The role of systemic therapy in advanced skull base chordomas: overview of the current state and the MD Anderson protocol.

The role of systemic therapy in primary or advanced and metastatic chordoma has been traditionally limited because of the inherent resistance to cytotoxic therapies and lack of specific or effective therapeutic targets. Despite resection and adjuvant radiation therapy, local recurrence rates in clival chordoma remain high and the risk of systemic metastases is not trivial, leading to significant morbidity and mortality. Recently, molecular targeted therapies (MTTs) and immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic avenues in chordoma. In recent years, preclinical studies have identified potential targets based on intrinsic genetic dependencies, epigenetic modulators, or newly identified tumor-associated cell populations driving treatment resistance and recurrence. Nonetheless, the role of systemic therapies in the neoadjuvant or adjuvant setting for primary, locally progressive, and distant metastatic chordomas is still being investigated. Herein, an overview of current and emerging systemic treatment strategies in advanced clival chordoma is provided. Furthermore, several molecular biomarkers have been recently uncovered as potential predictors of the response to specific molecular therapeutics. The authors describe the recently discovered role of 1p36 and 9p21 deletions as biomarkers capable of guiding drug selection. Then they discuss completed and ongoing clinical trials of MTTs, including several tyrosine kinase inhibitors used as monotherapy or in combination, such as imatinib, sorafenib, dasatinib, and lapatinib, among others, as well as mammalian target of rapamycin inhibitors such as everolimus and rapamycin. They present their experience and other recent studies demonstrating vast benefits in advanced chordoma from ICIs. Additionally, they provide a brief overview of novel systemic strategies such as adoptive cell transfer (CAR-T and NK cells), oncolytic viruses, epigenetic targeting (KDM6, HDAC, and EZH2 inhibitors), and several promising preclinical studies with high translational potential. Finally, the authors present their institutional multidisciplinary protocol for the incorporation of systemic therapy for both newly diagnosed and recurrent chordomas based on molecular studies including upfront enrollment in MTT trials in patients with epidermal growth factor receptor upregulation or INI-1 deficiency or enrollment in ICI clinical trials for patients with high tumor mutational burden or high PD-L1 expression on tumor cells or in the tumor microenvironment.

Predictors of postoperative performance status after surgical management of infratemporal fossa malignancies.

Infratemporal fossa (ITF) tumors are difficult to access surgically due to anatomical constraints. Moreover, aggressive ITF carcinomas and sarcomas necessitate aggressive treatment strategies that, along with tumor-related symptoms, contribute to decreases in patient performance status. To assess factors that predict postoperative performance in patients undergoing surgery for ITF tumors. We reviewed medical records for all patients surgically treated for an ITF malignancy between January 1, 1999, and December 31, 2017, at our institution. We collected patient demographics, preoperative performance, tumor stage, tumor characteristics, treatment modalities, pathological data, and postoperative performance data. The 5-year survival rate was 62.2%. Higher preoperative Karnofsky Performance Status (KPS) score (n = 64; p < 0.001), short length of stay (p = 0.002), prior surgery at site (n = 61; p = 0.0164), and diagnosis of sarcoma (n = 62; p = 0.0398) were predictors of higher postoperative KPS scores. Percutaneous endoscopic gastrostomy (PEG) (n = 9; p = 0.0327), and tracheostomy tube placement (n = 20; p = 0.0436) were predictors of lower postoperative KPS scores, whereas age at presentation (p = 0.72), intracranial tumor spread (p = 0.8197), and perineural invasion (n = 40; p = 0.2195) were not. Male patients and patients with carcinomas showed the greatest decreases in KPS scores between pretreatment and posttreatment. Higher preoperative KPS score and short length of stay were the best predictors of higher postoperative KPS scores. This work provides treatment teams and patients with better information on outcomes for shared decision-making.

The impact of expanded endoscopic approaches on oncologic and functional outcomes for clival malignancies:a case series.

