Application of transcranial transmission ultrasound in the detection of vasospasm in patients with aneurysmal subarachnoid hemorrhage: illustrative cases.

BACKGROUND: Effective management of patients with aneurysmal subarachnoid hemorrhage (aSAH) demands vigilant monitoring and treatment, given the risks of complications such as cerebral vasospasm and delayed ischemic neurological deficits (DINDs). Transcranial transmission ultrasound (TTUS) is a well-established technique for assessing brain pulsatility. This pilot study aims to explore the utility of TTUS in detecting impaired intracerebral blood flow associated with DINDs. OBSERVATIONS: The authors examined 2 male patients, ages 45 and 52 years, with aSAH Hunt and Hess grades 4 and 2, respectively, who developed DINDs during their clinical course. Simultaneous recordings of arterial blood pressure, heart rate, and TTUS measurements were obtained in the intensive care unit. TTUS analysis revealed abnormal arrhythmic wave patterns during DIND episodes, whereas baseline measurements on DIND-free days showed no abnormalities. Following endovascular spasmolysis, TTUS demonstrated a normalization of abnormal waves, returning to baseline levels, alongside the resolution of neurological symptoms. LESSONS: TTUS, a noninvasive method for assessing brain pulsatility, shows promise as a novel tool for monitoring aSAH patients, potentially aiding in prompt diagnostics and additional therapeutic interventions. Its capacity to provide further insights for individuals at risk of delayed cerebral ischemia warrants further investigation in clinical studies. https://thejns.org/doi/10.3171/CASE24146.

Transcranial Transmission Ultrasound for Reliable Noninvasive Exclusion of Intracranial Hypertension in Traumatic Brain Injury Patients: A Proof of Concept Study.

For many years, noninvasive methods to measure intracranial pressure (ICP) have been unsuccessful. However, such methods are crucial for the assessment of patients with nonpenetrating traumatic brain injuries (TBIs) who are unconscious. In this study, we explored the use of transcranial transmission ultrasound (TTUS) to gather experimental data through brain pulsatility, assessing its effectiveness in detecting high ICP using machine learning analysis. We included patients with severe TBI under invasive ICP monitoring in our intensive care unit. During periods of both normal and elevated ICP, we simultaneously recorded ICP, arterial blood pressure, heart rate, and TTUS measurements. Our classification model was based on data from 9 patients, encompassing 387 instances of elevated ICP (>15 mmHg) and 345 instances of normal ICP (<10 mmHg), and validated through a leave-one-subject-out method. The study, conducted from October 2021 to October 2022, involved 25 patients with an average age of 61.6 ± 17.6 years, producing 279 datasets with an average ICP of 11.3 mmHg (1st quartile 6.1 mmHg; 3rd quartile 14.8 mmHg). The automated TTUS analysis effectively identified ICP values over 15 mmHg with 100% sensitivity and 47% specificity. It achieved a 100% negative predictive value and a 14% positive predictive value. This suggests that TTUS can accurately rule out high ICP above 15 mmHg in TBI patients, indicating patients who may need immediate imaging or intervention. These promising results, if confirmed and expanded in larger studies, could lead to the first reliable, noninvasive screening tool for detecting elevated ICP.

PLK1 inhibitors as a new targeted treatment for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. Polo-like kinase 1 (PLK1) is a promising drug target; PLK1 inhibitors (PLK1i) have been investigated in solid cancers and are more effective in TP53-mutated cases. We evaluated PLK1 expression in ACC samples and the efficacy of two PLK1i in ACC cell lines with different genetic backgrounds. PLK1 protein expression was investigated by immunohistochemistry in tissue samples and correlated with clinical data. The efficacy of rigosertib (RGS), targeting RAS/PI3K, CDKs and PLKs, and poloxin (Pol), specifically targeting the PLK1 polo-box domain, was tested in TP53-mutated NCI-H295R, MUC-1, and CU-ACC2 cells and in TP53 wild-type CU-ACC1. Effects on proliferation, apoptosis, and viability were determined. PLK1 immunostaining was stronger in TP53-mutated ACC samples vs wild-type (P = 0.0017). High PLK1 expression together with TP53 mutations correlated with shorter progression-free survival (P= 0.041). NCI-H295R showed a time- and dose-dependent reduction in proliferation with both PLK1i (P< 0.05at 100 nM RGS and 30 µM Pol). In MUC-1, a less pronounced decrease was observed (P< 0.05at 1000 nM RGS and 100 µM Pol). 100 nM RGS increased apoptosis in NCI-H295R (P< 0.001), with no effect on MUC-1. CU-ACC2 apoptosis was induced only at high concentrations (P < 0.05 at 3000 nM RGS and 100 µM Pol), while proliferation decreased at 1000 nM RGS and 30 µM Pol. CU-ACC1 proliferation reduced, and apoptosis increased, only at 100 µM Pol. TP53-mutated ACC cell lines demonstrated better response to PLK1i than wild-type CU-ACC1. These data suggest PLK1i may be a promising targeted treatment of a subset of ACC patients, pre-selected according to tumour genetic signature.

