Phase IIa Study of SurVaxM Plus Adjuvant Temozolomide for Newly Diagnosed Glioblastoma.

PURPOSE: Despite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557). METHODS: Sixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 µg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed. RESULTS: SurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients. CONCLUSION: SurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.

Prospective prediction of clinical drug response in high-grade gliomas using an ex vivo 3D cell culture assay.

BACKGROUND: Clinical outcomes in high-grade glioma (HGG) have remained relatively unchanged over the last 3 decades with only modest increases in overall survival. Despite the validation of biomarkers to classify treatment response, most newly diagnosed (ND) patients receive the same treatment regimen. This study aimed to determine whether a prospective functional assay that provides a direct, live tumor cell-based drug response prediction specific for each patient could accurately predict clinical drug response prior to treatment. METHODS: A modified 3D cell culture assay was validated to establish baseline parameters including drug concentrations, timing, and reproducibility. Live tumor tissue from HGG patients were tested in the assay to establish response parameters. Clinical correlation was determined between prospective ex vivo response and clinical response in ND HGG patients enrolled in 3D-PREDICT (ClinicalTrials.gov Identifier: NCT03561207). Clinical case studies were examined for relapsed HGG patients enrolled on 3D-PREDICT, prospectively assayed for ex vivo drug response, and monitored for follow-up. RESULTS: Absent biomarker stratification, the test accurately predicted clinical response/nonresponse to temozolomide in 17/20 (85%, P = .007) ND patients within 7 days of their surgery, prior to treatment initiation. Test-predicted responders had a median overall survival post-surgery of 11.6 months compared to 5.9 months for test-predicted nonresponders (P = .0376). Case studies provided examples of the clinical utility of the assay predictions and their impact upon treatment decisions resulting in positive clinical outcomes. CONCLUSION: This study both validates the developed assay analytically and clinically and provides case studies of its implementation in clinical practice.

Symptomatic Cavum Septum Pellucidum Cyst: A Rare Presentation.

A cavum septum pellucidum is a cerebrospinal fluid (CSF) filled cavity situated between the lateral ventricles and is considered as a normal anatomic variant sporadically seen on neuroimaging. While a cavum septum pellucidum is a relatively uncommon incidental neuroimaging finding, symptomatic cysts of the cavum septum pellucidum are very rare, with only a few cases reported in the literature so far. They are defined as fluid-filled structures with lateral bowing of the walls and membranes separated by at least 10 mm or more. We present the case of a 25-year-old male patient with a rapidly expanding cyst of the septum pellucidum with headaches refractory to conventional pharmacological therapy. A 3T magnetic resonance imaging (MRI) of the brain with contrast was performed, which confirmed the diagnosis. Due to the failure of non-interventional treatment, he was treated with therapeutic endoscopic fenestration of the cyst. Postoperatively, he reported a complete resolution of the presenting symptoms.

Neuroimaging of Multiple Sclerosis Mimics.

Multiple sclerosis (MS) is the most common immune-mediated disease of the central nervous system, characterized by demyelinating lesions of the brain and the spinal cord. Although it is extremely important to diagnose this condition in a timely manner, to initiate and monitor treatment to prevent permanent neurologic damage and disability, it is also necessary that other demyelinating conditions collectively referred to as MS mimics be identified and excluded. This article describes the in-depth neuroimaging characteristics and morphology of the pathologic lesions on the various neuroimaging modalities.

Imaging of Brain Tumors.

PURPOSE OF REVIEW: Neuroimaging is an essential tool for the diagnosis and management of brain tumors. RECENT FINDINGS: Advances in neuroimaging have allowed for noninvasive visualization of tumors and have changed how brain tumors are diagnosed and treated. Presurgical planning with the use of functional MRI (fMRI) and diffusion tensor MRI helps to preserve eloquent regions of the brain and fiber tracts, thereby decreasing patients' postsurgical morbidity. With the use of susceptibility-weighted imaging (SWI) filtered phase images, diffusion-weighted studies, and perfusion imaging techniques, deciphering posttreatment effects versus tumor progression can be facilitated. SUMMARY: With recent advancements and novel approaches, various MRI techniques can be used to help diagnose and assist in presurgical planning and posttreatment management of brain tumors.

Neuroimaging of spine tumors.

