Imaging Errors in Distinguishing Pituitary Adenomas From Other Sellar Lesions.

BACKGROUND: Pituitary adenomas and nonadenomatous lesions in the sellar region may be difficult to distinguish by imaging yet that distinction is critical in guiding management. The nature of the diagnostic errors in this setting has not been well documented. METHODS: Two neurosurgeons and 2 neuroradiologists of differing experience levels viewed deidentified MRIs of 18 nonadenomatous sellar lesions and 21 adenomas. They recorded their diagnoses, the imaging features they used to make those diagnoses, and their confidence in making those diagnoses. RESULTS: Among the 18 nonadenoma cases, 11 (61%) were incorrectly diagnosed as adenoma by at least 1 reader, including Rathke cleft cyst, plasmacytoma, aneurysm, craniopharyngioma, chordoma, Langerhans cell histiocytosis, metastasis, and undifferentiated sinonasal carcinoma. Among the 21 adenoma cases, 8 (38%) were incorrectly diagnosed by at least 1 reader as craniopharyngioma, Rathke cleft cyst, sinonasal carcinoma, hemangioblastoma, and pituitary hyperplasia. Incorrect imaging diagnoses were made with high confidence in 13% of readings. Avoidable errors among the nonadenomatous cases occurred when readers failed to appreciate that the lesion was separate from the pituitary gland. Unavoidable errors in those cases occurred when the lesions were so large that the pituitary gland had been obliterated or the imaging features of a nonadenomatous lesion resembled those of a cystic pituitary adenoma. Avoidable errors in misdiagnosis of adenomas as nonadenomas occurred when readers failed to appreciate features highly characteristic of adenomas. An unavoidable error occurred because a cystic adenoma had features correctly associated with craniopharyngioma. CONCLUSIONS: Errors in imaging differentiation of pituitary adenoma from nonadenomatous lesions occurred often and sometimes with high confidence among a small sample of neurosurgeons and neuroradiologists. In the misdiagnosis of nonadenomatous lesions as adenomas, errors occurred largely from failure to appreciate a separate pituitary gland, but unavoidable errors occurred when large lesions had obliterated this distinguishing feature. In the misdiagnosis of adenomas as nonadenomatous lesions, avoidable errors occurred because readers failed to recognize imaging features more characteristic of adenomas and because cystic adenomas share features with craniopharyngiomas and Rathke cleft cysts. Awareness of these errors should lead to improved management of sellar lesions.

Ventricular Volume Change as a Predictor of Shunt-Dependent Hydrocephalus in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH) that often requires acute placement of an external ventricular drain (EVD). The current systems available for determining which patients will require long-term cerebrospinal fluid diversion remain subjective. We investigated the ventricular volume change (ΔVV) after EVD clamping as an objective predictor of shunt dependence in patients with aSAH. METHODS: We performed a retrospective medical record review and image analysis of patients treated for aSAH at a single academic institution who had required EVD placement for acute hydrocephalus and had undergone 1 EVD weaning trial. Head computed tomography (CT) scans obtained before and after EVD clamping were analyzed using a custom semiautomated MATLAB program (MathWorks, Natick, Massachusetts, USA), which segments each CT scan into 5 tissue types using k-means clustering. Differences in the pre- and postclamp ventricular volumes were calculated. RESULTS: A total of 34 patients with an indwelling shunt met the inclusion criteria and were sex- and age-matched to 34 controls without a shunt. The mean ΔVV was 19.8 mL in the shunt patients and 3.8 mL in the nonshunt patients (P < 0.0001). The area under the receiver operating characteristic curve was 0.84. The optimal ΔVV threshold was 11.4 mL, with a sensitivity of 76.5% and specificity of 88.2% for predicting shunt dependence. The mean ΔVV was significantly greater for the patients readmitted for shunt placement compared with the patients not requiring cerebrospinal fluid diversion (18.69 mL vs. 3.84 mL; P = 0.005). Finally, 70% of the patients with delayed shunt dependence had ΔVV greater than the identified threshold. CONCLUSIONS: The ΔVV volume between head CT scans taken before and after EVD clamping was predictive of early and delayed shunt dependence.

Using a Mobile Application for Evaluation of Procedural Learning in Neurosurgery.

