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Provision of rapid and specific ex vivo diagnosis of central nervous system lymphoma from rodent xenograft biopsies by a fluorescent aptamer

Joseph Georges, Xiaodong Qi, Xiaowei Liu, Yu Zhou, Eric C. Woolf, Amber Valeri, Zein Al-Atrache, Evgenii Belykh, Burt G. Feuerstein, Mark Preul, Adrienne C. Scheck, Mark Reiser, Trent Anderson, Jonas Gopez, Denah Appelt, Steven Yocom, Jennifer Eschbacher, Hao Yan, and Peter Nakaji

OBJECTIVE

Differentiating central nervous system (CNS) lymphoma from other intracranial malignancies remains a clinical challenge in surgical neuro-oncology. Advances in clinical fluorescence imaging contrast agents and devices may mitigate this challenge. Aptamers are a class of nanomolecules engineered to bind cellular targets with antibody-like specificity in a fraction of the staining time. Here, the authors determine if immediate ex vivo fluorescence imaging with a lymphoma-specific aptamer can rapidly and specifically diagnose xenografted orthotopic human CNS lymphoma at the time of biopsy.

METHODS

The authors synthesized a fluorescent CNS lymphoma-specific aptamer by conjugating a lymphoma-specific aptamer with Alexa Fluor 488 (TD05-488). They modified human U251 glioma cells and Ramos lymphoma cells with a lentivirus for constitutive expression of red fluorescent protein and implanted them intracranially into athymic nude mice. Three to 4 weeks postimplantation, acute slices (biopsies, n = 28) from the xenografts were collected, placed in aptamer solution, and imaged with a Zeiss fluorescence microscope. Three aptamer staining concentrations (0.3, 1.0, and 3.0 μM) and three staining times (5, 10, and 20 minutes) followed by a 1-minute wash were tested. A file of randomly selected images was distributed to neurosurgeons and neuropathologists, and their ability to distinguish CNS lymphoma from negative controls was assessed.

RESULTS

The three staining times and concentrations of TD05-488 were tested to determine the diagnostic accuracy of CNS lymphoma within a frozen section time frame. An 11-minute staining protocol with 1.0-μM TD05-488 was most efficient, labeling 77% of positive control lymphoma cells and less than 1% of negative control glioma cells (p < 0.001). This protocol permitted clinicians to positively identify all positive control lymphoma images without misdiagnosing negative control images from astrocytoma and normal brain.

CONCLUSIONS

Ex vivo fluorescence imaging is an emerging technique for generating rapid histopathological diagnoses. Ex vivo imaging with a novel aptamer-based fluorescent nanomolecule could provide an intraoperative tumor-specific diagnosis of CNS lymphoma within 11 minutes of biopsy. Neurosurgeons and neuropathologists interpreted images generated with this molecular probe with high sensitivity and specificity. Clinical application of TD05-488 may permit specific intraoperative diagnosis of CNS lymphoma in a fraction of the time required for antibody staining.

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Influence of cross-linked hyaluronic acid hydrogels on neurite outgrowth and recovery from spinal cord injury

Eric M. Horn, Michael Beaumont, Xiao Zheng Shu, Adrian Harvey, Glenn D. Prestwich, Kris M. Horn, Alan R. Gibson, Mark C. Preul, and Alyssa Panitch

Object

Therapies that use bioactive materials as replacement extracellular matrices may hold the potential to mitigate the inhibition of regeneration observed after central nervous system trauma. Hyaluronic acid (HA), a nonsulfated glycosaminoglycan ubiquitous in all tissues, was investigated as a potential neural tissue engineering matrix.

Methods

Chick dorsal root ganglia were cultured in 3D hydrogel matrices composed of cross-linked thiol-modified HA or fibrin. Samples were cultured and images were acquired at 48-, 60-, and 192-hour time points. Images of all samples were analyzed at 48 hours of incubation to quantify the extent of neurite growth. Cultures in cross-linked thiolated HA exhibited more than a 50% increase in neurite length compared with fibrin samples. Furthermore, cross-linked thiolated HA supported neurites for the entire duration of the culture period, whereas fibrin cultures exhibited collapsed and degenerating extensions beyond 60 hours.

