NF2 mutations are associated with resistance to radiation therapy for grade 2 and grade 3 recurrent meningiomas.

PURPOSE: High grade meningiomas have a prognosis characterized by elevated recurrence rates and radiation resistance. Recent work has highlighted the importance of genomics in meningioma prognostication. This study aimed to assess the relationship between the most common meningioma genomic alteration (NF2) and response to postoperative radiation therapy (RT). METHODS: From an institutional tissue bank, grade 2 and 3 recurrent meningiomas with both > 30 days of post-surgical follow-up and linked targeted next-generation sequencing were identified. Time to radiographic recurrence was determined with retrospective review. The adjusted hazard of recurrence was estimated using Cox-regression for patients treated with postoperative RT stratified by NF2 mutational status. RESULTS: Of 53 atypical and anaplastic meningiomas (29 NF2 wild-type, 24 NF2 mutant), 19 patients underwent postoperative RT. When stratified by NF2 wild-type, postoperative RT in NF2 wild-type patients was associated with a 78% reduction in the risk of recurrence (HR 0.216; 95%CI 0.068-0.682; p = 0.009). When stratified by NF2 mutation, there was a non-significant increase in the risk of recurrence for NF2 mutant patients who received postoperative RT compared to those who did not (HR 2.43; 95%CI 0.88-6.73, p = 0.087). CONCLUSION: This study demonstrated a protective effect of postoperative RT in NF2 wild-type patients with recurrent high grade meningiomas. Further, postoperative RT may be associated with no improvement and perhaps an accelerated time to recurrence in NF2 mutant tumors. These differences in recurrence rates provide evidence that NF2 may be a valuable prognostic marker in treatment decisions regarding postoperative RT. Further prospective studies are needed to validate this relationship.

NF2 mutation associated with accelerated time to recurrence for older patients with atypical meningiomas.

PURPOSE: Meningiomas occur more frequently in older adults, with the incidence rates increasing from 5.8/100,000 for adults 35-44 years old to 55.2/100,000 for those 85+. Due to the increased risk of surgical management in older adults, there is a need to characterize the risk factors for aggressive disease course to inform management decisions in this population. We therefore sought to determine age-stratified relationships between tumour genomics and recurrence after resection of atypical meningiomas. METHODS: We identified 137 primary and recurrent Grade 2 meningiomas from our existing meningioma genomic sequencing database. We examined the differential distribution of genomic alterations in those older than 65 compared to younger. We then performed an age stratified survival analysis to model recurrence for a mutation identified as differentially present. RESULTS: In our cohort of 137 patients with grade 2 meningiomas, alterations in NF2 were present at a higher rate in older adults compared to younger (37.8% in < 65 vs. 55.3% in > 65; recurrence adjusted p-value =0.04). There was no association between the presence of NF2 and recurrence in the whole cohort. In the age-stratified model for those less than 65 years old, there was again no relationship. For patients in the older age stratum, there is a relationship between NF2 and worsened recurrence outcomes (HR = 3.64 (1.125 - 11.811); p = 0.031). CONCLUSIONS: We found that mutations in NF2 were more common in older adults. Further, the presence of mutant NF2 was associated with an increased risk of recurrence in older adults.

Baseline Histological Findings Do Not Predict the Risk of Subsequent Extension in Patients with Limited Ulcerative Colitis.

BACKGROUND: Among patients with limited ulcerative colitis (UC), 30% ultimately extend to pancolitis and are at increased risk of adverse clinical outcomes. Risk of endoscopic extension has been found to correlate with clinical features such as early age of onset. AIMS: We sought to determine whether histologic features correlate with disease extension. METHODS: The study population consisted of 40 patients with UC from two large academic centers diagnosed between 2006 and 2017. Eligible cases had a diagnosis of endoscopically limited UC (Montreal E1 or E2) at baseline and ≥ 2 subsequent endoscopic examinations with biopsies. Severity of inflammation was scored using both the Mount Sinai Activity Index and Nancy Histological Index. RESULTS: Patients were divided into two cohorts: those who progressed to pancolitis (Montreal E3) were defined as "Extenders" (n = 21), whereas "Non-extenders" (n = 19) were cases without progression in the follow-up period. The median follow-up time was 58.4 months. The histologic scores in the endoscopically involved mucosa of the index biopsies were not associated with subsequent extension of disease, overall. However, among extender cohort, the index histology scores correlated with biopsy scores at extension (r = 0.455, P = 0.044) and index severity was associated with a shorter time to extension (r = - 0.611, P = 0.003). Furthermore, female patients had a shorter time to extension (P = 0.013). CONCLUSIONS: Histological severity of limited UC is not an independent predictor of extension in UC. However, among patients who subsequently extend, severe inflammation at baseline correlates with shorter progression time and severe inflammation when extension occurs. Patients with limited UC but severe histologic inflammation may warrant more frequent endoscopic surveillance.

