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The density and distribution of the tumor immune microenvironment associated with brain metastases (BM) from gynecologic malignancies are unknown and have not been previously reported. We sought to describe the clinical features of a cohort of patients with BM from gynecologic malignancies and to characterize the tumor immune microenvironment from available archival surgical specimens. We performed a retrospective review of electronic medical records from 2002 to 2018 for patients with BM from gynecologic malignancies. Data on patient characteristics, treatment regimens, and clinical outcomes were procured. CD4, CD8, CD45RO, CD68, CD163, and FOXP3 immunohistochemistry were evaluated from available archival surgical specimens from primary disease site and neurosurgical resection. A cohort of 44 patients with BM from gynecologic malignancies was identified, 21 (47.7%) endometrial primaries and 23 (52.3%) ovarian primaries. Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) were evaluated in 13 primary cases and 15 BM cases. For the 13 primary cases, CD4+ TILs were evident in 76.9% of cases, CD8+ in 92.3%, CD45RO+ in 92.3%, and FOXP3+ in 46.2%, as well as CD68+ TAMs in 100% and CD163+ in 100%. For the 15 BM cases, CD4+ TILs were evident in 60.0% of cases, CD8+ in 93.3%, CD45RO+ in 73.3%, and FOXP3+ in 35.7%, as well as CD68+ TAMs in 86.7% and CD163+ in 100%. An active tumor immune microenvironment is present with similar distribution in the primary disease site and BM from patients with gynecologic malignancies.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.

Objective This article aims to characterize 14 patients who underwent purely endoscopic surgical debridement of acute invasive skull base fungal rhinosinusitis, and to evaluate postoperative outcomes and risk for recurrence.Design Retrospective cohort study.Setting Tertiary single-institution neurosurgery department.Participants We performed a retrospective analysis of all patients with skull base fungal infections treated with a purely endoscopic surgical approach at Mount Sinai Hospital from 1998 to 2018.Main Outcome Measures Clinical presentation, number of recurrences, and mortality rate.Results The most common underlying medical comorbidities were hematologic malignancy in 8 (57.1%) patients and poorly controlled diabetes mellitus in 7 (50%) patients. Presenting symptoms included headache (50%), eye pain (35.7%), facial pain (28.6%), visual changes (21.4%), and nasal congestion (14.3%). The fungal organisms identified on culture were Aspergillus (42.9%), Mucorales (28.6%), Fusarium (14.3%), Penicillium (7.1%), and unspecified (7.1%). Eight (57.1%) patients developed recurrence and required multiple surgical debridements. Patients who had only a hematologic malignancy were more likely to require multiple surgical debridements compared with those who did not have a hematologic malignancy or those who had both hematologic malignancy and underlying diabetes mellitus (p = 0.03). The mortality rate from surgery was 42.9%.Conclusion Surgical endoscopic intervention is an option for definitive management of acute invasive skull base fungal rhinosinusitis; however, postoperative mortality and risk of recurrence requiring additional surgical interventions remains high. Patients with hematologic malignancy may be more susceptible to recurrent infection requiring multiple surgical debridements. We recommend early aggressive multimodal treatment. Multiple debridements may be warranted in most cases; close clinical surveillance is needed during neurosurgical intervention.

The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed whole-exome sequencing (WES) on 36 PCNSL patients and targeted MYD88 sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified MYD88 mutation in 67% (42 of 63) of patients, CDKN2A biallelic loss in 44% (16 of 36), and CD79b mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, CDKN2A), with few areas of amplification. CD79b mutations were associated with improved progression-free and overall survival. We did not identify amplification at the PD-1/PD-L1 loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified MYD88 mutation and CDKN2A loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of PD-L1 amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions.

Objective Posterior fossa meningiomas are surgically challenging tumors that are associated with high morbidity and mortality. We sought to investigate the anatomical distribution of clinically actionable mutations in posterior fossa meningioma to facilitate identifying patients amenable for systemic targeted therapy trials. Methods Targeted sequencing of clinically targetable AKT1, SMO, and PIK3CA mutations was performed in 61 posterior fossa meningioma using Illumina NextSeq 500 to a target depth of >500 × . Samples were further interrogated for 53 cancer-relevant RNA fusions by the Archer FusionPlex panel to detect gene rearrangements. Results AKT1 (E17K) mutations were detected in five cases (8.2%), four in the foramen magnum and one in the cerebellopontine angle. In contrast, none of the posterior fossa tumors harbored an SMO (L412F) or a PIK3CA (E545K) mutation. Notably, the majority of foramen magnum meningiomas (4/7, 57%) harbored an AKT1 mutation. In addition, common clinically targetable gene fusions were not detected in any of the cases. Conclusion A large subset of foramen magnum meningiomas harbor AKT1 E17K mutations and are therefore potentially amenable to targeted medical therapy. Genotyping of foramen magnum meningiomas may enable more therapeutic alternatives and guide their treatment decision process.

