Development of a Triple-Negative Breast Cancer Leptomeningeal Disease Model in Zebrafish.

Leptomeningeal disease occurs when cancer cells migrate into the ventricles of the brain and spinal cord and then colonize the meninges of the central nervous system. The triple-negative subtype of breast cancer often progresses toward leptomeningeal disease and has a poor prognosis because of limited treatment options. This is due, in part, to a lack of animal models with which to study leptomeningeal disease. Here, we developed a translucent zebrafish casper (roy-/-; nacre-/-) xenograft model of leptomeningeal disease in which fluorescent labeled MDA-MB-231 human triple-negative breast cancer cells are microinjected into the ventricles of zebrafish embryos and then tracked and measured using fluorescent microscopy and multimodal plate reader technology. We then used these techniques to measure tumor area, cell proliferation, and cell death in samples treated with the breast cancer drug doxorubicin and a vehicle control. We monitored MDA-MB-231 cell localization and tumor area, and showed that samples treated with doxorubicin exhibited decreased tumor area and proliferation and increased apoptosis compared to control samples.

Case report: Side-firing intraoperative ultrasound guided endoscopic endonasal resection of a clival chordoma.

Clival chordomas are locally invasive midline skull base tumors arising from remnants of the primitive notochord. Intracranial vasculature and cranial nerve involvement of tumors in the paraclival region necessitates image guidance that provides accurate real-time feedback during resection. Several intraoperative image guidance modalities have been introduced as adjuncts to endoscopic endonasal surgery, including stereotactic neuronavigation, intraoperative ultrasound, intraoperative MRI, and intraoperative CT. Gross total resection of chordomas is associated with a lower recurrence rate; therefore, intraoperative imaging may improve long-term outcomes by enhancing the extent of resection. However, among these options, effectiveness and accessibility vary between institutions. We previously published the first use of an end-firing probe in the resection of a clival chordoma. End-firing probes provide a single field of view, primarily limited to depth estimation. In this case report, we discuss the benefits of employing a novel minimally invasive side-firing ultrasound probe as a cost-effective and time-efficient option to navigate the anatomy of the paraclival region and guide endoscopic endonasal resection of a large complex clival chordoma.

Intraoperative Predictor of Remission in Cushing Disease.

BACKGROUND: Cushing disease represents a challenge for neurosurgeons, with high recurrence rates reported. Characteristics associated with remission are incompletely understood; thus, an intraoperative predictor for outcome would be valuable for assessing resection of adrenocorticotropic hormone (ACTH) secreting tissue. OBJECTIVE: To evaluate whether intraoperative ACTH measurement could predict outcome after surgery for Cushing disease. METHODS: Retrospective cohort study of 55 consecutive encounters with Cushing disease who had peripheral plasma ACTH levels measured intraoperatively before, during, and after tumor resection. The primary outcome measure was remission, defined by either 2 negative 24-hour urine free cortisol or 2 negative midnight salivary cortisol measurements. A logistic regression machine learning model was generated using recursive feature elimination. RESULTS: Fifty-five operative encounters, comprising 49 unique patients, had a mean follow-up of 2.73 years (±2.11 years) and a median follow-up of 2.07 years. Remission was achieved in 69.1% (n = 38) of all operations and in 78.0% (n = 32) of those without cavernous sinus invasion. The final ACTH level measured intraoperatively correctly predicted outcome (area under the curve = 0.766; P value = .002). The odds ratio of remission in patients with the lowest quartile vs highest quartile final intraoperative ACTH was 23.4 ( P value = .002). Logistic regression machine learning model resulted in incorporating postoperative day 1 morning cortisol, final intraoperative ACTH that predicted outcome with an average area under the curve of 0.80 ( P = .0027). CONCLUSION: Intraoperative ACTH may predict outcome after surgery in Cushing disease; furthermore, investigation is warranted.

Intraoperative Prediction of Long-Term Remission in Acromegaly.

