Martha R. Neagu

Pitfalls in the Neuroimaging of Glioblastoma in the Era of Antiangiogenic and Immuno/Targeted Therapy – Detecting Illusive Disease, Defining Response

Glioblastoma, the most common malignant primary brain tumor in adults is a devastating diagnosis with an average survival of 14–16 months using the current standard of care treatment. The determination of treatment response and clinical decision making is based on the accuracy of radiographic assessment. Notwithstanding, challenges exist in the neuroimaging evaluation of patients undergoing treatment for malignant glioma. Differentiating treatment response from tumor progression is problematic and currently combines long-term follow-up using standard magnetic resonance imaging (MRI), with clinical status and corticosteroid-dependency assessments. In the clinical trial setting, treatment with gene therapy, vaccines, immunotherapy, and targeted biologicals similarly produces MRI changes mimicking disease progression. A neuroimaging method to clearly distinguish between pseudoprogression and tumor progression has unfortunately not been found to date. With the incorporation of antiangiogenic therapies, a further pitfall in imaging interpretation is pseudoresponse. The Macdonald criteria that correlate tumor burden with contrast-enhanced imaging proved insufficient and misleading in the context of rapid blood–brain barrier normalization following antiangiogenic treatment that is not accompanied by expected survival benefit. Even improved criteria, such as the RANO criteria, which incorporate non-enhancing disease, clinical status, and need for corticosteroid use, fall short of definitively distinguishing tumor progression, pseudoresponse, and pseudoprogression. This review focuses on advanced imaging techniques including perfusion MRI, diffusion MRI, MR spectroscopy, and new positron emission tomography imaging tracers. The relevant image analysis algorithms and interpretation methods of these promising techniques are discussed in the context of determining response and progression during treatment of glioblastoma both in the standard of care and in clinical trial context.

Rindopepimut vaccine and bevacizumab combination therapy: improving survival rates in relapsed glioblastoma patients?

Glioblastoma (GBM), the most common malignant primary tumor in adults, carries a dismal prognosis. Median overall survival (OS) following currently available standard therapy for newly diagnosed patients, which includes maximal safe resection followed by fractionated radiotherapy plus concurrent and adjuvant temozolomide is under 15 months [1] and has failed to improve despite recently reported randomized Phase III studies evaluating dose dense temozolomide [2], VEGF blockade [3,4] and anti-integrin therapy [5]. Effective therapy for patients following recurrence has been even more problematic. Although the genetic complexity of GBM tumors has recently been elegantly articulated [6,7], exploitation of this information using targeted molecular therapeutics in multiple clinical studies has been uniformly disappointing to date [8]. Furthermore, although GBM tumors are highly angiogenic and express high levels of VEGF; VEGF targeting therapeutics such as bevacizumab have modestly improved progression-free survival at best for recurrent patients [9]. Therapeutics capable of improving OS for GBM have remained elusive, underscoring the critical need for innovative treatment approaches for this major unmet need in oncology. A variety of immunotherapy approaches, including cancer vaccines, immune checkpoint blockade and chimeric antigen receptor T cells, have recently demonstrated exciting benefit across a spectrum of cancers. Nonetheless, the role of these agents for GBM patients remains undefined [10]. Furthermore, many speculate that immunotherapies are unlikely to be of value for GBM patients based on historical dogma supporting immuno privilege of the CNS. Despite this bias, growing data argues against the concept of CNS immunosanctity, and in fact demonstrates that a dynamic and effective interaction exists between the CNS and systemic immune systems. Accordingly, a wide array of immune-based therapies is currently under clinical evaluation for GBM patients. The most advanced immuno therapeutic in the clinical arena for GBM patients is rindopepimut, a peptide vaccine targeting EGFRvIII. In contrast to early GBM vaccines utilizing either whole tumor lysate or tumor-associated antigen (TAA) cocktail approaches, rindopepimut was developed to attack EGFRvIII, a target that is exquisitely tumor specific. EGFRvIII is present in approximately 30% of GBM tumors and can be readily detected by available immunohistochemistry or RT-PCR assays. EGFRvIII results from an in-frame deletion of exons 2–7 that leads to the physical approximation of two normally separated portions of Rindopepimut vaccine and bevacizumab combination therapy: improving survival rates in relapsed glioblastoma patients?

Imaging in Neurologic Infections I: Bacterial and Parasitic Diseases

Often presenting as medical emergencies, nervous system infections can be diagnostically challenging. Knowledgeable utilization of neuroimaging modalities and the understanding of characteristic imaging findings facilitate early diagnosis and treatment. In the first part of this two-part review, we address common and unique diagnostic imaging features of bacterial and parasitic nervous system infections.

Diffusion tensor imaging in brainstem tuberculoma.

Integrity of descending white matter tracts can be evaluated by diffusion tensor imaging. In rim-enhancing intraparenchymal lesions, this technique can assist in the differentiation of demyelinating disease from tumor or abscess. Diffusion tensor imaging characteristics of tuberculoma have not been previously reported to our knowledge. A patient with headaches, dizziness, and mild left-sided weakness underwent MRI with diffusion tensor imaging. A large, rim-enhancing lesion within the pons was discovered, which subsequently was diagnosed as tuberculoma. Tractography maps prepared from diffusion tensor imaging data revealed predominantly displaced descending fiber tracts in the region of the rim-enhancing lesion. A few tracts adjacent to the lesion appeared truncated, and this abnormal finding correlated to the patients clinical deficit. The tractography characteristics of diffusion tensor imaging in this patient potentially are distinct from those seen with demyelinating lesions, which may show more extensive tract truncation. Together with the consonance of exam findings and tract truncation seen in this patient, tractography may prove useful in the diagnosis of suspected tuberculoma.

Neurological Complications of Immune-Based Therapies

While immune-based cancer therapies are generally more easily tolerated than cytotoxic or targeted therapies, and serious neurological complications occur rarely, they carry their own unique neurological complications. With the increasing use of immunotherapy in the treatment of multiple cancers, it is increasingly important for oncologists and neuro-oncologists to familiarize themselves with the toxicity profiles of these agents. This chapter highlights the neurologic complications described with the use of cancer vaccines, cytokines, and immune-active antibodies including checkpoint blockade.

A 20-Year-Old Man With Back Pain and Lower Extremity Weakness

A 20-year-old man presented with 1 week of low back pain and progressive lower extremity weakness. Results of cerebrospinal fluid analysis demonstrated elevated total protein and a mildly elevated white blood cell count with lymphocytic predominance. Findings from imaging studies revealed a multifocal, heterogeneously enhancing, intramedullary lesion involving the cervicothoracic spinal cord and nodular enhancement of the cauda equina. The patient eventually underwent spinal surgery for tissue diagnosis. The differential diagnosis, pathologic findings, and diagnosis are discussed.

Imaging in Neurologic Infections II: Fungal and Viral Diseases

Infections of the nervous system have a significant impact on global mortality and morbidity. These infections are medical emergencies that are frequently diagnostically challenging. Incorporation of neuroimaging can be essential for early diagnosis and initiation of proper treatment. In this second part of this two-part review, we focus on diagnostic imaging features of selected fungal and viral nervous system infections.