Soonmee Cha

Role of Extent of Resection in the Long-Term Outcome of Low-Grade Hemispheric Gliomas

PURPOSE The prognostic role of extent of resection (EOR) of low-grade gliomas (LGGs) is a major controversy. We designed a retrospective study to assess the influence of EOR on long-term outcomes of LGGs. PATIENTS AND METHODS The study population (N = 216) included adults undergoing initial resection of hemispheric LGG. Region-of-interest analysis was performed to measure tumor volumes based on fluid-attenuated inversion-recovery (FLAIR) imaging. RESULTS Median preoperative and postoperative tumor volumes and EOR were 36.6 cm(3) (range, 0.7 to 246.1 cm(3)), 3.7 cm(3) (range, 0 to 197.8 cm(3)) and 88.0% (range, 5% to 100%), respectively. There was no operative mortality. New postoperative deficits were noted in 36 patients (17%); however, all but four had complete recovery. There were 34 deaths (16%; median follow-up, 4.4 years). Progression and malignant progression were identified in 95 (44%) and 44 (20%) cases, respectively. Patients with at least 90% EOR had 5- and 8-year overall survival (OS) rates of 97% and 91%, respectively, whereas patients with less than 90% EOR had 5- and 8-year OS rates of 76% and 60%, respectively. After adjusting each measure of tumor burden for age, Karnofsky performance score (KPS), tumor location, and tumor subtype, OS was predicted by EOR (hazard ratio [HR] = 0.972; 95% CI, 0.960 to 0.983; P < .001), log preoperative tumor volume (HR = 4.442; 95% CI, 1.601 to 12.320; P = .004), and postoperative tumor volume (HR = 1.010; 95% CI, 1.001 to 1.019; P = .03), progression-free survival was predicted by log preoperative tumor volume (HR = 2.711; 95% CI, 1.590 to 4.623; P <or= .001) and postoperative tumor volume (HR = 1.007; 95% CI, 1.001 to 1.014; P = .035), and malignant progression-free survival was predicted by EOR (HR = 0.983; 95% CI, 0.972 to 0.995; P = .005) and log preoperative tumor volume (HR = 3.826; 95% CI, 1.632 to 8.969; P = .002). CONCLUSION Improved outcome among adult patients with hemispheric LGG is predicted by greater EOR.

Mutational Analysis Reveals the Origin and Therapy-driven Evolution of Recurrent Glioma

Back with a Vengeance After surgery, gliomas (a type of brain tumor) recur in nearly all patients and often in a more aggressive form. Johnson et al. (p. 189, published online 12 December 2013) used exome sequencing to explore whether recurrent tumors harbor different mutations than the primary tumors and whether the mutational profile in the recurrences is influenced by postsurgical treatment of patients with temozolomide (TMZ), a chemotherapeutic drug known to damage DNA. In more than 40% of cases, at least half of the mutations in the initial glioma were undetected at recurrence. The recurrent tumors in many of the TMZ-treated patients bore the signature of TMZ-induced mutagenesis and appeared to follow an evolutionary path to high-grade glioma distinct from that in untreated patients. Primary brain tumors and their recurrences can exhibit vastly different mutational profiles. Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.

Differentiation of recurrent glioblastoma multiforme from radiation necrosis after external beam radiation therapy with dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging.

PURPOSE To investigate whether cerebral blood volume (CBV), peak height (PH), and percentage of signal intensity recovery (PSR) measurements derived from the results of T2-weighted dynamic susceptibility-weighted contrast material-enhanced (DSC) magnetic resonance (MR) imaging performed after external beam radiation therapy (EBRT) can be used to distinguish recurrent glioblastoma multiforme (GBM) from radiation necrosis. MATERIALS AND METHODS Fifty-seven patients were enrolled in this HIPAA-compliant institutional review board-approved retrospective study after they received a diagnosis of GBM, underwent EBRT, and were examined with DSC MR imaging, which revealed progressive contrast enhancement within the radiation field. A definitive diagnosis was established at subsequent surgical resection or clinicoradiologic follow-up. Regions of interest were retrospectively drawn around the entire contrast-enhanced region. This created T2-weighted signal intensity-time curves that produced three cerebral hemodynamic MR imaging measurements: CBV, PH, and PSR. Welch t tests were used to compare measurements between groups. RESULTS Mean, maximum, and minimum relative PH and relative CBV were significantly higher (P < .01) in patients with recurrent GBM than in patients with radiation necrosis. Mean, maximum, and minimum relative PSR values were significantly lower (P < .05) in patients with recurrent GBM than in patients with radiation necrosis. CONCLUSION These findings suggest that DSC perfusion MR imaging may be used to differentiate recurrent GBM from EBRT-induced radiation necrosis.

