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Phase 0 Clinical Trial of Everolimus in Patients with Vestibular Schwannoma or Meningioma

Karajannis, Matthias A; Mauguen, Audrey; Maloku, Ekrem; Xu, Qingwen; Dunbar, Erin M; Plotkin, Scott R; Yaffee, Anna; Wang, Shiyang; Roland, J Thomas; Sen, Chandranath; Placantonakis, Dimitris G; Golfinos, John G; Allen, Jeffrey C; Vitanza, Nicholas A; Chiriboga, Luis A; Schneider, Robert J; Deng, Jingjing; Neubert, Thomas A; Goldberg, Judith D; Zagzag, David; Giancotti, Filippo G; Blakeley, Jaishri O
Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of NF2 patients with vestibular schwannoma (VS). To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for VS or meningiomas. Eligible patients with meningioma or VS requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and post-operative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to control tissues from untreated patients (p=0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and will inform the design of future pre-clinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.
PMID: 34224367
ISSN: 1538-8514
CID: 4932142

Skull Base Aerosol Generating Cases Amidst the COVID-19 Pandemic: An Experience from the Epicenter

Dastagirzada, Yosef; Klauberg, Olga; Sheerin, Kathleen; Lieberman, Seth; Lebowitz, Richard; McMenomey, Sean; Sen, Chandranath; Roland, J. Thomas; Golfinos, John G.; Pacione, Donato
Soon after the World Health Organization declared the severe acute respiratory syndrome coronavirus 2 a global health emergency on January 30, 2020, New York City was plagued by the virus and its health system and economy pushed to their limits. The majority of the limited neurosurgical data in relation to COVID-19 is anecdotal and the higher theoretical risk of transmission of the virus among skull base aerosol generating (SBAG) cases has not been investigated or discussed in a neurosurgical population. We discuss a series of 13 patients who underwent 15 SBAG surgical procedures during the peak of COVID-19 in our hospital system and the protocols use perioperatively for their procedures. Our data support that with proper preoperative testing, a well-delineated surgical algorithm, and appropriate personal protective equipment, emergent/urgent cases can be done safely in hospitals that are currently experiencing high volumes of COVID-19 cases as we did in March to May of 2020.
ISSN: 2193-634x
CID: 4832592

Clival Chordomas: Contemporary Results

Sen, Chandranath
PMID: 33109848
ISSN: 1998-4022
CID: 4660382

Orbital Rosai-Dorfman disease initially diagnosed as IgG4-related disease: a case report

Iyengar, Nishanth S; Golub, Danielle; McQuinn, Michelle W; Hill, Travis; Tang, Karen; Gardner, Sharon L; Harter, David H; Sen, Chandranath; Staffenberg, David A; Thomas, Kristen; Elkin, Zachary; Belinsky, Irina; William, Christopher
Inflammatory orbital lesions include a broad list of diagnoses, many of them with overlapping clinical and radiographic features. They often present a diagnostic conundrum, even to the most experienced orbital specialist, thus placing considerable weight on surgical biopsy and histopathological analysis. However, histopathological diagnosis is also inherently challenging due to the rarity of these lesions and the overlaps in histologic appearance among distinct disease entities. We herein present the case of an adolescent male with a subacutely progressive orbital mass that generated a significant diagnostic dilemma. Early orbital biopsy was consistent with a benign fibro-inflammatory lesion, but corticosteroid therapy was ineffective in halting disease progression. After an initial substantial surgical debulking, histopathological analysis revealed several key features consistent with IgG4-related disease (IgG4-RD), a systemic fibro-inflammatory process typically accompanied by multifocal tumor-like lesions. Surprisingly, within months, there was clear evidence of clinical and radiographic disease progression despite second-line rituximab treatment, prompting a second surgical debulking. This final specimen displayed distinctive features of Rosai-Dorfman disease (RDD), a systemic inflammatory disease characterized by uncontrolled histiocytic proliferation. Interestingly, certain features of this re-excision specimen were still reminiscent of IgG4-RD, which not only reflects the difficulty in differentiating RDD from IgG4-RD in select cases, but also illustrates that these diagnoses may exist along a spectrum that likely reflects a common underlying pathogenetic mechanism. This case emphasizes the importance of surgical biopsy or resection and histopathological analysis in diagnosing-and, ultimately, treating-rare, systemic inflammatory diseases involving the orbit, and, furthermore, highlights the shared histopathological features between RDD and IgG4-RD.
PMID: 32682450
ISSN: 2051-5960
CID: 4531782

