20 radiation necrosis recurrence will be observed in some cases. = It is=20 anticipated that current efforts to further refine = investigational=20 radiologic techniques will lead to less ambiguous diagnoses = of=20 radiation-induced necrosis in the near future.

Radiation-induced enhancement of the white matter and=20 cortex.=97Radiation-induced enhancement, a milder form of = brain=20 injury, usually occurs within the white matter, can be single = or=20 multiple, and appears in varying sizes. This enhancement = mostly=20 affects the white matter at variable distances from the = primary tumor=20 site (Fig=20 8). The contralateral cerebral hemisphere or cerebellar = white=20 matter is affected less often. The pattern of enhancement can = be=20 nodular (Fig=20 8), linear (Fig=20 1), or curvilinear. These lesions are frequently seen at = MR=20 imaging and do not warrant biopsy if they remain stable (Fig=20 9) or regress (Fig=20 8) in size. However, progression to radiation necrosis = should be=20 suspected, and if they have an increase in size, accompanied = by edema=20 and mass effect (Fig=20 2). In such instances, surgery is recommended.=20 Radiation-induced damage of this type can also occur within = the=20 cortex. For example, cortical gyral enhancement may simulate = subacute=20 infarction (Fig=20 9).

Radiation-induced necrosis of the cranial=20 nerves.=97Radiation-induced cranial neuropathy is = relatively rare.=20 Radiation-induced optic neuropathy (Fig=20 10) is likely to occur when focused radiation is = delivered to=20 tumors in the perioptic regions (34).=20 The pathologic process of this neuropathy consists of optic = pathway=20 vasculopathy with secondary hemorrhage, reactive gliosis, = necrosis,=20 and atrophy. A similar process can occur around other cranial = nerves,=20 as demonstrated in a patient in our series with necrosis at = and=20 around the lateral lemniscus of the central auditory pathway=20 (Fig=20 11).

In summary, the frequent diagnostic dilemma of recurrent = neoplasm=20 versus radiation necrosis is addressed in this study through = a=20 description of the varying spatial and temporal patterns of = radiation=20 necrosis that may be encountered at MR imaging:

1. If the tumor was a nonenhancing lesion before surgery and=20 enhancing foci subsequently developed within and = circumscribing=20 the tumor, the enhancing lesions often do not represent = progression=20 to a higher grade, but rather they are often the result of = radiation=20 necrosis.

2. If an enhancing focus develops at a distance from the primary = glioma, radiation necrosis should be suspected; multiple = enhancing=20 areas do not necessarily represent multifocal glioma.

3. If an enhancing focus develops in the periventricular white=20 matter, particularly capping the ventricles or within the = corpus=20 callosum, radiation necrosis should be suspected. The = periventricular=20 white matter is among the areas most susceptible to radiation = necrosis.

4. Radiation necrosis should be suspected if a new enhancing=20 lesion exhibits a soap bubble or Swiss cheese pattern.

The key point in any of these scenarios is that radiation = necrosis=20 should be included high in the differential diagnosis. It is=20 important to recognize the spectrum of MR imaging features of = radiation necrosis, because this tissue damage can mimic = other=20 pathologic processes.


3D"   =20 ACKNOWLEDGMENTS
 
We = thank Marites A.=20 Trevino and Kari Maloney for help in the preparation of this=20 manuscript and Don Norwood, BS, for editorial = assistance.


3D"   =20 FOOTNOTES
 
2 Current address: = Department of=20 Radiology, Medical University of South Carolina, = Charleston.=20

Author contributions: Guarantors of = integrity of=20 entire study, A.J.K., N.E.L., G.N.F., V.A.L.; study concepts = and=20 design, V.A.L., A.J.K.; definition of intellectual content, = V.A.L.,=20 N.E.L., A.J.K.; literature research, N.E.L., A.J.K., V.A.L.;=20 clinical studies, all authors; data acquisition and analysis, = V.A.L., N.E.L., A.J.K.; manuscript preparation and editing,=20 A.J.K., N.E.L., G.N.F.; manuscript review, all authors. =


3D"   =20 REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
3D"REFERENCES
&nb= sp;