BACKGROUND: The features of long-term remission in acromegaly adenomectomy are incompletely understood. An intraoperative predictor for long-term outcome would be valuable for assessing resection of growth hormone (GH)-secreting tumors in real-time. OBJECTIVE: To evaluate whether intraoperative GH measurement could predict long-term outcomes for acromegaly. METHODS: In 47 patients, peripheral blood GH levels were measured thrice intraoperatively: once before tumor dissection, once during tumor dissection, and once after tumor dissection. Long-term remission was defined by age-appropriate, normalized insulin-like growth factor-1 at most recent follow-up and a random GH less than 1.0 ng/mL. Patients were only considered to be in long-term remission without the use of postoperative medical therapy for acromegaly or radiation therapy. RESULTS: The median length of follow-up was 4.51 (range: 0.78-9.80) years. Long-term remission was achieved in 61.7% (29/47) of operations. Like previous studies, cavernous sinus invasion (odds ratio [OR]: 0.060; 95% CI: 0.014-0.260; P value < .01), suprasellar extension (OR: 0.191; 95% CI: 0.053-0.681; P value<.01), and tumor size greater than 1 cm (OR: 0.177; 95% CI: 0.003-0.917; P value = .03) were associated with not being in long-term remission. The minimum GH measured intraoperatively predicted long-term outcome (area under the curve: 0.7107; 95% CI: 0.537-0.884; P value < .01). The odds ratio of remission in patients with the lowest quartile minimum intraoperative GH compared with patients with the highest quartile minimum intraoperative GH was 27.0 (95% CI: 2.343-311.171; P value < .01). CONCLUSION: Minimum intraoperative GH may predict long-term outcome for acromegaly, which in principle could provide the pituitary neurosurgeon with real-time feedback and inform intraoperative decision making.

Side-firing intraoperative ultrasound applied to resection of pituitary macroadenomas and giant adenomas: A single-center retrospective case-control study.

Introduction: Multiple intraoperative navigation and imaging modalities are currently available as an adjunct to endoscopic transsphenoidal resection of pituitary adenomas, including intraoperative CT and MRI, fluorescence guidance, and neuronavigation. However, these imaging techniques have several limitations, including intraoperative tissue shift, lack of availability in some centers, and the increased cost and time associated with their use. The side-firing intraoperative ultrasound (IOUS) probe is a relatively new technology in endoscopic endonasal surgery that may help overcome these obstacles. Methods: A retrospective analysis was performed on patients admitted for resection of pituitary adenomas by a single surgeon at the University of Mississippi Medical Center. The control (non-ultrasound) group consisted of twelve (n=12) patients who received surgery without IOUS guidance, and the IOUS group was composed of fifteen (n=15) patients who underwent IOUS-guided surgery. Outcome measures used to assess the side-firing IOUS were the extent of tumor resection, postoperative complications, length of hospital stay (LOS) in days, operative time, and self-reported surgeon confidence in estimating the extent of resection intraoperatively. Results: Preoperative data analysis showed no significant differences in patient demographics or presenting symptoms between the two groups. Postoperative data revealed no significant difference in the rate of gross total resection between the groups (p = 0.716). Compared to the non-US group, surgeon confidence was significantly higher (p < 0.001), and operative time was significantly lower for the US group in univariate analysis (p = 0.011). Multivariate analysis accounting for tumor size, surgeon confidence, and operative time confirmed these findings. Interestingly, we noted a trend for a lower incidence of postoperative diabetes insipidus in the US group, although this did not quite reach our threshold for statistical significance. Conclusion: Incorporating IOUS as an aid for endonasal resection of pituitary adenomas provides real-time image guidance that increases surgeon confidence in intraoperative assessment of the extent of resection and decreases operative time without posing additional risk to the patient. Additionally, we identified a trend for reduced diabetes insipidus with IOUS.

Coronavirus Disease 2019 and Pituitary Apoplexy: A Single-Center Case Series and Review of the Literature.

