Multicenter comparison of Chiari malformation type I presentation in children versus adults.

OBJECTIVE: Treatment for Chiari malformation type I (CM-I) often includes surgical intervention in both pediatric and adult patients. The authors sought to investigate fundamental differences between these populations by analyzing data from pediatric and adult patients who required CM-I decompression. METHODS: To better understand the presentation and surgical outcomes of both groups of patients, retrospective data from 170 adults and 153 pediatric patients (2000-2019) at six institutions were analyzed. RESULTS: The adult CM-I patient population requiring surgical intervention had a greater proportion of female patients than the pediatric population (p < 0.0001). Radiographic findings at initial clinical presentation showed a significantly greater incidence of syringomyelia (p < 0.0001) and scoliosis (p < 0.0001) in pediatric patients compared with adult patients with CM-I. However, presenting signs and symptoms such as headaches (p < 0.0001), ocular findings (p = 0.0147), and bulbar symptoms (p = 0.0057) were more common in the adult group. After suboccipital decompression procedures, 94.4% of pediatric patients reported symptomatic relief compared with 75% of adults with CM-I (p < 0.0001). CONCLUSIONS: Here, the authors present the first retrospective evaluation comparing adult and pediatric patients who underwent CM-I decompression. Their analysis reveals that pediatric and adult patients significantly differ in terms of demographics, radiographic findings, presentation of symptoms, surgical indications, and outcomes. These findings may indicate different clinical conditions or a distinct progression of the natural history of this complex disease process within each population, which will require prospective studies to better elucidate.

Pituitary Adenoma Coexistent with Sellar Clear Cell Meningioma Unattached to the Dura: Case Report and Treatment Considerations.

Collision tumors involving the sella are rare. Intrasellar collision tumors are most commonly composed of a combination of pituitary adenomas and pituitary neuroendocrine tumors; however, collision tumors consisting of a pituitary adenoma and intrasellar meningioma are exceedingly rare. The authors present the case of a 47-year-old man who presented with progressive right eye vision loss. Magnetic resonance imaging showed a large, heterogeneously enhancing sellar mass with suprasellar extension. Using a transcranial approach with a right subfrontal craniotomy, near-total resection of the mass was achieved. Histologic analysis confirmed a diagnosis of a gonadotroph adenoma with concomitant clear cell meningioma (CCM). This patient was discharged with improvement in visual acuity and no signs of diabetes insipidus. Given the indistinguishable radiographic characteristics of pituitary adenoma and CCM, a preoperative diagnosis of a collision tumor was difficult. This case was uniquely challenging since the CCM component lacked the classic dural attachment that is associated with meningiomas on neuroimaging. CCMs are classified as central nervous system (CNS) World Health Organization (WHO) grade 2 tumors and tend to behave more aggressively, therefore warranting close surveillance for signs of tumor recurrence. This is the first case to report a collision tumor consisting of pituitary adenoma and CCM.

Biomechanics of sacroiliac joint fixation using lag screws: a cadaveric study.

BACKGROUND: Iliosacral screw placement is ubiquitous and now part of the surgeon's pelvic trauma armamentarium. More recent evidence supports sacroiliac arthrodesis for treating sacroiliac joint (SIJ) dysfunction in select patients. Regardless of the surgical indication, there are currently no studies examining lag screw compression biomechanics across the SIJ. The objective of this biomechanical investigation was to quantify iliosacral implant compressive loads and to examine the insertion torque and compressive load profile over time. METHODS: Eight human cadaveric pelvic specimens underwent SIJ fixation at S1 and S2 using 11.5 and 10.0 mm iFuse-TORQ Lag implants, respectively, and standard 7.3 mm trauma lag screws. Load decay analysis was performed, and insertion and removal torques were measured. RESULTS: For both implants at S1 and S2 levels, the load relaxed 50% in approximately 67 min. Compressive load decay was approximately 70% on average occurring approximately 15 h post-insertion. Average insertion torque for the 11.5 mm TORQ implant at S1 was significantly greater than the trauma lag screw. Similarly, at S2, insertion torque of the 10.0 mm TORQ implant was greater than the trauma lag screw. At S1, removal torque for the 11.5 mm TORQ implant was higher than the trauma lag screw; there was no significant difference in the removal torque at S2. CONCLUSIONS: In this study, we found that a novel posterior pelvic implant with a larger diameter, roughened surface, and dual pitch threads achieved improved insertion and removal torques compared to a standard screw. Load relaxation characteristics were similar between all implants.

