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OBJECTIVE Long-term follow-up of meningiomas has demonstrated recurrence rates ranging from 2.5% to 48% after 10 years, depending on histology grade. There are limited data available to guide the management of recurrent and previously irradiated skull base meningiomas, and challenges related to salvage surgery, reirradiation, and lack of clear systemic therapy strategies remain. In this study, the authors analyzed data from their experience with recurrent and previously irradiated meningiomas to assess the impact of salvage surgery and reirradiation on progression-free survival (PFS). METHODS A retrospective cohort study of 48 patients with recurrent and previously irradiated meningiomas who were treated between 1995 and 2021 was conducted. Data were extracted from medical records and included clinical, radiological, and pathologic reports. Patients were clustered according to WHO grades. The authors analyzed the complications related to reirradiation and salvage surgery and the impact of different treatment modalities on PFS using Cox proportional hazard ratios. RESULTS Forty-eight patients (33 with WHO grade I, 11 with WHO grade II, and 4 with WHO grade III meningiomas) were treated for 143 recurrences after their first radiation treatment. For WHO grade I meningiomas, there was no change in tumor control rates with adjuvant repeat radiotherapy (HR 0.784, 95% CI 0.349–1.759; p = 0.55), and in terms of extent of resection (EOR), subtotal resection (STR) alone was associated with an increased risk of recurrence when compared with gross-total resection (GTR) (HR 3.38, 95% CI 1.268–9.036; p = 0.0189). For WHO grade II meningiomas, GTR did not significantly confer improved tumor control relative to STR (HR 0.42, 95% CI 0.17–1.037; p = 0.055), but adjuvant repeat radiotherapy after STR was associated with improved outcomes (HR 0.316, 95% CI 0.13–0.768; p = 0.0029). Finally, for WHO grade III meningiomas, EOR did not correlate with outcomes (HR 0.75, 95% CI 0.22–2.482; p = 0.588), but repeat radiotherapy alone was associated with a decreased odds of progression (HR 0.276, 95% CI 0.078–0.97; p = 0.0028). CONCLUSIONS This study examined the impact of retreatment on PFS in a large cohort of patients with recurrent meningiomas that had been previously irradiated. At the time of recurrence, WHO grade I meningiomas exhibited improved PFS with GTR, subtotally resected WHO grade II meningiomas appeared to have improved PFS when reirradiated, and reirradiation in WHO grade III meningiomas showed improved PFS.

OBJECTIVE In recurrent atypical meningioma, the survival impact of volumetric extent of resection (vEOR) and residual tumor volume (RTV) has not been previously studied. METHODS The authors performed a retrospective vEOR analysis of patients with recurrent World Health Organization grade II meningiomas treated with reresection from 2000 to 2019. The Kaplan-Meier method and multivariate Cox regression analysis were used to study progression-free survival (PFS) and overall survival (OS). RESULTS Fifty-nine patients with a median follow-up duration of 95 (95% CI 42–148) months were included. The median (range) vEOR was 100% (32%–100%) and the mean ± SD was 90.7% ± 15.3%. Among patients who underwent gross-total resection (GTR) (n = 32 [54%]), Simpson grade I and II resections were achieved in 23 (72%) and 9 (28%) patients, respectively. Among patients who underwent subtotal resection (n = 27 [46%]), the median (range) RTV was 4.3 (0.3–40) cm3. The 1-, 2-, and 5-year actuarial PFS rates for the cohort were 76%, 56%, and 34%, respectively. The 1-, 2-, and 5-year actuarial OS rates for the cohort were 98%, 78%, and 60%, respectively. Variables reflecting EOR significantly impacted both PFS and OS in multivariate analysis: GTR (p < 0.01) was significantly associated with longer PFS, and lower Simpson grade (p = 0.04) was significantly associated with longer OS. Additional factors including RTV, Ki-67 index, and pretreatment and posttreatment history also impacted survival outcomes (p < 0.05). CONCLUSIONS EOR and Simpson grade were independently associated with survival outcomes in patients with recurrent atypical meningioma. These findings support the practice of thorough reresection for maximal cytoreduction in appropriate surgical candidates.

Introduction Clival malignancies pose particular surgical challenges due to complex skull base anatomy and the involvement of vital neurovascular structures. While endoscopic endonasal approached are widely used, the outcomes for clival malignancies remain poorly understood. In this study we assessed the impact of endoscopic and open surgical approaches on PFS, time to initiation of radiotherapy, KPS, and GTR rates for clival malignancies. Methods A retrospective case series for clival malignancies operated between 1993 and 2019 was conducted. Inclusion criteria were age over 18 and a follow-up of at least a 6 months. Statistical analyses were conducted using STATA version 15 statistical software package StataCorp. Results For the whole cohort (113 patients), and for upper and middle lesions, open surgical approaches increased odds of disease progression, compared to EEA (HR 2.10 to HR 2.43), p

OBJECTIVE Infratemporal fossa (ITF) tumors are unique in histological characteristics and difficult to treat. Predictors of patient outcomes in this context are not known. The objective of this study was to identify independent predictors of outcome and to characterize patterns of failure in patients with ITF carcinoma. METHODS All patients who had been surgically treated for anterolateral skull base malignancy between 1999 and 2017 at the authors’ institution were retrospectively reviewed. Patient demographics, preoperative performance status, tumor stage, tumor characteristics, treatment modalities, and pathological data were collected. Primary outcomes were disease-specific survival (DSS) and local progression-free survival (LPFS) rates. Overall survival (OS) and patterns of progression were secondary outcomes. RESULTS Forty ITF malignancies with skull base involvement were classified as carcinoma. Negative margins were achieved in 23 patients (58%). Median DSS and LPFS were 32 and 12 months, respectively. Five-year DSS and OS rates were 55% and 36%, respectively. The 5-year LPFS rate was 69%. The 5-year overall PFS rate was 53%. Disease recurrence was noted in 28% of patients. Age, preoperative performance status, and margin status were statistically significant prognostic factors for DSS. Lower preoperative performance status and positive surgical margins increased the probability of local recurrence. CONCLUSIONS The ability to achieve negative margins was significantly associated with improved tumor control rates and DSS. Cranial base surgical approaches must be considered in multimodal treatment regimens for anterolateral skull base carcinomas.