Intramedullary, intradural/extramedullary, and extradural spine tumors comprise a wide range of neoplasms with an even wider range of clinical symptoms and prognostic features. Magnetic resonance imaging (MRI), commonly used to evaluate the spine in patients presenting with pain, can further characterize lesions that may be encountered on other imaging studies, such as bone scintigraphy or computed tomography (CT). The advantage of the MRI is its multiplane capabilities, superior contrast agent resolution, and flexible protocols that play an important role in assessing tumor location, extent in directing biopsy, in planning proper therapy, and in evaluating therapeutic results. A multimodality approach can be used to fully characterize the lesion and the combination of information obtained from the different modalities usually narrows the diagnostic possibilities significantly. The diagnosis of spinal tumors is based on patient age, topographic features of the tumor, and lesion pattern, as seen at CT and MRI. The shift to high-end imaging incorporating diffusion-weighted imaging, diffusion tensor imaging, magnetic resonance spectroscopy, whole-body short tau inversion recovery, positron emission tomography, intraoperative and high-field MRI as part of the mainstream clinical imaging protocol has provided neurologists, neuro-oncologists, and neurosurgeons a window of opportunity to assess the biologic behavior of spine neoplasms. This chapter reviews neuroimaging of spine tumors, primary and secondary, discussing routine and newer modalities that can reduce the significant morbidity associated with these neoplasms.

Radiologic response to radiation therapy concurrent with temozolomide for progressive simple dysembryoplastic neuroepithelial tumor.

Dysembryoplastic neuroepithelial tumors (DNETs) are low-grade neuroglial tumors that are traditionally considered to be benign hamartoma-like mass lesions. Malignant transformation and disease progression have been reported in complex DNETs. We report a case of a simple DNET with disease progression following subtotal resection. A 34-year-old woman underwent craniotomy with subtotal resection of a large nonenhancing right temporal lobe and insular mass. Histopathological analysis revealed a simple DNET. Magnetic resonance imaging obtained 6 months after surgery demonstrated disease progression with no enhancement or change in signal characteristics. Following concurrent therapy with temozolomide and external beam radiation therapy, a significant radiologic response was observed. Progressive DNET with malignant transformation exhibits predominantly glial transformation and occurs predominantly in complex DNETs. The histological classification of DNETs into simple, complex, and nonspecific are reviewed. Contrast-enhancing regions are more frequently seen in complex tumors, with nonenhancing regions having fewer complex histologic features. Close clinical and radiographic follow-up is important in all cases of DNET. Following tumor progression, radiation therapy with concurrent and adjuvant temozolomide chemotherapy may be an effective treatment.

ACR Appropriateness Criteria Myelopathy.

Patients presenting with myelopathic symptoms may have a number of causative intradural and extradural etiologies, including disc degenerative diseases, spinal masses, infectious or inflammatory processes, vascular compromise, and vertebral fracture. Patients may present acutely or insidiously and may progress toward long-term paralysis if not treated promptly and effectively. Noncontrast CT is the most appropriate first examination in acute trauma cases to diagnose vertebral fracture as the cause of acute myelopathy. In most nontraumatic cases, MRI is the modality of choice to evaluate the location, severity, and causative etiology of spinal cord myelopathy, and predicts which patients may benefit from surgery. Myelopathy from spinal stenosis and spinal osteoarthritis is best confirmed without MRI intravenous contrast. Many other myelopathic conditions are more easily visualized after contrast administration. Imaging performed should be limited to the appropriate spinal levels, based on history, physical examination, and clinical judgment. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals, and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Papillary tumor of the pineal region with extended clinical and radiologic follow-up.

BACKGROUND: Papillary tumor of the pineal region (PTPR) is a rare neoplasm with only anecdotal data to guide the treatment. Results of treatment with surgery, radiation therapy, and chemotherapy have been reported to have varying degrees of success. Here we report a patient with a PTPR, who underwent subtotal resection, gamma knife stereotactic radiosurgery, and adjuvant temozolomide chemotherapy. CASE DESCRIPTION: During 9 years of clinical and radiographic follow-up, the patient has had regression of residual tumor and remains asymptomatic. CONCLUSION: When gross total resection of a PTPR is not possible, treatment with gamma knife stereotactic radiosurgery and temozolomide chemotherapy may provide long-term tumor control.

ACR Appropriateness Criteria Headache.