Two concentrations of the thiolated HA (0.5 and 1%) were then placed at the site of a complete thoracic spinal cord transection in rats. The ability of the polymer to promote regeneration was tested using motor evoked potentials, retrograde axonal labeling, and behavioral assessments. There were no differences in any of the parameters between rats treated with the polymer and controls.

Conclusions

The use of a cross-linked HA scaffold promoted robust neurite outgrowth. Although there was no benefit from the polymer in a rodent spinal cord injury model, the findings in this study represent an early step in the development of semisynthetic extracellular matrice scaffolds for the treatment of neuronal injury.

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Contralateral anterior interhemispheric-transcallosal-transrostral approach to the subcallosal region: a novel surgical technique

Feres Chaddad-Neto, Marcos Devanir Silva da Costa, Baran Bozkurt, Hugo Leonardo Doria-Netto, Daniel de Araujo Paz, Ricardo da Silva Centeno, Andrew W. Grande, Sergio Cavalheiro, Kaan Yağmurlu, Robert F. Spetzler, and Mark C. Preul

OBJECTIVE

The authors report a novel surgical route from a superior anatomical aspect—the contralateral anterior interhemispheric-transcallosal-transrostral approach—to a lesion located in the subcallosal region. The neurosurgical approach to the subcallosal region is challenging due to its deep location and close relationship with important vascular structures. Anterior and inferior routes to the subcallosal region have been described but risk damaging the branches of the anterior cerebral artery.

METHODS

Three formalin-fixed and silicone-injected adult cadaveric heads were studied to demonstrate the relationships between the transventricular surgical approach and the subcallosal region. The surgical, clinical, and radiological history of a 39-year-old man with a subcallosal cavernous malformation was retrospectively used to document the neurological examination and radiographic parameters of such a case.

RESULTS

The contralateral anterior interhemispheric-transcallosal-transrostral approach provides access to the subcallosal area that also includes the inferior portion of the pericallosal cistern, lamina terminalis cistern, the paraterminal and paraolfactory gyri, and the anterior surface of the optic chiasm. The approach avoids the neurocritical perforating branches of the anterior communicating artery.

CONCLUSIONS

The contralateral anterior interhemispheric-transcallosal-transrostral approach may be an alternative route to subcallosal area lesions, with less risk to the branches of the anterior cerebral artery, particularly the anterior communicating artery perforators.

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Immediate ex-vivo diagnosis of pituitary adenomas using confocal reflectance microscopy: a proof-of-principle study

Michael A. Mooney, Joseph Georges, Mohammedhassan Izady Yazdanabadi, Katherine Y. Goehring, William L. White, Andrew S. Little, Mark C. Preul, Stephen W. Coons, Peter Nakaji, and Jennifer M. Eschbacher

OBJECTIVE

The objective of this study was to evaluate the feasibility of using confocal reflectance microscopy (CRM) ex vivo to differentiate adenoma from normal pituitary gland in surgical biopsy specimens. CRM allows for rapid, label-free evaluation of biopsy specimens with cellular resolution while avoiding some limitations of frozen section analysis.

METHODS

Biopsy specimens from 11 patients with suspected pituitary adenomas were transported directly to the pathology department. Samples were immediately positioned and visualized with CRM using a confocal microscope located in the same area of the pathology department where frozen sections are prepared. An H & E–stained slide was subsequently prepared from imaged tissue. A neuropathologist compared the histopathological characteristics of the H & E–stained slide and the matched CRM images. A second neuropathologist reviewed images in a blinded fashion and assigned diagnoses of adenoma or normal gland.

RESULTS

For all specimens, CRM contrasted cellularity, tissue architecture, nuclear pleomorphism, vascularity, and stroma. Pituitary adenomas demonstrated sheets and large lobules of cells, similar to the matched H & E–stained slides. CRM images of normal tissue showed scattered small lobules of pituitary epithelial cells, consistent with matched H & E–stained images of normal gland. Blinded review by a neuropathologist confirmed the diagnosis in 15 (94%) of 16 images of adenoma versus normal gland.

