Citations

Abstract Adult spinal cord ependymomas are typically low grade and have a relatively favorable clinical course following gross total resection. We report 4 cases of anaplastic spinal cord ependymoma with MYCN amplification, an exceptionally rare finding. All cases occurred in the spinal cord of adolescent and young adult women and had morphological and immunohistochemical features of anaplastic ependymomas (World Health Organization grade III). Chromosomal microarray analysis demonstrated amplification of 2p24 (including MYCN) in all cases. One patient died 6 months after surgery. Another patient recently had removal of metastatic nodules in the thoracic region, following gross total resection and adjuvant radiation therapy of a lumbar ependymoma 1 year previously. One patient responded well after chemotherapy but died after multiple relapses 82 months after diagnosis. We found MYCN amplification reported in 2 other ependymomas, both anaplastic and arising in the spinal cord of adult females (Brain Pathol 2001;11:133–43). One patient had multiple recurrences in the spinal cord and an intracranial metastasis. Although MYCN amplification is rare in ependymomas, the current and previously reported cases suggest that this is associated with higher-grade histology, spinal location, and often unfavorable prognosis. The clinical significance and therapeutic implications of MYCN amplification in ependymomas require further evaluation.

AbstractCerebral amyloidomas, characterized by localized amyloid deposits in the nervous system in the absence of systemic disease, are rare. These typically consist of immunoglobulin light chain (AL)-type, predominantly lambda. Trigeminal nerve involvement is exceptionally rare with only 21 previously reported cases, three with bilateral disease. We report two additional cases of amyloid localized to Meckel’s cave with secondary involvement of the trigeminal nerves bilaterally, with protein characterization by mass spectrometry. The patients, both females, 39 and 49-years-old, respectively, presented with the insidious onset of progressive trigeminal neuropathy, including pain and numbness with sensory loss, refractory to medical therapy. One patient experienced bilateral symptoms. Magnetic resonance imaging demonstrated abnormal thickening and contrast enhancement along Meckel’s cave bilaterally in both cases. The clinical differential diagnosis included benign neoplasms and inflammatory disorders. At the time of biopsy, the trigeminal nerve was noted to be enlarged and multinodular in one case and associated with abnormal soft tan tissue in the other case. Microscopically, the nerve biopsies showed extensive Congo red-positive amyloid deposits. Liquid chromatography tandem mass spectrometry demonstrated that the amyloid was of (AL)-type in both cases (AL [kappa] in one case and AL [lambda] in the other). After extensive evaluation, there was no evidence of systemic involvement. Both patients received localized radiotherapy for their refractory symptoms. One patient has stable symptomatology and imaging. No follow-up is available for the other patient.

Although glioblastoma (GBM) is a fatal primary brain cancer with short median survival of 15 months, a small number of patients survive >5 years after diagnosis; they are known as extreme survivors (ES). Because of their rarity, very little is known about what differentiates these outliers from other patients with GBM. For the purpose of identifying unknown drivers of extreme survivorship in GBM, the ENDURES consortium (ENvironmental Dynamics Underlying Responsive Extreme Survivors of GBM) was developed. This consortium is a multicenter collaborative network of investigators focused on the integration of multiple types of clinical data and the creation of patient-specific models of tumor growth informed by radiographic and histologic parameters. Leveraging our combined resources, the goals of the ENDURES consortium are 2-fold: (1) to build a curated, searchable, multilayered repository housing clinical and outcome data on a large cohort of ES patients with GBM; and (2) to leverage the ENDURES repository for new insights into tumor behavior and novel targets for prolonging survival for all patients with GBM. In this article, the authors review the available literature and discuss what is already known about ES. The authors then describe the creation of their consortium and some preliminary results.

Abstract Background: Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods: Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results: Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Additionally, extent of resection, tumor laterality, and IDH1 mutation status were also found to have sex-specific effects on overall survival. Conclusion: Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

3579 Background: BRAFV600E ( BRAF) mutations (mts) portend poor prognosis in mCRC and patients (pts) may die before ascertainment. Since 2014, Vancouver Coastal Health (VCH) has performed reflex hereditary screening of CRCs with BRAF and mismatch repair (MMR) immunohistochemistry (IHC). We evaluated this BRAF mt population-based cohort ( BRAFPOP) to establish the true prognosis of BRAF mts in mCRC. Methods: We reviewed all mCRCs from VCH between 4/2014 and 5/2018 for BRAF by IHC (VE1 antibody). Overall survival (OS) from stage IV diagnosis was compared to mCRCs with next generation sequencing (NGS) determined BRAF mts ( BRAFNGS) from BC Cancer & MD Anderson. BRAFNGS OS did not differ by center (p = 0.77). Results: See table for BRAF cohort baseline characteristic comparison. BRAFPOP pts had worse OS than BRAFNGS pts (HR 2.5, 95% CI 1.6 – 3.9, P < 0.0001). Median OS for all BRAF mt pts was 17.9 mos. Both groups had worse OS than wild type pts (P < 0.0001). 52 (81%) of BRAFPOP pts were referred to oncology, 40 (63%) received chemotherapy, and 12 (19%) had NGS BRAF testing. BRAFPOP pts who had NGS testing with BRAF mts had OS comparable to other BRAFNGS pts (P = 0.89) and better OS than BRAFPOP pts that never had NGS testing (HR 0.37, 95% CI 0.18-0.76, P = 0.030). Pts with BRAF mts and MMR deficiency (dMMR) (n = 40) had worse OS than MMR proficiency (pMMR, n = 202) (1.6, 95% CI 1.0-2.5, P = 0.011). This was driven by BRAFPOP dMMR pts (HR 1.9, 95% CI 0.9-4.0, P = 0.036) as no difference was seen by MMR in BRAFNGS pts (HR 1.3, 95% CI 0.8-2.2, P = 0.30). Conclusions: Current estimates of prognosis for mCRC with BRAF mts likely underestimate its impact due to referral bias for NGS testing. BRAF mts with dMMR are associated with worse prognosis than pMMR. This appears driven by BRAFPOP pts. [Table: see text]

Humans are sexually dimorphic, with sex being the most persistent difference among humans over the course of our evolutionary history. Beyond the visible sex differences that can be considered true dimorphisms, there are also sex differences at the molecular and cellular scales. The role of these biological sex differences for human health, while being increasingly recognized, have long been underappreciated and underexplored. Frequently, these differences are only recognized in sex–specific diseases, such as genitourinary diseases and cancers. However, given the evidence for sex differences in the most basic aspects of human biology, including metabolism, cellular composition, and immune activity, these differences could have consequences for the etiology and pathophysiology of a majority of diseases. It is thus essential to consider the extent to which these differences may influence the various mechanisms underlying disease processes, response to treatment, and the maintenance of health in order to better improve patient outcomes. Here we review the evidence for a broad array of biological sex differences in humans and discuss how they may relate to observed sex differences in various diseases, with an emphasis on cancer, specifically glioblastoma. We further propose that mathematical approaches can be useful for exploring the extent to which sex differences affect disease outcomes and accounting for those in the development of therapeutic strategies.