Neurologic outcomes for adult spinal cord ependymomas stratified by tumor location: a retrospective cohort study and 2-year outlook.

Determine whether craniocaudal spinal cord tumor location affects long-term neurologic outcomes in adults diagnosed with spinal ependymomas (SE). A retrospective cohort analysis of patients aged ≥ 18 years who underwent surgical resection for SE over a ten-year period was conducted. Tumor location was classified as cervical, thoracic, or lumbar/conus. Primary endpoints were post-operative McCormick Neurologic Scale (MNS) scores at < 3 days, 6 weeks, 1 year, and 2 years. One-way ANOVA was performed to detect significant differences in MNS scores between tumor locations. Twenty-eight patients were identified. The average age was 44.2 ± 15.4 years. Sixteen were male, and 13 were female. There were 10 cervical-predominant SEs, 13 thoracic-predominant SEs, and 5 lumbar/conus-predominant SEs. No significant differences were observed in pre-operative MNS scores between tumor locations (p = 0.73). One-way ANOVA testing demonstrated statistically significant differences in post-operative MNS scores between tumor locations at < 3 days (p = 0.03), 6 weeks (p = 0.009), and 1 year (p = 0.003); however, no significant difference was observed between post-operative MNS scores at 2 years (p = 0.13). The mean MNS score for patients with thoracic SEs were higher at all follow-up time points. Tumors arising in the thoracic SE are associated with worse post-operative neurologic outcomes in comparison to SEs arising in other spinal regions. This is likely multifactorial in etiology, owing to both anatomical differences including spinal cord volume as well as variations in tumor characteristics. No significant differences in 2-year MNS scores were observed, suggesting that patients ultimately recover from neurological insult sustained at the time of surgery.

Establishing the Swiss Spinal Tumor Registry (Swiss-STR): a prospective observation of surgical treatment patterns and long-term outcomes in patients with primary and metastatic spinal tumors.

Background: Tumors of the vertebral column consist of primary spinal tumors and malignancies metastasizing to the spine. Although primary spine tumors are rare, metastases to the spine have gradually increased over past decades because of aging populations and improved survival for various cancer subtypes achieved by advances in cancer therapy. Metastases to the vertebral column occur in up to 70% of cancer patients, with 10% of patients demonstrating epidural spinal cord compression. Therefore, many cancer patients may face spinal surgical intervention during their chronic illness; such interventions range from simple cement augmentation over decompression of neural elements to extended instrumentation or spinal reconstruction. However, precise surgical treatment guidelines do not exist, likely due to the lack of robust, long-term clinical outcomes data and the overall heterogeneous nature of spinal tumors. Objectives of launching the Swiss Spinal Tumor Registry (Swiss-STR) are to collect and analyze high-quality, prospective, observational data on treatment patterns, clinical outcomes, and health-related quality of life (HRQoL) in adult patients undergoing spinal tumor surgery. This narrative review discusses our rationale and process of establishing this spinal cancer registry. Methods: A REDCap-based registry was created for the standardized collection of clinical, radiographic, surgical, histological, radio-oncologial and oncological variables, as well as patient-reported outcome measures (PROMs). Discussion: We propose that the Swiss-STR will inform on the effectiveness of current practices in spinal oncology and their impact on patient outcomes. Furthermore, the registry will enable better categorization of the various clinical presentations of spinal tumors, thereby facilitating treatment recommendations, defining the socio-economic burden on the healthcare system, and improving the quality of care. In cases of rare tumors, the multi-center data pooling will fill significant data gaps to yield better understanding of these entities. Finally, our two-step approach first implements a high-quality registry with efficient electronic data capture strategies across hospital sites in Switzerland, and second follows with potential to expand internationally, thus fostering future international scientific collaboration to further push the envelope in cancer research.

Clinical Validation of a Novel Musculoskeletal Modeling Framework to Predict Postoperative Sagittal Alignment.