BACKGROUND Orbital exenteration (OE) is an ablative procedure used in the management of malignancies of the orbit of either primary or secondary origin. Publications evaluating this procedure have suffered from small patient numbers, heterogeneity of pathologies, and poor patient follow-up. The purpose of this study was to assess patient outcomes in a large cohort of patients undergoing OE at a tertiary cancer center. METHODS A retrospective review was conducted of 180 consecutive patients who underwent OE at the authors' institution. Overall survival (OS) was the primary end point measured in the study. Time to locoregional recurrence (progression-free survival [PFS]) and disease-free survival were secondary end points. RESULTS Between the years 1993 and 2011, 180 consecutive patients received OE for craniofacial malignancy at the authors' institution. The median follow-up for the cohort was 9.7 years (116 months). The median OS was 73 months, and the median PFS was 96 months. The presence of perineural invasion was associated with shorter OS (P = .01) and PFS (P < .01). Magnetic resonance imaging was predictive of perineural invasion (P < .01). Positive margins were associated with shorter PFS than negative margins (P < .01) but with no change in OS (P = .15). The overall complication rate was 15%. The major complication rate (Clavien-Dindo 3b or greater) was 2.8% (n = 5), and there was 1 death observed (0.6%). CONCLUSIONS Used judiciously in the setting of a multidisciplinary management plan, OE for tumor control is a safe therapy. LAY SUMMARY Between the years 1993 and 2011, 180 consecutive patients received orbital exenteration for craniofacial malignancy at the MD Anderson Cancer Center. The median follow-up for the cohort was 9.7 years. The presence of perineural invasion was associated with shorter overall survival (P = .01) and progression-free survival (P < .01). Magnetic resonance imaging was predictive of perineural invasion (P < .01). Positive margins were associated with shorter progression-free survival than negative margins (P < .01). The overall complication rate was 15%. The major complication rate (Clavien-Dindo 3b or greater) was 2.8% (n = 5).

Objective To evaluate the rate of incidental detection of central nervous system (CNS) meningioma in patients undergoing 18F-fluciclovine PET/computed tomography (CT) imaging for the evaluation of prostate cancer. Methods The reports of 850 18F-fluciclovine PET/CT scans in 566 patients with pathologically proven prostate cancer performed from April 2017 to July 2019, were retrospectively reviewed for the presence of CNS meningioma. Results A total of 14 patients (2.8%) (age range: 54-82 years old) had abnormal focal intracranial 18F-fluciclovine uptake, all extra-axial in location (SUVmax range: 3.2-19.3). Two cases out of 14 (0.35%) were diagnosed as metastatic lesions. Twelve out of the 14 patients, had 18F-fluciclovine PET/CT imaging findings suspicious for CNS meningioma, 2 of them received another diagnosis on further imaging, and only 10 cases (2%) had the diagnosis of meningioma according to follow-up MRI and 18F-fluciclovine PET/CT. Conclusion Focal 18F-fluciclovine avid intracranial lesions incidentally detected in patients undergoing PET/CT imaging for prostate cancer are most often CNS meningiomas.

Background Squamous cell carcinoma is the most common type of sinonasal malignancy. Despite improvements in surgical resection and adjuvant therapy, which are considered the standard of care, the outcome for patients with locoregionally advanced disease remains poor. The objective of this study was to investigate the role of induction chemotherapy in patients with locoregionally advanced sinonasal squamous cell carcinoma and to determine the oncologic outcomes in those patients. Methods The study included 123 consecutive patients with previously untreated, locoregionally advanced (stage III and IV) sinonasal squamous cell carcinoma who were treated with curative intent at The University of Texas MD Anderson Cancer Center between 1988 and 2017 with induction chemotherapy followed by definitive local therapy. Patient demographics, tumor staging, treatment details, and oncologic outcomes were reviewed. The outcomes of this study included response to induction chemotherapy, recurrence, organ preservation, and survival. Results The median follow-up was 32.6 months (range, 12.4-240 months). Of the 123 patients, 110 (89%) had T4 disease, and 13 (11%) had T3 disease. Lymph node metastasis at the time of presentation was observed in 36 patients (29.3%). The overall stage was stage IV in 111 patients (90.2%) and stage III in 12 patients (9.8%). The chemotherapy regimen consisted of the combination of a platinum and taxanes in most cases (109 patients; 88.6%), either as a doublet (41 patients) or in combination with a third agent, such as 5-fluorouracil (34 patients), ifosfamide (26 patients), or cetuximab (8 patients). After induction chemotherapy, 71 patients (57.8%) achieved at least a partial response, and 6 patients had a complete response. Subsequent treatment after induction chemotherapy was either: 1) definitive chemoradiation or radiation followed by surgical salvage for any residual disease, or 2) surgery followed by adjuvant radiation or chemoradiation. Overall, 54 patients (49.5%) underwent surgical resection. The 2-year overall and disease-free survival rates for the whole cohort were 61.4% and 67.9%, respectively. The rate of orbital preservation was 81.5%. The recurrence rate was 26.8% (33 patients), and distant metastases occurred in 8 patients (6.5%). Patients who had at least a partial response or stable disease had significantly better overall and disease-free survival than those who had progressive disease (P = .028 and P = .021, respectively). Conclusions The current results indicate that a high proportion of patients with sinonasal squamous cell carcinoma achieved a favorable response to induction chemotherapy. The data suggest that response to induction chemotherapy is associated with an improved outcome and a good chance of organ preservation. The oncologic outcomes in this cohort with locally advanced (mostly T4) disease are better than those historically reported in the literature. Further study of induction chemotherapy in patients with advanced sinonasal squamous carcinoma is warranted.

