Advances in MRI Assessment of Gliomas and Response to Anti-VEGF Therapy

Bevacizumab is thought to normalize tumor vasculature and restore the blood–brain barrier, decreasing enhancement and peritumoral edema. Conventional measurements of tumor response rely upon dimensions of enhancing tumor. After bevacizumab treatment, glioblastomas are more prone to progress as nonenhancing tumor. The RANO (Response Assessment in Neuro-Oncology) criteria for glioma response use fluid-attenuated inversion recovery (FLAIR)/T2 hyperintensity as a surrogate for nonenhancing tumor; however, nonenhancing tumor can be difficult to differentiate from other causes of FLAIR/T2 hyperintensity (eg, radiation-induced gliosis). Due to these difficulties, recent efforts have been directed toward identifying new biomarkers that either predict treatment response or accurately measure response of both enhancing and nonenhancing tumor shortly after treatment initiation. This will allow for earlier treatment decisions, saving patients from the adverse effects of ineffective therapies while allowing them to try alternative therapies sooner. An active area of research is the use of physiologic imaging, which can potentially detect treatment effects before changes in tumor size are evident

Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS): features and potential applications in oncology

Diffusion-weighted magnetic resonance imaging (DWI) provides functional information and can be used for the detection and characterization of pathologic processes, including malignant tumors. The recently introduced concept of “diffusion-weighted whole-body imaging with background body signal suppression” (DWIBS) now allows acquisition of volumetric diffusion-weighted images of the entire body. This new concept has unique features different from conventional DWI and may play an important role in whole-body oncological imaging. This review describes and illustrates the basics of DWI, the features of DWIBS, and its potential applications in oncology

Proctitis following stereotactic body radiation therapy for prostate cancer

Background Proctitis after radiation therapy for prostate cancer remains an ongoing clinical challenge and critical quality of life issue. SBRT could minimize rectal toxicity by reducing the volume of rectum receiving high radiation doses and offers the potential radiobiologic benefits of hypofractionation. This study sought to evaluate the incidence and severity of proctitis following SBRT for prostate cancer. Methods Between February 2008 and July 2011, 269 men with clinically localized prostate cancer were treated definitively with SBRT monotherapy at Georgetown University Hospital. All patients were treated to 35-36.25Gy in 5 fractions delivered with the CyberKnife Radiosurgical System (Accuray). Rectal bleeding was recorded and scored using the CTCAE v.4. Telangiectasias were graded using the Vienna Rectoscopy Score (VRS). Proctitis was assessed via the Bowel domain of the Expanded Prostate Index Composite (EPIC)-26 at baseline and at 1, 3, 6, 9, 12, 18 and 24 months post-SBRT. Results The median age was 69 years with a median prostate volume of 39 cc. The median follow-up was 3.9 years with a minimum follow-up of two years. The 2-year actuarial incidence of late rectal bleeding ≥ grade 2 was 1.5%. Endoscopy revealed VRS Grade 2 rectal telangiectasias in 11% of patients. All proctitis symptoms increased at one month post-SBRT but returned to near-baseline with longer follow-up. The most bothersome symptoms were bowel urgency and frequency. At one month post-SBRT, 11.2% and 8.5% of patients reported a moderate to big problem with bowel urgency and frequency, respectively. The EPIC bowel summary scores declined transiently at 1 month and experienced a second, more protracted decline between 6 months and 18 months before returning to near-baseline at two years post-SBRT. Prior to treatment, 4.1% of men felt their bowel function was a moderate to big problem which increased to 11.5% one month post-SBRT but returned to near-baseline at two years post-SBRT. Conclusions In this single institution cohort, the rate and severity of proctitis observed following SBRT is low. QOL decreased on follow-up; however, our results compare favorably to those reported for patients treated with alternative radiation modalities. Future prospective randomized studies are needed to confirm these observations

DW-MRI as a Biomarker to Compare Therapeutic Outcomes in Radiotherapy Regimens Incorporating Temozolomide or Gemcitabine in Glioblastoma

The effectiveness of the radiosensitizer gemcitabine (GEM) was evaluated in a mouse glioma along with the imaging biomarker diffusion-weighted magnetic resonance imaging (DW-MRI) for early detection of treatment effects. A genetically engineered murine GBM model [Ink4a-Arf−/− PtenloxP/loxP/Ntv-a RCAS/PDGF(+)/Cre(+)] was treated with gemcitabine (GEM), temozolomide (TMZ) +/− ionizing radiation (IR). Therapeutic efficacy was quantified by contrast-enhanced MRI and DW-MRI for growth rate and tumor cellularity, respectively. Mice treated with GEM, TMZ and radiation showed a significant reduction in growth rates as early as three days post-treatment initiation. Both combination treatments (GEM/IR and TMZ/IR) resulted in improved survival over single therapies. Tumor diffusion values increased prior to detectable changes in tumor volume growth rates following administration of therapies. Concomitant GEM/IR and TMZ/IR was active and well tolerated in this GBM model and similarly prolonged median survival of tumor bearing mice. DW-MRI provided early changes to radiosensitization treatment warranting evaluation of this imaging biomarker in clinical trials