STUDY DESIGN: A retrospective radiographic and biomechanical analysis of 108 thoracolumbar fusion patients from two clinical centers. OBJECTIVE: This study aimed to determine the validity of a computational framework for predicting postoperative patient posture based on preoperative imaging and surgical data in a large clinical sample. SUMMARY OF BACKGROUND DATA: Short-term and long-term studies on thoracolumbar fusion patients have discussed that a preoperative predictive model would benefit surgical planning and improve patient outcomes. Clinical studies have shown that postoperative alignment changes at the pelvis and intact spine levels may negatively affect postural balance and quality of life. However, it remains challenging to predict such changes preoperatively because of confounding surgical and patient factors. MATERIALS AND METHODS: Patient-specific musculoskeletal models incorporated weight, height, body mass index, age, pathology-associated muscle strength, preoperative sagittal alignment, and surgical treatment details. The sagittal alignment parameters predicted by the simulations were compared with those observed radiographically at a minimum of three months after surgery. RESULTS: Pearson correlation coefficients ranged from r=0.86 to 0.95, and mean errors ranged from 4.1° to 5.6°. The predictive accuracies for postoperative spinopelvic malalignment (pelvic incidence minus lumbar lordosis>10°) and sagittal imbalance parameters (TPA>14°, T9PA>7.4°, or LPA>7.2°) were between 81% and 94%. Patients treated with long fusion (greater than five segments) had relatively lower prediction errors for lumbar lordosis and spinopelvic mismatch than those in the local and short groups. CONCLUSIONS: The overall model performance with long constructs was superior to those of the local (one to two segments) and short (three to four segments) fusion cases. The clinical framework is a promising tool in development to enhance clinical judgment and to help design treatment strategies for predictable surgical outcomes. LEVEL OF EVIDENCE: 3.

Impact of Surgical Timing on Neurological Outcomes for Spinal Arachnoid Cyst: A Single Institution Series.

OBJECTIVE: Spinal arachnoid cysts (SACs) are rare lesions that often present with back pain and myelopathy. There is a paucity of literature evaluating the impact of surgical timing on neurological outcomes for primary SAC management. To compare long-term neurological outcomes in patients who were managed differently and to understand natural progression of SAC. METHODS: We conducted a retrospective analysis of adult patients treated for SAC at our institution from 2010 to 2021, stratified into 3 groups (conservative management only, surgical management, or conservative followed by surgical management). Study outcome measures were neurological outcomes as measured by modified McCormick Neurologic Scale (MNS), postoperative complications, and cyst recurrence. Nonparametric analysis was performed to evaluate differences between groups for selected endpoints. RESULTS: Thirty-six patients with SAC were identified. Eighteen patients were managed surgically. The remaining 18 patients were managed conservatively with outpatient serial imaging, 7 of whom (38.9%) ultimately underwent surgical treatment due to neurological decline. Most common presenting symptoms included back pain (50.0%), extremity weakness (36.1%), and numbness/paresthesia (36.1%). Initial/preoperative (p = 0.017) and 1-year postoperative (p = 0.006) MNS were significantly different between the 3 groups, but not at 6 weeks or 6 months postoperatively (p > 0.05). Additionally, at 1 year, there was no difference in MNS between patients managed surgically and those managed conservatively but ultimately underwent surgery (p > 0.99). CONCLUSION: Delayed surgical intervention in minimally symptomatic patients does not seem to result in worse long-term neurofunctional outcomes. At 1 year, postoperative MNS were significantly higher in both surgical groups, when compared to the conservative group highlighting worsening clinical picture regardless of preoperative observational status.

Long-term Neurologic Outcome After Spinal Ependymoma Resection With Multimodal Intraoperative Electrophysiological Recording: Cohort Study and Review of the Literature.