BACKGROUND: Feedback is a major component of any educational process. Competency assessment and feedback are essential tools for teaching surgical skills. Most current systems of assessment within neurosurgical residency programs use evaluations aggregated over a period of time, which lead to significant bias, rather than case-specific feedback. We describe the use of a mobile device application called SIMPL (System for Improving and Measuring Procedural Learning) to allow for immediate surgical competency assessment and improve the quality of feedback after every operative experience. METHODS: We retrospectively assessed our use of this program and neurosurgery residents' response to the program. Institutional review board approval was not required, and no patients were involved in the study. This application has already been implemented within general surgery programs with promising results. We document its implementation in a neurosurgery program and the output of the program for residents and program directors. RESULTS: This is the first documentation of such an application within a neurosurgical residency program. In a 6-month period at a single institution, around 300 evaluations were completed by residents and faculty, with a >80% response rate within both groups. Furthermore, these evaluations were companied by a 60% dictation rate from faculty, which contains verbal feedback that is available to residents for playback at any time. CONCLUSIONS: The telephone-based SIMPL application allows for assessment of surgical competency and remains quick and easy to use, giving it the potential to improve individual neurosurgical training experiences across the United States.

Normal cerebral ventricular volume growth in childhood.

OBJECTIVE: Normal percentile growth charts for head circumference, length, and weight are well-established tools for clinicians to detect abnormal growth patterns. Currently, no standard exists for evaluating normal size or growth of cerebral ventricular volume. The current standard practice relies on clinical experience for a subjective assessment of cerebral ventricular size to determine whether a patient is outside the normal volume range. An improved definition of normal ventricular volumes would facilitate a more data-driven diagnostic process. The authors sought to develop a growth curve of cerebral ventricular volumes using a large number of normal pediatric brain MR images. METHODS: The authors performed a retrospective analysis of patients aged 0 to 18 years, who were evaluated at their institution between 2009 and 2016 with brain MRI performed for headaches, convulsions, or head injury. Patients were excluded for diagnoses of hydrocephalus, congenital brain malformations, intracranial hemorrhage, meningitis, or intracranial mass lesions established at any time during a 3- to 10-year follow-up. The volume of the cerebral ventricles for each T2-weighted MRI sequence was calculated with a custom semiautomated segmentation program written in MATLAB. Normal percentile curves were calculated using the lambda-mu-sigma smoothing method. RESULTS: Ventricular volume was calculated for 687 normal brain MR images obtained in 617 different patients. A chart with standardized growth curves was developed from this set of normal ventricular volumes representing the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles. The charted data were binned by age at scan date by 3-month intervals for ages 0-1 year, 6-month intervals for ages 1-3 years, and 12-month intervals for ages 3-18 years. Additional percentile values were calculated for boys only and girls only. CONCLUSIONS: The authors developed centile estimation growth charts of normal 3D ventricular volumes measured on brain MRI for pediatric patients. These charts may serve as a quantitative clinical reference to help discern normal variance from pathologic ventriculomegaly.

Prospects of biological and synthetic pharmacotherapies for glioblastoma.

Introduction: The field of neuro-oncology has experienced significant advances in recent years. More is known now about the molecular and genetic characteristics of glioma than ever before. This knowledge leads to the understanding of glioma biology and pathogenesis, guiding the development of targeted therapeutics and clinical trials. The goal of this review is to describe the state of basic, translational, and clinical research as it pertains to biological and synthetic pharmacotherapy for gliomas.Areas covered: Challenges remain in designing accurate preclinical models and identifying patients that are likely to respond to a particular targeted therapy. Preclinical models for therapeutic assessment are critical to identify the most promising treatment approaches.Expert opinion: Despite promising new therapeutics, there have been no significant breakthroughs in glioma treatment and patient outcomes. Thus, there is an urgent need to better understand the mechanisms of treatment resistance and to design effective clinical trials.

BDNF, COMT, and DRD2 polymorphisms and ability to return to work in adult patients with low- and high-grade glioma.

BACKGROUND: Cognitive and language dysfunction is common among patients with glioma and has a significant impact on survival and health-related quality of life (HRQOL). Little is known about the factors that make individual patients more or less susceptible to the cognitive sequelae of the disease. A better understanding of the individual and population characteristics related to cognitive function in glioma patients is required to appropriately stratify patients, prognosticate, and develop more efficacious treatment regimens. There is evidence that allelic variation among genes involved in neurotransmission and synaptic plasticity are related to neurocognitive performance in states of health and neurologic disease. METHODS: We studied the association of single-nucleotide polymorphism variations in brain-derived neurotrophic factor (BDNF, rs6265), dopamine receptor 2 (DRD2, rs1076560), and catechol-O-methyltransferase (COMT, rs4680) with neurocognitive function and ability to return to work in glioma patients at diagnosis and at 3 months. We developed a functional score based on the number of high-performance alleles that correlates with the capacity for patients to return to work. RESULTS: Patients with higher-performing alleles have better scores on neurocognitive testing with the Repeatable Battery for the Assessment of Neuropsychological Status and Stroop test, but not the Trail Making Test. CONCLUSIONS: A better understanding of the genetic contributors to neurocognitive performance in glioma patients and capacity for functional recovery is necessary to develop improved treatment strategies based on patient-specific factors.