Association of mutations in DNA polymerase epsilon with increased CD8+ cell infiltration and prolonged progression-free survival in patients with meningiomas.

OBJECTIVE: Prior studies have demonstrated a relationship between underlying tumor genetics and lymphocyte infiltration in meningiomas. In this study, the authors aimed to further characterize the relationship between meningioma genomics, CD4+ and CD8+ T-cell infiltration, and oncological outcomes of meningiomas. Understanding specific characteristics of the inflammatory infiltration could have implications for treatment and prognostication. METHODS: Immunohistochemically stained meningioma slides were reviewed to assess the CD4+ and CD8+ cell infiltration burden. The relationship between immune cell infiltration and tumor genomics was then assessed using an adjusted ANOVA model. For a specific gene identified by the ANOVA, the relationship between that mutation and tumor recurrence was assessed using Cox regression. RESULTS: In immunohistochemically stained samples from a subcohort of 25 patients, the mean number of CD4+ cells was 42.2/400× field and the mean number of CD8+ cells was 69.8/400× field. Elevated CD8+ cell infiltration was found to be associated with the presence of a mutation in the gene encoding for DNA polymerase epsilon, POLE (51.6 cells/hpf in wild-type tumors vs 95.9 cells/hpf in mutant tumors; p = 0.0199). In a retrospective cohort of 173 patients, the presence of any mutation in POLE was found to be associated with a 46% reduction in hazard of progression (HR 0.54, 95% CI 0.311-0.952; p = 0.033). The most frequent mutation was a near-C-terminal nonsense mutation. CONCLUSIONS: A potential association was found between mutant POLE and both an increase in CD8+ cell infiltration and progression-free survival. The predominant mutation was found outside of the known exonuclease hot spot; however, it was still associated with a slight increase in mutational burden, CD8+ cell infiltration, and progression-free survival. Alterations in gene expression, resulting from alterations in POLE, may yield an increased presentation of neoantigens, and, thus, greater CD8+ cell-mediated apoptosis of neoplastic cells. These findings have suggested the utility of checkpoint inhibitors in the treatment of POLE-mutant meningiomas.

NF2 mutation status and tumor mutational burden correlate with immune cell infiltration in meningiomas.

BACKGROUND: The tumor microenvironment is an emerging biomarker of underlying genomic heterogeneity and response to immunotherapy-based treatment regimens in solid malignancies. How tumor mutational burden influences the density, distribution, and presence of a localized immune response in meningiomas is unknown. METHODS: Representative hematoxylin and eosin slides were reviewed at 40X to assess for the density of inflammatory cells. Lymphocytes and macrophages were quantified in the following ordinal manner: 0 = not present, 1 = 1-25 cells present, and 2 = greater than 26 cells present. Immune cell infiltrate grade was scored for both scattered and aggregated distributions. Next generation targeted sequencing was performed on all meningiomas included in this study. RESULTS: One hundred and forty-five meningiomas were evaluated in this study. Lymphocytes were observed in both scattered (95.9%) and aggregated (21.4%) distributions. A total of 115 (79.3%) meningiomas had 1-25 scattered lymphocytes, and 24 (16.6%) had > 25 scattered lymphocytes, and 6 (4.1%) had no scattered lymphocytes. Twenty (13.8%) meningiomas had 1-25 aggregated lymphocytes. Eleven (7.6%) had > 25 aggregated lymphocytes and 114 (78.6%) had no aggregated lymphocytes. Six (4.1%) meningiomas had 1-25 aggregated macrophages, 5 (3.4%) had > 25 aggregated macrophages, and 134 (92.4%) had no aggregated macrophages. Density of aggregated lymphocytes and aggregated macrophages were associated with higher tumor grade, P = 0.0071 and P = 0.0068, respectively. Scattered lymphocyte density was not associated with meningioma grade. The presence of scattered lymphocytes was associated with increased tumor mutational burden. Meningiomas that did not have scattered lymphocytes had a mean number of single mutations of 2.3 ± 2.9, compared with meningiomas that had scattered lymphocytes, 6.9 ± 20.3, P = 0.03. NF2 mutations were identified in 59 (40.7%) meningiomas and were associated with increased density of scattered lymphocytes. NF2 mutations were seen in 0 (0%) meningiomas that did not have scattered lymphocytes, 46 (40.0%) meningiomas that had 1-25 scattered lymphocytes, and 13 (54.2%) meningiomas that had > 25 scattered lymphocytes, P = 0.046. CONCLUSIONS: Our findings suggest that distribution of immune cell infiltration in meningiomas is associated with tumor mutational burden. NF2 mutational status was associated with an increasing density of scattered lymphocytes. As the role of immunotherapy in meningiomas continues to be elucidated with clinical trials that are currently underway, these results may serve as a novel biomarker of tumor mutational burden in meningiomas.