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 < 0.05. EEA had a shorter time interval from surgery to initiation of radiotherapy. No difference in 6 and 12 month KPS was found between surgical groups. Patients undergoing open surgery were less likely to achieve GTR for upper clival lesions. CONCLUSIONS: EEA was found to be associated with increased PFS, for upper and middle clival malignancies. The time to initiation of radiotherapy was shorter for patients undergoing EEA compared to open surgery for patients with middle clival involvement. GTR rates were found to be significantly better with EEA for patients with upper clival malignancies.

Long term outcomes following surgery for pineal region tumors.

PURPOSE: Pineal region tumors are surgically demanding tumors to resect. Long term neuro-oncologic outcomes following surgical excision of tumors from this region have been underreported. We sought to define the long term outcomes of patients undergoing resection of pineal region tumors. METHODS: A retrospective analysis of a prospectively maintained database was performed on patients who underwent intended surgical excision of pineal region tumors. Overall survival (OS) and progression free survival (PFS) were the primary endpoints of this study. Factors associated with OS, PFS and the degree of resection were analyzed, along with 30-day complication rates and dependence on CSF diversion. RESULTS: Sixty-eight patients with a mean age of 30.9 ± 15.3 years were analyzed. The median clinical and radiographic follow-up was 95.7 and 48.2 months, respectively. The supracerebellar infratentorial and the occipital transtentorial corridors were utilized in the majority of cases (80.9%). The gross total resection (GTR) rate was 52.9% (n=36). The 5-year OS and PFS rates were 70.2% and 58.5%, respectively. Achieving GTR was associated with improved OS (HR 0.39, p = 0.03) and PFS (HR 0.4, p = 0.006). The 30-day mortality rate was 5.9%. The need for CSF diversion was high with 77.9% of patients requiring a shunt or ETV by last follow-up. CONCLUSIONS: This is the first modern surgical series providing long term follow-up for patients undergoing surgical resection of pineal region tumors. Obtaining a GTR of these challenging tumors is beneficial with regards to PFS/OS. Higher grade tumors have diminished PFS/OS and are treated with adjuvant chemotherapy and/or radiotherapy.

High-grade transformation of low-grade biphenotypic sinonasal sarcoma: Radiological, morphophenotypic variation and confirmatory molecular analysis.

Biphenotypic sinonasal sarcoma (BSNS) is a recently described spindle cell sarcoma with neural and myogenic differentiation which arises exclusively in the sinonasal region. A man presented with swelling of left eyelid, and history of resection of a low-grade spindle cell mesenchymal tumor of left sinonasal cavity performed 15 years before. The original diagnosis was synovial sarcoma. Current MRI showed left supraorbital mass with intracranial extension. IR biopsy confirmed recurrence, and a left orbital craniotomy was done. NGS identified PAX3-MAML3 fusion in both, current and original tumor. The sarcoma was reclassified as BSNS, recurrent, with higher grade transformation. While the morphology, phenotype and molecular signature were in keeping with BSNS, the tumor showed biological progression towards a high-grade sarcoma. High-grade transformation of low-grade BSNS has not been described so far. High-grade transformation was not appreciated at the time of initial diagnosis, and it occurred in the local recurrence 15 years after.

Outcomes of orbital exenteration for craniofacial lesions.

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).

Neoadjuvant chemotherapy for locoregionally advanced squamous cell carcinoma of the paranasal sinuses.

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.

Surgical Management of Skull Base and Spine Chordomas.

OPINION STATEMENT: 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.

Advances in the management of primary bone sarcomas of the skull base.

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.

Management of olfactory neuroblastoma, neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma involving the skullbase.

INTRODUCTION: 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. METHODS: A comprehensive literature review on contemporary management of olfactory neuroblastoma, sinonasal neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma was performed. RESULTS: 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. CONCLUSIONS: 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.

Approaches to regional lymph node metastasis in patients with head and neck mucosal melanoma.

