The effects of anti-angiogenic therapy on the formation of radiation-induced microbleeds in normal brain tissue of patients with glioma.

BACKGROUND: Radiotherapy (RT) is an integral component in managing patients with glioma, but the damage it may cause to healthy brain tissue and quality of life is of concern. Susceptibility-weighted imaging (SWI) is highly sensitive to the detection of microbleeds that occur years after RT. This study's goals were to characterize the evolution of radiation-induced microbleeds in normal-appearing brain and determine whether the administration of an anti-angiogenic agent altered this process. METHODS: Serial high-resolution SWI was acquired on 17 patients with high-grade glioma between 8 months and 4.5 years posttreatment with RT and adjuvant chemotherapy. Nine of these patients were also treated with the anti-angiogenic agent enzastaurin. Microbleeds were identified as discrete foci of susceptibility not corresponding to vessels, tumor, or postoperative infarct, and counted in normal-appearing brain. Analysis of covariance was performed to compare slopes of regression of individual patients' microbleed counts over time, Wilcoxon rank-sum tests examined significant differences in rates of microbleed formation between groups, and linear and quadratic mixed-effects models were employed. RESULTS: The number of microbleeds increased with time for all patients, with initial onset occurring at 8-22 months. No microbleeds disappeared once formed. The average rate of microbleed formation significantly increased after 2 years post-RT (P < .001). Patients receiving anti-angiogenic therapy exhibited fewer microbleeds overall (P < .05) and a significant reduction in initial rate of microbleed appearance (P = .01). CONCLUSIONS: We have demonstrated a dramatic increase in microbleed formation after 2 years post-RT that was decelerated by the concomitant administration of anti-angiogenic therapy, which may aid in determining brain regions susceptible to RT.

Using susceptibility-weighted imaging to determine response to combined anti-angiogenic, cytotoxic, and radiation therapy in patients with glioblastoma multiforme.

BACKGROUND: The goal of this study was to investigate whether the amount of hypointense signal on susceptibility-weighted imaging within the contrast-enhancing lesion (%SWI-h) on the pretreatment scan could determine response in patients with newly diagnosed glioblastoma multiforme who received external beam radiation therapy with concomitant anti-angiogenic therapy (enzastaurin) and cytotoxic chemotherapy (temozolomide). METHODS: Twenty-five patients were imaged before therapy (postsurgical resection) and scanned serially every 2 months until progression. Standard clinical MR imaging and SWI were performed on a 3T scanner. %SWI-h was quantified for each patient's pretreatment scan. Time to progression and death were used to characterize patients into non-, immediate-, and sustained-response groups for both events. Cox proportional hazards models were used to assess the association between %SWI-h and both progression-free survival (PFS) and overall survival (OS). Classification and regression tree analysis were used to determine optimal cutoffs on which to split %SWI-h. RESULTS: For both death- and progression-based response categories, %SWI-h was significantly higher in sustained responders than in nonresponders. Cox model coefficients showed an association between %SWI-h and PFS and OS, both in univariate analysis (PFS: hazard ratio [HR] = 0.966, 95% confidence interval [CI] = 0.942-0.988; and OS: HR = 0.945, 95% CI = 0.915-0.976) and when adjusting for baseline KPS, age, sex, and resection extent (PFS: HR = 0.968, 95% CI = 0.940 -0.994; and OS: HR = 0.943, 95% CI = 0.908 -0.976). A cutoff value of 38.1% significantly differentiated patients into 2 groups based on censored OS and into non- and intermediate-response categories based on time to progression. CONCLUSIONS: These early differences suggest that SWI may be able to predict which patients would benefit most from similar combination therapies and may assist clinicians in making important decisions about patient care.

Optical patient interface in femtosecond laser-assisted cataract surgery: contact corneal applanation versus liquid immersion.

PURPOSE: To compare 2 optical patient interface designs used for femtosecond laser-assisted cataract surgery. SETTING: Optimedica Corp., Santa Clara, California, USA, and Centro Laser, Santo Domingo, Dominican Republic. DESIGN: Experimental and clinical studies. METHODS: Laser capsulotomy was performed during cataract surgery with a curved contact lens interface (CCL) or a liquid optical immersion interface (LOI). The presence of corneal folds, incomplete capsulotomy, subconjunctival hemorrhage, and eye movement during laser treatment were analyzed using video and optical coherence tomography. The induced rise of intraocular pressure (IOP) was measured in porcine and cadaver eyes. RESULTS: Corneal folds were identified in 70% of the CCL cohort; 63% of these had areas of incomplete capsulotomies beneath the corneal folds. No corneal folds or incomplete capsulotomies were identified in the LOI cohort. The mean eye movement during capsulotomy creation (1.5 sec) was 50 µm with a CCL and 20 µm with an LOI. The LOI cohort had 36% less subconjunctival hemorrhage than the CCL cohort. During suction, the mean IOP rise was 32.4 mm Hg ± 3.4 (SD) in the CCL group and 17.7 ± 2.1 mm Hg in the LOI group. CONCLUSIONS: Curved contact interfaces create corneal folds that can lead to incomplete capsulotomy during laser cataract surgery. A liquid interface eliminated corneal folds, improved globe stability, reduced subconjunctival hemorrhage, and lowered IOP rise.