The aim of this study is to evaluate the outcomes and tolerance of immune checkpoint inhibitors (ICIs) for patients with recurrent chordoma. We reviewed the records of 17 patients with recurrent chordomas who received ICIs for progressing disease as part of their treatment between 2016 and 2020. Response was assessed using response evaluation criteria in solid tumors 1.1 criteria. The Kaplan-Meier method was used to estimate the duration of response, progression-free survival (PFS), and overall survival (OS). Clinical benefit was defined as having stable disease (SD), a partial response, or a complete response. The median follow-up from the start of ICIs was 29 months [interquartile range (IQR): 13-35 m]. The majority received pembrolizumab (n=9, 53%), and the median number of cycles delivered was 8 (IQR: 7-12). The 1-year OS was 87%, and the 1-year PFS was 56% with a median PFS of 14 months (95% CI, 5-17 mo). After ICI initiation, most patients (n=15, 88%) had clinical benefit consisting of a complete response (n=1, 6%), partial response (n=3, 18%), and stable disease (n=11, 65%). Among all responders (n=15), the median duration of response was 12 months. Toxicities were limited: 2 (12%) patients having grade 3/4 immune-related toxicities (colitis, grade 3; myocarditis, grade 4). We observed a high rate of clinical benefit and favorable durability from ICI use for patients with recurrent chordoma. These data provide support for the integration of ICIs as a standard first-line systemic therapy option for patients with recurrent chordoma. Prospective studies are warranted to further evaluate efficacy and enhance response rates.

Recurrent skull base chondrosarcomas (CSA) are difficult to treat, and limited data are available to help guide subsequent therapy.To further characterize the natural history of CSA and identify treatment modalities that were most effective in prolonging progression-free (PFS) and disease-specific survival (DSS).We conducted a single-institution retrospective review of patients with recurrent skull base CSA from 1993 to 2021. Kaplan-Meier survival analyses for PFS and DSS were completed. Univariable and multivariable Cox proportional hazards regression models were used to identify patient-related, treatment-related, and disease-related factors that predicted PFS and DSS.A total of 28 patients and 84 episodes of recurrence were included. One-year PFS was 70.6%, 5-year PFS was 28.9%, and 10-year DSS was 78.5%. The median time to first progression was 23.9 months (range, 2.8-282 months). In univariable Cox proportional hazards regression, male sex, higher grade histology, fourth or greater progression episode status, distal pattern of recurrence, and treatment of recurrence without surgery or with chemotherapy alone predicted worse PFS. Multivariable regression predicted shortened DSS in male patients (hazard ratio [HR] 0.16; P = .021) and higher-grade tumors (HR 0.22; P = .039). Treatment of recurrence with surgery was associated with, but did not significantly predict, improved DSS (HR 1.78; P = .11).Several patient and disease-specific factors were associated with shorter PFS and DSS in recurrent skull base chondrosarcoma. For recurrences amenable to resection, surgery is recommended for treatment of recurrent CSA. Local recurrence management without surgery results in shorter PFS and DSS.

Background Chordomas are aggressive bone tumors that often recur despite maximal resection and adjuvant radiation. To date there are no Food and Drug Administration (FDA)-approved chemotherapies. Computational drug repositioning is an expanding approach to identify pharmacotherapies for clinical trials. Objective To identify FDA-approved compounds for repurposing in chordoma. Methods Previously identified highly differentially expressed genes from chordoma tissue samples at our institution were compared with pharmacogenomic interactions in the Comparative Toxicogenomics Database (CTD) using ksRepo, a drug-repositioning platform. Compounds selected by ksRepo were then validated in CH22 and UM-Chor1 human chordoma cells in Vitro. Results A total of 13 chemical compounds were identified in silico from the CTD, and 6 were selected for preclinical validation in human chordoma cell lines based on their clinical relevance. Of these, 3 identified drugs are FDA-approved chemotherapies for other malignancies (cisplatin, cytarabine, and lucanthone). Cytarabine, a deoxyribonucleic acid polymerase inhibitor approved for the treatment of various leukemias, exhibited a significant concentration-dependent effect against CH22 and UM-Chor1 cells when compared to positive (THZ1) and negative (venetoclax) controls. Tretinoin exhibited a significant concentration-dependent cytotoxic effect in CH22, sacral chordoma-derived cell lines but to a much lesser extent in UM-Chor1, a cell line derived from skull base chordoma. Conclusion Cytarabine administration reduces the viability of human chordoma cells. The equally effective reduction in viability seen with tretinoin seems to be cell line dependent. Based on our findings, we recommend the evaluation of cytarabine and tretinoin in an expanded set of human chordoma cell lines and animal models.