The density and distribution of the tumor immune microenvironment associated with brain metastases (BM) from gynecologic malignancies are unknown and have not been previously reported. We sought to describe the clinical features of a cohort of patients with BM from gynecologic malignancies and to characterize the tumor immune microenvironment from available archival surgical specimens.We performed a retrospective review of electronic medical records from 2002 to 2018 for patients with BM from gynecologic malignancies. Data on patient characteristics, treatment regimens, and clinical outcomes were procured. CD4, CD8, CD45RO, CD68, CD163, and FOXP3 immunohistochemistry were evaluated from available archival surgical specimens from primary disease site and neurosurgical resection.A cohort of 44 patients with BM from gynecologic malignancies was identified, 21 (47.7%) endometrial primaries and 23 (52.3%) ovarian primaries. Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) were evaluated in 13 primary cases and 15 BM cases. For the 13 primary cases, CD4An active tumor immune microenvironment is present with similar distribution in the primary disease site and BM from patients with gynecologic malignancies.

Introduction: Every year, thousands of women flee gender-based violence in Honduras, El Salvador, and Guatemala (sometimes collectively referred to as the Northern Triangle) in an attempt to seek asylum in the United States. Once in the United States, their legal teams may refer them for a psychological evaluation as part of their application for asylum. Licensed clinicians conduct in-depth interviews in order to document the psychological impact of the reported human rights violations. Method: Using archival de-identified data from a human rights program, this study gathered the experiences of gender-based violence reported by 70 asylum-seeking women from Honduras, El Salvador, and Guatemala who participated in pro bono psychological evaluation. Descriptive data were analyzed using a modified consensual qualitative research (CQR-M) method.Results: These asylum seekers reported exposure to systemic violence, including severe intimate partner violence, as well as physical and sexual assaults, and threats of death by organized criminal groups in their communities. Additionally, over a third of women reported experiences of violence during their migration. The majority of asylum seekers endorsed symptoms associated with anxiety (80%) and depression (91%), as well as trauma-and stressor-related symptoms (80%). Discussion: The results of this study elucidate the manyforms of gender-based violence experienced by women in this region, the physical and psychological sequelae of this persecution, and the systemic forces that prevent them from remaining in their countries of origin. The research results also highlight the potential impact of trauma on the women’s ability to testify effectively during asylum legal hearings, elucidate factors that may contribute to their resilience in light of the human rights violations they survived, and suggest implications for clinical practice.

Glioblastomas are malignant neoplasms composed of diverse cell populations. This intratumoral diversity has an underlying architecture, with a hierarchical relationship through clonal evolution from a common ancestor. Therapies are limited by emergence of resistant subclones from this phylogenetic reservoir. To characterize this clonal ancestral origin of recurrent tumors, we determined phylogenetic relationships using whole exome sequencing of pre-treatment IDH1/2 wild-type glioblastoma specimens, matched to post-treatment autopsy samples (n = 9) and metastatic extracranial post-treatment autopsy samples (n = 3). We identified “truncal” genetic events common to the evolutionary ancestry of the initial specimen and later recurrences, thereby inferring the identity of the precursor cell population. Mutations were identified in a subset of cases in known glioblastoma genes such as NF1(n = 3), TP53(n = 4) and EGFR(n = 5). However, by phylogenetic analysis, there were no protein-coding mutations as recurrent truncal events across the majority of cases. In contrast, whole copy-loss of chromosome 10 (12 of 12 cases), copy-loss of chromosome 9p21 (11 of 12 cases) and copy-gain in chromosome 7 (10 of 12 cases) were identified as shared events in the majority of cases. Strikingly, mutations in the TERT promoter were also identified as shared events in all evaluated pairs (9 of 9). Thus, we define four truncal non-coding genomic alterations that represent early genomic events in gliomagenesis, that identify the persistent cellular reservoir from which glioblastoma recurrences emerge. Therapies to target these key early genomic events are needed. These findings offer an evolutionary explanation for why precision therapies that target protein-coding mutations lack efficacy in GBM., Brain cancer: Non-coding genomic changes fuel glioblastoma growth Non-coding and structural alterations may be early drivers of brain cancer development. A team led by Priscilla Brastianos and Tracy Batchelor from Massachusetts General Hospital, Boston, USA, analyzed the genetic landscape of glioblastoma by comparing pre-treatment and autopsy tumor specimens from 12 patients who died of the aggressive brain cancer. They identified a common set of four genetic events that occurred early in the evolution of nearly every patient’s cancer: three losses or gains of chromosome regions or entire chromosomes, and mutations in the gene-activating promoter of TERT, which encodes an enzyme implicated in the cancer’s growth. The findings help explain why therapies that target protein-coding mutations don’t work in brain cancer when they do in other tumor types. They also point to new drug targets.

