Apostolos John Tsiouris

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.

BACKGROUND Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). METHODS In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. FINDINGS Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. INTERPRETATION Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. FUNDING Merck and the Yale Cancer Center.

Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier disruption for recurrent malignant glioma. Clinical article.

OBJECT The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma. METHODS A total of 30 patients with recurrent malignant glioma were included in the current study. RESULTS The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients. CONCLUSIONS The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.

Intra-Arterial Delivery of Bevacizumab after Blood-Brain Barrier Disruption for the Treatment of Recurrent Glioblastoma: Progression-Free Survival and Overall Survival

BACKGROUND This prospective, single-center study assesses progression-free survival (PFS) and overall survival (OS) in patients with recurrent glioblastoma multiforme (GBM) treated with a single dose of superselective intra-arterial cerebral infusion (SIACI) of bevacizumab (BV) after blood-brain barrier disruption (BBBD). Patients were initially enrolled in our phase I study, for which the primary end point was to determine the safety and maximum tolerated dose of SIACI BV. METHODS Fourteen patients with recurrent GBM were recruited between August 2009 and November 2010 after failing the standard treatment with radiation therapy and temozolomide. None of these patients were previously treated with BV. After receiving a single dose of IA BV (2 to 15 mg/kg), standard IV BV chemotherapy was continued in 12 of 14 patients (86%). The recently updated Response Assessment in Neuro-Oncology Working Group (RANO) criteria were used to evaluate PFS, and the Kaplan-Meier estimator was used to evaluate PFS and OS. RESULTS Using RANO criteria, the median PFS in these patients was 10 months. The median OS estimation for this cohort was 8.8 months. The OS was less than the PFS because 4 patients died without progressing. Toxicity attributed to the IA BV treatment was present in 2 patients (wound dehiscence and rash). Another patient suffered from seizures 1 week after the SIACI procedure; however, this patient had epilepsy before and seizure type/frequency were similar before and after therapy. CONCLUSIONS Our study shows that for patients naïve to BV, a single dose of SIACI BV after BBBD followed by IV BV offers an encouraging outcome in terms of PFS when compared with previous trials using IV BV with and without concomitant irinotecan (CPT-11). Larger phase II trials are warranted to determine whether repeated IA BV alone is superior to IV BV for recurrent GBM.

Using Quantitative CT Perfusion for Evaluation of Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage

BACKGROUND AND PURPOSE: DCI is a serious complication following aneurysmal SAH leading to permanent neurologic deficits, infarction, and death. Our aim was to prospectively evaluate the diagnostic accuracy of CTP and to determine a quantitative threshold for DCI in aneurysmal SAH. MATERIALS AND METHODS: Patients with SAH were prospectively enrolled in a protocol approved by the institutional review board. CTP was performed during the typical time period for DCI, between days 6 and 8 following SAH. Quantitative CBF, CBV, and MTT values were obtained by using standard region-of-interest placement sampling of gray matter. The reference standard for DCI is controversial and consisted of clinical and imaging criteria in this study. In a subanalysis of vasospasm, DSA was used as the reference standard. ROC curves determined the diagnostic accuracy by using AUC. Optimal threshold values were calculated by using the patient population utility method. RESULTS: Ninety-seven patients were included; 41% (40/97) had DCI. Overall diagnostic accuracy was 93% for CBF, 88% for MTT, and 72% for CBV. Optimal threshold values were 35 mL/100 g/min (90% sensitivity, 68% specificity) for CBF and 5.5 seconds (73% sensitivity, 79% specificity) for MTT. In the subanalysis (n = 57), 63% (36/57) had vasospasm. Overall diagnostic accuracy was 94% for CBF, 85% for MTT, and 72% for CBV. Optimal threshold values were 36.5 mL/100 g/min (95% sensitivity, 70% specificity) for CBF and 5.4 seconds (78% sensitivity, 70% specificity) for MTT. CONCLUSIONS: CBF and MTT have the highest overall diagnostic accuracy. Threshold values of 35 mL/100 g/min for CBF and 5.5-second MTT are suggested for DCI on the basis of the patient population utility method. Absolute threshold values may not be generalizable due to differences in scanner equipment and postprocessing methods.

Reproducibility of Postprocessing of Quantitative CT Perfusion Maps

OBJECTIVE The purpose of this study was to assess interobserver and intraobserver variability in evaluation of the reproducibility of quantitative data obtained in semiautomated postprocessing of CT perfusion data sets by observers of different levels of skill and experience and in fully automated postprocessing. MATERIALS AND METHODS Twenty CT perfusion data sets were postprocessed by a neuroradiologist using an automated postprocessing program and by five observers (neuroradiology attending, neurology attending, radiology resident, senior and junior CT technologists) who received a brief training session in use of software for semiautomated postprocessing. For assessment of intraobserver variability, each observer repeated postprocessing of 10 CT perfusion data sets. Standard regions of interest were placed on identical locations for each observers cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps of three brain regions: an ischemia-infarct region, normal cortical gray matter, and white matter. RESULTS The variability in mean quantitative values of CBF, CBV, and MTT was 2.5-9.5% among all observers. Greater variability (20.4%) was introduced with the automated program. High correlation was found among all possible pairings of observers (r = 0.87-0.99). Low correlation was observed between automated postprocessing and postprocessing by all observers. Intraobserver variability in quantitative CT perfusion data ranged from 0.29% to 10.8%. High intraobserver correlation (r = 0.91-0.99) was found for the observers. CONCLUSION Quantitative CBF, CBV, and MTT data obtained from postprocessing of CT perfusion data sets are reproducible among observers with varying levels of skill and experience. Observer interaction with the software is an important component for correct identification of user-defined parameters. Establishing a uniform and standard postprocessing technique is essential for maintaining good reproducibility.