Sinonasal tumors that harbor neuroendocrine histologic features include olfactory neuroblastoma (previously known as esthesioneuroblastoma), sinonasal neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma. These tumors represent a diverse spectrum of clinical behavior and as such require histology-specific management. Herein, we review the management of these sinonasal tumors with neuroendocrine features and discuss fundamentals of multi-modality care for each histology. An emphasis is placed on olfactory neuroblastomas, given their relative frequency and skullbase origin. A comprehensive literature review on contemporary management of olfactory neuroblastoma, sinonasal neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma was performed. Management of sinonasal tumors with neuroendocrine features can include surgical resection, radiation therapy, and/or chemotherapy. Due to their site of origin, these tumors can frequently involve the skullbase, which can require site-specific care. The optimal treatment modalities and the sequence in which they are performed are largely dependent on histology. In most cases, olfactory neuroblastoma is best managed with surgical resection followed by radiation therapy. Sinonasal neuroendocrine carcinomas represent a variety of histologic phenotypes (carcinoid, atypical carcinoid, small cell, and large cell), which determine the optimal treatment modality. Finally, sinonasal undifferentiated carcinoma is likely best managed by induction chemotherapy with subsequent therapy dictated by the initial response. A team approach to multi-modality care is essential in the treatment of olfactory neuroblastoma, sinonasal neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma. Early biopsy, histologic diagnosis, and comprehensive imaging are critical to determining the appropriate management paradigm.

Skull base primary malignancies represent a heterogeneous group of histologic diagnoses and sarcomas of the skull base are specific malignant tumors that arise from mesenchymal cells and can be classified by site of origin into bony and soft tissue sarcomas. The most common bony sarcomas include: chondrosarcoma, osteosarcoma, chordoma, Ewing's sarcoma. Given the relative rarity of each histologic diagnosis, especially in the skull base, there is limited published data to guide the management of patients with skull base sarcomas. An electronic search of the literature was performed to obtain key publications in the management of bony sarcomas of the skull base published within the last decade. This article is thus a review of the multi-disciplinary management principles of primary bony sarcomas of the skull base. Of note, there have been several recent advancements in the realm of skull base sarcoma management that have resulted in improved survival. These include advances in: imaging and diagnostic techniques, surgical techniques that incorporate oncologic surgical principles, conformal radiation paradigms and targeted systemic therapies. Early access to coordinated multi-disciplinary subspecialty care immediately at suspicion of diagnosis has further improved outcomes. There are several ongoing trials in the realms of radiation therapy and systemic therapy that will hopefully provide further insight about the optimal management of bony sarcomas of the skull base.

OBJECTIVE Patients with recurrent sinonasal cancers (RSNCs) often present with extensive involvement of the skull base and exhibit high rates of subsequent recurrence and death after therapy. The impact of salvage surgery and margin status on progression-free survival (PFS) and overall survival (OS) has yet to be demonstrated. The goal of this study was to determine whether skull base resection with negative margins has an impact on outcomes in the recurrent setting. METHODS A retrospective chart review of 47 patients who underwent surgery for RSNC with skull base invasion between November 1993 and June 2020 was conducted. The following variables were extracted from the clinical records: patient demographic characteristics (age and sex), tumor pathology, dural and orbital invasion, and prior radiation exposure and induction chemotherapy. Metastatic disease status, surgical approach, margin status, and history of postoperative chemotherapy and/or postoperative radiation therapy were noted. The primary and secondary outcomes were PFS and OS, respectively. RESULTS The cohort included 30 males (63.8%) and 17 females (36.2%), with a mean ± SD age of 54.8 ± 14.4 years. Thirty-five (74.5%) patients showed disease progression, and 29 (61.7%) patients died during the study period. The mean ± SD patient follow-up period was 61.8 ± 64.4 months. Dural invasion was associated with increased risk of death (HR 2.62, 95% CI 1.13–6.08). High-risk histopathology (HR 3.14, 95% CI 1.10–8.95) and induction chemotherapy (HR 2.32, 95% CI 1.07–5.06) were associated with increased odds of disease progression. When compared to patients with positive margins or gross-total resection with unknown margin status, those with negative margins had decreased odds of disease progression (HR 0.30, 95% CI 0.14–0.63) and death (HR 0.38, 95% CI 0.17–0.85). CONCLUSIONS RSNCs show high rates of subsequent disease progression and mortality. This study demonstrated that negative margins may be associated with improved PFS and OS in carefully selected patients who have undergone salvage surgery for RSNC.

Chondrosarcomas of the skull base are malignant tumors for which surgery is the primary therapeutic option. Gross-total resection has been demonstrated to improve survival in patients with these tumors. Chondrosarcomas arising from the petroclival synchondrosis harbor particularly unique anatomical considerations that have long been a barrier to achieving such a resection. Endoscopic endonasal transpterygoid approaches have been recently used to gain improved access to such lesions; however, these approaches have classically relied on a medial to lateral transclival trajectory, which provides limited exposure for complete resection of lateral disease. In this paper the authors describe an endoscopic endonasal transpterygoid transnasopharyngeal approach that provides comprehensive access to the petroclival region through dissection of the eustachian tube with resection of the cartilaginous torus tubarius. Of note, the authors have previously demonstrated the superior outcomes and validity of this approach relative to other cranial base techniques for petroclival chondrosarcomas. Surgical outcomes in 5 cases of chondrosarcoma without medial extension are detailed. Gross-total resection was achieved in 4 of 5 patients. Postoperative complications included transient palatal numbness in all patients and eustachian tube dysfunction due to the approach. With tympanostomy tube placement, no patient had persistent hearing loss. Overall, this approach appears to be a safe and effective technique for resection of petroclival chondrosarcomas.