Improving tractography in brainstem cavernoma patients by distortion correction.

Introduction: The resection of brainstem cerebral cavernous malformations (CCM) harbors the risk of damaging the corticospinal tract (CST) and other major tracts. Hence, visualization of eloquent fiber tracts supports pre- and intraoperative planning. However, diffusion tensor imaging fiber tracking at brainstem level suffers from distortion due to field inhomogeneities and eddy currents by steep diffusion gradients. Research question: This study aims to analyze the effect of distortion correction for CST tractography in brainstem CCM patients. Material and methods: 25 patients who underwent resection of brainstem CCM were enrolled, 24 suffered from hemorrhage. We performed an anatomically based tractography of the CST with a mean minimal fractional anisotropy of 0.22 ± 0.04 before and after cranial distortion correction (CDC). Accuracy was measured by anatomical plausibility and aberrant fibers. Results: CDC led to a more precise CST tractography, further approximating its assumed anatomical localization in all cases. CDC resulted in a significantly more ventral location of the CST of 1.5 ± 0.6 mm (6.1 ± 2.7 mm before CDC vs. 4.6 ± 2.1 mm after CDC; p < .0001) as measured by the distance to the basilar artery and of 1.7 ± 0.6 mm (8.9 ± 2.7 mm vs. 7.2 ± 2.1 mm; p < .0001) in relation to the clivus. Aberrant fibers were reduced by CDC in 44% of cases. We found a mean difference in CST volume of 0.6 ± 0.8 ccm. We could not detect motor deficits after resection of irregular fibers. Discussion and conclusion: CDC effectively corrects tractography for distortion at brainstem level, especially in patients suffering from brainstem CCM, further approximating its actual anatomical localization.

Spinal Navigation for Lateral Instrumentation of the Thoracolumbar Spine.

BACKGROUND AND OBJECTIVES: Three-dimensional imaging-based navigation in spine surgery is mostly applied for pedicle screw placement. However, its potential reaches beyond. In this study, we analyzed the incorporation of spinal navigation for lateral instrumentation of the thoracolumbar spine in clinical routine at a high-volume spine center. METHODS: Patients scheduled for lateral instrumentation were prospectively enrolled. A reference array was attached to the pelvis, and a computed tomography scan was acquired intraoperatively. A control computed tomography scan was routinely performed after final cage placement, replacing conventional 2-dimensional X-ray imaging. RESULTS: 145 cases were enrolled from April to October 2021 with a median of 1 (1-4) level being instrumented. Indications for surgery were trauma (35.9%), spinal infection (31.7%), primary and secondary tumors of the spine (17.2%), and degenerative spine disease (15.2%). The duration of surgery after the first scan was 98 ± 41 (20-342) minutes. In total, 190 cages were implanted (94 expandable cages for vertebral body replacement (49.5%) and 96 cages for interbody fusion [50.5%]). Navigation was successfully performed in 139 cases (95.9%). The intraoperative mental load was rated on a scale from 0 to 150 (maximal effort) by the surgeons, showing a moderate effort (median 30 [10-120]). CONCLUSION: Three-dimensional imaging-based spinal navigation can easily be incorporated in clinical routine and serves as a reliable tool to achieve precise implant placement in lateral instrumentation of the spine. It helps to minimize radiation exposure to the surgical staff.

The one-stop-shop approach: Navigating lumbar 360-degree instrumentation in a single position.

