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Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals., Patients and Methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation., Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years., Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD., Competing Interests: Hagit N. BarisConsulting or Advisory Role: Sanofi, Igentify LtdSpeakers' Bureau: Sanofi, Takeda, Pfizer Donald BaselHonoraria: BioMarinConsulting or Advisory Role: iQvia Deborah T. BlumenthalConsulting or Advisory Role: AstraZeneca, Novocure, Takeda Miriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmune Sara RhodeHonoraria: Myriad GeneticsSpeakers' Bureau: Myriad GeneticsTravel, Accommodations, Expenses: Myriad Genetics Roula FarahHonoraria: Novo NordiskConsulting or Advisory Role: Novo Nordisk William D. FoulkesResearch Funding: AstraZeneca David GassEmployment: X4 PharmaceuticalsHonoraria: X4 PharmaceuticalsSpeakers' Bureau: Precisionscientia Heather HampelStock and Other Ownership Interests: Genome MedicalConsulting or Advisory Role: InVitae, Genome Medical, Promega, 23andMe Jordan R. HansfordConsulting or Advisory Role: Bayer Craig HarlosTravel, Accommodations, Expenses: GlaxoSmithKline Nobuko HijiyaHonoraria: NovartisConsulting or Advisory Role: Novartis, IncyteResearch Funding: Pfizer Junne KamiharaStock and Other Ownership Interests: PanTher Therapeutics, ROME Therapeutics, TellBioHonoraria: Pfizer, NanoString Technologies, Third Rock Ventures, Foundation MedicineConsulting or Advisory Role: ROME Therapeutics, Third Rock VenturesResearch Funding: PureTech, Ribon Therapeutics, ACD BiotechnePatents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics, Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics, Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc Jeffrey KnipsteinEmployment: PRA Health SciencesConsulting or Advisory Role: Atheneum Alvaro LassalettaStock and Other Ownership Interests: Gilead SciencesConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche, ServierTravel, Accommodations, Expenses: Shire, Gilead Sciences Simon C. LingHonoraria: AbbvieResearch Funding: Abbvie, Gilead Sciences Michael P. LinkConsulting or Advisory Role: Incyte, ADC Therapeutics, Lilly, Steba Biotech, Mesoblast, GlaxoSmithKline, SyndaxResearch Funding: Seattle Genetics, Janssen Oncology Rebecca Loret de MolaEmployment: Huron Consulting Maura MassiminoConsulting or Advisory Role: Oncoscience, Novartis Gary MasonEmployment: Janssen Research & Development, MerckStock and Other Ownership Interests: Johnson & Johnson, MerckTravel, Accommodations, Expenses: Janssen Research & Development Kim E. NicholsStock and Other Ownership Interests: IncyteResearch Funding: Incyte/Novartis, Alpine Immune Sciences Enrico OpocherConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca Michael OsbornTravel, Accommodations, Expenses: Amgen, Pfizer Benjamin OshrineHonoraria: Mesoblast Alyssa ReddyConsulting or Advisory Role: Novartis, AstraZeneca Lara ReichmanResearch Funding: Illumina Marc RemkeStock and Other Ownership Interests: Bayer, BB Biotech Ventures, BioNTech AG, InVitae, IDEXX Laboratories Kami Wolfe SchneiderOther Relationship: Journal of Genetic Counseling Duncan StearnsConsulting or Advisory Role: AstraZenecaOpen Payments Link: https://openpaymentsdata.cms.gov/physician/792397 Patrick TombocHonoraria: Unicare Health PlanConsulting or Advisory Role: UniCare Health Plan An Van DammeConsulting or Advisory Role: Octapharm, Pfizer, BayerResearch Funding: Johnson & JohnsonTravel, Accommodations, Expenses: Pfizer, Sobi, Shire, Roche Ira WinerResearch Funding: Oncoceutics David S. ZieglerConsulting or Advisory Role: Bayer, AmgenTravel, Accommodations, Expenses: Bayer Cynthia HawkinsConsulting or Advisory Role: BayerPatents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel David MalkinConsulting or Advisory Role: Bayer Eric BouffetConsulting or Advisory Role: NovartisResearch Funding: Roche, Bristol Myers SquibbNo other potential conflicts of interest were reported.