OBJECTIVEThe objective of this study was to assess outcomes after Gamma Knife radiosurgery (GKRS) re-irradiation for palliation of patients with trigeminal pain secondary to recurrent malignant skull base tumors.METHODSFrom 2009 to 2016, 26 patients who had previously undergone radiation treatment to the head and neck received GKRS for palliation of trigeminal neuropathic pain secondary to recurrence of malignant skull base tumors. Twenty-two patients received single-fraction GKRS to a median dose of 17 Gy (range 15–20 Gy) prescribed to the 50% isodose line (range 43%–55%). Four patients received fractionated Gamma Knife Extend therapy to a median dose of 24 Gy in 3 fractions (range 21–27 Gy) prescribed to the 50% isodose line (range 45%–50%). Those with at least a 3-month follow-up were assessed for symptom palliation. Self-reported pain was evaluated by the numeric rating scale (NRS) and MD Anderson Symptom Inventory–Head and Neck (MDASI-HN) pain score. Frequency of as-needed (PRN) analgesic use and opioid requirement were also assessed. Baseline opioid dose was reported as a fentanyl-equivalent dose (FED) and PRN for breakthrough pain use as oral morphine-equivalent dose (OMED). The chi-square and Student t-tests were used to determine differences before and after GKRS.RESULTSSeven patients (29%) were excluded due to local disease progression. Two experienced progression at the first follow-up, and 5 had local recurrence from disease outside the GKRS volume. Nineteen patients were assessed for symptom palliation with a median follow-up duration of 10.4 months (range 3.0–34.4 months). At 3 months after GKRS, the NRS scores (n = 19) decreased from 4.65 ± 3.45 to 1.47 ± 2.11 (p < 0.001); MDASI-HN pain scores (n = 13) decreased from 5.02 ± 1.68 to 2.02 ± 1.54 (p < 0.01); scheduled FED (n = 19) decreased from 62.4 ± 102.1 to 27.9 ± 45.5 mcg/hr (p < 0.01); PRN OMED (n = 19) decreased from 43.9 ± 77.5 to 10.9 ± 20.8 mg/day (p = 0.02); and frequency of any PRN analgesic use (n = 19) decreased from 0.49 ± 0.55 to 1.33 ± 0.90 per day (p = 0.08). At 6 months after GKRS, 9 (56%) of 16 patients reported being pain free (NRS score 0), with 6 (67%) of the 9 being both pain free and not requiring analgesic medications. One patient treated early in our experience developed a temporary increase in trigeminal pain 3–4 days after GKRS requiring hospitalization. All subsequently treated patients were given a single dose of intravenous steroids immediately after GKRS followed by a 2–3-week oral steroid taper. No further cases of increased or new pain after treatment were observed after this intervention.CONCLUSIONSGKRS for palliation of trigeminal pain secondary to recurrent malignant skull base tumors demonstrated a significant decrease in patient-reported pain and opioid requirement. Additional patients and a longer follow-up duration are needed to assess durability of symptom relief and local control.

Objective The objective of this study was to identify factors associated with improved tumor control at individual sites of recurrence and to define the role of stereotactic radiosurgery (SRS) in the management of local or distant progression following prior radiotherapy. Study Design Clinical data of patients with recurrent skull base chordoma following prior radiotherapy were retrospectively reviewed. Setting and Participants This is a single-center retrospective study including 16 patients from the University of Texas MD Anderson Cancer Center Houston, Texas, United States. Main Outcome Measures Each site of recurrence was considered independently, and the primary outcome was freedom from treatment site progression (FFTSP). Results There were 40 episodes of either local or distant progression treated in 16 patients with skull base chordoma. Tumor recurrence was classified as either local, distant, or both local and distant involving the skull base, spinal column, or leptomeninges. Patients were treated with repeat surgical resection (n = 16), SRS (n = 21), or chemotherapy (n = 25). In multivariate analysis, SRS was the only treatment modality associated with improved FFTSP (p = 0.006). For tumors treated with SRS, there was no evidence of tumor progression or adverse radiation events. Other factors associated with worse FFTSP included the number of progressive episodes (>3), tumor histology, and leptomeningeal disease. Conclusions For local recurrence following prior radiotherapy, SRS was associated with improved FFTSP. SRS may represent an effective palliative treatment offering durable tumor control at the treated site without significant treatment-related morbidity.