Comparison of navigated versus non-navigated pedicle screw placement in 260 patients and 1434 screws: screw accuracy, screw size, and the complexity of surgery.

Objective: Computer 3D navigation (3D NAV) techniques in spinal instrumentation can theoretically improve screw placement accuracy and reduce injury to critical neurovascular structures, especially in complex cases. In this series, we analyze the results of 3D NAV in pedicle screw placement accuracy, screw outer diameter, and case complexity in comparison with screws placed with conventional lateral fluoroscopy. Methods: Pedicle screws placed in the cervical, thoracic, or lumbar spine using either standard lateral fluoroscopy or 3D NAV using isocentric fluoroscopy were retrospectively analyzed. The accuracy of each individual screw was graded on a 4-tiered classification system. Screw and pedicle diameter measurements were also made in both cohorts, and case complexity was compared between the 2 cohorts. Complex cases were defined as deformity surgery, re-do cases, and minimally invasive surgery. Results: A total of 708 screws were placed under 3D NAV guidance and 726 screws were placed without stereotaxy. Eighty-eight percent of 3D NAV-guided pedicle screws were graded nonbreach versus 82% of cases with lateral fluoroscopy (P<0.001). The ratio of screw/pedicle diameter was significantly larger in the 3D NAV cohort (0.71 vs. 0.63, P<0.05). Seventy-six percent of 3D NAV cases had a predefined aspect of complexity, whereas 44% of non-3D NAV cases met criteria to be labeled complex (P<0.001). Reoperation occurred less frequently in 3D NAV cases than fluoroscopy alone. Conclusions: The use of 3D NAV was associated with improved screw placement accuracy, improved screw-to-pedicle diameter measurements, and was used in cases with a higher degree of surgical complexity. We conclude that 3D NAV is a valuable tool in current spinal instrumentation, especially for more complex surgeries.

Imaging Evidence and Recommendations for Traumatic Brain Injury: Advanced Neuro- and Neurovascular Imaging Techniques

Beyond the initial noncontrast CT, patients with brain trauma may be subjected to a variety of imaging studies. Here, the working group from the ACR Head Injury Institute discusses the use of these advanced imaging methods. SUMMARY: Neuroimaging plays a critical role in the evaluation of patients with traumatic brain injury, with NCCT as the first-line of imaging for patients with traumatic brain injury and MR imaging being recommended in specific settings. Advanced neuroimaging techniques, including MR imaging DTI, blood oxygen level–dependent fMRI, MR spectroscopy, perfusion imaging, PET/SPECT, and magnetoencephalography, are of particular interest in identifying further injury in patients with traumatic brain injury when conventional NCCT and MR imaging findings are normal, as well as for prognostication in patients with persistent symptoms. These advanced neuroimaging techniques are currently under investigation in an attempt to optimize them and substantiate their clinical relevance in individual patients. However, the data currently available confine their use to the research arena for group comparisons, and there remains insufficient evidence at the time of this writing to conclude that these advanced techniques can be used for routine clinical use at the individual patient level. TBI imaging is a rapidly evolving field, and a number of the recommendations presented will be updated in the future to reflect the advances in medical knowledge.

The transplanum transtuberculum approaches for suprasellar and sellar-suprasellar lesions: avoidance of cerebrospinal fluid leak and lessons learned.

OBJECTIVE To present a large series of patients and examine the learning curve of the endonasal endoscopic transplanum, transtuberculum approach for primarily suprasellar or sellar-suprasellar tumors. METHODS We identified 122 patients who underwent 126 surgeries using the transplanum, transtuberculum approach. Extent of resection was determined with volumetric analysis of magnetic resonance imagings. Results concerning vision, endocrine function, and complications were noted. RESULTS Average tumor volume was 14 cm(3). The most frequent pathologies were pituitary macroadenoma (51.6%), craniopharyngioma (20.6%), and meningioma (15.9%). A total of 73% patients presented with visual compromise. Rates of gross total resection (GTR) and near total resection for the group as a whole were 58.1% and 13.7%, and for the patients in whom GTR was intended (n = 90), rates of GTR and near total resection were 77.5% and 12.5% for a total of 90%. Extent of resection in this group was 97.6%. Vision improved in 52.4% and deteriorated in 4.8%. Favorable endocrine outcome occurred in 63.5%. The cerebrospinal fluid leak rate was 3.1% for the series as a whole. It improved from 6.3% in the first half of the series to 0 in the second half. Leak rates varied with technique from 11% (fat graft only) to 4.2% (gasket seal only) to 1.8% (fat plus nasoseptal flap) to 0 (gasket plus nasoseptal flap). The rate of other complications was 14.3% in the first half of the series and 1.6% in the second half. There was one infection (0.8%). CONCLUSIONS The endonasal endoscopic transtuberculum transplanum approach is a safe and effective minimal access approach to midline pathology in the suprasellar cistern.