Peritumoral edema correlates with mutational burden in meningiomas.

PURPOSE: Meningiomas are the most common primary central nervous system tumor. Emerging data supports that higher mutational burden portends worse clinical outcomes in meningiomas. However, there is a lack of imaging biomarkers that are associated with tumor genomics in meningiomas. METHODS: We performed next-generation targeted sequencing in a cohort of 75 primary meningiomas and assessed preoperative imaging for tumor volume and peritumoral brain edema (PTBE). An Edema Index was calculated. RESULTS: Meningiomas that were high grade (WHO grade II or grade III) had significantly larger tumor volume and were more likely to present with PTBE. Moreover, PTBE was associated with brain invasion on histopathology and reduced overall survival. There was a direct association between Edema Index and mutational burden. For every one increase in Edema Index, the number of single nucleotide variants increased by 1.09-fold (95% CI: 1.02, 1.2) (P = 0.01). CONCLUSION: These data support that Edema Index may serve as a novel imaging biomarker that can inform underlying mutational burden in patients with meningiomas.

STK11 mutation status is associated with decreased survival in meningiomas.

BACKGROUND: Emerging evidence suggests that STK11 mutations may influence clinical outcome and response to immunotherapy in cancer. MATERIALS AND METHODS: Next-generation targeted sequencing of STK11 mutation status in a large cohort of 188 meningiomas. RESULTS: STK11 loss-of-function mutations were identified in 3.7% of meningiomas. STK11 mutations were found in both low- and high-grade lesions and samples from primary and recurrent disease. There was a 2.8-fold increased risk of death for patients whose meningioma harbored an STK11 mutation, after controlling for lesion grade and occurrence status. The median overall survival for patients with STK11-mutated meningiomas was 4.4 years compared with 16.8 years. CONCLUSION: These data identify recurrent STK11 mutations in a subset of meningiomas. Genotyping of STK11 is encouraged for meningioma patients undergoing immunotherapy-based therapy.

Increased Risk of Oral Cancer in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Epidemiology studies have consistently found an increased risk of oral malignancies in organ transplant recipients, patients with graft-versus-host disease, and people with human immunodeficiency virus infection. We assessed the risk of oral cancer in patients with inflammatory bowel diseases (IBD). METHODS: We collected data on 7294 patients with IBD (3785 women) seen at Mount Sinai Medical Center, New York, from 2000 through 2011. The expected incidence of oral cancer was calculated for each sex-specific and 5-year age-specific stratum by specific incidence rates using the Surveillance, Epidemiology and End Results 18 registry data (2000-2011), adjusted for age to the 2000 United States population (census P25-1130). RESULTS: Eleven patients (7 men) were found to have biopsy-proven oral cancer. Six patients had cancer of the tongue; 2 patients had cancer of the hard palate; and the remaining 3 had tonsillar, buccal, or mandibular sarcoma. Before the cancer diagnosis, IBD had been treated in 4 patients with azathioprine or mercaptopurine, in 1 patient with infliximab, and 3 in patients with combination of biologic agents and azathioprine; 4 of the patients had not been treated for IBD. The age- and sex-adjusted standardized incidence ratio (SIR) for oral cancer in patients with IBD was 9.77 (95% confidence interval [CI], 5.14-16.98). In women, the SIR was 12.07 (95% CI, 3.84-29.11), and in men the SIR was 8.49 (95% CI, 3.71-16.78). The age-adjusted SIR for tongue cancer was 18.91 (95% CI, 7.66-39.33): 17.06 for men (95% CI, 5.42-41.15) and 22.10 for women (95% CI, 3.70-73.01). CONCLUSIONS: We found patients with IBD to be at increased risk for oral cancers, especially tongue cancer. Women are at higher risk than men.