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XMLHttpRequest v1.2=0A= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=0A= =0A= Emulate Gecko 'XMLHttpRequest()' functionality in IE and Opera. Opera = requires=0A= the Sun Java Runtime Environment .=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_00A8_01C913FB.8F2EFC70 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://radiology.rsnajnls.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else if (name =3D=3D "margin-right") {=0A= e.style.marginRight =3D value;=0A= }=0A= else if (name =3D=3D "margin-top") {=0A= e.style.marginTop =3D value;=0A= }=0A= else if (name =3D=3D "min-height") {=0A= e.style.minHeight =3D value;=0A= }=0A= else if (name =3D=3D "overflow") {=0A= e.style.overflow =3D value;=0A= }=0A= else if (name =3D=3D "overflow-x") {=0A= e.style.overflowX =3D value;=0A= }=0A= else if (name =3D=3D "overflow-y") {=0A= e.style.overflowY =3D value;=0A= }=0A= else if (name =3D=3D "padding") {=0A= e.style.padding =3D value;=0A= }=0A= else if (name =3D=3D "padding-bottom") {=0A= e.style.paddingBottom =3D value;=0A= }=0A= else if (name =3D=3D "padding-left") {=0A= e.style.paddingLeft =3D value;=0A= }=0A= else if (name =3D=3D "padding-right") {=0A= e.style.paddingRight =3D value;=0A= }=0A= else if (name =3D=3D "padding-top") {=0A= e.style.paddingTop =3D value;=0A= }=0A= else if (name =3D=3D "page-break-after") {=0A= e.style.pageBreakAfter =3D value;=0A= }=0A= else if (name =3D=3D "page-break-before") {=0A= e.style.pageBreakBefore =3D value;=0A= }=0A= else if (name =3D=3D "pixelBottom") {=0A= e.style.pixelBottom =3D value;=0A= }=0A= else if (name =3D=3D "pixelHeight") {=0A= e.style.pixelHeight =3D value;=0A= }=0A= else if (name =3D=3D "pixelLeft") {=0A= e.style.pixelLeft =3D value;=0A= }=0A= else if (name =3D=3D "pixelRight") {=0A= e.style.pixelRight =3D value;=0A= }=0A= else if (name =3D=3D "pixelTop") {=0A= e.style.pixelTop =3D value;=0A= }=0A= else if (name =3D=3D "pixelWidth") {=0A= e.style.pixelWidth =3D value;=0A= }=0A= else if (name =3D=3D "posBottom") {=0A= e.style.posBottom =3D value;=0A= }=0A= else if (name =3D=3D "posHeight") {=0A= e.style.posHeight =3D value;=0A= }=0A= else if (name =3D=3D "position") {=0A= e.style.position =3D value;=0A= }=0A= else if (name =3D=3D "posLeft") {=0A= e.style.posLeft =3D value;=0A= }=0A= else if (name =3D=3D "posRight") {=0A= e.style.posRight =3D value;=0A= }=0A= else if (name =3D=3D "posTop") {=0A= e.style.posTop =3D value;=0A= }=0A= else if (name =3D=3D "posWidth") {=0A= e.style.posWidth =3D value;=0A= }=0A= else if (name =3D=3D "right") {=0A= e.style.right =3D value;=0A= }=0A= else if (name =3D=3D "ruby-align") {=0A= e.style.rubyAlign =3D value;=0A= }=0A= else if (name =3D=3D "ruby-overhang") {=0A= e.style.rubyOverhang =3D value;=0A= }=0A= else if (name =3D=3D "ruby-position") {=0A= e.style.rubyPosition =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-3dlight-color") {=0A= e.style.scrollbar3dLightColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-arrow-color") {=0A= e.style.scrollbarArrowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-base-color") {=0A= e.style.scrollbarBaseColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-darkshadow-color") {=0A= e.style.scrollbarDarkShadowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-face-color") {=0A= e.style.scrollbarFaceColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-highlight-color") {=0A= e.style.scrollbarHighlightColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-shadow-color") {=0A= e.style.scrollbarShadowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-track-color") {=0A= e.style.scrollbarTrackColor =3D value;=0A= }=0A= else if (name =3D=3D "float") {=0A= e.style.styleFloat =3D value;=0A= }=0A= else if (name =3D=3D "table-layout") {=0A= e.style.tableLayout =3D value;=0A= }=0A= else if (name =3D=3D "text-align") {=0A= e.style.textAlign =3D value;=0A= }=0A= else if (name =3D=3D "text-align-last") {=0A= e.style.textAlignLast =3D value;=0A= }=0A= else if (name =3D=3D "text-autospace") {=0A= e.style.textAutospace =3D value;=0A= }=0A= else if (name =3D=3D "text-decoration") {=0A= e.style.textDecoration =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationBlink") {=0A= e.style.textDecorationBlink =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationLineThrough") {=0A= e.style.textDecorationLineThrough =3D value;=0A= }=0A= else if (name =3D=3D 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quoted-printable Content-Location: http://radiology.rsnajnls.org/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. For now we have to disable=0A= * the callback until we can track down a proper fix=0A= * (or everybody sanely upgrades to version 6 or 7!).=0A= */=0A= if (navigator) {=0A= var appname =3D navigator.appName;=0A= if (appname =3D=3D "Microsoft Internet Explorer") {=0A= var userAgent =3D navigator["userAgent"];=0A= var s =3D "MSIE ";=0A= var n =3D -1; =0A= if ((n =3D userAgent.indexOf(s)) !=3D -1) {=0A= var v =3D parseFloat(userAgent.substring(n+s.length));=0A= if (v < 6) {=0A= return;=0A= }=0A= }=0A= }=0A= }=0A= =0A= /*=0A= * Acquire table row element to update, initiate callback=0A= * to update table with Entrez Links.=0A= */=0A= var tr =3D document.getElementById('entrez_callback_'+pmid);=0A= if (!tr) {=0A= return;=0A= }=0A= var req =3D new XMLHttpRequest();=0A= if (!req) {=0A= return;=0A= }=0A= req.onreadystatechange =3D function() {=0A= if (req.readyState =3D=3D 4 && (req.status =3D=3D 200 || req.status = =3D=3D 304)) {=0A= var src =3D req.responseXML.documentElement;=0A= var dst =3D document.createDocumentFragment();=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], dst);=0A= }=0A= var tbl =3D tr.parentNode;=0A= tbl.replaceChild(dst, tr);=0A= }=0A= }=0A= req.open('GET', callback_url, true);=0A= req.send(null);=0A= }=0A= ------=_NextPart_000_00A8_01C913FB.8F2EFC70--