PURPOSE Multimodal therapy is a well-established approach for the treatment of sinonasal undifferentiated carcinoma (SNUC); however, the optimal sequence of the various treatments modalities is yet to be determined. This study aimed to assess the role of induction chemotherapy (IC) in guiding definitive therapy in patients with SNUC. METHODS Ninety-five previously untreated patients diagnosed with SNUC and treated between 2001 and 2018 at The University of Texas MD Anderson Cancer Center were included in the analysis. Patients were treated with curative intent and received IC before definitive locoregional therapy. The primary end point was disease-specific survival (DSS). Secondary end points included overall and disease-free survival, disease recurrence, and organ preservation. RESULTS A total of 95 treatment-naïve patients were included in the analysis. For the entire cohort, the 5-years DSS probability was 59% (95% CI, 53% to 66%). In patients who had partial or complete response to IC, the 5-year DSS probabilities were 81% (95% CI, 69% to 88%) after treatment with definitive concurrent chemoradiotherapy (CRT) after IC and 54% (95% CI, 44% to 61%) after definitive surgery and postoperative radiotherapy or CRT after IC (log-rank P = .001). In patients who did not experience at least a partial response to IC, the 5-year DSS probabilities were 0% (95% CI, 0% to 4%) in patients who were treated with concurrent CRT after IC and 39% (95% CI, 30% to 46%) in patients who were treated with surgery plus radiotherapy or CRT (adjusted hazard ratio of 5.68 [95% CI, 2.89 to 9.36]). CONCLUSION In patients who achieve a favorable response to IC, definitive CRT results in improved survival compared with those who undergo definitive surgery. In patients who do not achieve a favorable response to IC, surgery when feasible seems to provide a better chance of disease control and improved survival.

Purpose: Fractionated stereotactic radiosurgery (FSRS) can be given with at least three modalities: Gamma Knife, with the noninvasive frameless extend system (GKE); linear accelerator-based volumetric modulated arc therapy (VMAT); and intensity-modulated proton therapy (IMPT). We extracted treatment plans for patients who had received FSRS with GKE for recurrent skull base or intracranial tumors, created corresponding plans for VMAT and IMPT, and compared the quality of the three sets of plans. Methods and materials: Plans were extracted for 9 patients with recurrent malignant skull-base tumors (n = 6) or large intracranial tumors (n = 3) who had received FSRS with GKE (median dose 24 Gy in 3 fractions) in 2013 through 2015. Plans for VMAT were generated with a TrueBeam STx LINAC machine using 6-MV photons, and plans for IMPT were generated with multi-field optimization. The optimized VMAT and IMPT plans were normalized to achieve the best possible target coverage while meeting the same dose-volume constraints on organs at risk (OARs) as the GKE plans. Plans were evaluated on the basis of target coverage, conformity index, homogeneity index, gradient index, and treatment efficiency. Results: The median target volume was 10.2 cm3 (range 1.9 - 33.8 cm3). The VMAT and IMPT plans met all OAR constraints, and target coverage and conformity were comparable among all plans. VMAT and IMPT plans showed significantly better target uniformity and treatment delivery efficiency (P < 0.001). The gradient index and low-dose-bath were superior in the GKE plans (P < 0.001), indicating smaller irradiated volumes. When inverse planning was used, VMAT plans could achieve a similar or steeper dose drop-off at the target-OAR boundary than GKE plans. Conclusion: FSRS for skull base and large intracranial lesions delivered by VMAT and IMPT can achieve comparable target coverage, conformity, and sparing of critical structure as the GKE while providing superior target uniformity and treatment delivery efficiency. The GKE had superior high-dose gradients outside the target and thus better protected surrounding normal structures.

Objectives/hypothesis Olfactory neuroblastoma (ONB) is a rare sinonasal malignant neoplasm that is known to develop late recurrence. The aim of this study is to evaluate the long-term outcomes of patients with ONB and to determine the factors associated with prognosis. Study design Retrospective study. Methods A retrospective review of the medical records of 139 patients diagnosed with ONB at MD Anderson Cancer Center was performed between 1991 and 2016. Descriptive statistics were calculated, and Kaplan-Meier curves were utilized to assess survival. Results Median follow-up time was 75 months. Overall, 129 patients (92.8%) had surgery as part of their treatment and 82 (58.9%) patients received postoperative radiation therapy (PORT) or concurrent chemoradiotherapy. Endoscopic approaches were utilized for 72 patients, 69.4% of whom had pure endoscopic endonasal approaches. Five-year overall survival and disease-specific survival were 85.6% and 93.4%, respectively. Recurrence rate was 39.6% with a median time to recurrence of 42 months. Among the 31 patients who received elective nodal irradiation (ENI), two patients developed neck recurrence (6.4%) compared with 20 who developed neck recurrence when ENI was omitted (34.4%) (P = .003). Advanced Kadish stage, orbital invasion, intracranial invasion, and presence of cervical lymphadenopathy at the time of presentation were significantly associated with poor survival. Conclusion ONB has an excellent survival. Surgical resection with PORT when indicated is the mainstay of treatment. Endoscopic approaches can be used as a good tool. Elective neck irradiation reduces the risk of nodal recurrence among patients with clinically N0 neck. Despite the excellent survival, recurrence rate remains high and delayed, highlighting the need for long-term surveillance. Level of evidence Level 4 Laryngoscope, 2021.