Health Related Quality of Life in Adult Low and High-Grade Glioma Patients Using the National Institutes of Health Patient Reported Outcomes Measurement Information System (PROMIS) and Neuro-QOL Assessments.

Health related quality of life (HRQOL) measures have become increasingly important in the management of glioma patients in both research and clinical practice settings. Functional impairment is common in low-grade and high-grade glioma patients as the disease has both oncological and neurological manifestations. Natural disease history as well as medical or surgical treatment can negatively influence HRQOL. There are no universal standards for HRQOL assessment in glioma patients. In this study, we examine patient perspectives on functional outcome domains and report the prevalence of impairments rates using the National Institutes of Health (NIH) Patient Reported Outcomes Measurement Information System (PROMIS) and Neuro-QOL item banks as measures of HRQOL. Retrospective analysis of a prospectively collected dataset involving 79 glioma patients reveals that quality of life concerns are the most important consideration behind making decisions about treatment in 80.7% of patients. The prevalence of functional impairment by PROMIS and NEURO-QOL assessment is high, ranging from 28.6% in the physical function domain to 43.9% in the cognitive function domain. Pain and anxiety related to physical decline is higher in LGG patients compared to HGG patients. Aphasia severity also impacts HRQOL. The results of this study suggest that the PROMIS and NEURO-QOL assessments may be important HRQOL metrics for future use in larger clinical research and clinical trial settings.

STAT3 Inhibition as a Therapeutic Strategy for Chordoma.

Objective Signal transducer and activator of transcription (STAT) proteins regulate key cellular fate decisions including proliferation and apoptosis. STAT3 overexpression induces tumor growth in multiple neoplasms. STAT3 is constitutively activated in chordoma, a tumor with a high recurrence rate despite maximal surgical and radiation treatment. We hypothesized that a novel small molecule inhibitor of STAT3 (FLLL32) would induce significant cytotoxicity in sacral and clival chordoma cells. Methods Sacral (UCh1) and clival (UM-CHOR-1) chordoma cell lines were grown in culture (the latter derived from primary tumor explants). FLLL32 dosing parameters were optimized using cell viability assays. Antitumor potential of FLLL32 was assessed using clonal proliferation assays. Potential mechanisms underlying observed cytotoxicity were examined using immunofluorescence assays. Results FLLL32 induced significant cytotoxicity in UCh1 and UM-CHOR-1 chordoma cells, essentially eliminating all viable cells, correlating with observed downregulation in activated, phosphorylated STAT3 upon administration of FLLL32. Mechanisms underlying the observed cytotoxicity included increased apoptosis and reduced cellular proliferation through inhibition of mitosis. Conclusion As a monotherapy, FLLL32 induces potent tumor kill in vitro in chordoma cell lines derived from skull base and sacrum. This effect is mediated through inhibition of STAT3 phosphorylation, increased susceptibility to apoptosis, and suppression of cell proliferation.

The role of CD133+ cells in a recurrent embryonal tumor with abundant neuropil and true rosettes (ETANTR).

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a recently described embryonal neoplasm of the central nervous system, consisting of a well-circumscribed embryonal tumor of infancy with mixed features of ependymoblastoma (multilayer ependymoblastic rosettes and pseudorosettes) and neuroblastoma (neuroblastic rosettes) in the presence of neuropil-like islands. We present the case of a young child with a very aggressive tumor that rapidly recurred after gross total resection, chemotherapy and radiation. Prominent vascular sclerosis and circumscribed tumor led to the diagnosis of malignant astroblastoma; however, rapid recurrence and progression of this large tumor after gross total resection prompted review of the original pathology. ETANTR is histologically distinct with focal glial fibrillary acid protein (GFAP) and synaptophysin expression in the presence of neuronal and ependymoblastic rosettes with focal neuropil islands. These architectural features, combined with unique chromosome 19q13.42 amplification, confirmed the diagnosis. In this report, we describe tumor stem cell (TSC) marker CD133, CD15 and nestin alterations in ETANTR before and after chemotherapy. We found that TSC marker CD133 was richly expressed after chemotherapy in recurrent ETANTR, while CD15 is depleted compared with that expressed in the original tumor, suggesting that CD133+ cells likely survived initial treatment, further contributing to formation of the recurrent tumor.