Chromoendoscopy Is More Effective Than Standard Colonoscopy in Detecting Dysplasia During Long-term Surveillance of Patients With Colitis.

BACKGROUND & AIMS: Patients with colitis have an increased risk of colorectal cancer, compared with persons without colitis. Many studies have shown chromoendoscopy (CE) to be superior to standard methods of detecting dysplasia in patients with colitis at index examination. We performed a prospective, longitudinal study to compare standard colonoscopy vs CE in detecting dysplasia in patients with inflammatory bowel diseases in a surveillance program. METHODS: We analyzed data from 68 patients (44 men, 24 women) diagnosed with ulcerative colitis (n = 55) or Crohn's disease (n = 13) at Mount Sinai Medical Center from September 2005 through October 2011. The patients were followed from June 2006 through October 2011 (median, 27.8 months); each patient was analyzed by random biopsy, targeted white light examination (WLE), and CE. Specimens were reviewed by a single blinded pathologist. The 3 methods were compared by using the generalized estimating equations method, and the odds ratios (ORs) for detection of dysplasia were calculated (primary outcome). Time to colectomy was analyzed by using the Cox model. RESULTS: In the 208 examinations conducted, 44 dysplastic lesions were identified in 24 patients; 6 were detected by random biopsy, 11 by WLE, and 27 by CE. Ten patients were referred for colectomy, and no carcinomas were found. At any time during the study period, CE (OR, 5.4; 95% confidence interval [CI], 2.9-9.9) and targeted WLE (OR, 2.3; 95% CI, 1.0-5.3) were more likely than random biopsy analysis to detect dysplasia. CE was superior to WLE (OR, 2.4; 95% CI, 1.4-4.0). Patients identified as positive for dysplasia were more likely to need colectomy (hazard ratio, 12.1; 95% CI, 3.2-46.2). CONCLUSIONS: In a prospective study of 68 patients with inflammatory bowel diseases, CE was superior to random biopsy or WLE analyses in detecting dysplasia in patients with colitis during an almost 28-month period. A negative result from CE examination was the best indicator of a dysplasia-free outcome, whereas a positive result was associated with earlier referral for colectomy.

Serrated colorectal polyps in inflammatory bowel disease.

Serrated colorectal polyps, which, besides hyperplastic polyps, comprise sessile serrated adenomas/polyps and traditional serrated adenomas, are presumptive precursors of at least 20% of sporadic colorectal carcinomas; however, their significance in patients with inflammatory bowel disease is unclear. We retrospectively evaluated 78 serrated polyps, removed over a 14-year period from 6602 inflammatory bowel disease patients undergoing endoscopic surveillance, with respect to morphologic, clinicopathologic, and molecular features, and compared rates of advanced neoplasia (high-grade dysplasia and carcinoma) development following the index serrated polyp diagnosis to reference inflammatory bowel disease cohorts without serrated polyps. Serrated polyps negative for dysplasia, which morphologically resembled sporadic sessile serrated adenoma/polyps, occurred mainly in females, in the proximal colon, and contained BRAF mutations. Serrated polyps with low-grade dysplasia resembled sporadic traditional serrated adenomas and occurred mainly in males, in the distal colon, and contained KRAS mutations. Serrated polyps indefinite for dysplasia were morphologically heterogeneous, but similar to serrated polyps positive for low-grade dysplasia with respect to male predominance, left-sided location, and KRAS mutation rates. Rates of prevalent neoplasia associated with serrated polyps positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 76, 39, and 11%, respectively (P<0.001). Actuarial 10-year rates of incident advanced neoplasia after an initial diagnosis of serrated polyp positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 17, 8, and 0%, respectively, the first and last being significantly different (P=0.02) and comparable to those of corresponding reference populations of inflammatory bowel disease patients with and without low-grade dysplasia at baseline, respectively. We conclude that in serrated polyps from inflammatory bowel disease patients, dysplasia grade correlates with morphology, sex, anatomic location, BRAF and KRAS mutation status, prevalent conventional neoplasia, and rates of advanced neoplasia development.