Comparison of DSC-MRI post-processing techniques in predicting microvascular histopathology in patients newly diagnosed with GBM.

PURPOSE: To evaluate which common post-processing method applied to gradient-echo DSC-MRI data, acquired with a single gadolinium injection and low flip-angle, most accurately reflects microvascular histopathology for patients with de novo, treatment-naive glioblastoma multiforme (GBM). MATERIALS AND METHODS: Seventy-two tissue samples were collected from 35 patients with treatment-naive GBM. Sample locations were co-registered to preoperative gradient-echo dynamic susceptibility contrast (DSC) MRI acquired with 35° flip-angle and 0.1 mmol/kg gadolinium. Estimates of blood volume and leakiness at each sample location were calculated using four common postprocessing methods (leakage-corrected nonlinear gamma-variate, non-parametric, scaled MR-signal, and unscaled MR-signal). Tissue sample microvascular morphology was characterized using Factor VIII immunohistochemical analysis. A random-effects regression model, adjusted for repeated measures and contrast-enhancement (CE), identified whether MR parameter estimates significantly predicted IHC findings. RESULTS: Elevated blood volume estimates from nonlinear and non-parametric methods significantly predicted increased microvascular hyperplasia. Abnormal microvasculature existed beyond the CE-lesion and was significantly reflected by increased blood volume from nonlinear, non-parametric, and scaled MR-signal analysis. CONCLUSION: This study provides histopathological support for both non-parametric and nonlinear post-processing of low flip-angle DSC-MRI for characterizing microvascular hyperplasia within GBM. Non-parametric analysis with a single gadolinium injection may be a particularly useful strategy clinically, as it requires less computational expense and limits gadolinium exposure.

Regional variation in histopathologic features of tumor specimens from treatment-naive glioblastoma correlates with anatomic and physiologic MR Imaging.

Histopathologic evaluation of glioblastoma multiforme (GBM) at initial diagnosis is typically performed on tissue obtained from regions of contrast enhancement (CE) as depicted on gadolinium-enhanced, T1-weighted images. The non-enhancing (NE) portion of the lesion, which contains both reactive edema and infiltrative tumor, is only partially removed due to concerns about damaging functioning brain. The purpose of this study was to evaluate histopathologic and physiologic MRI features of image-guided tissue specimens from CE and NE regions to investigate correlations between imaging and histopathologic parameters. One hundred nineteen tissue specimens (93 CE and 26 NE regions) were acquired from 51 patients with newly diagnosed GBM by utilizing stereotactic image-guided sampling. Variables of anatomic, diffusion-weighted imaging (DWI), and dynamic susceptibility-weighted, contrast-enhanced perfusion imaging (DSC) from each tissue sample location were obtained and compared with histopathologic features such as tumor score, cell density, proliferation, architectural disruption, hypoxia, and microvascular hyperplasia. Tissue samples from CE regions had increased tumor score, cellular density, proliferation, and architectural disruption compared with NE regions. DSC variables such as relative cerebral blood volume, peak height, and recovery factor were significantly higher, and the percentage of signal intensity recovery was significantly lower in the CE compared with the NE regions. DWI variables were correlated with histopathologic features of GBM within NE regions. Image-guided tissue acquisition and assessment of residual tumor from treatment-naive GBM should be guided by DSC in CE regions and by DWI in NE regions.

Assessment of perfusion MRI-derived parameters in evaluating and predicting response to antiangiogenic therapy in patients with newly diagnosed glioblastoma.

The paradigm for treating patients with glioblastoma multiforme (GBM) is shifting from a purely cytotoxic approach to one that incorporates antiangiogenic agents. These are thought to normalize the tumor vasculature and have shown improved disease management in patients with recurrent disease. How this vascular remodeling evolves during the full course of therapy for patients with newly diagnosed GBM and how it relates to radiographic response and outcome remain unclear. In this study, we examined 35 patients who were newly diagnosed with GBM using dynamic susceptibility contrast (DSC) MRI in order to identify early predictors of radiographic response to antiangiogenic therapy and to evaluate changes in perfusion parameters that may be predictive of progression. After surgical resection, patients received enzastaurin and temozolomide, both concurrent with and adjuvant to radiotherapy. Perfusion parameters, peak height (PH) and percent recovery, were calculated from the dynamic curves to assess vascular density and leakage. Six-month radiographic responders showed a significant improvement in percent recovery between baseline and 2 months into therapy, whereas 6-month radiographic nonresponders showed significantly increased PH between baseline and 1 month. At 2 months into therapy, percent recovery was predictive of progression-free survival. Four months prior to progression, there was a significant increase in the standard deviation of percent recovery within the tumor region. DSC perfusion imaging provides valuable information about vascular remodeling during antiangiogenic therapy, which may aid clinicians in identifying patients who will respond at the pretherapy scan and as an early indicator of response to antiangiogenic therapy.