Objective: Treatment strategies of patients suffering from pyogenic spondylodiscitis are a controverse topic. Percutaneous dorsal instrumentation followed by surgical debridement and fusion of the infectious vertebral disc spaces is a common approach for surgical treatment. Technical advances enable spinal navigation for dorsal and lateral instrumentation. This report investigates combined navigated dorsal and lateral instrumentation in a single surgery and positioning for lumbar spondylodiscitis in a pilot series. Methods: Patients diagnosed with 1- or 2-level discitis were prospectively enrolled. To enable posterior navigated pedicle screw placement and lateral interbody fusion (LLIF) patients were positioned semi-prone in 45-degree fashion. For spinal referencing, a registration array was attached to the pelvic or spinal process. 3D scans were acquired intraoperatively for registration and implant control. Results: 27 patients suffering from 1- or 2-level spondylodiscitis with a median ASA of 3 (1-4) and a mean BMI of 27.9 ± 4.9 kg/m2 were included. Mean duration of surgery was 146 ± 49 min. Mean blood loss was 367 ± 307 ml. A median of 4 (4-8) pedicle screws were placed for dorsal percutaneous instrumentation with an intraoperative revision rate of 4.0%. LLIF was performed on 31 levels with an intraoperative cage revision rate of 9.7%. Conclusions: Navigated lumbar dorsal and lateral instrumentation in a single operation and positioning is feasible and safe. It enables rapid 360-degree instrumentation in these critically ill patients and potentially reduces overall intraoperative radiation exposure for patient and staff. Compared to purely dorsal approaches it allows for optimal discectomy and fusion while overall incisions and wound size are minimized. Compared to prone LLIF procedures, semi-prone in 45-degree positioning allows for a steep learning curve due to minor changes of familiar anatomy.

Targeted Gene Expression Profile Reveals CDK4 as Therapeutic Target for Selected Patients With Adrenocortical Carcinoma.

Adrenocortical carcinomas (ACC) are aggressive tumors with a heterogeneous prognosis and limited therapeutic options for advanced stages. This study aims to identify novel drug targets for a personalized treatment in ACC. RNA was isolated from 40 formalin-fixed paraffin-embedded ACC samples. We evaluated gene expression of 84 known cancer drug targets by reverse transcriptase quantitative real time-PCR and calculated fold change using 5 normal adrenal glands as reference (overexpression by fold change >2.0). The most promising candidate cyclin-dependent kinase 4 (CDK4) was investigated at protein level in 104 ACC samples and tested by in vitro experiments in two ACC cell lines (NCI-H295R and MUC1). The most frequently overexpressed genes were TOP2A (100% of cases, median fold change = 16.5), IGF2 (95%, fold change = 52.9), CDK1 (80%, fold change = 6.7), CDK4 (62%, fold change = 2.6), PLK4 (60%, fold change = 2.8), and PLK1 (52%, fold change = 2.3). CDK4 was chosen for functional validation, as it is actionable by approved CDK4/6-inhibitors (e.g., palbociclib). Nuclear immunostaining of CDK4 significantly correlated with mRNA expression (R = 0.52, P < 0.005). We exposed both NCI-H295R and MUC1 cell lines to palbociclib and found a concentration- and time-dependent reduction of cell viability, which was more pronounced in the NCI-H295R cells in line with higher CDK4 expression. Furthermore, we tested palbociclib in combination with insulin-like growth factor 1/insulin receptor inhibitor linsitinib showing an additive effect. In conclusion, we demonstrate that RNA profiling is useful to discover potential drug targets and that CDK4/6 inhibitors are promising candidates for treatment of selected patients with ACC.

Targeted Molecular Analysis in Adrenocortical Carcinomas: A Strategy Toward Improved Personalized Prognostication.

Context: Adrenocortical carcinoma (ACC) has a heterogeneous prognosis, and current medical therapies have limited efficacy in its advanced stages. Genome-wide multiomics studies identified molecular patterns associated with clinical outcome. Objective: Here, we aimed at identifying a molecular signature useful for both personalized prognostic stratification and druggable targets, using methods applicable in clinical routine. Design: In total, 117 tumor samples from 107 patients with ACC were analyzed. Targeted next-generation sequencing of 160 genes and pyrosequencing of 4 genes were applied to formalin-fixed, paraffin-embedded (FFPE) specimens to detect point mutations, copy number alterations, and promoter region methylation. Molecular results were combined with clinical/histopathological parameters (tumor stage, age, symptoms, resection status, and Ki-67) to predict progression-free survival (PFS). Results: In addition to known driver mutations, we detected recurrent alterations in genes not previously associated with ACC (e.g., NOTCH1, CIC, KDM6A, BRCA1, BRCA2). Best prediction of PFS was obtained integrating molecular results (more than one somatic mutation, alterations in Wnt/ß-catenin and p53 pathways, high methylation pattern) and clinical/histopathological parameters into a combined score (P < 0.0001, χ2 = 68.6). Accuracy of prediction for early disease progress was 83.3% (area under the receiver operating characteristic curve: 0.872, 95% confidence interval 0.80 to 0.94). Furthermore, 17 potentially targetable alterations were found in 64 patients (e.g., in CDK4, NOTCH1, NF1, MDM2, and EGFR and in DNA repair system). Conclusions: This study demonstrates that molecular profiling of FFPE tumor samples improves prognostication of ACC beyond clinical/histopathological parameters and identifies new potential drug targets. These findings pave the way to precision medicine in this rare disease.