Density of Biopsy Sampling Required to Ensure Accurate Histological Assessment of Inflammation in Active Ulcerative Colitis.

BACKGROUND: Histological response to treatment is an important outcome in patients with ulcerative colitis (UC). The accuracy of biopsy-based measurements of inflammation may be limited by error imposed by natural microscopic heterogeneity on the scale of individual biopsies. We determined the magnitude of this error, its histological correlates, and the density of biopsy sampling within mucosal regions of interest required to meet specified benchmarks for accuracy. METHODS: A total of 994 sequential 1-mm digital microscopic images (virtual biopsies) from consecutive colectomies from patients with clinically severe UC were scored by 2 pathologists. Agreement statistics for Geboes subscores and Nancy (NHI) and Robarts Histological Indices (RHI) between random samples from 1 to 10 biopsies and a reference mean score across a 2-cm region of mucosa were calculated using bootstrapping with 2500 iterations. RESULTS: The agreement statistics improved across all indices as the biopsy density increased, with the largest proportional gains occurring with addition of the second and third biopsies. One biopsy achieved moderate to good agreement with 95% confidence for NHI and RHI corresponding to scale-specific errors of 0.40 (0.25-0.66) and 3.02 (2.08-5.36), respectively; and 3 biopsies achieved good agreement with 95% confidence corresponding to scale-specific errors of 0.22 (0.14-0.39) and 1.87 (1.19-3.25), respectively. Of the individual histological features, erosions and ulcers had the greatest impact on the agreement statistics. CONCLUSIONS: In the setting of active colitis, up to 3 biopsy samples per region of interest may be required to overcome microscopic heterogeneity and ensure accurate histological grading.

ARID1A mutation associated with recurrence and shorter progression-free survival in atypical meningiomas.

PURPOSE: The oncologic outcomes for atypical meningiomas can be poor. Generally, patients that have had a prior recurrence have a substantially elevated risk of a future recurrence. Additionally, certain tumor genomic profiles have been shown as markers of poor prognosis. We sought to characterize the genomic differences between primary and recurrent tumors as well as assess if those differences had implications on recurrence. METHODS: We identified primary and recurrent gross totally resected WHO grade II meningiomas with > 30 days of post-surgical follow-up at our institution. For genes with a prevalence of > 5% in the cohort, we compared the mutational prevalence in primary and recurrent tumors. For a gene of interest, we assessed the time to radiographic recurrence using adjusted cox-regression. RESULTS: We identified 88 meningiomas (77 primary, 16 recurrent) with a median follow-up of 5.33 years. Mutations in ARID1A found in association with recurrent tumors (7/16 recurrent tumors vs 5/72 primary tumors, p < 0.001). In the whole cohort, mutations in ARID1A were not associated with alterations in time to recurrence after adjusting for recurrence status (p = 0.713). When restricted to primary tumors, ARID1A is associated with a 625% increase in the hazard of recurrence (HR = 7.26 [1.42-37.0]; p = 0.017). CONCLUSION: We demonstrate mutations in ARID1A, a chromatin remodeling gene, in a higher prevalence in recurrent tumors. We further demonstrate that when mutations in ARID1A are present in primary atypical meningiomas, these tumors tend to have worse prognosis. Further prospective study may validate ARID1A as a prognostic marker.

Incidence of subsequent pancreatic adenocarcinoma in patients with a history of nonpancreatic primary cancers.