CONCLUSIONS

CRM is a simple, reliable approach for rapidly evaluating pituitary adenoma specimens ex vivo. This technique can be used to accurately differentiate between pituitary adenoma and normal gland while preserving biopsy tissue for future permanent analysis, immunohistochemical studies, and molecular studies.

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Travels to the tropics: Deutschtum and Fedor Krause’s visits to Brazil

Eberval Gadelha Figueiredo, Saul Almeida da Silva, Manoel Jacobsen Teixeira, Evgenii Belykh, Alessandro Carotenuto, Leandro Borba Moreira, Robert F. Spetzler, T. Forcht Dagi, and Mark C. Preul

Fedor Krause, the father of German neurosurgery, traveled to Latin America twice in the final years of his career (in 1920 and 1922). The associations and motivations for his travels to South America and his work there have not been well chronicled. In this paper, based on a review of historical official documents and publications, the authors describe Krause’s activities in South America (focusing on Brazil) within the context of the Germanism doctrine and, most importantly, the professional enjoyment Krause reaped from his trips as well as his lasting influence on neurosurgery in South America. Fedor Krause’s visits to Brazil occurred soon after World War I, when Germany sought to reestablish economic, political, cultural, and scientific power and influence. Science, particularly medicine, had been chosen as a field capable of meeting these needs. The advanced German system of academic organization and instruction, which included connections and collaborations with industry, was an optimal means to reestablish the economic viability of not only Germany but also Brazil. Krause, as a de facto ambassador, helped rebuild the German image and reconstruct diplomatic relations between Germany and Brazil. Krause’s interactions during his visits helped put Brazilian neurosurgery on a firm foundation, and he left an indelible legacy of advancing professionalism and specialization in neurosurgery in Brazil.

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Combined subtarsal contralateral transmaxillary retroeustachian and endoscopic endonasal approaches to the infrapetrous region

Mohamed A. Labib, Irakliy Abramov, Lena Mary Houlihan, Visish M. Srinivasan, Lea Scherschinski, Daniel M. Prevedello, Ricardo L. Carrau, Hussam Abou-Al-Shaar, Mark C. Preul, and Michael T. Lawton

OBJECTIVE

The eustachian tube (ET) limits endoscopic endonasal access to the infrapetrous region. Transecting or mobilizing the ET may result in morbidities. This study presents a novel approach in which a subtarsal contralateral transmaxillary (ST-CTM) corridor is coupled with the standard endonasal approach to facilitate access behind the intact ET.

METHODS

Eight cadaveric head specimens were dissected. Endoscopic endonasal approaches (EEAs) (i.e., transpterygoid and inferior transclival) were performed on one side, followed by ST-CTM and sublabial contralateral transmaxillary (SL-CTM) approaches on the opposite side, along with different ET mobilization techniques on the original side. Seven comparative groups were generated. The length of the cranial nerves, areas of exposure, and volume of surgical freedom (VSF) in the infrapetrous regions were measured and compared.

RESULTS

Without ET mobilization, the combined ST-CTM/EEA approach provided greater exposure than EEA alone (mean ± SD 288.9 ± 40.66 mm2 vs 91.7 ± 49.9 mm2; p = 0.001). The VSFs at the ventral jugular foramen (JF), entrance to the petrous internal carotid artery (ICA), and lateral to the parapharyngeal ICA were also greater in ST-CTM/EEA than in EEA alone (p = 0.002, p = 0.002, and p < 0.001, respectively). EEA alone, however, provided greater VSF at the hypoglossal canal (HGC) than did ST-CTM/EEA (p = 0.01). The SL-CTM approach did not increase the EEA exposure (p = 0.48). The ST-CTM/EEA approach provided greater exposure than EEA with extended inferolateral (EIL) or anterolateral (AL) ET mobilization (p = 0.001 and p = 0.02, respectively). The ST-CTM/EEA also increased the VSF lateral to the parapharyngeal ICA in comparison with EEA/EIL ET mobilization (p < 0.001) but not with EEA/AL ET mobilization (p = 0.36). Finally, the VSFs at the HGC and JF were greater in EEA/AL ET mobilization than in ST-CTM/EEA without ET mobilization (p = 0.002 and p = 0.004, respectively).