BACKGROUND: Mucosal melanomas in the head and neck region are most often located in the nasal cavity and paranasal sinuses. To the authors' knowledge, the prognostic effects of lymph node metastasis in patients with sinonasal mucosal melanoma (SNMM) have not been established. Therefore, the objective of the current study was to determine the effects of lymph node metastasis on survival. METHODS: The current study included 198 patients with SNMM who had been treated between 1985 and 2016 at The University of Texas MD Anderson Cancer Center in Houston. Patients' clinical and pathologic lymph node statuses were evaluated and characterized. A multivariate analysis was used to assess the associations between regional spread and survival outcomes. RESULTS: Therapeutic neck dissection was performed in 23 patients with SNMM (11.6%). Regional disease recurrence occurred in 7 of the patients who had lymph node metastasis at the time of presentation (30.4%) and in 30 of those who had N0 disease at the time of presentation (17.1%) (P = .15). Metastasis to the contralateral lymph nodes was present in 7 patients (3.5%). The 5-year disease-specific survival rate was 66% in patients with lymph node spread compared with 45% in patients with N0 status (P = .04, log-rank test). A multivariate analysis demonstrated that distant metastasis was the only variable found to be independently associated with both overall survival (hazard ratio, 2.96; 95% confidence interval, 1.54-6.95 [P = .01]) and disease-specific survival (hazard ratio, 3.32; 95% confidence interval, 1.79-7.14 [P = 0.01]). CONCLUSIONS: The results of the current study demonstrated that lymph node status in patients with SNMM was not a significant predictor of outcome. This finding, together with the low incidence of lymph node metastases in patients with SNMM, suggests that elective treatment of the neck should be highly selective in this patient population. Cancer 2018;124:514-20. © 2017 American Cancer Society.

Patterns of Treatment Failure in Patients with Sinonasal Mucosal Melanoma.

BACKGROUND: Head and neck mucosal melanoma is a locally aggressive tumor with a high recurrence rate. The paranasal sinuses and nasal cavity are the most common primary tumor sites. OBJECTIVE: The purpose of this retrospective study was to identify independent predictors of outcome in sinonasal mucosal melanoma (SNMM) and characterize the patterns of treatment failure. METHODS: This study included 198 patients with SNMM who had been treated at The University of Texas MD Anderson Cancer Center from 1 January 1991 through 31 December 2016. The survival outcomes included overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), local recurrence-free survival, and distant metastasis-free survival. A stepwise regression analysis was used to assess associations in the multivariate models. RESULTS: The 5-year OS, DSS, and DFS rates were 38, 58, and 27%, respectively. Independent predictors of poor OS and DSS were the paranasal sinuses as the primary tumor site [hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.11-2.66; and HR 2.12, 95% CI 1.21-3.74, respectively] and the presence of distant metastases at presentation (HR 4.53, 95% CI 2.24-7.83; and HR 3.6, 95% CI 1.12-7.1). Recurrence occurred in 96 patients (48%). The most common cause of treatment failure was distant metastasis in 69 of 198 patients (35%), followed by local [36 (18%)] and regional [22 (11%)] recurrence. CONCLUSION: The most common cause of treatment failure in SNMM is distant metastasis. The tumor site and the presence of metastatic disease at presentation were the only independent predictors of survival. These data can be used to inform quality improvement efforts and the counseling of high-risk SNMM patients.

Endoscopic endonasal resection of sinonasal/anterior skull base malignancy (Kadish C esthesioneuroblastoma).

BACKGROUND: The surgical management of anterior skull base malignancies requires the full complement of open and endoscopic skull base approaches. Due to the evolution of endoscopic techniques, endoscopic approaches are now being employed for complex skull base tumors. METHODS: We present our technique for endoscopic management for an advanced (T4) anterior skull base malignancy that provides a systematic approach to resection, margin assessment, and reconstruction. CONCLUSION: Our surgical strategy provides a systematic approach by which an oncologic resection can be performed within the context of a spectrum of surgical strategies necessary to manage skull base malignancies.

Impact of early access to multidisciplinary care on treatment outcomes in patients with skull base chordoma.