OBJECTIVE Sinonasal malignancies that extend to the anterior skull base frequently require neurosurgical intervention. The development of techniques for craniofacial resection revolutionized the management of these neoplasms, but modern and long-term data are lacking, particularly those related to the incorporation of endoscopic techniques and novel adjuvant chemotherapeutics into management schema. The present study was performed to better define the utility of surgical management and to determine factors related to outcome. METHODS Patients who underwent surgery between 1993 and 2020 were included in this retrospective cohort study. Only patients with greater than 6 months of clinical and radiological follow-up were included. Outcome measures included progression, survival, and treatment-related complications. RESULTS Two hundred twenty-five patients were included. The mean clinical follow-up was 6.5 years. The most common histological diagnosis was olfactory neuroblastoma (33%). Overall, metastatic disease and brain invasion were present in 8% and 19% of patients, respectively, at the time of surgery. A lumbar drain was used in 54% of patients. When stratified by decade, higher-stage disease at surgery became more frequent over time (15% of patients had metastatic disease in the 3rd decade of the study period vs 4% in the 1st decade). Despite the inclusion of patients with progressively higher-stage disease, median overall survival (OS) remained stable in each decade at approximately 10 years (p = 0.16). OS was significantly worse in patients with brain invasion (p = 0.006) or metastasis at the time of surgery (p = 0.014). Complications occurred after 28% of operations, but typically resulted in no long-term negative sequelae. Use of a lumbar drain was a significant predictor of complications (p = 0.02). Permanent ophthalmological disabilities were observed after 4% of surgical procedures. One patient died during the perioperative period. Finally, major complications (Clavien-Dindo grade ≥ IIIb) decreased from 27% of patients in the 1st decade to 10% in the 3rd decade (p = 0.007). CONCLUSIONS The surgical management of sinonasal malignancies with anterior skull base involvement is effective and generally safe. Surgical management, however, is only one facet of the overall multimodal management paradigms created to optimize patient outcomes. Survival outcomes have remained stable despite more extensive disease at surgery in patients who have presented in recent decades. The safety of such surgery has improved over time owing to the incorporation of endoscopic surgical techniques and the avoidance of lumbar spinal drainage with open resection.

Management of chordoma along the cranial-spinal axis is a major challenge for both skull base and spinal surgeons. Although chordoma remains a rare tumor, occurring in approximately 1 per 1 million individuals, its treatment poses several challenges. These tumors are generally poorly responsive to radiation and chemotherapy, leading to surgical resection as the mainstay of treatment. Due to anatomic constraints and unique challenges associated with each primary site of disease, gross total resection is often not feasible and is associated with high rates of morbidity. Additionally, chordoma is associated with high rates of recurrence due to the tumor's aggressive biologic features, and postoperative radiation is increasingly incorporated as a treatment option for these patients. Despite these challenges, modern-day surgical techniques in both skull base and spinal surgery have facilitated improved patient outcomes. For example, endoscopic endonasal techniques have become the mainstay in resection of skull base chordomas, improving the ability to achieve gross total resection, while reducing associated morbidity of open transfacial techniques. Resection of spinal chordomas has been facilitated by emerging techniques in preoperative imaging, intraoperative navigation, spinal reconstruction, and radiotherapy. Taken collectively, the treatment of chordoma affecting the skull base and spinal requires a multidisciplinary team of surgeons, radiation oncologists, and medical oncologists who specialize in the treatment of this challenging disease.

Objective Different surgical set-ups for endoscopic transsphenoidal surgery (ETS) have been described, but studies on their ergonomics are limited. The aim of this article is to describe present trends in the ergonomics of ETS. Design and Participants A 33-question, web-based survey was sent to North American Skull Base Society members in 2018 and 116 responded to it (16% of all members). Most respondents were from North America (76%), in academic practice (87%), and neurosurgeons (65%); they had more than 5 years of experience in ETS (73%), had received specific training (66%), and performed at least 5 procedures/mo (55%). Results Mean reported time for standard and complex procedures were 3.7 and 6.3 hours, respectively. The patient's body is usually positioned in a straight, supine position (84%); the head is in a neutral position (46%) or rotated to the side (38%). Most surgeons perform a binostril technique, work with a partner (95%), and operate standing (94%), holding suction (89%) and dissector (83%); sometimes the endoscope is held by the primary surgeon (22–24%). The second surgeon usually holds the endoscope (72%) and irrigation (42%). During tumor removal most surgeons stand on the same side (65–66%). Many respondents report strain at the dorsolumbar (50%) or cervical (26%) level. Almost one-third of surgeons incorporate a pause during surgery to stretch, and approximately half exercise to be fit for surgery; 16% had sought medical attention for ergonomic-related symptoms. Conclusion Most respondents value ergonomics in ETS. The variability in surgical set-ups and the relatively high report of complaints underline the need for further studies to optimize ergonomics in ETS.

Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region that leads to debilitating symptoms and poor survival. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there is interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated four pituitary carcinoma patients with pembrolizumab as part of a phase II clinical trial (NCT02721732). Here, we present their clinical course and outcomes and correlate responses with available molecular data: hypermutation status, PD-L1 staining, tumor-infiltrating lymphocyte score, microsatellite status and tumor mutational burden. Patients 1 and 2, with heavily pretreated, refractory corticotroph pituitary carcinoma, had partial radiographic (60% and 32% per irRECIST, respectively) and hormonal responses. Patient 1’s response continues 42 months after initiation of pembrolizumab and his baseline tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2’s tumor was not sampled after exposure to temozolomide, but prior somatic mutational testing was negative. Patient 3 (non-functioning corticotroph tumor) had a best response of stable disease for four months. Patient 4 (prolactin-secreting carcinoma) had progressive disease. The latter two patients’ tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. PD-L1 staining was negative in all tumors. TIL score was 2 in Patients 1 and 4, negative in Patient 3 and not available in Patient 2. All patients tolerated the treatment well with mild adverse events. Our study generates the hypothesis that an alkylating agent-induced hypermutator phenotype may be an indicator of response to CPIs in pituitary carcinomas. The role of CPI in treating patients with pituitary carcinoma and mechanisms of hypermutation in this population require further study.