CONCLUSIONS

Combining the EEA with the more laterally and superiorly originating ST-CTM approach allows greater exposure of the infrapetrous and ventral JF regions while obviating the need for mobilizing the ET. The surgical freedom afforded by the combined approaches is greater than that obtained by EEA alone.

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Comparative analysis of the combined petrosal and the pretemporal transcavernous anterior petrosal approach to the petroclival region

Mohamed A. Labib, Xiaochun Zhao, Lena Mary Houlihan, Irakliy Abramov, Joshua S. Catapano, Komal Naeem, Mark C. Preul, A. Samy Youssef, and Michael T. Lawton

OBJECTIVE

The combined petrosal (CP) approach has been traditionally used to resect petroclival meningioma (PCM). The pretemporal transcavernous anterior petrosal (PTAP) approach has emerged as an alternative. A quantitative comparison of both approaches has not been made. This anatomical study compared the surgical corridors afforded by both approaches and identified key elements of the approach selection process.

METHODS

Twelve cadaveric specimens were dissected, and 10 were used for morphometric analysis. Groups A and B (n = 5 in each) underwent the CP and PTAP approaches, respectively. The area of drilled clivus, lengths of cranial nerves (CNs) II–X, length of posterior circulation vessels, surgical area of exposure of the brainstem, and angles of attack anterior and posterior to a common target were measured and compared.

RESULTS

The area of drilled clivus was significantly greater in group A than group B (mean ± SD 88.7 ± 17.1 mm2 vs 48.4 ± 17.9 mm2, p < 0.01). Longer segments of ipsilateral CN IV (52.4 ± 2.33 mm vs 46.5 ± 3.71 mm, p < 0.02), CN IX, and CN X (9.91 ± 3.21 mm vs 0.00 ± 0.00 mm, p < 0.01) were exposed in group A than group B. Shorter portions of CN II (9.31 ± 1.28 mm vs 17.6 ± 6.89 mm, p < 0.02) and V1 (26.9 ± 4.62 mm vs 32.4 ± 1.93 mm, p < 0.03) were exposed in group A than group B. Longer segments of ipsilateral superior cerebellar artery (SCA) were exposed in group A than group B (36.0 ± 4.91 mm vs 25.8 ± 3.55 mm, p < 0.02), but there was less exposure of contralateral SCA (0.00 ± 0.00 mm vs 7.95 ± 3.33 mm, p < 0.01). There was no statistically significant difference between groups with regard to the combined area of the exposed cerebral peduncles and pons (p = 0.75). Although exposure of the medulla was limited, group A had significantly greater exposure of the medulla than group B (p < 0.01). Finally, group A had a smaller anterior angle of attack than group B (24.1° ± 5.62° vs 34.8° ± 7.51°, p < 0.03).

CONCLUSIONS

This is the first study to quantitatively identify the advantages and limitations of the CP and PTAP approaches from an anatomical perspective. Understanding these data will aid in designing maximally effective yet minimally invasive approaches to PCM.

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The biportal transorbital approach: quantitative comparison of the anterior subfrontal craniotomy, bilateral transorbital endoscopic, and microscopic approaches

Lena Mary Houlihan, Thanapong Loymak, Irakliy Abramov, Jubran H. Jubran, Ann J. Staudinger Knoll, Jacob T. Howshar, Michael G. J. O’Sullivan, Michael T. Lawton, and Mark C. Preul

OBJECTIVE

The aim of this study was to assess the surgical use and applicability of a biportal bitransorbital approach. Single-portal transorbital and combined transorbital transnasal approaches have been used in clinical practice, but no study has assessed the surgical use and applicability of a biportal bitransorbital approach.