BACKGROUND: Several environmental risk factors are known to predispose individuals to pancreatic cancer, and up to 15% of pancreatic cancers have an inherited component. Understanding metachronous cancer associations can modify pancreas cancer risk. The objective of this study was to investigate the association of nonpancreatic cancers with subsequent pancreatic adenocarcinoma. METHODS: The authors used data from the US Surveillance, Epidemiology, and End Results (SEER) registries to identify 1,618,834 individuals who had a primary malignancy and subsequent pancreatic adenocarcinoma (n = 4013). Standardized incidence ratios were calculated as an approximation of relative risk (RR) for the occurrence of pancreatic adenocarcinoma after another primary malignancy. RESULTS: Among patients who were diagnosed with a first primary malignancy at ages 20 to 49 years, the risk of subsequent pancreatic adenocarcinoma was increased among patients who had cancers of the ascending colon (relative risk [RR], 4.62; 95% confidence interval [CI], 1.86-9.52), hepatic flexure (RR, 5.42; 95% CI, 1.12-15.84), biliary system (RR, 13.14; 95% CI, 4.27-30.66), breast (RR, 1.32; 95% CI, 1.09-1.59), uterine cervix (RR, 1.61; 95% CI, 1.02-2.41), testes (RR, 2.78; 95% CI, 1.83-4.05), and hematopoietic system (RR, 1.83; 95% CI, 1.28-2.53). Among patients who had a first malignancy at ages 50 to 64 years, the risk was increased after cancers of the stomach (RR, 1.88; 95% CI, 1.13-2.93), hepatic flexure (RR, 2.25; 95% CI, 1.08-4.13), lung and bronchus (RR, 1.46; 95% CI, 1.16-1.82), pharynx (RR, 2.26; 95% CI, 1.13-4.04), and bladder (RR, 1.24; 95% CI, 1.03-1.48). Among patients who had a primary cancer after age 65 years, the risk was increased after cancers of the stomach (RR, 1.79; 95% CI, 1.23-2.53), hepatic flexure (RR, 1.76; 95% CI, 1.06-2.75), biliary system (RR, 2.35; 95% CI, 1.17-4.20), and uterus (RR, 1.23; 95% CI, 1.03-1.47). CONCLUSIONS: The results from the current population-based data set suggested that pancreatic adenocarcinoma is associated with certain primary cancers. Genetic predisposition and common environmental and behavioral risk factors all may contribute to this observation. Specific tumor associations will guide future risk-stratification efforts.

Creating Surveillance Data Infrastructure Using Laboratory Analytics: Leveraging Visiun and Epic Systems to Support COVID-19 Pandemic Response.

BACKGROUND: Pandemics are unpredictable and can rapidly spread. Proper planning and preparation for managing the impact of outbreaks is only achievable through continuous and systematic collection and analysis of health-related data. We describe our experience on how to comply with required reporting and develop a robust platform for surveillance data during an outbreak. MATERIALS AND METHODS: At Mount Sinai Health System, New York City, we applied Visiun, a laboratory analytics dashboard, to support main response activities. Epic System Inc.'s SlicerDicer application was used to develop clinical and research reports. We followed World Health Organization (WHO); federal and state guidelines; departmental policies; and expert consultation to create the framework. RESULTS: The developed dashboard integrated data from scattered sources are used to seamlessly distribute reports to key stakeholders. The main report categories included federal, state, laboratory, clinical, and research. The first two groups were created to meet government and state reporting requirements. The laboratory group was the most comprehensive category and included operational reports such as performance metrics, technician performance assessment, and analyzer metrics. The close monitoring of testing volumes and lab operational efficiency was essential to manage increasing demands and provide timely and accurate results. The clinical data reports were valuable for proper managing of medical surge requirements, such as healthcare workforce and medical supplies. The reports included in the research category were highly variable and depended on healthcare setting, research priorities, and available funding. We share a few examples of queries that were included in the designed framework for research projects. CONCLUSION: We reviewed here the key components of a conceptual surveillance framework required for a robust response to COVID-19 pandemics. We demonstrated leveraging a lab analytics dashboard, Visiun, combined with Epic reporting tools to function as a surveillance system. The framework could be used as a generic template for possible future outbreak events.

Association between tumor mutations and meningioma recurrence in Grade I/II disease.