Autopsy studies suggest that skull base metastases are likely underrecognized in patients with cancer. Patients frequently present with one or a combination of skull base clinical syndromes that manifest as pain or cranial neuropathy. Once a skull base metastasis is suspected, establishing a histologic diagnosis, dedicated imaging, and restaging (if appropriate) are the first steps in management. A multidisciplinary approach should then be used to identify the optimal histology-based treatment strategy, taking into account the burden of systemic disease. Finally, definitive treatment may include one or a combination of surgical management, radiation therapy, or chemotherapy."

OBJECTIVES To evaluate the incidence of histopathologic diagnostic discrepancy for patients referred to our institution, identify pathologies susceptible to diagnostic error, and assess the impact on survival of histopathologic diagnostic discrepancies. METHODS Three hundred ninety-seven patients with sinonasal cancers were identified, and discordance between the outside pathologic report and MD Anderson Cancer Center pathologic report was assessed. Overall survival and disease-specific survival were analyzed using Kaplan-Meier and log rank methods. RESULTS Discordance of major histopathologic diagnoses was present in 24% (97 of 397) of reports, with sinonasal undifferentiated carcinoma, sarcoma, neuroendocrine carcinoma, and poorly differentiated carcinoma pathologies having the highest change in diagnosis (P

Meningiomas of the olfactory groove and planum sphenoidale are relatively common skullbase meningiomas. They are typically of low grade but may grow to large size due to the insidious nature of their growth. Surgical resection remains the mainstay of treatment.

Background Skull base osteoradionecrosis (ORN) is a challenging treatment-related complication sometimes seen in patients with cancer. Although ORN management strategies for other anatomic sites have been reported, there is a paucity of data guiding the management of skull base ORN. Objective To report a single-center tertiary care series of skull base ORN and to better understand the factors affecting ORN recurrence after surgical management. Methods We conducted a retrospective cohort study of patients with skull base ORN treated at our center between 2003 and 2017. Univariate and multivariate binary logistic regressions were performed to identify predictors of recurrence. Results A total of 31 patients were included in this study. The median age at ORN diagnosis was 61.1 yr (range, 32.8-84.9 yr). Of these 31 patients, 15 (48.4%) patients were initially treated medically. All 31 patients underwent surgery. Three (14.3%) of 21 patients treated with a free flap and 4 (50.0%) of 8 patients who underwent primary closure experienced recurrence. Cox regression analysis revealed that reconstruction with local tissue closure (P = .044) and ongoing treatment for active primary cancer (P = .022) were significant predictors of recurrence. The median overall survival from index surgery for ORN treatment was 83.9 mo. At 12-mo follow-up, 78.5% of patients were alive. Conclusion In this study, we assess the outcomes of our treatment approach, surgical debridement with vascularized reconstruction, on recurrence-free survival in patients with skull base ORN. Further studies with larger cohorts are needed to assess current treatment paradigms.

Sinonasal tumors that harbor neuroendocrine histologic features include olfactory neuroblastoma (previously known as esthesioneuroblastoma), sinonasal neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma. These tumors represent a diverse spectrum of clinical behavior and as such require histology-specific management. Herein, we review the management of these sinonasal tumors with neuroendocrine features and discuss fundamentals of multi-modality care for each histology. An emphasis is placed on olfactory neuroblastomas, given their relative frequency and skullbase origin.A comprehensive literature review on contemporary management of olfactory neuroblastoma, sinonasal neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma was performed.Management of sinonasal tumors with neuroendocrine features can include surgical resection, radiation therapy, and/or chemotherapy. Due to their site of origin, these tumors can frequently involve the skullbase, which can require site-specific care. The optimal treatment modalities and the sequence in which they are performed are largely dependent on histology. In most cases, olfactory neuroblastoma is best managed with surgical resection followed by radiation therapy. Sinonasal neuroendocrine carcinomas represent a variety of histologic phenotypes (carcinoid, atypical carcinoid, small cell, and large cell), which determine the optimal treatment modality. Finally, sinonasal undifferentiated carcinoma is likely best managed by induction chemotherapy with subsequent therapy dictated by the initial response.A team approach to multi-modality care is essential in the treatment of olfactory neuroblastoma, sinonasal neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma. Early biopsy, histologic diagnosis, and comprehensive imaging are critical to determining the appropriate management paradigm.

Background Skull base chondrosarcomas (CSA) are difficult tumors to cure and there is little data regarding salvage therapy. Objective This study aims to identify presentation and treatment-related factors which impact the progression free survival (PFS) and disease specific survival (DSS) for recurrent CSA, and to identify salvage treatment factors associated with successful restoration to the natural history following primary treatment. Methods This single-institution retrospective review included patients with recurrent/progressive CSA over a 25-year period. Survival analysis for factors impacting PFS and DSS was performed. Salvage treatment factors associated with achieving PFS ≥newly diagnosed median PFS were identified using univariate statistics. Analysis was performed on first recurrences and all recurrences combined. Results A total of 47 recurrence/progression events were analyzed from 17 patients (median two events/patient, range = 1–8). The overall PFS and DSS for the initial recurrence was 32 (range = 3–267) and 79 (range = 3–285) months, respectively. Conventional grade III or mesenchymal histology significantly predicted shorter PFS and DSS (p Conclusion In this series, high grade histology and prior radiation treatment negatively impacted salvage treatment outcomes, while GTR was associated with restoration to natural history following primary treatment. Careful consideration of histology, systemic disease status, previous treatments, and the anatomic extent of the skull base disease can optimize the outcomes of salvage intervention.