Identification of noninvasive imaging surrogates for brain tumor gene-expression modules

Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults. We combined neuroimaging and DNA microarray analysis to create a multidimensional map of gene-expression patterns in GBM that provided clinically relevant insights into tumor biology. Tumor contrast enhancement and mass effect predicted activation of specific hypoxia and proliferation gene-expression programs, respectively. Overexpression of EGFR, a receptor tyrosine kinase and potential therapeutic target, was also directly inferred by neuroimaging and was validated in an independent set of tumors by immunohistochemistry. Furthermore, imaging provided insights into the intratumoral distribution of gene-expression patterns within GBM. Most notably, an “infiltrative” imaging phenotype was identified that predicted patient outcome. Patients with this imaging phenotype had a greater tendency toward having multiple tumor foci and demonstrated significantly shorter survival than their counterparts. Our findings provide an in vivo portrait of genome-wide gene expression in GBM and offer a potential strategy for noninvasively selecting patients who may be candidates for individualized therapies.

Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype

Neural stem cells with astrocyte-like characteristics exist in the human brain subventricular zone (SVZ), and these cells may give rise to glioblastoma multiforme (GBM). We therefore analyzed MRI features of GBMs in specific relation to the SVZ. We reviewed the preoperative and serial postoperative MR images of 53 patients with newly diagnosed GBM. The spatial relationship of the contrast-enhancing lesion (CEL) with the SVZ and cortex was determined preoperatively. Classification was as follows: group I, CEL contacting SVZ and infiltrating cortex; group II, CEL contacting SVZ but not involving cortex; group III, CEL not contacting SVZ but involving cortex; and group IV, CEL neither contacting SVZ nor infiltrating cortex. Patients with group I GBMs (n = 16) were most likely to have multifocal disease at diagnosis (9 patients, 56%, p = 0.001). In contrast, group IV GBMs (n = 14) were never multifocal. Group II (n = 14) and group III (n = 9) GBMs were multifocal in 11% and 29% of cases, respectively. Group I GBMs always had tumor recurrences noncontiguous with the initial lesion(s), while group IV GBM recurrences were always bordering the primary lesion. Group I GBMs may be most related to SVZ stem cells; these tumors were in intimate contact with the SVZ, were most likely to be multifocal at diagnosis, and recurred at great distances to the initial lesion(s). In contrast, group IV GBMs were always solitary lesions; these may arise from non-SVZ, white matter glial progenitors. Our MRI-based classification of GBMs may further our understanding of GBM histogenesis and help predict tumor recurrence pattern.

Impact of extent of resection for recurrent glioblastoma on overall survival: clinical article.