Cavernous sinus lesions

Munawar, Kamran; Nayak, Gopi; Fatterpekar, Girish M; Sen, Chandra; Zagzag, David; Zan, Elcin; Hagiwara, Mari
The cavernous sinus is a complex structure susceptible to a wide variety of vascular, neoplastic and inflammatory pathologies. Vascular pathologies include ICA aneurysms, carotid-cavernous fistulas, cavernous sinus thrombosis, and cavernous hemangioma. Neoplasms that involve the cavernous sinus include pituitary adenoma, meningioma, schwannoma, lymphoma, perineural tumor spread, metastases, and direct tumor invasion. Infectious and inflammatory diseases include Tolosa-Hunt syndrome, sarcoidosis, granulomatosis with polyangiitis, IgG-4 related disease and invasive fungal infections. In this article, we review the clinical and imaging findings of a number of pathologies involving the cavernous sinus, focusing on key features that can narrow the differential diagnosis and, in some cases, support a particular diagnosis.
PMID: 32574933
ISSN: 1873-4499
CID: 4493082

Volumetric growth rates of untreated cavernous sinus meningiomas [Meeting Abstract]

Benjamin, C; Pacione, D; Mullen, R; Kazi, E; Ashayeri, K; Sen, C; Golfinos, J G; Placantonakis, D; Kondziolka, D; Jafar, J
Cavernous Sinus Meningiomas are indolent tumors that initiate within the cavernous sinus and can expand along the skull base as well as intracranially. Given the involvement of vital neurovascular structures within the cavernous sinus including the internal carotid artery as well as cranial nerves II-VI, cavernous sinus meningiomas can have significant neurologic deficits. Management includes observation with serial imaging, stereotactic radiosurgery, or microsurgical debulking of the extracavernous components and decompression of neural elements. Prior studies suggest that such tumors are indolent, and favor observation with symptomatic medical management.1 Between January 2013 and July 31, 2017, 38 patients with cavernous sinus meningiomas were retrospectively evaluated. The average age of patients was 60 years. There was a female preponderance in this cohort, with 82% of patients being females. Most patients (79%) were asymptomatic. All MR images preceded any intervention. Of the 38 patients analyzed, 66% never underwent treatment, 21% underwent stereotactic radiosurgery (SRS), 8% underwent microsurgical resection, and 5% underwent a combined approach with SRS, and craniotomy. To precisely calculate tumor volumes, the tumor area was outlined on every slice, and the products of the area and slice thickness were summed (55% of scans were done). The mean cavernous sinus volumetric growth rate was 35% per year. An assessment of the frequencies of individual tumor annual growth rates revealed that 21% demonstrated growth (5% fast growing), 79% were stable on an average interval of 51 months. There was no relationship between patient age and tumor growth rate. This study is a comprehensive measure of cavernous sinus meningioma volumetric growth rates using high-resolution imaging. The majority of the tumors remained stable over time, as predicted in previous studies. These findings provide volumetric data regarding the tumor behavior which can assist in the clinical decision making for the management of cavernous sinus meningiomas
ISSN: 2193-6331
CID: 4387102

Role of intraoperative MRI in endoscopic endonasal transsphenoidal pituitary surgery [Meeting Abstract]