OBJECTIVE: To determine if early access to multidisciplinary surgical care affects outcomes in patients with skull base chordoma. METHOD: A retrospective chart review of prospectively collected data was performed on 51 patients treated from 1993 to 2014. The cohort was divided into those presenting (1) for initial management (ID, n = 21) or (2) with persistent/progressive disease after prior biopsy/surgery (PD, n = 30) outside of a multidisciplinary setting. The impact of initial surgical management in a multidisciplinary center on progression-free survival (PFS) was assessed with Kaplan-Meier and log-rank analyses. RESULTS: Mean follow-up, median PFS, median overall survival (OS), and 10-year OS for the entire cohort was 70 months, 47 months, 159 months, and 19%, respectively. Initial management in a multidisciplinary center resulted in a significant improvement in PFS versus initial surgery with or without radiotherapy (XRT) outside of this setting (64 vs 25 months, p = 0.035). Initial surgical resection outside of a multidisciplinary setting increased the risk of recurrence/progression on univariate (HR, 2.276; p = 0.022) and multivariate analysis (HR, 2.831; p = 0.006), respectively. CONCLUSIONS: The results from this study emphasize the impact that coordinated multidisciplinary surgical care has on patient outcomes for chordomas of the clivus. Biopsy followed by attempted radical resection at a dedicated center does not affect PFS and, therefore, represents a reasonable first step in management for patients presenting outside of multidisciplinary setting.

Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial.

BACKGROUND: After brain metastasis resection, whole brain radiotherapy decreases local recurrence, but might cause cognitive decline. We did this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved time to local recurrence compared with that for surgical resection alone. METHODS: In this randomised, controlled, phase 3 trial, we recruited patients at a single tertiary cancer centre in the USA. Eligible patients were older than 3 years, had a Karnofsky Performance Score of 70 or higher, were able to have an MRI scan, and had a complete resection of one to three brain metastases (with a maximum diameter of the resection cavity ≤4 cm). Patients were randomly assigned (1:1) with a block size of four to either SRS of the resection cavity (within 30 days of surgery) or observation. Patients were stratified by histology of the primary tumour, metastatic tumour size, and number of metastases. The primary endpoint was time to local recurrence in the resection cavity, assessed by blinded central review of brain MRI scans by the study neuroradiologist in the modified intention-to-treat population that analysed patients by randomised allocation but excluded patients found ineligible after randomisation. Participants and other members of the treatment team (excluding the neuroradiologist) were not masked to treatment allocation. The trial is registered with ClinicalTrials.gov, number NCT00950001, and is closed to new participants. FINDINGS: Between Aug 13, 2009, and Feb 16, 2016, 132 patients were randomly assigned to the observation group (n=68) or SRS group (n=64), with 128 patients available for analysis; four patients were ineligible (three from the SRS group and one from the observation group). Median follow-up was 11·1 months (IQR 4·8-20·4). 12-month freedom from local recurrence was 43% (95% CI 31-59) in the observation group and 72% (60-87) in the SRS group (hazard ratio 0·46 [95% CI 0·24-0·88]; p=0·015). There were no adverse events or treatment-related deaths in either group. INTERPRETATION: SRS of the surgical cavity in patients who have had complete resection of one, two, or three brain metastases significantly lowers local recurrence compared with that noted for observation alone. Thus, the use of SRS after brain metastasis resection could be an alternative to whole-brain radiotherapy. FUNDING: National Institutes of Health.

Mutation status among patients with sinonasal mucosal melanoma and its impact on survival.

BACKGROUND: Sinonasal mucosal melanoma (SNMM) comprises <1% of all melanomas and lacks well-characterised molecular markers. Our aim was to determine the frequencies of common mutations and examine their utility as molecular markers in a large series of primary SNMMs. METHODS: SNMM patients seen at our institution from August 1991 through July 2016 were identified. Genomic DNA was extracted from 66 formalin-fixed paraffin-embedded tumours and screened for mutations by direct sequencing. We investigated the association of mutations with clinicopathological features and survival outcomes. RESULTS: Overall, 41% (27 out of 66) of the SNMMs harboured mutations. BRAF and KIT mutations were identified in 8% (five patients) and 5% (three patients) of SNMMs, respectively, whereas NRAS mutations were detected in 30% (20 patients) of SNMMs. Mutation rates in these oncogenes were similar between SNMMs located in the paranasal sinuses and those in the nasal cavity (30% and 13%, respectively, P=0.09). In a multivariate analysis, patients with negative margins had significantly better overall survival (hazard ratio 5.43, 95% confidence interval 1.44-21.85, P=0.01) and disease-specific survival (hazard ratio 21.9, 95% confidence interval 3.71-180, P=0.0004). The mutation status of the tumours showed no association with survival outcomes. CONCLUSIONS: In SNNM, mutation status does not affect survival outcomes, but NRAS mutations are relatively frequent and could be targeted in this disease by MEK inhibitors.