BACKGROUND: Meningiomas are common intracranial tumors with variable prognoses not entirely captured by commonly used classification schemes. We sought to determine the relationship between meningioma mutations and oncologic outcomes using a targeted next-generation sequencing panel. MATERIALS AND METHODS: We identified 184 grade I and II meningiomas with both >90 days of post-surgical follow-up and linked targeted next-generation sequencing. For mutated genes in greater than 5% of the sample, we computed progression-free survival Cox-regression models stratified by gene. We then built a multi-gene model by including all gene predictors with a p-value of less than 0.20. Starting with that model, we performed backward selection to identify the most predictive factors. RESULTS: ATM (HR = 4.448; 95% CI: 1.517-13.046), CREBBP (HR = 2.727; 95% CI = 1.163-6.396), and POLE (HR = 0.544; HR = 0.311-0.952) were significantly associated with alterations in disease progression after adjusting for clinical and pathologic factors. In the multi-gene model, only POLE remained a significant predictor of recurrence after adjusting for the same clinical covariates. Backwards selection identified recurrence status, resection extent, and mutations in ATM (HR = 7.333; 95% CI = 2.318-23.195) and POLE (HR = 0.413; 95% CI = 0.229-0.743) as predictive of recurrence. CONCLUSIONS: Mutations in ATM and CREBBP were associated with accelerated meningioma recurrence, and mutations in POLE were protective of recurrence. Each mutation has potential implications for treatment. The effect of these mutations on oncologic outcomes and as potential targets for intervention warrants future study.

SWI/SNF chromatin remodeling complex alterations in meningioma.

PURPOSE: While SWI/SNF chromatin remodeling complex alterations occur in approximately 20% of cancer, the frequency and potential impact on clinical outcomes in meningiomas remains to be comprehensively elucidated. METHODS: A large series of 255 meningiomas from a single institution that was enriched for high grade and recurrent lesions was identified. We performed next-generation targeted sequencing of known meningioma driver genes, including NF2, AKT1, PIK3CA, PIK3R1, and SMO and SWI/SNF chromatin remodeling complex genes, including ARID1A, SMARCA4, and SMARCB1 in all samples. Clinical correlates focused on clinical presentation and patient outcomes are presented. RESULTS: The series included 63 grade I meningiomas and 192 high-grade meningiomas, including 173 WHO grade II and 19 WHO grade III. Samples from recurrent surgeries comprised 37.3% of the series. A total of 41.6% meningiomas were from the skull base. NF2, AKT1, PIK3CA, PIK3R1, and SMO were mutated in 40.8, 7.1, 3.5, 3.9, and 2.4% of samples, respectively. ARID1A, SMARCA4, and SMARCB1 mutations were observed in 17.3, 3.5, and 5.1% of samples, respectively. A total of 68.2% of ARID1A-mutant meningiomas harbored a p.Gln1327del in-frame deletion. ARID1A mutations were seen in 19.1% of Grade I, 16.8% of Grade II, and 15.8% of Grade III meningiomas (P = 0.9, Fisher's exact). Median overall survival was 16.3 years (95% CI 10.9, 16.8). With multivariable analysis, the presence of an ARID1A mutation was significantly associated with a 7.421-fold increased hazard of death (P = 0.04). CONCLUSION: ARID1A mutations occur with similar frequency between low and high-grade meningiomas, but ARID1A mutations are independently prognostic of worse prognosis beyond clinical and histopathologic features.

Alcohol and Tobacco Use in Relation to Mammographic Density in 23,456 Women.

BACKGROUND: Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood. METHODS: We examined associations of alcohol and tobacco use with PD, DA, and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric. MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis. RESULTS: Alcohol use was positively associated with PD (P trend = 0.01), unassociated with DA (P trend = 0.23), and inversely associated with NDA (P trend = 0.02) adjusting for age, body mass index, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (P trend = 0.0008), unassociated with DA (P trend = 0.93), and positively associated with NDA (P trend<0.0001). These trends were stronger in normal and overweight women than in obese women. CONCLUSIONS: These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA. IMPACT: PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health.

Identification of 31 loci for mammographic density phenotypes and their associations with breast cancer risk.

Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P < 5 × 10-8, tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis (P < 0.05). Mendelian randomization analyses show that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are all significantly associated with breast cancer risk (P < 0.05). Pathway analyses reveal distinct biological processes involving DA, NDA and PD loci. These findings provide additional insights into the genetic basis of MD phenotypes and their associations with breast cancer risk.

Surgeon characteristics and use of breast conservation surgery in women with early stage breast cancer.

BACKGROUND: Most women with localized breast cancer have a choice between mastectomy and breast conserving surgery (BCS). Aside from clinical factors, this decision may be associated with surgeon and patient characteristics. We investigated the effect of surgeon characteristics on the BCS rate. METHODS: We used the Surveillance, Epidemiology, and End Results-Medicare database to identify women >65 years, diagnosed with stages I-II BC, between 1991 and 2002, and used the Physician Unique Identification Number linked to the American Medical Association Masterfile to obtain information on surgeons. We investigated the association of patient demographic, tumor, and surgeon-related factors with receipt of BCS, using Generalized Estimating Equations to control for clustering. RESULTS: Of 56,768 women with breast cancer, 30,006 (53%) underwent BCS, whereas 26,762 (47%) underwent mastectomy. Between 1991 and 2002, the proportion of patients undergoing BCS increased from 35% to 60%. In a multivariate analysis, patients who received BCS were younger, of higher SES, and had more favorable tumor characteristics. They were also more likely to be black and live in metropolitan areas. Women who underwent BCS were more likely to have surgeons who were female (OR = 1.40; 95% CI: 1.25-1.55), US-trained (OR = 1.12; 95% CI: 1.02-1.22), with a larger patient panel (OR = 1.29; 95% CI: 1.21-1.39), and completed training after 1975 (OR = 1.16; 95% CI: 1.08-1.25), than surgeons of patients who underwent mastectomy. CONCLUSIONS: Surgeon characteristics, such as gender, training, year of graduation, and volume, are small but significant independent predictor of BCS. Efforts to differentiate whether these associations reflect patients' preferences, quality of physician training, surgeon attitudes, physician-patient communication, or other effects on decision-making are warranted.

Diagnosis of Pancreatic Cystic Lesions by Virtual Slicing: Comparison of Diagnostic Potential of Needle-Based Confocal Laser Endomicroscopy versus Endoscopic Ultrasound-Guided Fine-Needle Aspiration.

BACKGROUND: Pancreatic cystic lesions are often challenging entities for diagnosis and management. EUS-FNA diagnostic accuracy is limited by paucicellularity of cytology specimens and sampling errors. Needle-based confocal laser endomicroscopy (nCLE) provides real-time imaging of the microscopic structure of the cystic lesion and could result in a more accurate diagnosis. AIMS AND OBJECTIVES: To determine the diagnostic utility of in vivo nCLE and EUS-FNA in the diagnosis and histologic characterization of pancreatic cystic lesions (PCL). MATERIALS AND METHODS: All patients diagnosed with PCL who had undergone nCLE and FNA over a 10-year period within a major urban teaching hospital were included in this study. All gastroenterology reports of the nCLE images and corresponding pathologist findings from the EUS-FNA were collected and compared with, a final diagnosis prospectively collected from clinicopathological and imaging data. RESULTS: A total of n=32 patients were included in this study, which consisted of n=13 serous cystadenoma (SCA), n=7 intraductal papillary mucinous neoplasms (IPMN), n=2 mucinous cystic neoplasms (MCN), n=3 well-differentiated neuroendocrine tumors, n=2 cysts, n=2 benign pancreatic lesions, n=1 adenocarcinoma, n=1 gastrointestinal stromal tumor (GIST) and n=1 lymphangioma. The overall diagnostic rate was higher in nCLE (87.5%) vs. EUS-FNA (71.9%) While the diagnostic accuracy of nCLE and EUS-FNA were comparable in characterization of benign vs. malignant lesions, the nCLE diagnosis demonstrated higher accuracy rate in identifying mucinous cystic neoplasms compared to EUS-FNA. CONCLUSION: nCLE is a useful companion diagnostic tool for pancreatic cystic lesions and could assist the cytopathologist to better triage the sample for required ancillary testing and treatment planning. The combination of nCLE and EUS-FNA may be especially helpful in reducing the proportion of cases categorized as non-diagnostic.