METHODS

Ten cadaver specimens underwent midline anterior subfrontal (ASub), bilateral transorbital microsurgery (bTMS), and bilateral transorbital neuroendoscopic surgery (bTONES) approaches. Morphometric analyses included the length of the bilateral cranial nerves I and II, the optic tract, and A1; the area of exposure of the anterior cranial fossa floor; craniocaudal and mediolateral angles of attack (AOAs); and volume of surgical freedom (VSF; maximal available working volume for a specific surgical corridor and surgical target structure normalized to a height of 10 mm) of the bilateral paraclinoid internal carotid arteries (ICAs), bilateral terminal ICAs, and anterior communicating artery (ACoA). Analyses were conducted to determine whether the biportal approach was associated with greater instrument freedom.

RESULTS

The bTMS and bTONES approaches provided limited access to the bilateral A1 segments and the ACoA, which were inaccessible in 30% (bTMS) and 60% (bTONES) of exposures. The average total frontal lobe area of exposure (AOE) was 1648.4 mm2 (range 1516.6–1958.8 mm2) for ASub, 1658.9 mm2 (1274.6–1988.2 mm2) for bTMS, and 1914.9 mm2 (1834.2–2014.2 mm2) for bTONES exposures, with no statistically significant superiority between any of the 3 approaches (p = 0.28). The bTMS and bTONES approaches were significantly associated with decreases of 8.7 mm3 normalized volume (p = 0.005) and 14.3 mm3 normalized volume (p < 0.001) for VSF of the right paraclinoid ICA compared with the ASub approach. No statistically significant difference in surgical freedom was noted between all 3 approaches when targeting the bilateral terminal ICA. The bTONES approach was significantly associated with a decrease of 105% in the (log) VSF of the ACoA compared with the ASub (p = 0.009).

CONCLUSIONS

Although the biportal approach is intended to improve maneuverability within these minimally invasive approaches, these results illustrate the pertinent issue of surgical corridor crowding and the importance of surgical trajectory planning. A biportal transorbital approach provides improved visualization but does not improve surgical freedom. Furthermore, although it affords impressive anterior cranial fossa AOE, it is unsuitable for addressing midline lesions because the preserved orbital rim restricts lateral movement. Further comparative studies will elucidate whether a combined transorbital transnasal route is preferable to minimize skull base destruction and maximize instrument access.

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The side door and front door to the upper retroclival region: a comparative analysis of the open pretemporal and the endoscopic endonasal transcavernous approaches

Mohamed A. Labib, Leandro Borba Moreira, Xiaochun Zhao, Sirin Gandhi, Claudio Cavallo, Ali Tayebi Meybodi, A. Samy Youssef, Andrew S. Little, Peter Nakaji, Mark C. Preul, and Michael T. Lawton

OBJECTIVE

The pretemporal transcavernous approach (PTA) and the endoscopic endonasal transcavernous approach (EETA) are both used to access the retroclival region. A direct quantitative comparison of both approaches has not been made. The authors compared the technical nuances of, and surgical exposure afforded by, each approach and identified the key elements of the approach selection process.

METHODS

Fourteen cadaveric specimens underwent either PTA (group A) or EETA with unilateral (group B) followed by bilateral (group C) interdural pituitary gland transposition. The percentage of drilled clivus; length of exposed oculomotor nerve (cranial nerve [CN] III), posterior cerebral artery (PCA), and superior cerebellar artery (SCA); and surgical area of exposure of both cerebral peduncles and the pons for the 3 groups were measured and compared.