OBJECTIVEMeningiomas located in the skull base are surgically challenging. Recent genomic research has identified oncogenic SMO and AKT1 mutations in a small subset of meningiomas.METHODSThe authors performed targeted sequencing in a large cohort of patients with anterior skull base meningiomas (n = 62) to better define the frequency of SMO and AKT1 mutations in these tumors.RESULTSThe authors found SMO mutations in 7 of 62 (11%) and AKT1 mutations in 12 of 62 (19%) of their cohort. Of the 7 meningiomas with SMO mutations, 6 (86%) occurred in the olfactory groove. Meningiomas with an SMO mutation presented with significantly larger tumor volume (70.6 ± 36.3 cm3) compared with AKT1-mutated (18.2 ± 26.8 cm3) and wild-type (22.7 ± 23.9 cm3) meningiomas, respectively.CONCLUSIONSCombined, these data demonstrate clinically actionable mutations in 30% of anterior skull base meningiomas and suggest an association between SMO mutation status and tumor volume. Genotyping of SMO and AKT1 is likely to be high yield in anterior skull base meningiomas with available surgical tissue.

Although lung adenocarcinomas frequently metastasize to the brain, treatment options for lung adenocarcinoma brain metastases are limited. We discovered novel candidate drivers of progression by using case-control analyses to compare whole-exome sequencing data from a cohort of 73 lung adenocarcinoma brain metastases to a control cohort of 503 primary lung adenocarcinomas. We identified 3 genomic regions with significantly more frequent amplifications in brain metastases compared to the control cohort: MYC (12% vs 6%), YAP1 (7% vs 0.8%) and MMP13 (10% vs 0.6%). We also identified CDKN2A/B as a region deleted at a significantly greater frequency in brain metastases compared to primary lung adenocarcinomas (27% vs 13%, respectively). We confirmed frequent amplifications of MYC and YAP1/MMP13 in an independent validation cohort of 105 lung adenocarcinoma brain metastasis samples using fluorescence in situ hybridization. We further validated that MYC, YAP1 and MMP13 can drive brain metastases in a patient-derived xenograft mouse model. We found a higher incidence of metastases to the brain in mice receiving intracardiac injections of tumor cells expressing the candidate drivers compared to tumor cells expressing LacZ as a control. These results indicate that somatic alterations can drive lung adenocarcinomas to metastasize to the brain. The candidate brain metastasis drivers that we identified may serve as therapeutic targets in patients with lung adenocarcinomas who develop this devastating complication.

Background Biliary tract cancers (BTCs) are highly fatal malignancies that make up less than 1% of all cancers. BTC is often diagnosed at an unresectable stage; surgical resection remains the only definitive treatment. Brain metastases (BMs) from BTC are extremely rare, and few studies on patients with BMs from BTC exist. The aim of this study was to identify clinical characteristics associated with poor prognosis for patients with BMs from BTC. Materials and Methods We performed a retrospective review of electronic medical records for patients with BMs from BTC managed at Mount Sinai Hospital from 2000 to 2017. Data on patient characteristics, magnetic resonance imaging findings, treatment regimens, and clinical outcomes were analyzed. Results We identified 1,910 patients with BTC. Nine patients developed BMs, with an incidence of 0.47%. Of these nine patients, six had intrahepatic cholangiocarcinoma, two had extrahepatic cholangiocarcinoma, and one had gallbladder cancer. Six (66.7%) patients had one BM, one (11.1%) patient had two BMs, and two (22.2%) patients had three or more BMs. Four (44.4%) patients underwent BM resection, and seven (77.8%) received BM radiation. Median overall survival from time of BM diagnosis was 3.8 months (95% confidence interval 0.1–16.9). Conclusion Development of BMs from BTC is rare; however, prognosis is less than 4 months. BM diagnosis can occur within 2 years of primary diagnosis. As targeted therapeutics emerge, future studies ought to focus on identifying genomic BM markers associated with BTC subtypes. Implications for Practice In the largest retrospective study of biliary tract cancer brain metastases, the clinical presentation and outcomes are reported of nine patients with an extremely rare clinical entity. The genomic literature and potential therapeutic targets for these patients with limited treatment options is comprehensively and exhaustively discussed.