Evaluating CT perfusion using outcome measures of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage

Ninety-six patients with SAH were evaluated with CT perfusion for cortical deficits and these were correlated with primary (permanent neurologic deficits and infarctions) and secondary (delayed cerebral ischemia manifesting as clinical deterioration) outcome measures. One-third of patients developed permanent neurologic deficits (78% showed CT perfusion defects), infarctions developed in 18% (88% had perfusion defects), and delayed cerebral ischemia was found in 50% (81% had perfusion defects). The most common perfusion abnormalities were reduced CBF and prolonged MTT. BACKGROUND AND PURPOSE: DCI is a serious complication following aneurysmal SAH and remains a leading cause of morbidity and mortality. Our aim was to evaluate CTP in aneurysmal SAH by using outcome measures of DCI. MATERIALS AND METHODS: This was a retrospective study of consecutive patients with SAH enrolled in a prospective institutional review board–approved clinical accuracy trial. Qualitative CTP deficits were determined by 2 neuroradiologists blinded to clinical and imaging data. Quantitative CTP was performed by using a standardized protocol with region-of-interest placement sampling of the cortex. Primary outcome measures were permanent neurologic deficits and infarction. The secondary outcome measure was DCI, defined as clinical deterioration. CTP test characteristics (95% CI) were determined for each outcome measure. Statistical significance was calculated by using the Fisher exact and Student t tests. ROC curves were generated to determine accuracy and threshold analysis. RESULTS: Ninety-six patients were included. Permanent neurologic deficits developed in 33% (32/96). CTP deficits were seen in 78% (25/32) of those who developed permanent neurologic deficits and 34% (22/64) of those without (P < .0001). CTP deficits had 78% (61%–89%) sensitivity, 66% (53%–76%) specificity, and 53% (39%–67%) positive and 86% (73%–93%) negative predictive values. Infarction occurred in 18% (17/96). CTP deficits were seen in 88% (15/17) of those who developed infarction and 41% (32/79) of those without (P = .0004). CTP deficits had an 88% (66%–97%) sensitivity, 59% (48%–70%) specificity, and 32% (20%–46%) positive and 96% (86%–99%) negative predictive values. DCI was diagnosed in 50% (48/96). CTP deficits were seen in 81% (39/48) of patients with DCI and in 17% (8/48) of those without (P < .0001). CTP deficits had 81% (68%–90%) sensitivity, 83% (70%–91%) specificity, and 83% (70%–91%) positive and 82% (69%–90%) negative predictive values. Quantitative CTP revealed significantly reduced CBF and prolonged MTT for DCI, permanent neurologic deficits, and infarction. ROC analysis showed that CBF and MTT had the highest accuracy. CONCLUSIONS: CTP may add prognostic information regarding DCI and poor outcomes in aneurysmal SAH.

MR perfusion-weighted imaging in the evaluation of high-grade gliomas after treatment: a systematic review and meta-analysis

Background. Distinction between tumor and treatment related changes is crucial for clinical management of patients with high-grade gliomas. Our purpose was to evaluate whether dynamic susceptibility contrast-enhanced (DSC) and dynamic contrast enhanced (DCE) perfusion-weighted imaging (PWI) metrics can effectively differentiate between recurrent tumor and posttreatment changes within the enhancing signal abnormality on conventional MRI. Methods. A comprehensive literature search was performed for studies evaluating PWI-based differentiation of recurrent tumor and posttreatment changes in patients with high-grade gliomas (World Health Organization grades III and IV). Only studies published in the “temozolomide era” beginning in 2005 were included. Summary estimates of diagnostic accuracy were obtained by using a random-effects model. Results. Of 1581 abstracts screened, 28 articles were included. The pooled sensitivities and specificities of each studys best performing parameter were 90% and 88% (95% CI: 0.85–0.94; 0.83–0.92) and 89% and 85% (95% CI: 0.78–0.96; 0.77–0.91) for DSC and DCE, respectively. The pooled sensitivities and specificities for detecting tumor recurrence using the 2 most commonly evaluated parameters, mean relative cerebral blood volume (rCBV) (threshold range, 0.9–2.15) and maximum rCBV (threshold range, 1.49–3.1), were 88% and 88% (95% CI: 0.81–0.94; 0.78–0.95) and 93% and 76% (95% CI: 0.86–0.98; 0.66–0.85), respectively. Conclusions. PWI-derived thresholds separating viable tumor from treatment changes demonstrate relatively good accuracy in individual studies. However, because of significant variability in optimal reported thresholds and other limitations in the existing body of literature, further investigation and standardization is needed before implementing any particular quantitative PWI strategy across institutions.