RESULTS

Group A had a significantly lower percentage of drilled area than group B (mean [SD], 35.6% [11.2%] vs 91.3% [4.9%], p < 0.01). In group C, 100% of the upper third of the clivus was drilled in all specimens. Significantly longer segments of the ipsilateral PCA (p < 0.01) and SCA (p < 0.01) were exposed in group A than in group B. There was no significant difference in the length of the ipsilateral CN III exposed among the 3 groups. There was also no significant difference between group A and either group B or group C for the contralateral CN III or PCA exposure. However, longer segments of the contralateral SCA were exposed in group C than in group A (p = 0.02). Furthermore, longer segments of CN III (p < 0.01), PCA (p < 0.01), and SCA (p < 0.01) were exposed in group C than in group B. For brainstem exposure, there was greater exposure of the pons in group C than in group A (mean [SD], 211.4 [19.5] mm2 vs 157.7 [25.3] mm2, p < 0.01) and group B (211.4 [19.5] mm2 vs 153.9 [34.1] mm2, p < 0.01). However, significantly greater exposure of the ipsilateral peduncle was observed in group A (mean [SD], 125.6 [43.1] mm2) than in groups B and C (56.3 [6.0] mm2, p < 0.01). Group C had significantly greater exposure of the contralateral peduncle than group B (p = 0.02).

CONCLUSIONS

This study is the first to quantitatively identify the advantages and limitations of the PTA and EETA from an anatomical perspective. Understanding these data may help the skull base surgeon design a maximally effective yet minimally invasive approach to individual lesions.

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Quantitative analysis of ipsilateral and contralateral supracerebellar infratentorial and occipital transtentorial approaches to the cisternal pulvinar: laboratory anatomical investigation

Qing Sun, Xiaochun Zhao, Sirin Gandhi, Ali Tayebi Meybodi, Evgenii Belykh, Daniel Valli, Claudio Cavallo, Leandro Borba Moreira, Peter Nakaji, Michael T. Lawton, and Mark C. Preul

OBJECTIVE

The cisternal pulvinar is a challenging location for neurosurgery. Four approaches for reaching the pulvinar without cortical transgression are the ipsilateral supracerebellar infratentorial (iSCIT), contralateral supracerebellar infratentorial (cSCIT), ipsilateral occipital transtentorial (iOCTT), and contralateral occipital transtentorial/falcine (cOCTF) approaches. This study quantitatively compared these approaches in terms of surgical exposure and maneuverability.

METHODS

Each of the 4 approaches was performed in 4 cadaveric heads (8 specimens in total). A 6-sided anatomical polygonal region was configured over the cisternal pulvinar, defined by 6 reachable anatomical points in different vectors. Multiple polygons were subsequently formed to calculate the areas of exposure. The surgical freedom of each approach was calculated as the maximum allowable working area at the proximal end of a probe, with the distal end fixed at the posterior pole of the pulvinar. Areas of exposure, surgical freedom, and the working distance (surgical depth) of all approaches were compared.

RESULTS

No significant difference was found among the 4 different approaches with regard to the surgical depth, surgical freedom, or medial exposure area of the pulvinar. In the pairwise comparison, the cSCIT approach provided a significantly larger lateral exposure (39 ± 9.8 mm2) than iSCIT (19 ± 10.3 mm2, p < 0.01), iOCTT (19 ± 8.2 mm2, p < 0.01), and cOCTF (28 ± 7.3 mm2, p = 0.02) approaches. The total exposure area with a cSCIT approach (75 ± 23.1 mm2) was significantly larger than with iOCTT (43 ± 16.4 mm2, p < 0.01) and iSCIT (40 ± 20.2 mm2, p = 0.01) approaches (pairwise, p ≤ 0.01).

CONCLUSIONS

The cSCIT approach is preferable among the 4 compared approaches, demonstrating better exposure to the cisternal pulvinar than ipsilateral approaches and a larger lateral exposure than the cOCTF approach. Both contralateral approaches described (cSCIT and cOCTF) provided enhanced lateral exposure to the pulvinar, while the cOCTF provided a larger exposure to the lateral portion of the pulvinar than the iOCTT. Medial exposure and maneuverability did not differ among the approaches. A short tentorium may negatively impact an ipsilateral approach because the cingulate isthmus and parahippocampal gyrus tend to protrude, in which case they can obstruct access to the cisternal pulvinar ipsilaterally.