OBJECTIVE: To evaluate how multimodal intraoperative neuromonitoring (IONM) changes during spinal ependymoma (SE) resection correlate with long-term neuro-functional outcomes. METHODS: A retrospective analysis of patients aged 18 years or older who underwent surgical resection for SE over a 10-year period was conducted. IONM changes were defined as sustained transcranial motor evoked potential (TcMEP) and/or somatosensory evoked potential (SSEP) signal decrease of 50% or greater from baseline. Primary endpoints were postoperative modified McCormick Neurologic Scale (MNS) scores at postoperative day (POD) < 2, 6 weeks, 1 year, and 2 years. Univariate and multivariate analyses were performed. RESULTS: Twenty-nine patients were identified. Average age was 44.2 ± 15.4 years. Sixteen (55.2%) were male and 13 (44.8%) were female. Tumor location was 10 cervical-predominant (34.5%), 13 thoracic-predominant (44.8%), and 6 lumbar/conus-predominant (20.7%). A majority (69.0%) were World Health Organization grade 2 tumors. Twentyfour patients (82.8%) achieved gross total resection. Thirteen patients (44.8%) had a sustained documented IONM signal change and 10 (34.5%) had a TcMEP change with or without derangement in SSEP. At POD < 2, 6 weeks, 1 year, and 2 years, MNS was significantly higher for those when analyzing subgroups with either any sustained IONM or TcMEP ± SSEP signal attenuation > 50% below baseline (all p < 0.05). CONCLUSION: Sustained IONM derangements > 50% below baseline, particularly for TcMEP, are significantly associated with higher MNS postoperatively out to 2 years. Intraoperative and postoperative management of these patients warrant special consideration to limit neurologic morbidity.

Application of sodium fluorescein for spinal cord lesions: intraoperative localization for tissue biopsy and surgical resection.

Sodium fluorescein (NaFL) has been used to aid in the resection of primary and secondary lesions within the brain. Comparatively, there is limited research on clinical applications for lesions within the spinal cord. Fluorescein-guided microsurgery may increase the ability to localize and safely surgically treat spinal lesions. Twelve patients with spinal cord lesions received fluorescein sodium 10% (Alcon Laboratories INC, Fort Worth, TX, USA) at 3 mg/kg prior to surgical resection. Intraoperative visualization of fluorescence was performed using a Zeiss Pentero (Carl Zeiss AG, Oberkochen, Germany) microscope equipped with a Yellow560 filter or a Leica OH6 (Leica Microsystems, Wetzlar, Germany) equipped with a FL560 filter. Administration of NaFL resulted in lesional fluorescent contrast extravasation and facilitated surgical resection and localization in all twelve patients. In patients with a goal of complete resection, NaFL aided in complete resection of the spinal lesions in seven patients. In surgical resection patients, pathology was consistent with WHO grade I myxopapillary ependymoma in one patient, WHO grade II ependymoma in five patients, and nerve sheath tumor in one patient. In the other five patients, NaFL allowed for intraoperative tissue identification and successful tissue biopsy. In patients undergoing biopsy, tissue samples were positive for an intramedullary abscess, EBV-driven lymphoproliferative disease, and primary glial neoplasms. Fluorescein is a helpful microsurgical tool in guiding surgical resection and in the localization of intramedullary spinal lesions. Further research is necessary to explore fluorescein sodium applications in the resection of spinal cord lesions.

The role of medical school prestige and location in neurosurgery residency placement: An analysis of data from 2016 to 2020.

OBJECTIVE: There remains a gap in the literature analyzing how categorical variables may affect the highly competitive neurosurgery residency application process for MD Seniors in the United States. We aimed to improve understanding of the impact of medical school prestige and geographic location on candidacy for neurosurgery residency. METHODS: Schools were stratified into high and low prestige cohorts based on the U.S. News and World Report Rankings and by geographic location. Publicly available match data displayed by websites of included medical schools from 2016 to 2020 were examined, and neurosurgery residency placement rates were then compared. Analysis was performed using Fisher's exact test and chi-square analysis, with a p-value of 0.05. RESULTS: There were 6685 total matches in the high-prestige cohort and 12,997 total matches in the low-prestige cohort, with 115 (1.72%) and 113 (0.87%) neurosurgery matches, respectively (OR = 2.00, p < 0.0001). Considering geographic location, there were 5244 total matches in the Midwest, 3456 total matches in the West, 4994 total matches in the South, and 6053 total matches in the Northeast, with 51 (0.97%), 24 (0.69%), 83 (1.66%), and 114 (1.88%) being neurosurgery residency placements, respectively (p < 0.0001). CONCLUSIONS: Neurosurgery residency placement may be correlated with attending more prestigious medical schools and those located in the Northeast or South United States. Further elucidation of similar variables may prove to be important as neurosurgery residency becomes more competitive and the evaluation process changes.

Development of a Technical Skills Test to Improve Assessment and Evaluation in Neuroendoscopic Education.