OBJECT Extent of resection (EOR) has been shown to be an important prognostic factor for survival in patients undergoing initial resection of glioblastoma (GBM), but the significance of EOR at repeat craniotomy for recurrence remains unclear. In this study the authors investigate the impact of EOR at initial and repeat resection of GBM on overall survival. METHODS Medical records were reviewed for all patients undergoing craniotomy for GBM at the University of California San Francisco Medical Center from January 1, 2005, through August 15, 2009. Patients who had a second craniotomy for pathologically confirmed recurrence following radiation and chemotherapy were evaluated. Volumetric EOR was measured and classified as gross-total resection (GTR, > 95% by volume) or subtotal resection (STR, ≤ 95% by volume) after independent radiological review. Overall survival was compared between groups using univariate and multivariate analysis accounting for known prognostic factors, including age, eloquent location, Karnofsky Performance Status (KPS), and adjuvant therapies. RESULTS Multiple resections were performed in 107 patients. Fifty-two patients had initial GTR, of whom 31 (60%) had GTR at recurrence, with a median survival of 20.4 months (standard error [SE] 1.0 months), and 21 (40%) had STR at recurrence, with a median survival of 18.4 months (SE 0.5 months) (difference not statistically significant). Initial STR was performed in 55 patients, of whom 26 (47%) had GTR at recurrence, with a median survival of 19.0 months (SE 1.2 months), and 29 (53%) had STR, with a median survival of 15.9 months (SE 1.2 months) (p = 0.004). A Cox proportional hazards model was constructed demonstrating that age (HR 1.03, p = 0.004), KPS score at recurrence (HR 2.4, p = 0.02), and EOR at repeat resection (HR 0.62, p = 0.02) were independent predictors of survival. Extent of initial resection was not a statistically significant factor (p = 0.13) when repeat EOR was included in the model, suggesting that GTR at second craniotomy could overcome the effect of an initial STR. CONCLUSIONS Extent of resection at recurrence is an important predictor of overall survival. If GTR is achieved at recurrence, overall survival is maximized regardless of initial EOR, suggesting that patients with initial STR may benefit from surgery with a GTR at recurrence.

Differentiation of Glioblastoma Multiforme and Single Brain Metastasis by Peak Height and Percentage of Signal Intensity Recovery Derived from Dynamic Susceptibility-Weighted Contrast-Enhanced Perfusion MR Imaging

BACKGROUND AND PURPOSE: Glioblastoma multiforme (GBM) and single brain metastasis (MET) are the 2 most common malignant brain tumors that can appear similar on anatomic imaging but require vastly different treatment strategy. The purpose of our study was to determine whether the peak height and the percentage of signal intensity recovery derived from dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion MR imaging could differentiate GBM and MET. MATERIALS AND METHODS: Forty-three patients with histopathologic diagnosis of GBM (n = 27) or MET (n = 16) underwent DSC perfusion MR imaging in addition to anatomic MR imaging before surgery. Regions of interest were drawn around the nonenhancing peritumoral T2 lesion (PTL) and the contrast-enhancing lesion (CEL). T2* signal intensity-time curves acquired during the first pass of gadolinium contrast material were converted to the changes in relaxation rate to yield T2* relaxivity (ΔR2*) curve. The peak height of maximal signal intensity drop and the percentage of signal intensity recovery at the end of first pass were measured for each voxel in the PTL and CEL regions of the tumor. RESULTS: The average peak height for the PTL was significantly higher (P = .04) in GBM than in MET. The average percentage of signal intensity recovery was significantly reduced in PTL (78.4% versus 82.8%; P = .02) and in CEL (62.5% versus 80.9%, P < .01) regions of MET compared with those regions in the GBM group. CONCLUSIONS: The findings of our study show that the peak height and the percentage of signal intensity recovery derived from the ΔR2* curve of DSC perfusion MR imaging can differentiate GBM and MET.

Distinguishing Recurrent Intra-Axial Metastatic Tumor from Radiation Necrosis Following Gamma Knife Radiosurgery Using Dynamic Susceptibility-Weighted Contrast-Enhanced Perfusion MR Imaging