Dastagirzada, Y; Benjamin, C G; Bevilacqua, J; Gurewitz, J; Golfinos, J G; Placantonakis, D; Sen, C; Jafar, J; Fatterpekar, G; Lieberman, S; Lebowitz, R; Pacione, D
The transsphenoidal corridor for pituitary adenoma surgery was established as early as 1906 by Schloffer and was subsequently refined by Cushing throughout the early 20thcentury [1]. The use of intraoperative magnetic resonance imaging (iMRI) in endoscopic endonasal transsphenoidal resections, however, is a relatively contemporary addition to the surgical treatment of pituitary tumors. The morbidity of these cases has decreased over the years in light of advances in intraoperative navigation as well as improvements in endoscope dynamics and surgical instruments. Despite such improvements, a substantial number of patients require repeat surgeries or subsequent radiotherapy for residual and/or recurrent disease. This can be largely attributed to cavernous sinus invasion or suprasellar extension, which pose technical challenges to achieving gross total resections (GTRs). The rate of GTR for pituitary tumors cited in the literature varies from 59-88%.[2-3] The advantage of iMRI is that it provides the surgeon with immediate feedback regarding their progress and ability to safely achieve GTR which, in pituitary surgery, is critical for long term cure. Additionally, although there is concern for increased risk of postoperative endocrine dysfunction, Zhibin et al prove that this is not necessarily the case. In their series, 133 patients who underwent iMRI had higher rates of GTR and did not have a significant difference in postoperative hypopituitarism. [4] This study includes a combined retrospective and prospective comparative analysis of 238 patients who underwent transsphenoidal resection of a pituitary tumor from January 2013 until May 2019. All patients were operated on by one of four experienced neurosurgeons and one of three experienced otolaryngologists. There were 203 patients who did not undergo iMRI and 25 patients who did. A 3 tesla MRI magnet was used in all cases. All intraoperative images were read and interpreted by a senior neuroradiologist at our institution. Amongst the two groups, there was no statistically significant difference in patient age (p = 0.488), tumor size (microadenoma versus macroadenoma, p = 0.878), and primary versus recurrent tumor (p = 0.837). The use of iMRI did not yield a decrease in the length of stay (4.84 days in the no iMRI group and 5 in the iMRI group, p = 0.777). There were zero cases of a return to the OR for residual tumor in the intraoperative MRI group versus the non-MRI group. However, this did not reach statistical significance. This study did not yield a statistically significant difference in GTR (p = 0.75), near total resection (NTR, p = 0.167), or subtotal resection (p = 0.083). This is likely secondary to a low sample size and therefore power in the iMRI group. Finally, there was no significant difference in the number of patients requiring postoperative DDAVP (p = 0.099) or hydrocortisone (p = 0.873) after discharge. Preliminary results reveal a potential benefit of iMRI use to assess for residual disease which can be addressed immediately during the initial operation, thus decreasing the need for re-operations. Furthermore, the ability to correlate intraoperative findings with an intraoperative structure may lead to more precise identification and preservation of normal gland, which can possibly decrease the incidence of postoperative endocrine dysfunction
ISSN: 2193-6331
CID: 4387122

Discontinuation of postoperative prophylactic antibiotics for endoscopic endonasal surgery [Meeting Abstract]