BACKGROUND: Endoscopy requires a unique set of skills that are difficult to acquire in most training programs. A method to test technical skills, in a validated manner, has rarely been attempted. The purpose of this study was to develop a technical skills examination for objective assessment in neuroendoscopic education. METHODS: Twenty-nine participants were included for analysis and divided by seniority level into 2 groups defined as before or upon postgraduation year (PGY) 5 (n = 18, junior surgeons) or after PGY5 (n = 11, senior surgeons). Study participants were assessed for baseline performance and then again following a 4-hour neuroendoscopy course. Wilcoxon test was used to evaluate for performance differences between cohorts. Correlation analyses were performed using the Pearson or Spearman coefficient. RESULTS: Increasing PGY level was correlated with a decreased average time to complete all 3 tasks (r = -0.44, P = 0.03) at baseline. Overall performance improved in both cohorts following the course (P < 0.001). When comparing junior surgeons after endoscopy training (posttest) to senior surgeons at their baseline (pretest), the junior surgeons were faster after endoscopic training than the senior surgeons were before training (P < 0.001). CONCLUSIONS: A neuroendoscopic skills test can distinguish between more or less experienced surgeons. Significant overall performance improvement, regardless of seniority level, following neuroendoscopic training demonstrates the accuracy of the test at detecting operating improvement in all stages of learning.

Compassionate use of a custom 3D-printed sacral implant for revision of failing sacrectomy: case report.

Reconstruction of the spinopelvic continuity after sacral resection for primary sacral tumors remains challenging. Complex anatomical and biomechanical factors of this transition zone may be addressed with the advancement of 3D-printed implants. Here, the authors report on a 67-year-old patient with a sacral chordoma who initially underwent total en bloc sacrectomy followed by standard spinopelvic reconstruction. Pseudarthrosis and instrumentation failure of the lumbosacral junction construct subsequently developed. A custom 3D-printed sacral prosthesis was created using high-resolution CT images. Emergency Food and Drug Administration approval was obtained, and the custom device was implanted as a salvage reconstruction surgery. Made of porous titanium mesh, the custom artificial sacrum was placed in the defect based on the anticipated osteotomic planes and was fixed with a screw-rod system along with a fibular bone strut graft. At the 18-month follow-up, the patient was disease free and walking short distances with assistance. CT revealed excellent bony incorporation into the graft.The use of a custom 3D-printed prosthesis in spinal reconstruction has been rarely reported, and its application in sacral reconstruction and long-term outcome are novel. While the implant was believed to be critical in endowing the region with enough biomechanical stability to promote healing, the procedure was difficult and several key learning points were discovered along the way.

Reliability of fluorescein-assisted stereotactic brain biopsies in predicting conclusive tissue diagnosis.

BACKGROUND: The purpose of this study was to assess the reliability of fluorescein sodium in predicting conclusive tissue diagnosis in stereotactic brain biopsies and to characterize features of contrast-enhancing and non-enhancing MRI lesions associated with fluorescence. METHODS: A total of 19 patients were studied, 14 of which had contrast-enhancing and 5 of which had non-enhancing lesions on preoperative T1 post-gadolinium MRI scan. All patients received 3 mg/kg fluorescein sodium during anesthesia induction. Biopsy specimens were photographed under the operating microscope, using the Yellow560 module, prior to histopathological analysis. Two observers blinded to the MRI scans and histopathological results categorized the photographs retrospectively as "fluorescent" or "not fluorescent." Inter-rater agreement was assessed using Cohen's kappa coefficient. Sensitivity, specificity, and positive predictive value of fluorescence reliability were calculated for MRI contrast-enhancing lesions and confirmed location-concordance of tumor pathology based on rater's fluorescence status assessment. Results were correlated finally with final results on permanent sections. RESULTS: Strength of inter-rater fluorescence status agreement was found to be "substantial" (kappa = 0.771). Sensitivity, specificity, and positive predictive value for "fluorescent" and "not fluorescent" specimen in comparison with MRI contrast-enhancing lesions were 97%, 40%, and 82%, respectively. Sensitivity, specificity, and positive predictive value for confirmed tumor pathology were 100%, 63%, and 91%, respectively. Permanent pathology revealed high-grade glioma n = 5, low-grade glioma n = 3, lymphoma n = 5, pineal tumor n = 2, hamartoma n = 1, and nonspecific hypercellularity n = 3. CONCLUSIONS: Fluorescein-assisted stereotactic brain biopsies demonstrated a high likelihood to manifest fluorescence in contrast-enhancing MRI lesions, while adequately predicting conclusive tumor pathology.