Most patients presenting with uncomplicated, nontraumatic, primary headache do not require imaging. When history, physical, or neurologic examination elicits "red flags" or critical features of the headache, then further investigation with imaging may be warranted to exclude a secondary cause. Imaging procedures may be diagnostically useful for patients with headaches that are: associated with trauma; new, worse, or abrupt onset; thunderclap; radiating to the neck; due to trigeminal autonomic cephalgia; persistent and positional; and temporal in older individuals. Pregnant patients, immunocompromised individuals, cancer patients, and patients with papilledema or systemic illnesses, including hypercoagulable disorders may benefit from imaging. Unlike most headaches, those associated with cough, exertion, or sexual activity usually require neuroimaging with MRI of the brain with and without contrast to exclude potentially underlying pathology before a primary headache syndrome is diagnosed. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Neuroimaging of neurocutaneous diseases.

An in-depth knowledge of the imaging characteristics of the common neurocutaneous diseases (NCD) described in this article will help neurologists understand the screening imaging modalities in these patients. The future of neuroimaging is geared towards developing and refining magnetic resonance imaging (MRI) sequences. The detection of tumors in NCD has greatly improved with availability of high-field strength 3T MRI machines. Neuroimaging will remain at the heart and soul of the multidisciplinary care of such complex diagnoses to guide early detection and monitor treatment.

Steroid-sparing effect of corticorelin acetate in peritumoral cerebral edema is associated with improvement in steroid-induced myopathy.

PURPOSE: To compare the safety and efficacy of corticorelin acetate (CrA) and placebo in patients with malignant brain tumors requiring chronic administration of dexamethasone (DEX) to control the signs and symptoms of peritumoral brain edema (PBE). PATIENTS AND METHODS: Prospective, randomized, double-blind study of 200 patients with PBE on a stable dose of DEX. Initially, DEX dose was decreased by 50% over a 2-week period and then held at this level for 3 weeks. The primary end point was the proportion of patients who responded to treatment-patients who achieved a ≥ 50% DEX reduction from baseline and achieved stable or improved neurologic examination score and Karnofsky performance score at week 2, and then continued to respond at week 5. RESULTS: One hundred patients received subcutaneous injections of 1 mg twice per day of CrA and 100 patients received placebo for the duration of the study period. Although results did not attain statistical significance (at the P < .05 level), a clinically important difference in the proportion of responders between the CrA group (57.0%) and the placebo group (46.0%; P = .12) was observed. In addition, the maximum percent reduction in DEX dose achieved during the double-blind 12-week study was significantly greater in the CrA group (62.7%) than in placebo group (51.4%; P < .001). Patients receiving CrA demonstrated an improvement in myopathy and were less likely to develop signs of Cushing syndrome. CONCLUSION: CrA enables a reduction in steroid requirement for patients with PBE and is associated with a reduction in the incidence and severity of common steroid adverse effects, including myopathy.

Spinal cord tumors: new views and future directions.

Spinal cord tumors are uncommon neoplasms that, without treatment, can cause significant neurologic morbidity and mortality. The historic classification of spine tumors is based on the use of myelography with 3 main groups: (1) extramedullary extradural, (2) intradural extramedullary, and (3) intradural intramedullary. This chapter focuses on intramedullary spinal cord tumors (ISCTs), with an emphasis on new diagnostic imaging modalities and treatment options. The common ISCTs include ependymoma, astrocytoma and hemangioblastoma, which together account for over 90% of primary ISCTs. Rare tumors such as gangliglioma, oligodendroglioma, paraganglioma, melanocytoma, lipoma, and primary spinal cord lymphoma are also included in this review, in addition to spinal cord metastatic disease.

Novel treatment for radiation optic neuropathy with intravenous bevacizumab.

Radiation optic neuropathy is a devastating form of vision loss that can occur months to years after radiation therapy for tumors and other lesions located in close proximity to the visual pathways. We present the case of a 24-year-old woman who underwent external beam radiation for treatment of a tectal pilocytic astrocytoma, and 5 years later she developed bilateral radiation optic neuropathy and radiation necrosis of the right temporal lobe. We opted to treat her with intravenous bevacizumab with 3 doses every 3 weeks, as well as dexamethasone and pentoxifylline. After the first infusion of bevacizumab, the patient noted improvement in vision and color vision, and a follow-up magnetic resonance imaging study showed that the previous enhancement of the optic nerves and chiasm was diminishing. Her vision improved dramatically and has remained stable over a 3-year period.