BACKGROUND: Pituitary apoplexy (PA) is a rare, but life-threatening, condition characterized by pituitary infarction and hemorrhage, most often in the setting of a preexisting adenoma. The risk factors and mechanisms associated with PA are poorly understood. Although neurovascular manifestations of coronavirus disease 2019 (COVID-19) infection have been documented, its association with PA has not yet been determined. METHODS: From a prospectively collected database of patients treated at a tertiary care center for pituitary adenoma, we conducted a retrospective medical record review of PA cases during the COVID-19 pandemic from March 2020 to December 2020. We also conducted a literature review to identify other reported cases. RESULTS: We identified 3 consecutive cases of PA and concomitant COVID-19 infection. The most common symptoms at presentation were headache and vision changes. The included patients were successfully treated with surgical decompression and medical management of the associated endocrinopathy, ultimately experiencing improvement in their visual symptoms at the latest follow-up examination. COVID-19 infection in the perioperative period was corroborated by polymerase chain reaction test results in all the patients. CONCLUSIONS: With the addition of our series to the literature, 10 cases of PA in the setting of COVID-19 infection have been confirmed. The present series was limited in its ability to draw conclusions about the relationship between these 2 entities. However, COVID-19 infection might represent a risk factor for the development of PA. Further studies are required.

Suction mask device: a simple, inexpensive, and effective method of reducing spread of aerosolized particles during endoscopic endonasal surgery in the era of COVID-19.

OBJECTIVE: Aerosol-generating procedures, including endoscopic endonasal surgery (EES), are a major risk for physicians during the COVID-19 pandemic. Techniques for reducing aerosolization and risk of transmission of COVID-19 during these procedures would be valuable to the neurosurgical community. The authors aimed to simulate the generation of small-particle aerosols during EES and craniectomy in order to develop methods to reduce the spread of aerosolized particles, and to test the effectiveness of these methods. METHODS: This study was performed at the Anatomical Laboratory for Visuospatial Innovations in Otolaryngology and Neurosurgery at The Ohio State University. The following two scenarios were used to measure three different particle sizes (0.3, 2.5, and 10 µm) generated: 1) drilling frontotemporal bone, simulating a craniectomy; and 2) drilling sphenoid bone, simulating an endonasal approach. A suction mask device was created with the aim of reducing particle release. The presence of particles was measured without suction, with a single Frazier tip suction in the field, and with the suction mask device in addition to the Frazier suction tip. Particles were measured 12 cm from the craniectomy or endonasal drilling region. RESULTS: In the absence of any aerosol-reducing devices, the number of particles measured during craniectomy was significantly higher than that generated by endonasal drilling. This was true regardless of the particle size measured (0.3 µm, p < 0.001; 2.5 µm, p < 0.001; and 10 µm, p < 0.001). The suction mask device reduced the release of particles of all sizes measured in the craniectomy simulation (0.3 µm, p < 0.001; 2.5 µm, p < 0.001; and 10 µm, p < 0.001) and particles of 0.3 µm and 2.5 µm in the single Frazier suction simulation (0.3 µm, p = 0.031; and 2.5 µm, p = 0.026). The suction mask device further reduced the release of particles of all sizes during EES simulation (0.3 µm, p < 0.001; and 2.5 µm, p < 0.001) and particles of 0.3 µm and 2.5 µm in the single Frazier suction simulation (0.3 µm, p = 0.033; and 2.5 µm, p = 0.048). Large particles (10 µm) were not detected during EES. CONCLUSIONS: The suction mask device is a simple and effective means of reducing aerosol release during EES, and it could potentially be used during mastoidectomies. This could be a valuable tool to reduce the risk of procedure-associated viral transmission during the COVID-19 pandemic.

Predicting Discharge Disposition Following Meningioma Resection Using a Multi-Institutional Natural Language Processing Model.