Surgical management considerations in cystic prolactinomas-a single center case series.

PURPOSE: The optimal treatment of prolactinomas with a predominantly cystic component remains poorly defined. The cystic tumor component is considered to respond less favorably to medical treatment, thereby advocating surgical management. The purpose of this study was to assess remission rates in surgically treated cystic prolactinomas, and to compare outcomes to similarly treated solid micro- and macroprolactinomas. METHODS: Clinical and imaging data were retrospectively compiled from 56 patients who underwent transsphenoidal resection, for symptomatic prolactinomas, from 2004 to 2018, at a single academic institution. Pituitary adenomas were subdivided according to tumor size and tumor consistency: cystic prolactinomas (>50% cystic tumor component) n = 17; solid microprolactinomas (<10 mm) n = 10; and solid macroprolactinomas (≥10 mm) n = 29. Remission was defined as a prolactin level of <10 ng/dl either immediately postoperative or at a later time point. RESULTS: Median tumor size was 15 mm for cystic prolactinomas, 7 mm for solid microprolactinomas, and 25.5 mm for solid macroprolactinomas. Remission was achieved in 76% (n = 13/17) of surgically treated cystic prolactinomas, 100% (n = 10/10) of solid microprolactinomas, and 24% (n = 7/29) of solid macroprolactinomas. More than 44% of solid macroprolactinomas had a Knosp grade > 3, while most cystic prolactinomas (93.8%) and all solid microprolactinomas (100%) had a Knosp grade ≤ 2. CONCLUSIONS: Despite their large tumor size (≥10 mm), high remission rates can be expected with surgically treated cystic prolactinomas. This case series of cystic prolactinomas demonstrates the successful use of transsphenoidal surgery as a favorable, and a potentially curative alternative to dopaminergic therapy in this patient population.

CRH stimulation improves 18F-FDG-PET detection of pituitary adenomas in Cushing's disease.

OBJECTIVE: In MRI-negative cases Cushing's disease (CD), surgeons perform a more extensive exploration of the pituitary gland, with fewer instances of hormonal remission. 18F-fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) has a limited role in detecting adenomas that cause CD (corticotropinomas). Our previous work demonstrated corticotropin-releasing hormone (CRH) stimulation leads to delayed, selective glucose uptake in corticotropinomas. Here, we prospectively evaluated the utility of CRH stimulation in improving 18F-FDG-PET detection of adenomas in CD. METHODS: Subjects with a likely diagnosis of CD (n = 27, 20 females) each underwent two 18F-FDG-PET studies [without and with ovine-CRH (oCRH) stimulation] on a high-resolution PET platform. Standardized-uptake-values (SUV) in the sella were calculated. Two blinded neuroradiologists independently read 18F-FDG-PET images qualitatively. Adenomas were histopathologically confirmed, analyzed for mutations in the USP8 gene and for glycolytic pathway proteins. RESULTS: The mean-SUV of adenomas was significantly increased from baseline (3.6 ± 1.5) with oCRH administration (3.9 ± 1.7; one-tailed p = 0.003). Neuroradiologists agreed that adenomas were visible on 21 scans, not visible on 26 scans (disagreed about 7, kappa = 0.7). oCRH-stimulation led to the detection of additional adenomas (n = 6) not visible on baseline-PET study. Of the MRI-negative adenomas (n = 5), two were detected on PET imaging (one only after oCRH-stimulation). USP8 mutations or glycolytic pathway proteins were not associated with SUV in corticotropinomas. CONCLUSIONS: The results of the current study suggest that oCRH-stimulation may lead to increased 18F-FDG uptake, and increased rate of detection of corticotropinomas in CD. These results also suggest that some MRI invisible adenomas may be detectable by oCRH-stimulated FDG-PET imaging. CLINICAL TRIAL INFORMATION: 18F-FDG-PET imaging with and without CRH stimulation was performed under the clinical trial NIH ID 12-N-0007 (clinicaltrials.gov identifier NCT01459237). The transsphenoidal surgeries and post-operative care was performed under the clinical trial NIH ID 03-N-0164 (clinicaltrials.gov identifier NCT00060541).

Potential utility of FLAIR in MRI-negative Cushing's disease.