Background In 2016, around 65 000 women fled gender-based violence in the Northern Triangle (NTCA) countries of El Salvador, Honduras, and Guatemala, and attempted to seek asylum in the USA. Some women participate in medical evaluations by clinicians to document the effect of these human rights violations as part of the asylum process. The aim of this study is to elucidate the forms of persecution experienced by women in this region, and the physical and psychological sequelae of this violence. Methods We undertook a retrospective, qualitative study of asylum-seeking adult women fleeing gender-based violence from the NTCA who were seen by evaluators in the Mount Sinai Human Rights Program from February, 2014, to August, 2018. We included any case in which the client self-identified as female, came from an NTCA country, and received a psychological evaluation. This study was approved by the Mount Sinai Institutional Review Board. We used a modified consensual qualitative research (CQR-M) approach to identify themes found across the archived and de-identified affidavits written as part of the medical evaluation. Findings We included data from 70 women; mean age was 29·4 years (SD 6·5; range 18–55 years]. 24 women identified as Salvadoran, 15 as Guatemalan, and 31 as Honduran. All women reported violence perpetrated by their communities, families, intimate partners, and/or powerful gangs, and faced justice systems in their countries that they felt would not protect them. They had been subject to: verbal (50 women [71%]), physical (57 [81%]), and sexual (59 [84%]) assaults; death threats (58 [83%]); control (40 [57%]); extortion (24 [34%]); and harm, or threats of harm, to their children (50 [43%] and 22 [31%], respectively). Evaluators identified psychological symptoms associated with anxiety (56 women [80%]), depression (64 [91%]), and post-traumatic stress disorder (56 [80%]), as well as suicidality (33 [47%]). Women also reported physical injury including bruising, head injury and loss of consciousness, and gynaecological harm including miscarriage and forced sterilisation. Many women had been displaced within their own countries before fleeing and stated that they travelled with their children, experienced hazardous conditions and violence during their journey, and were detained on arrival in the USA. Finally, the women reported resilience associated with their religious beliefs, family, temperament, and ability to make meaning from their experiences. Interpretation This study highlights the systemic nature of gender-based violence in the NTCA. The results also describe the perils that women from the NTCA encountered during their migration and demonstrate the continued structural violence that awaits them if they are denied asylum and returned to their countries of origin. Funding None.

Although lung adenocarcinomas frequently metastasize to the brain, treatment options for lung adenocarcinoma brain metastases (BM-LUAD) are limited. We discovered novel candidate drivers of progression by using case-control analyses to compare whole-exome sequencing data from a cohort of 73 BM-LUAD to a control cohort of 503 primary lung adenocarcinomas. We identified MYC, YAP1 and MMP13 as genomic regions with significantly more frequent amplifications in BM-LUAD compared to control cohort. We validated that MYC, YAP1 and MMP13 can drive brain metastases in a patient-derived xenograft mouse model, where incidence of brain metastases was higher in mice injected with tumor cells expressing the candidate drivers compared to tumor cells expressing LacZ. These results indicate that somatic alterations can drive lung adenocarcinomas to metastasize to the brain. These candidate drivers may serve as therapeutic targets in patients with brain metastatic lung adenocarcinomas. Citation Format: Naema Nayyar, David J. Shih, Ivanna Bihun, Ibiayi Dagogo-Jack, Corey M. Gill, Elisa Aquilanti, Mia Bertalan, Alexander Kaplan, Megan R. D'Andrea, Ugonma Chukwueke, Christopher Alvarez-Breckenridge, Matthew Lastrapes, Ben Kuter, Matthew R. Strickland, Juan Carlos Martinez-Gutierrez, Deepika Nagabhushan, Magali De Sauvage, Michael D. White, Brandyn A. Castro, Kaitlin Hoang, Sun Ha Paek, Sun Hye Park, Maria Martinez-Lage, Anna S. Berghoff, Parker Merrill, Elizabeth R. Gerstner, Tracy T. Batchelor, Matthew P. Frosch, Ryan P. Frazier, Darrell R. Borger, A John Iafrate, Sandro Santagata, Matthias Preusser, Daniel P. Cahill, Scott L. Carter, Priscilla K. Brastianos. Identifying genomic drivers of lung adenocarcinoma brain metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4729.