BACKGROUND: Machine learning (ML)-based predictive models are increasingly common in neurosurgery, but typically require large databases of discrete variables for training. Natural language processing (NLP) can extract meaningful data from unstructured text. OBJECTIVE: To present an NLP model that predicts nonhome discharge and a point-of-care implementation. METHODS: We retrospectively collected age, preoperative notes, and radiology reports from 595 adults who underwent meningioma resection in an academic center from 1995 to 2015. A total of 32 algorithms were trained with the data; the 3 best performing algorithms were combined to form an ensemble. Predictive ability, assessed by area under the receiver operating characteristic curve (AUC) and calibration, was compared to a previously published model utilizing 52 neurosurgeon-selected variables. We then built a multi-institutional model by incorporating notes from 693 patients at another center into algorithm training. Permutation importance was used to analyze the relative importance of each input to model performance. Word clouds and non-negative matrix factorization were used to analyze predictive features of text. RESULTS: The single-institution NLP model predicted nonhome discharge with AUC of 0.80 (95% CI = 0.74-0.86) on internal and 0.76 on holdout validation compared to AUC of 0.77 (95% CI = 0.73-0.81) and 0.74 for the 52-variable ensemble. The multi-institutional model performed similarly well with AUC = 0.78 (95% CI = 0.74-0.81) on internal and 0.76 on holdout validation. Preoperative notes most influenced predictions. The model is available at http://nlp-home.insds.org. CONCLUSION: ML and NLP are underutilized in neurosurgery. Here, we construct a multi-institutional NLP model that predicts nonhome discharge.

HIF1A signaling selectively supports proliferation of breast cancer in the brain.

Blood-borne metastasis to the brain is a major complication of breast cancer, but cellular pathways that enable cancer cells to selectively grow in the brain microenvironment are poorly understood. We find that cultured circulating tumor cells (CTCs), derived from blood samples of women with advanced breast cancer and directly inoculated into the mouse frontal lobe, exhibit striking differences in proliferative potential in the brain. Derivative cell lines generated by serial intracranial injections acquire selectively increased proliferative competency in the brain, with reduced orthotopic tumor growth. Increased Hypoxia Inducible Factor 1A (HIF1A)-associated signaling correlates with enhanced proliferation in the brain, and shRNA-mediated suppression of HIF1A or drug inhibition of HIF-associated glycolytic pathways selectively impairs brain tumor growth while minimally impacting mammary tumor growth. In clinical specimens, brain metastases have elevated HIF1A protein expression, compared with matched primary breast tumors, and in patients with brain metastases, hypoxic signaling within CTCs predicts decreased overall survival. The selective activation of hypoxic signaling by metastatic breast cancer in the brain may have therapeutic implications.

Quantitative Anatomic Study of the Minipterional Craniotomy in the Paraclinoid Region: Benefits of Extradural Anterior Clinoidectomy.

BACKGROUND: Extradural anterior clinoidectomy (eAC) via the minipterional craniotomy (MPT) approach (MPT+eAC) has been recently introduced to the neurosurgical armamentarium to improve access to anterior and middle fossa skull base structures using a minimally invasive approach. However, the effect of extradural clinoidectomy on surgical exposure with the minipterional approach has not been evaluated. Moreover, the effect of eAC on surgical maneuverability has not been established for either traditional pterional or minipterional craniotomy. We sought to illustrate the microsurgical anatomy of the MPT+eAC and to evaluate the effect of eAC on surgical exposure and maneuverability. METHODS: The area of exposure, area of surgical freedom, and maneuverability score for the MPT approach and MPT+eAC were compared in 5 cadaveric heads. RESULTS: Compared with the MPT approach, the MPT+eAC enlarged the area of exposure approximately twofold (93 cm2 vs. 184 cm2; P < 0.001). All targets considered in the paraclinoid region, including the posterior communicating artery origin, prechiasmatic region, and ophthalmic artery origin, showed an increase in surgical freedom and maneuverability after performing eAC. Targets remote from the clinoid such as the internal carotid bifurcation were not affected. CONCLUSIONS: MPT+eAC offers a larger area of exposure and greater surgical freedom and maneuverability at the paraclinoid region using this minimally invasive approach.

Blood-based biomarkers for the diagnosis and monitoring of gliomas.

