Faculty Bibliography

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

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

OBJECTIVE:The goal of this study was to describe the clinical presentation associated with atypical schwannoma of the cerebellopontine angle, characterize the pathologic findings and describe the long-term outcome. MATERIALS AND METHODS/METHODS:The study design was retrospective case review of patients with the histopathologic diagnosis of atypical and benign schwannoma of the cerebellopontine angle diagnosed at the study institution over a 10-year period. SETTING/METHODS:Tertiary referral center. MAIN OUTCOMES MEASURE/METHODS:Demographic data of the cohort were recorded. Findings on pathology were evaluated. Initial treatment and post-operative course was recorded. Main outcome measures were clinical presentation, including cranial nerve deficits at the time of presentation, complication and recurrence rates. RESULTS:At presentation, a somewhat accelerated course of cranial nerve deficit was noted among patients with atypical schwannoma as compared to benign schwannoma. In the immediate post-operative period, there were no differences noted in the complication rate. Atypical schwannomas appear to have higher recurrence rate compared to benign schwannomas. CONCLUSIONS:Atypical schwannoma is an intermediate disease process with an accelerated clinical course and higher recurrence rate as compared to vestibular schwannoma. Traditional operative approaches may be employed without increased concern for post-operative complications. Thorough counseling and close follow-up should be offered to these patients given the higher recurrence rate. Larger studies are required to determine if these patients need more frequent MRIs for long-term surveillance.

BACKGROUND: There is no effective therapy for patients (pts) with IDH-mutant gliomas that progress after RT and chemotherapy. At time of progression, these tumors have often transformed to glioblastoma (GBM) and have increased numbers of somatic mutations, i.e. have a ?hypermutator phenotype?. We hypothesized that there is synergistic efficacy of Avelumab (anti-PD-L1) combined with HFRT in pts with secondarily trans- formed IDH-mutant GBMs. Safety-lead-in results will be presented.
METHOD(S): This is a phase II, open-label, single-arm, multicenter study of Avelumab with HFRT in adults with transformed IDH-mutant GBM who previously received RT and TMZ and/or PCV. All pts received Avelumab 10 mg/kg IV followed at Day 8 by HFRT (25 Gy in 5 daily 5-Gy fractions) and then Avelumab 10 mg/kg IV every 2 weeks. A 3 + 3 design was used for a 6-patient safety-lead-in cohort. Adverse events were recorded according to CTCAE.
RESULT(S): Six pts (F=4, M=2) with a median age= 45.5 yrs (range 31.5-54.4 yrs) were enrolled in the safety-lead-in cohort. No DLT was observed. Grade >= 3 AEs included increased cerebral edema (3 pts), hyponatremia (1 pt) and worsening hemiparesis (3 pts). Grade <= 2 AEs included nausea, hypothyroidism, lymphopenia, thrombocytopenia, transaminase elevation, and fever/chills. Median follow-up time was 8.9 mo. Best treatment response was SD in 1 patient. At time of last follow-up all pts have discontinued treatment for PD. Median PFS was 4.2 mo (range 1.4-5.7). Median OS was 10.1 (range 6.8-21+) mo. 4 pts (67%) died, 2 pts remain alive in follow-up at 6.9 and 21.6 months after treatment initiation. The study was closed after the safety lead-in completed enrollment due to slow accrual.
CONCLUSION(S): Avelumab combined with HFRT was tolerable without dose-limiting toxicity in this safety-lead-in cohort of adult patients with transformed IDH-mutant GBM. Further studies are necessary to determine efficacy of this treatment regimen

IDH1/2 mutations are early drivers present in diverse human cancer types arising in various tissue sites. IDH1/2 mutation is known to induce a global hypermethylator phenotype. However, the effects on DNA methylation across IDH mutant cancers and functionally different genome regions, remain unknown. We analyzed DNA methylation data from IDH1/2 mutant acute myeloid leukemia, oligodendroglioma, astrocytoma, solid papillary breast carcinoma with reverse polarity, sinonasal undifferentiated carcinoma and cholangiocarcinoma, which clustered by their embryonal origin. Hypermethylated common probes affect predominantly gene bodies while promoters in IDH1/2 mutant cancers remain unmethylated. Enhancers showed global hypermethylation, however commonly hypomethylated enhancers were associated with tissue differentiation and cell fate determination. We demonstrate that some chromosomes, chromosomal arms and chromosomal regions are more affected by IDH1/2 mutations while others remain resistant to IDH1/2 mutation induced methylation changes. Therefore IDH1/2 mutations have different methylation effect on different parts of the genome, which may be regulated by different mechanisms.

Following publication of the original article [1], it was reported that the given name of the fourteenth author was incorrectly published. The incorrect and the correct names are given below.