Benjamin, C G; Dastagirzada, Y; Bevilacqua, J; Gurewitz, J; Sen, C; Golfinos, J G; Placantonakis, D; Jafar, J J; Lebowtiz, R; Lieberman, S; Lewis, A; Pacione, D
Direct access through the sinuses and nasopharyngeal mucosa in the endoscopic endonasal approach (EEA) raises concern for a contaminated operative environment and subsequent infection. The reported rate of meningitis in endoscopic endonasal skull base surgery in the literature ranges from 0.7 to 3.0% [1, 2]. The only factor identified as being independently associated with meningitis in a statistically significant manner is cerebrospinal fluid (CSF) leak [1-5]. However, many centers performing high volume of EEAs use postoperative antibiotic coverage independent of the presence intraoperative or postoperative CSF leak. Furthermore, while meningitis remains a severe concern, most centers use postoperative gram-positive coverage to prevent toxic shock syndrome caused by Staphylococcus aureus infection in the setting of prolonged nasal packing. There are currently a multitude of approaches regarding perioperative antibiotic coverage in EEAs [1-4]. Given the lack of consensus in the literature and our experience regarding the benefit of discontinuation of prolonged prophylactic antibiotics throughout the breadth of neurosurgical procedures, we sought to analyze the need for postoperative antibiotics in EEAs further. As such, we performed a prospective analysis compared with a retrospective cohort to delineate whether discontinuation of postoperative antibiotics leads to a change in the rate of postoperative infections. The retrospective cohort consisted of patients who underwent an EEA from January 1, 2013 to May 31, 2019. These patients all received postoperative antibiotics while nasal packing was in place (median 7 days). Starting on April 1, 2019 until August 1, 2019, we discontinued postoperative antibiotic use. Patients from this group made up the prospective cohort. The retrospective cohort had 315 patients (66% pituitary macroadenomas vs. 7% microadenomas, 4% meningiomas, 4% craniopharyngiomas, 4% chordomas, and 15% others) while the prospective group had 23 patients (57% pituitary macroadenomas, 30% craniopharyngiomas, 8% meningiomas/chordomas, and 5% others). The primary endpoint was rate of postoperative infections and specifically, meningitis and multidrug resistant organism (MDRO) infections. There was no statistically significant difference in the use of nasal packing (p = 0.085), intraoperative CSF leak (p = 0.133), and postoperative CSF leak (p = 0.507) between the two groups. There was also no significant difference in the number of patients with positive preoperative MSSA and MRSA nasal swabs (p = 0.622). There was a significant decrease in the number of patients discharged with antibiotics (55.1% in the retrospective and 4.5% in the prospective group, p = 0.000). The number of patients with positive blood cultures (p = 0.701) and positive urine cultures (p = 0.691) did not differ significantly between the two groups. Finally, there was no statistically significant difference in postoperative CSF infections (p = 0.34) or MDRO infections (0.786) between the two groups. We describe promising preliminary results that demonstrate that discontinuation of postoperative antibiotics in EEAs do not lead to a statistically significant increase in the rate of postoperative CSF or MDRO infections. The previous algorithm for postoperative antibiotic coverage in our center, like many centers, called for gram-positive coverage, which may have contributed to the overall preponderance of gram-negative meningitis cases in this cohort
ISSN: 2193-6331
CID: 4387132

Gamma Knife Radiosurgery and Immunotherapy as Primary Treatment for a Malignant Tumor of the Cranial Base beginning as Lentigo Maligna: A Case Report

Mureb, Monica; Benjamin, Carolina; Sen, Chandranath; Spino, Marissa; Krasnozhen-Ratush, Olga; Zagzag, David; Pavlick, Anna C; Kondziolka, Douglas
Melanoma in the head and neck is known to metastasize to cranial nerves. Prompt treatment is critical for preventing progression and reducing neuropathy. We report a patient who presented with cranial neuropathy related to a malignant skull base lesion that originated as lentigo maligna. The diagnosis was challenging, requiring two surgeries to obtain tissue and neither biopsy leading to a definitive diagnosis. Pathological analyses demonstrated positive immunoreactivity for SOX10 and S100, preservation of H3K27me3, and PTEN and STK11 mutations. The patient was managed with Gamma Knife Radiosurgery and combination immunotherapy. Imaging at 9 months post-SRS showed resolution of the mass lesion. Clinically, the patient has occasional left-sided facial pain requiring no medication and denies facial numbness. We favor a diagnosis of desmoplastic neurotropic melanoma due to the neurotropic spread and response to melanoma-targeted immunotherapy.
PMID: 31129314
ISSN: 1879-8519
CID: 3921222

Intraosseous Petrous Apex Schwannoma: Case Report and Review of Literature

Rozman, Peter A; Benjamin, Carolina G; Kondziolka, Douglas; Sen, Chandranath; Roland, J Thomas; Zagzag, David; Snuderl, Matija; Gordon, David
BACKGROUND:Intraosseous petrous apex schwannomas are an exceedingly rare entity; little is known about their epidemiology, natural history, and post-operative outcomes. CASE DESCRIPTION/METHODS:Here, we present the fourth known case of a primary intraosseous schwannoma of the petrous apex: a 68-year-old woman presenting with diplopia, facial numbness, progressive intermittent vertigo, tinnitus, diminished hearing, and ataxia. She underwent a transtemporal approach for subtotal resection of the tumor with subsequent stereotactic radiosurgery. CONCLUSIONS:Our two-year follow-up demonstrates slow growth and success of multimodal management in the treatment of these tumors. We review the three prior reports of petrous apex schwannomas, and identify unifying radiographic and clinical characteristics in order to aid in future diagnostic considerations of lesions of the petrous apex.
PMID: 31476472
ISSN: 1878-8769
CID: 4066982