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma.

Meningioma is the most common primary brain tumor and carries a substantial risk of local recurrence. Methylation profiles of meningioma and their clinical implications are not well understood. We hypothesized that aggressive meningiomas have unique DNA methylation patterns that could be used to better stratify patient management. Samples (n = 140) were profiled using the Illumina HumanMethylation450BeadChip. Unsupervised modeling on a training set (n = 89) identified 2 molecular methylation subgroups of meningioma (MM) with significantly different recurrence-free survival (RFS) times between the groups: a prognostically unfavorable subgroup (MM-UNFAV) and a prognostically favorable subgroup (MM-FAV). This finding was validated in the remaining 51 samples and led to a baseline meningioma methylation classifier (bMMC) defined by 283 CpG loci (283-bMMC). To further optimize a recurrence predictor, probes subsumed within the baseline classifier were subject to additional modeling using a similar training/validation approach, leading to a 64-CpG loci meningioma methylation predictor (64-MMP). After adjustment for relevant clinical variables [WHO grade, mitotic index, Simpson grade, sex, location, and copy number aberrations (CNAs)] multivariable analyses for RFS showed that the baseline methylation classifier was not significant (p = 0.0793). The methylation predictor, however, was significantly associated with tumor recurrence (p < 0.0001). CNAs were extracted from the 450k intensity profiles. Tumor samples in the MM-UNFAV subgroup showed an overall higher proportion of CNAs compared to the MM-FAV subgroup tumors and the CNAs were complex in nature. CNAs in the MM-UNFAV subgroup included recurrent losses of 1p, 6q, 14q and 18q, and gain of 1q, all of which were previously identified as indicators of poor outcome. In conclusion, our analyses demonstrate robust DNA methylation signatures in meningioma that correlate with CNAs and stratify patients by recurrence risk.

Non-contiguous meningeal metastases of olfactory neuroblastoma.

Olfactory neuroblastoma (ONB) is a malignant neoplasm centered along the roof of the nasal cavity near the cribriform plate. Although metastasis of this tumor has been reported, non-contiguous spread to the dura is rare. Here, we report the largest series of intracranial meningeal metastases of ONBs from M.D. Anderson Cancer Center and the University of Toronto. The unique natural history and geographical distribution of these metastatic lesions suggest a common mechanism of tumor spread along the dural vascular arborization.

Contrast-enhanced Reformatted MR Images for Preoperative Assessment of the Bridging Veins of the Skull Base.

Magnetic resonance (MR) venography and computed tomographic (CT) venography are suited for displaying the convexity veins that drain the medial and lateral surfaces of the brain hemispheres. However, such is not the case for the bridging veins of the skull base. Technical factors prevent contrast material-enhanced MR or CT images obtained in standard axial, coronal, and sagittal planes from fully displaying the curved pathways of these clinically important venous structures. This limitation can be overcome by using a reconstruction technique that depicts these venous structures and their interconnections. Curved and multiplanar reformatted images that distill the important venous features often require knowledgeable manipulation of source images by an operator who is familiar with numerous venous variants and their surgical implications. The normal anatomy of the draining veins is detailed-anatomy that radiologists must master before they can show the surgeon the important venous anatomy that is often missing at standard imaging; this information will foster better communication between radiologists and their surgical colleagues. As a practical matter, the skull base veins are arbitrarily subdivided into those that are at greatest risk with the pterional approach and the subtemporal approach, respectively. These approaches can be expanded to define connections between the superficial venous system and the other valveless venous networks that drain the deep portions of the cerebral hemisphere, the scalp, face, muscles of the neck, diploë of the skull, and meninges. As radiologists gain experience, their image interpretations should mature beyond simple analysis of the primary hemodynamic changes induced by intraoperative sacrifice or injury.