OBJECTIVE Accurate presurgical localization of microadenomas in Cushing's disease (CD) leads to improved remission rates and decreased adverse events. Volumetric gradient recalled echo (3D-GRE) MRI detects pituitary microadenomas in CD in up to 50%-80% cases as a focus of hypointensity due to delayed contrast wash-in. The authors have previously reported that postcontrast FLAIR imaging may be useful in detecting otherwise MRI-negative pituitary microadenomas as foci of hyperintensity. This reflects theoretically complementary imaging of microadenomas due to delayed contrast washout. The authors report on the diagnostic accuracy and clinical utility of FLAIR imaging in the detection of microadenomas in patients with CD. METHODS The authors prospectively analyzed imaging findings in 23 patients (24 tumors) with biochemically proven CD who underwent transsphenoidal surgery for CD. Preoperatively, the patients underwent pituitary MRI with postcontrast FLAIR and postcontrast 3D-GRE sequences. RESULTS Postcontrast FLAIR hyperintensity was detected in macroadenomas, and in 3D-GRE-positive or -negative microadenomas. Overall, 3D-GRE was superior in detecting surgically and histopathologically confirmed, location-concordant microadenomas. Of 24 pituitary adenomas, 18 (75%; sensitivity 82%, positive predictive value 95%) were found on 3D-GRE, and 13 (50% [1 was false positive]; sensitivity 55%, positive predictive value 92%) were correctly identified on FLAIR. The stand-alone specificity of 3D-GRE and FLAIR was similar (50%). These results confirm the superiority of 3D-GRE as a stand-alone imaging modality. The authors then tested the utility of FLAIR as a complementary tool to 3D-GRE imaging. All 5 patients with negative 3D-GRE MRI displayed a distinct focus of FLAIR enhancement. Four of those 5 cases (80%) had location-concordant positive histopathological results and achieved postsurgical biochemical remission. The remaining patient was not cured, because resection did not include the region of FLAIR hyperintensity. CONCLUSIONS This study suggests that delayed microadenoma contrast washout may be detected as FLAIR hyperintensity in otherwise MRI-negative CD cases. The authors propose adding postcontrast FLAIR sequences to complement 3D-GRE for surgical planning in patients with CD. Clinical trial registration no.: NIH protocol 03-N-0164, NCT00060541 (clinicaltrials.gov).

Corticotropin releasing hormone can selectively stimulate glucose uptake in corticotropinoma via glucose transporter 1.

BACKGROUND: Pre-operative detection of corticotropin (ACTH) secreting microadenomas causing Cushing's disease (CD) improves surgical outcomes. Current best magnetic resonance imaging fails to detect up to 40% of these microadenomas. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is specific, but not sensitive in detecting corticotropinomas. Theoretically, secretagogue stimulation with corticotropin releasing hormone (CRH) could improve detection of adenomas with 18F-FDG PET. Previous attempts with simultaneous CRH stimulation have failed to demonstrate increased 18F-FDG uptake in corticotropinomas. We hypothesized that CRH stimulation leads to a delayed elevation in glucose uptake in corticotropinomas. METHODS: Clinical data was analyzed for efficacy of CRH in improving 18FDG-PET detection of corticotropinomas in CD. Glucose transporter 1 (GLUT1) immunoreactivity was performed on surgical specimens. Ex-vivo, viable cells from these tumors were tested for secretagogue effects (colorimetric glucose uptake), and for fate of intracellular glucose (glycolysis stress analysis). Validation of ex-vivo findings was performed with AtT-20 cells. RESULTS: CRH increased glucose uptake in human-derived corticotroph tumor cells and AtT-20, but not in normal murine or human corticotrophs (p < 0.0001). Continuous and intermittent (1 h) CRH exposure increased glucose uptake in AtT-20 with maximal effect at 4 h (p = 0.001). Similarly, CRH and 8-Br-cAMP led to robust GLUT1 upregulation and increased membrane translocation at 2 h, while fasentin suppressed baseline (p < 0.0001) and CRH-mediated glucose uptake. Expectedly, intra-operatively collected corticotropinomas demonstrated GLUT1 overexpression. Lastly, human derived corticotroph tumor cells demonstrated increased glycolysis and low glucose oxidation. CONCLUSION: Increased and delayed CRH-mediated glucose uptake differentially occurs in adenomatous corticotrophs. Delayed secretagogue-stimulated 18F-FDG PET could improve microadenoma detection.