In-Vivo Visualization of Tumor Microvessel Density and Response to Anti-Angiogenic Treatment by High Resolution MRI in Mice

Purpose: Inhibition of angiogenesis has shown clinical success in patients with cancer. Thus, imaging approaches that allow for the identification of angiogenic tumors and the detection of response to anti-angiogenic treatment are of high clinical relevance. Experimental Design: We established an in vivo magnetic resonance imaging (MRI) approach that allows us to simultaneously image tumor microvessel density and tumor vessel size in a NSCLC model in mice. Results: Using microvessel density imaging we demonstrated an increase in microvessel density within 8 days after tumor implantation, while tumor vessel size decreased indicating a switch from macro- to microvessels during tumor growth. Moreover, we could monitor in vivo inhibition of angiogenesis induced by the angiogenesis inhibitor PTK787, resulting in a decrease of microvessel density and a slight increase in tumor vessel size. Conclusions: We present an in vivo imaging approach that allows us to monitor both tumor microvessel density and tumor vessel size in the tumor. Moreover, this approach enables us to assess, early-on, treatment effects on tumor microvessel density as well as on tumor vessel size. Thus, this imaging-based strategy of validating anti-angiogenic treatment effects ha

Whole-body diffusion-weighted imaging for staging malignant lymphoma in children

CT is currently the mainstay in staging malignant lymphoma in children, but the risk of second neoplasms due to ionizing radiation associated with CT is not negligible. Whole-body MRI techniques and whole-body diffusion-weighted imaging (DWI) in particular, may be a good radiation-free alternative to CT. DWI is characterized by high sensitivity for the detection of lesions and allows quantitative assessment of diffusion that may aid in the evaluation of malignant lymphomas. This article will review whole-body MRI techniques for staging malignant lymphoma with emphasis on whole-body DWI. Furthermore, future considerations and challenges in whole-body DWI will be discussed

Comparison of ADC metrics and their association with outcome for patients with newly diagnosed glioblastoma being treated with radiation therapy, temozolomide, erlotinib and bevacizumab

To evaluate metrics that describe changes in apparent diffusion coefficient (ADC) and to examine their association with clinical outcome for patients with newly diagnosed GBM who were participating in a Phase II clinical trial of treatment with radiation (RT), temozolomide, erlatonib and bevacizumab. Thirty six patients were imaged after surgery but prior to therapy and at regular follow-up time points. The following ADC metrics were evaluated: (1) histogram percentiles within the T2-hyperintense lesion (T2L) at serial follow-ups; (2) parameters obtained by fitting a two-mixture normal distribution to the histogram within the contrast-enhancing lesion (CEL) at baseline; (3) parameters obtained using both traditional and graded functional diffusion maps within the CEL and T2L. Cox Proportional Hazards models were employed to assess the association of the ADC parameters with overall survival (OS) and progression-free survival (PFS). A lower ADC percentile value within the T2L at early follow-up time points was associated with worse outcome. Of particular interest is that, even when adjusting for clinical prognostic factors, the ADC(10%) within the T2L at 2 months was strongly associated with OS (p < 0.001) and PFS (p < 0.007). fDM metrics showed an association with OS and PFS within the CEL when considered by univariate analysis, but not in the T2L. Our study emphasizes the value of ADC metrics obtained from the T2L at the post-RT time point as non-invasive biomarkers for assessing residual tumor in patients with newly diagnosed GBM being treated with combination therapy that includes the anti-angiogenic agent bevacizumab

Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage

Tumor suppressor protein p53 is regulated by two structurally homologous proteins, Mdm2 and MdmX. In contrast to Mdm2, MdmX lacks ubiquitin ligase activity. Although the essential interactions of MdmX are known, it is not clear how they function to regulate p53. The regulation of tumor suppressor p53 by Mdm2 and MdmX in response to DNA damage was investigated by mathematical modeling of a simplified network. The simplified network model was derived from a detailed molecular interaction map (MIM) that exhibited four coherent DNA damage response pathways. The results suggest that MdmX may amplify or stabilize DNA damage-induced p53 responses via non-enzymatic interactions. Transient effects of MdmX are mediated by reservoirs of p53∶MdmX and Mdm2∶MdmX heterodimers, with MdmX buffering the concentrations of p53 and/or Mdm2. A survey of kinetic parameter space disclosed regions of switch-like behavior stemming from such reservoir-based transients. During an early response to DNA damage, MdmX positively or negatively regulated p53 activity, depending on the level of Mdm2; this led to amplification of p53 activity and switch-like response. During a late response to DNA damage, MdmX could dampen oscillations of p53 activity. A possible role of MdmX may be to dampen such oscillations that otherwise could produce erratic cell behavior. Our study suggests how MdmX may participate in the response of p53 to DNA damage either by increasing dependency of p53 on Mdm2 or by dampening oscillations of p53 activity and presents a model for experimental investigation