Objective Posterior fossa meningiomas are surgically challenging tumors that are associated with high morbidity and mortality. We sought to investigate the anatomical distribution of clinically actionable mutations in posterior fossa meningioma to facilitate identifying patients amenable for systemic targeted therapy trials. Methods Targeted sequencing of clinically targetable AKT1 , SMO , and PIK3CA mutations was performed in 61 posterior fossa meningioma using Illumina NextSeq 500 to a target depth of >500 × . Samples were further interrogated for 53 cancer-relevant RNA fusions by the Archer FusionPlex panel to detect gene rearrangements. Results AKT 1 ( E17K ) mutations were detected in five cases (8.2%), four in the foramen magnum and one in the cerebellopontine angle. In contrast, none of the posterior fossa tumors harbored an SMO ( L412F ) or a PIK3CA ( E545K ) mutation. Notably, the majority of foramen magnum meningiomas (4/7, 57%) harbored an AKT1 mutation. In addition, common clinically targetable gene fusions were not detected in any of the cases. Conclusion A large subset of foramen magnum meningiomas harbor AKT1 E17K mutations and are therefore potentially amenable to targeted medical therapy. Genotyping of foramen magnum meningiomas may enable more therapeutic alternatives and guide their treatment decision process.

Glioneuronal tumors constitute a histologically diverse group of primary central nervous system neoplasms that are typically slow-growing and managed conservatively. Genetic alterations associated with glioneuronal tumors include BRAF mutations and oncogenic fusions. To further characterize this group of tumors, we collected a cohort of 26 glioneuronal tumors and performed in-depth genomic analysis. We identified mutations in BRAF (34%) and oncogenic fusions (30%), consistent with previously published reports. In addition, we discovered novel oncogenic fusions involving members of the NTRK gene family in a subset of our cohort. One-patient with BCAN exon 13 fused to NTRK1 exon 11 initially underwent a subtotal resection for a 4th ventricular glioneuronal tumor but ultimately required additional therapy due to progressive, symptomatic disease. Given the patient’s targetable fusion, the patient was enrolled on a clinical trial with entrectinib, a pan-Trk, ROS1, and ALK (anaplastic lymphoma kinase) inhibitor. The patient was treated for 11 months and during this time volumetric analysis of the lesion demonstrated a maximum reduction of 60% in the contrast-enhancing tumor compared to his pre-treatment magnetic resonance imaging study. The radiologic response was associated with resolution of his clinical symptoms and was maintained for 11 months on treatment. This report of a BCAN-NTRK1 fusion in glioneuronal tumors highlights its clinical importance as a novel, targetable alteration.

Background The postpartum period is a high risk period for unintended pregnancies which can be associated with negative outcomes for mother and infant. Effective contraception is important during this time and thus the AAP advises pediatricians to ask mothers about family planning by the two-month visit. Previous work has shown family planning screening can be implemented in a pediatric resident clinic, with residents providing referrals to needed services. Objective To assess resident knowledge, attitudes and confidence around discussing family planning with mothers of their young patients. Methods Anonymous surveys were administered to pediatric residents in an inner city pediatric residency program. Group comparisons were made using Fisher's exact test and chi-square test. Results 39 residents completed the survey for a response rate of 65%. 39% of respondents were in their 1st year of residency, 36% were in the 2nd year, and 25% were in their 3rd year or higher. More than half (55%) of respondents felt knowledgeable or very knowledgeable about guidelines around providing contraceptive care for adolescents. These residents were more likely to be farther along in residency (p=0.04) and to correctly identify first line contraception for adolescents (p=0.006). Respondents who felt knowledgeable about providing contraceptive care for adolescents were more likely to feel confident speaking with mothers about their contraceptive needs (p Conclusions While most residents surveyed were not aware of guidelines recommending screening mothers of young children for family planning needs, they felt pediatricians have a role in such discussions. These data highlight resident willingness to screen mothers of infants for family planning needs and the opportunity to build on their current knowledge and practices.

Craniopharyngiomas are rare intracranial neoplasms that pose clinical challenges due to their location adjacent to vital structures. The authors have previously shown high mutation rates of BRAF V600E in papillary craniopharyngioma and of CTNNB1 in adamantinomatous craniopharyngioma. These activating driver mutations are potential therapeutic targets, and the authors have recently reported a significant response to BRAF/MEK inhibition in a patient with multiply recurrent PCP. As these targetable mutations warrant prospective research, the authors will be conducting a national National Cancer Institute–sponsored multicenter clinical trial to investigate BRAF/MEK inhibition in the treatment of craniopharyngioma. In this new era of genomic discovery, the treatment paradigm of craniopharyngioma is likely to change.