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.

Cannabis and Migraine: It's Complicated.

PURPOSE OF REVIEW: The use of cannabis for the treatment of migraine has become an area of interest with the legalization of medical cannabis in the USA. Understanding the mechanisms of cannabinoids, available studies, and best clinical recommendations is crucial for headache providers to best serve patients. RECENT FINDINGS: Patients utilizing medical cannabis for migraine have reported improvement in migraine profile and common comorbidities. Reduction in prescription medication is also common, especially opioids. Side effects exist, with the majority being mild. Not enough data is available for specific dose recommendations, but THC and CBD appear to mediate these observed effects. The purpose of this article is twofold: review the limited research surrounding cannabis for migraine disease and reflect on clinical management experiences to provide recommendations that best capture the potential use of cannabis for migraine.

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 for Migraine: The American Headache Society Systematic Review and Evidence-Based Guideline.

OBJECTIVE: To provide updated evidence-based recommendations about when to obtain neuroimaging in patients with migraine. METHODS: Articles were included in the systematic review if they studied adults 18 and over who were seeking outpatient treatment for any type of migraine and who underwent neuroimaging (MRI or CT). Medline, Web of Science, and Cochrane Clinical Trials were searched from 1973 to August 31, 2018. Reviewers identified studies, extracted data, and assessed the quality of the evidence in duplicate. We assessed study quality using the Newcastle-Ottawa Scale. RESULTS: The initial search yielded 2269 publications. Twenty three articles met inclusion criteria and were included in the final review. The majority of studies were retrospective cohort or cross-sectional studies. There were 4 prospective observational studies. Ten studies evaluated the utility of CT only, 9 MRI only, and 4 evaluated both. Common abnormalities included chronic ischemia or atrophy with CT and MRI scanning, and non-specific white matter lesions with MRI. Clinically meaningful abnormalities requiring intervention were relatively rare. Clinically significant neuroimaging abnormalities in patients with headaches consistent with migraine without atypical features or red flags appeared no more common than in the general population. RECOMMENDATIONS: There is no necessity to do neuroimaging in patients with headaches consistent with migraine who have a normal neurologic examination, and there are no atypical features or red flags present. Grade A Neuroimaging may be considered for presumed migraine for the following reasons: unusual, prolonged, or persistent aura; increasing frequency, severity, or change in clinical features, first or worst migraine, migraine with brainstem aura, migraine with confusion, migraine with motor manifestations (hemiplegic migraine), late-life migraine accompaniments, aura without headache, side-locked headache, and posttraumatic headache. Most of these are consensus based with little or no literature support. Grade C.

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.

Sherpas, Coca Leaves, and Planes: High Altitude and Airplane Headache Review with a Case of Post-LASIK Myopic Shift.

PURPOSE OF REVIEW: High altitude headache is a common neurological symptom that is associated with ascent to high altitude. It is classified by the International Classification of Headache Disorders, 3rd Edition (ICHD-3) as a disorder of homeostasis. In this article, we review recent clinical and insights into the pathophysiological mechanisms of high altitude and airplane headache. We also report a second case of post-LASIK myopic shift at high altitude exposure secondary hypoxia. Headache attributed to airplane travel is a severe typically unilateral orbital headache that usually improves after landing. This was a relative recent introduction to the ICHD-3 diagnostic criteria. Headache pain with flight travel has long been known and may have been previously considered as a part of barotrauma. Recent studies have helped identify this as a distinct headache disorder. RECENT FINDINGS: Physiologic, hematological, and biochemical biomarkers have been identified in recent high altitude studies. There have been recent advance in identification of molecular mechanisms underlying neurophysiologic changes secondary to hypoxia. Calcitonin gene-related peptide, a potent vasodilator, has been implicated in migraine pathophysiology. Recent epidemiological studies indicate that the prevalence of airplane headache may be more common than we think in the adult as well at the pediatric population. Simulated flight studies have identified potential biomarkers. Although research is limited, there have been advances in both clinical and pathophysiological mechanisms associated with high altitude and airplane headache.

Safety and efficacy of sphenopalatine ganglion stimulation for chronic cluster headache: a double-blind, randomised controlled trial.

BACKGROUND: Chronic cluster headache is the most disabling form of cluster headache. The mainstay of treatment is attack prevention, but the available management options have little efficacy and are associated with substantial side-effects. In this study, we aimed to assess the safety and efficacy of sphenopalatine ganglion stimulation for treatment of chronic cluster headache. METHODS: We did a randomised, sham-controlled, parallel group, double-blind, safety and efficacy study at 21 headache centres in the USA. We recruited patients aged 22 years or older with chronic cluster headache, who reported a minimum of four cluster headache attacks per week that were unsuccessfully controlled by preventive treatments. Participants were randomly assigned (1:1) via an online adaptive randomisation procedure to either stimulation of the sphenopalatine ganglion or a sham control that delivered a cutaneous electrical stimulation. Patients and the clinical evaluator and surgeon were masked to group assignment. The primary efficacy endpoint, which was analysed with weighted generalised estimated equation logistic regression models, was the difference between groups in the proportion of stimulation-treated ipsilateral cluster attacks for which relief from pain was achieved 15 min after the start of stimulation without the use of acute drugs before that timepoint. Efficacy analyses were done in all patients who were implanted with a device and provided data for at least one treated attack during the 4-week experimental phase. Safety was assessed in all patients undergoing an implantation procedure up to the end of the open-label phase of the study, which followed the experimental phase. This trial is registered with ClinicalTrials.gov, number NCT02168764. FINDINGS: Between July 9, 2014, and Feb 14, 2017, 93 patients were enrolled and randomly assigned, 45 to the sphenopalatine ganglion stimulation group and 48 to the control group. 36 patients in the sphenopalatine ganglion stimulation group and 40 in the control group had at least one attack during the experimental phase and were included in efficacy analyses. The proportion of attacks for which pain relief was experienced at 15 min was 62·46% (95% CI 49·15-74·12) in the sphenopalatine ganglion stimulation group versus 38·87% (28·60-50·25) in the control group (odds ratio 2·62 [95% CI 1·28-5·34]; p=0·008). Nine serious adverse events were reported by the end of the open-label phase. Three of these serious adverse events were related to the implantation procedure (aspiration during intubation, nausea and vomiting, and venous injury or compromise). A fourth serious adverse event was an infection that was attributed to both the stimulation device and the implantation procedure. The other five serious adverse events were unrelated. There were no unanticipated serious adverse events. INTERPRETATION: Sphenopalatine ganglion stimulation seems efficacious and is well tolerated, and potentially offers an alternative approach to the treatment of chronic cluster headache. Further research is need to clarify its place in clinical practice. FUNDING: Autonomic Technologies.