Monitoring patient response to treatment is challenging for most cancers, but it is particularly difficult in glioblastoma multiform, the most common and aggressive form of malignant brain tumor. These tumors exhibit a high degree of heterogeneity which may not be reflected in a biopsy. To determine if the current standard of care is effective, glioma patients are monitored using MRI or CT scans, an effective but sometimes misleading approach due to the phenomenon of pseudoprogression. As such, there is incredible need for a minimally invasive "liquid biopsy" to assist in molecularly characterizing the tumors while also aiding in the identification of true progression in glioblastoma. This review details the status and potential impact for circulating tumor cells, extracellular vesicles, ctDNA, and ctRNA, putative circulating biomarkers found in the blood in glioblastoma patients. As mutation-based therapy becomes more prevalent in gliomas, blood-based analyses may offer a non-invasive method of identifying mutations. The ability to obtain serial "liquid biopsies" will provide unique opportunities to study the evolution of tumors and mechanisms of treatment resistance and monitor for mutational changes in response to therapy.

Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction.

T cell egress from the thymus is essential for adaptive immunity, yet the requirements for and sites of egress are incompletely understood. We have shown that transgenic expression of sphingosine-1-phosphate receptor-1 (S1P1) in immature thymocytes leads to their perivascular accumulation and premature release into circulation. Using an intravascular procedure to label emigrating cells, we found that mature thymocytes exit via blood vessels at the corticomedullary junction. By deleting sphingosine kinases in neural crest-derived pericytes, we provide evidence that these specialized vessel-ensheathing cells contribute to the S1P that promotes thymic egress. Lymphatic endothelial cell-derived S1P was not required. These studies identify the major thymic egress route and suggest a role for pericytes in promoting reverse transmigration of cells across blood vessel endothelium.

Thymic egress: S1P of 1000.

Recent studies have begun to illuminate the mechanism of T-cell export from the thymus, with the identification of a required lysophospholipid receptor, two upstream transcription factors, and several downstream regulators of cytoskeleton dynamics. This work has generated immediate translational impact, aiding the design of immunosuppressant drugs and the identification of a novel form of human immunodeficiency.

Follicular shuttling of marginal zone B cells facilitates antigen transport.

The splenic marginal zone is a site of blood flow, and the specialized B cell population that inhabits this compartment has been linked to the capture and follicular delivery of blood-borne antigens. However, the mechanism of this antigen transport has remained unknown. Here we show that marginal zone B cells were not confined to the marginal zone but continuously shuttled between the marginal zone and follicular areas, such that many of the cells visited a follicle every few hours. Migration to the follicle required the chemokine receptor CXCR5, whereas return to the marginal zone was promoted by the sphingosine 1-phosphate receptors S1P1 and S1P3. Treatment with an S1P1 antagonist caused displacement of marginal zone B cells from the marginal zone. Marginal zone-follicle shuttling of marginal zone B cells provides an efficient mechanism for systemic antigen capture and delivery to follicular dendritic cells.

Identification of Aedes albopictus in urban Nicaragua.

Larvae of Aedes albopictus, a mosquito known for transmitting dengue virus, were identified in the city of León, Nicaragua, in 2003. Mosquito larvae were collected from a total of 2,225 residences in the 2 largest cities in Nicaragua during the period from June to September of 2003, and larval Ae. albopictus were identified in 4 homes in León. This represents the 1st detection of Ae. albopictus in a major Nicaraguan urban center, and increased control efforts appear to have eliminated the mosquito subsequently from León. The presence of Ae. albopictus in urban Nicaragua highlights the need for surveillance of areas thought to be free of the mosquito so that early detection and control activities can prevent its spread.

A generalized affine gap model significantly improves protein sequence alignment accuracy.

Sequence alignment underpins common tasks in molecular biology, including genome annotation, molecular phylogenetics, and homology modeling. Fundamental to sequence alignment is the placement of gaps, which represent character insertions or deletions. We assessed the ability of a generalized affine gap cost model to reliably detect remote protein homology and to produce high-quality alignments. Generalized affine gap alignment with optimal gap parameters performed as well as the traditional affine gap model in remote homology detection. Evaluation of alignment quality showed that the generalized affine model aligns fewer residue pairs than the traditional affine model but achieves significantly higher per-residue accuracy. We conclude that generalized affine gap costs should be used when alignment accuracy carries more importance than aligned sequence length.