ACR Appropriateness Criteria(®) myelopathy.

Myelopathy is a problem that requires imaging to distinguish among numerous specifically treatable causes. The first priority is to determine mechanical stability after trauma. Next, it is crucial to distinguish intrinsic disease from extrinsic compression-for example, by epidural abscess. Osteophytes or disc extrusions and metastatic compression are the most common causes of extrinsic lesions. Imaging approaches rely on clinical features such as pain, fever, trauma, and pattern of progression. CT is preferred initially in acute trauma and MRI in all other circumstances. Contrast-enhanced MRI is added when tumor or infection is suspected or with slow or stepwise progression, especially when pain is not prominent. Vascular imaging is used when arteriovenous malformation, fistula, or occlusive disease is suspected. Because the treatment of myelopathy is often complex, treatment planning may require more than one imaging study or sequential examination to assess interval change. The ACR Appropriateness Criteria(®) are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria® on cerebrovascular disease.

Stroke is the sudden onset of focal neurologic symptoms due to ischemia or hemorrhage in the brain. Current FDA-approved clinical treatment of acute ischemic stroke involves the use of the intravenous thrombolytic agent recombinant tissue plasminogen activator given <3 hours after symptom onset, following the exclusion of intracerebral hemorrhage by a noncontrast CT scan. Advanced MRI, CT, and other techniques may confirm the stroke diagnosis and subtype, demonstrate lesion location, identify vascular occlusion, and guide other management decisions but, within the first 3 hours after ictus, should not delay or be used to withhold recombinant tissue plasminogen activator therapy after the exclusion of acute hemorrhage on noncontrast CT scans. MR diffusion-weighted imaging is highly sensitive and specific for acute cerebral ischemia and, when combined with perfusion-weighted imaging, may be used to identify potentially salvageable ischemic tissue, especially in the period >3 hours after symptom onset. Advanced CT perfusion methods improve sensitivity to acute ischemia and are increasingly used with CT angiography to evaluate acute stroke as a supplement to noncontrast CT. The ACR Appropriateness Criteria(®) are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Diffuse dural gadolinium MRI enhancement associated with bilateral chronic subdural hematomas.

Chronic subdural hematomas (CSDHs) typically present with cognitive dysfunction and a history of trauma. Localized dural enhancement on postcontrast MRI scans associated with the surrounding membrane has been described in CSDH. We present an 83-year-old man with rapidly progressing cognitive dysfunction 4 weeks after head trauma related to a fall. MRI showed CSDHs, which in addition to localized dural gadolinium enhancement, showed a marked diffuse, symmetric, contiguous pachymeningeal enhancement of the supratentorial and infratentorial intracranial dural mater. Meningeal biopsy failed to disclose an infectious or neoplastic cause of the enhancement and instead showed fibrocollagenous change. We conclude that diffuse dural enhancement on MRI scans associated with CSDH cause does not necessarily indicate a superimposed process such as infection or malignancy. CSDH should be considered in the differential diagnosis of diffuse dural enhancement, especially when supported by appropriate clinical findings.

Role of fluorodeoxyglucose positron emission tomography in the diagnosis of neurosarcoidosis.

A 45-year-old man developed seizures and myelopathy. MRI showed bitemporal and cervical spinal cord hyperintense lesions on T2-weighted and FLAIR images that contrast-enhanced. Initial evaluation for sarcoidosis was negative, including serum angiotensin converting enzyme (ACE) and chest X-ray. Whole body fluorodeoxyglucose positron emission tomography (FDG-PET) revealed multiple hypermetabolic hilar and mediastinal foci and spinal cord hypermetabolism at the site of MRI abnormality. Temporal lobe MRI lesions were hypometabolic. Mediastinal lymph node biopsy was consistent with sarcoidosis. The brain, spinal cord, and chest metabolic abnormalities together with the clinical presentation were interpreted as being most consistent with sarcoidosis. FDG-PET helped target the site of biopsy that subsequently confirmed the diagnosis histologically. In patients with perplexing neurologic presentations, whole body FDG-PET can help secure a timely and minimally invasive diagnosis of neurosarcoidosis.