Histone Deacetylase Inhibitor SAHA Is a Promising Treatment of Cushing Disease.

Context: Remission failure following transsphenoidal surgery in Cushing disease (CD) from pituitary corticotroph tumors (CtTs) remains clinically challenging. Histone deacetylase inhibitors (HDACis) are antitumor drugs approved for clinical use, with the potential to affect adrenocorticotropin hormone (ACTH) hypersecretion by inhibiting pro-opiomelanocortin (POMC) transcription. Objective: Testing the efficacy of suberoylanilide hydroxamic acid (SAHA) on human and murine ACTH-secreting tumor (AtT-20) cells. Design: Cell viability, ACTH secretion (enzyme-linked immunosorbent assay), apoptosis, and gene expression profile were investigated on AtT-20 cells. In vivo efficacy was examined in an athymic nude mouse AtT-20 xenograft model. SAHA efficacy against human-derived corticotroph tumor (hCtT) (n = 8) was tested in vitro. Setting: National Institutes of Health. Intervention: SAHA (0.5 to 8 µM). Main Outcome Measures: AtT-20 and hCtT cell survival, in vitro/invivo ACTH measurements. Results: SAHA (1 µM) reduced AtT-20 viability to 75% at 24 hours, 43% at 48 hours (analysis of variance; P = 0.002). Apoptosis was confirmed with elevated BAX/Bcl2 ratio and FACS. Intriguingly, early (3-hour) significant decline (70%; P < 0.0001) of secreted ACTH and diminished POMC transcription was observed with SAHA (1 µM). Microarray analysis revealed a direct association between liver X receptor alpha (LXRα) and POMC expression. Accordingly, SAHA reduced LXRα in AtT-20 cells but not in normal murine corticotrophs. Xenografted nude-mice tumor involution (126 ± 33/160 ± 35 vs 337 ± 49 mm3; P = 0.0005) was observed with 5-day intraperitoneal SAHA, with reversal of elevated ACTH (P < 0.0001). SAHA did not affect serum ACTH in nontumor mice. Lastly, we confirmed that SAHA (1 µM/24 h) decreased hCtT survival (78.92%; P = 0.0007) and ACTH secretion (83.64%; P = 0.03). Conclusion: Our findings demonstrate SAHA's efficacy in reducing survival and ACTH secretion in AtT-20 and hCtT cells, providing a potential intervention for recurrent/unremitting CD.

Normalized Early Postoperative Cortisol and ACTH Values Predict Nonremission After Surgery for Cushing Disease.

Context: Perioperative increases in adrenocorticotropic hormone (ACTH) and cortisol mimic results of corticotropin-releasing hormone (CRH) stimulation testing. This phenomenon may help identify patients with residual adenoma after transsphenoidal surgery (TSS) for Cushing disease (CD). Objective: To predict nonremission after TSS for CD. Design: Retrospective case-control study of patients treated at a single center from December 2003 until July 2016. Early and medium-term remission were assessed at 10 days and 11 months. Patients and Setting: Two hundred and ninety-one consecutive TSS cases from 257 patients with biochemical evidence of CD seen at a clinical center. Interventions: Normalized early postoperative values (NEPVs) for cortisol and ACTH were calculated as immediate postoperative cortisol or ACTH levels minus preoperative post-CRH-stimulation test levels. Main Outcome Measures: Prediction of early nonremission was evaluated using logistic regression. Prediction of medium-term remission was assessed using Cox regression. Predictive ability was quantified by area under the receiver operating characteristic curve (AUROC). Results: NEPVs for cortisol and ACTH predicted early nonremission [adjusted odds ratio (OR): 1.1; 95% confidence interval (CI): 1.0, 1.1; P = 0.016 and adjusted OR: 1.0; 95% CI: 1.0, 1.0; P = 0.048, respectively]. AUROC for NEPV of cortisol was 0.78 (95% CI: 0.61, 0.95); for NEPV of ACTH, it was 0.80 (95% CI: 0.61, 0.98). NEPVs for cortisol and ACTH predicted medium-term nonremission [hazard ratio (HR): 1.1; 95% CI: 1.0, 1.1; P = 0.023 and HR: 1.0; 95% CI: 1.0, 1.0; P = 0.025, respectively]. Conclusions: NEPVs for cortisol and ACTH predicted nonremission after TSS for CD.