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.

Imaging of Spinal Cord Disorders.

PURPOSE OF REVIEW: Spinal cord disorders are common and can be caused by a myriad of pathologies. Confidently interpreting spine imaging studies is an essential skill for neurologists as many spinal cord disorders can produce significant disability if not diagnosed and treated correctly. RECENT FINDINGS: Advances in imaging have revolutionized the care of patients with spinal cord disorders by allowing noninvasive visualization of normal and abnormal structures. SUMMARY: This article summarizes the imaging patterns of common spinal cord disorders.

Potential Safety Issues Related to the Use of Gadolinium-based Contrast Agents.

PURPOSE OF REVIEW: This article reviews recent research on gadolinium deposit formation in the brain linked to contrast-enhanced MRI studies. RECENT FINDINGS: Human and animal studies have confirmed the presence of gadolinium in the brain following the serial administration of gadolinium-based contrast agents. This is a relatively new and growing field of research primarily driven by concerns regarding unknown and potentially harmful side effects of gadolinium-based contrast agents. Retrospective observational in vivo studies in humans demonstrated T1 shortening effects in the brain parenchyma resulting from gadolinium exposure. These studies were followed by postmortem human and animal studies. Evidence exists that gadolinium may cause deposits in the brain and that this may occur independently of impaired renal function and in the presence of an intact blood-brain barrier. Gadolinium deposition has been linked primarily with the use of linear, rather than macrocyclic, gadolinium-based contrast agents. SUMMARY: The formation of gadolinium deposits and its implications have been the focus of only a small number of research groups. The currently available data must be verified, and the potential factors that may be linked to this phenomenon and the clinical significance must be explored. Depending on future findings, changes in the clinical application of gadolinium-based contrast agents may be expected.

Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double-Blind, Sham-Controlled ACT1 Study.

OBJECTIVE: To evaluate non-invasive vagus nerve stimulation (nVNS) as an acute cluster headache (CH) treatment. BACKGROUND: Many patients with CH experience excruciating attacks at a frequency that is not sufficiently addressed by current symptomatic treatments. METHODS: One hundred fifty subjects were enrolled and randomized (1:1) to receive nVNS or sham treatment for ≤1 month during a double-blind phase; completers could enter a 3-month nVNS open-label phase. The primary end point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes. Secondary end points included the sustained response rate (15-60 minutes). Subanalyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were prespecified. RESULTS: The intent-to-treat population comprised 133 subjects: 60 nVNS-treated (eCH, n = 38; cCH, n = 22) and 73 sham-treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7% of nVNS-treated subjects and 15.1% of sham-treated subjects (P = .1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2%; sham, 10.6%; P = .008) but not the cCH cohort (nVNS, 13.6%; sham, 23.1%; P = .48). Sustained response rates were significantly higher with nVNS for the eCH cohort (P = .008) and total population (P = .04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double-blind phase and 18/128 subjects in the open-label phase. No serious ADEs occurred. CONCLUSIONS: In one of the largest randomized sham-controlled studies for acute CH treatment, the response rate was not significantly different (vs sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected results in the total population. This safe and well-tolerated treatment represents a novel and promising option for eCH. ClinicalTrials.gov identifier: NCT01792817.

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.

ACR Appropriateness Criteria Head Trauma.

Neuroimaging plays an important role in the management of head trauma. Several guidelines have been published for identifying which patients can avoid neuroimaging. Noncontrast head CT is the most appropriate initial examination in patients with minor or mild acute closed head injury who require neuroimaging as well as patients with moderate to severe acute closed head injury. In short-term follow-up neuroimaging of acute traumatic brain injury, CT and MRI may have complementary roles. In subacute to chronic traumatic brain injury, MRI is the most appropriate initial examination, though CT may have a complementary role in select circumstances. Advanced neuroimaging techniques are areas of active research but are not considered routine clinical practice at this time. In suspected intracranial vascular injury, CT angiography or venography or MR angiography or venography is the most appropriate imaging study. In suspected posttraumatic cerebrospinal fluid leak, high-resolution noncontrast skull base CT is the most appropriate initial imaging study to identify the source, with cisternography reserved for problem solving. 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.

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.

Advanced neuroimaging of mild traumatic brain injury.

This article focuses on advancements in neuroimaging techniques, compares the advantages of each of the modalities in the evaluation of mild traumatic brain injury, and discusses their contribution to our understanding of the pathophysiology as it relates to prognosis. Advanced neuroimaging techniques discussed include anatomic/structural imaging techniques, such as diffusion tensor imaging and susceptibility-weighted imaging, and functional imaging techniques, such as functional magnetic resonance imaging, perfusion-weighted imaging, magnetic resonance spectroscopy, and positron emission tomography.