BACKGROUND AND PURPOSE: MR image−guided gamma knife radiosurgery is often used to treat intra-axial metastatic neoplasms. Following treatment, it is often difficult to determine whether a progressively enhancing lesion is due to metastatic tumor recurrence or radiation necrosis. The purpose of our study was to determine whether relative cerebral blood volume (rCBV), relative peak height (rPH), and percentage of signal-intensity recovery (PSR) derived from dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging can distinguish recurrent metastatic tumor from radiation necrosis. MATERIALS AND METHODS: Twenty-seven patients with systemic cancer underwent gamma knife radiosurgery for metastatic lesions of the brain and subsequently developed enlarging regions of enhancement within the radiation field. Subsequent surgical resection or clinicoradiologic follow-up established a diagnosis of recurrent metastatic tumor or radiation necrosis. Perfusion MR imaging datasets were retrospectively reprocessed, and regions of interest were drawn around the entire contrast-enhancing region. The resulting T2* signal-intensity time curves produced rCBV, rPH, and PSR values for each examination. A Welch t test was used to compare imaging values between groups. RESULTS: The mean, minimum, and maximum PSR values were significantly lower (P < .01) in cases of recurrent metastatic tumor. The mean and maximum rCBV and rPH values were significantly higher (P < .02) in the recurrent metastatic tumor group. CONCLUSIONS: The findings of our study suggest that perfusion MR imaging may be used to differentiate recurrent intra-axial metastatic tumor from gamma knife−induced radiation necrosis.

Measuring blood volume and vascular transfer constant from dynamic, T*2-Weighted contrast-enhanced MRI

Dynamic, contrast‐enhanced MRI (deMRI) is increasingly being used to evaluate cerebral microcirculation. There are two different approaches for analyzing deMRI data. Intravascular indicator dilution theory has been used to estimate blood volume (and perfusion), usually from T2‐ or T  2* ‐weighted images of the first pass of the bolus. However, the theory assumes that the tracer (i.e., contrast agent) remains intravascular, which is often not the case when the blood–brain barrier (BBB) is damaged. Furthermore, the method provides no information on the vascular transfer constant. Pharmacokinetic modeling analyses of T1‐weighted images after first pass do give values of the vascular transfer constant and the volume of the extravascular, extracellular space (EES), but they generally are unable to give estimates of blood volume. In this study we apply pharmacokinetic modeling to dynamic T  2* ‐weighted imaging of the first pass of a tracer bolus. This method, which we call first‐pass pharmacokinetic modeling (FPPM), gives an estimate of the blood volume, vascular transfer constant, and EES volume. The method was applied to a group of 26 patients with surgically proven tumors (10 glioblastomas multiforme (GBMs), six lymphomas, and 10 meningiomas). The measurements of the blood volume and transfer constant were consistent with the known physiology of these tumors. Magn Reson Med 51:961–968, 2004.

Diffusion-Weighted MR Imaging Derived Apparent Diffusion Coefficient Is Predictive of Clinical Outcome in Primary Central Nervous System Lymphoma

BACKGROUND AND PURPOSE: There is evidence that increased tumor cellular density within diagnostic specimens of primary central nervous system lymphoma (PCNSL) may have significant prognostic implications. Because cellular density may influence measurements of apparent diffusion coefficient (ADC) by using diffusion-weighted MR imaging (DWI), we hypothesized that ADC measured from contrast-enhancing regions might correlate with clinical outcome in patients with PCNSL. MATERIALS AND METHODS: PCNSL tumors from 18 immunocompetent patients, treated uniformly with methotrexate-based chemotherapy, were studied with pretherapeutic DWI. Enhancing lesions were diagnosed by pathologic analysis as high-grade B-cell lymphomas. Regions of interest were placed around all enhancing lesions allowing calculation of mean, 25th percentile (ADC25%), and minimum ADC values. Histopathologic tumor cellularity was quantitatively measured in all patients. High and low ADC groups were stratified by the median ADC value of the cohort. The Welch t test assessed differences between groups. The Pearson correlation examined relationships between ADC measurements and tumor cellular density. Single and multivariable survival analysis was performed. RESULTS: We detected significant intra- and intertumor heterogeneity in ADC measurements. An inverse correlation between cellular density and ADC measurements was observed (P < .05). ADC25% measurements less than the median value of 692 (low ADC group) were associated with significantly shorter progression-free and overall survival. Patients with improved clinical outcome were noted to exhibit a significant decrease in ADC measurements following high-dose methotrexate chemotherapy. CONCLUSIONS: Our study provides evidence that ADC measurements within contrast-enhancing regions of PCNSL tumors may provide noninvasive insight into clinical outcome.