Ultrafine particles (UFP; diameter less than or equal to 100 nm) may reach the brain via systemic circulation or the olfactory tract and have been implicated in the risk of brain tumors. The effects of airport-related UFP on the risk of brain tumors are not known. Here we determined the association between airport-related UFP and risk of incident malignant brain cancer ( n = 155) and meningioma ( n = 420) diagnosed during 16.4 years of follow-up among 75,936 men and women residing in Los Angeles County from the Multiethnic Cohort study. UFP exposure from aircrafts was estimated for participants who lived within a 53 km × 43 km grid area around the Los Angeles International Airport (LAX) from date of cohort entry (1993-1996) through December 31, 2013. Cox proportional hazards models were used to estimate the effects of time-varying, airport-related UFP exposure on risk of malignant brain cancer and meningioma, adjusting for sex, race/ethnicity, education, and neighborhood socioeconomic status. Malignant brain cancer risk in all subjects combined increased 12% [95% confidence interval (CI), 0.98-1.27] per interquartile range (IQR) of airport-related UFP exposure (∼6,700 particles/cm 3 ) for subjects with any address in the grid area surrounding the LAX airport. In race/ethnicity-stratified analyses, African Americans, the subgroup who had the highest exposure, showed a HR of 1.32 (95% CI, 1.07-1.64) for malignant brain cancer per IQR in UFP exposure. UFP exposure was not related to risk of meningioma overall or by race/ethnicity. These results support the hypothesis that airport-related UFP exposure may be a risk factor for malignant brain cancers. SIGNIFICANCE: Malignant brain cancer risk increases with airport-related UFP exposure, particularly among African Americans, suggesting UFP exposure may be a modifiable risk factor for malignant brain cancer., (©2021 American Association for Cancer Research.)

Background: RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiation and growth. Identification and characterization of oncogenic RBPs and their regulatory networks provide new opportunities for targeted therapy., Results: We identify the RNA-binding protein SERBP1 as a novel regulator of glioblastoma (GBM) development. High SERBP1 expression is prevalent in GBMs and correlates with poor patient survival and poor response to chemo- and radiotherapy. SERBP1 knockdown causes delay in tumor growth and impacts cancer-relevant phenotypes in GBM and glioma stem cell lines. RNAcompete identifies a GC-rich region as SERBP1-binding motif; subsequent genomic and functional analyses establish SERBP1 regulation role in metabolic routes preferentially used by cancer cells. An important consequence of these functions is SERBP1 impact on methionine production. SERBP1 knockdown decreases methionine levels causing a subsequent reduction in histone methylation as shown for H3K27me3 and upregulation of genes associated with neurogenesis, neuronal differentiation, and function. Further analysis demonstrates that several of these genes are downregulated in GBM, potentially through epigenetic silencing as indicated by the presence of H3K27me3 sites., Conclusions: SERBP1 is the first example of an RNA-binding protein functioning as a central regulator of cancer metabolism and indirect modulator of epigenetic regulation in GBM. By bridging these two processes, SERBP1 enhances glioma stem cell phenotypes and contributes to GBM poorly differentiated state.

Background and Objective: To describe the incidence, characteristics, and risk factors of a pigmentary maculopathy in patients with primary central nervous system (CNS) lymphoma treated with blood-brain barrier disruption (BBBD) therapy., Patients and Methods: This retrospective chart review included patients with biopsy-proven primary CNS lymphoma treated with or without BBBD therapy who underwent an ophthalmic examination after starting systemic treatment. Clinical data and all available retinal imaging were analyzed., Results: Fifty-eight patients met inclusion criteria. Twenty-one of 36 patients treated with BBBD therapy had a bilateral pigmentary maculopathy. None of the 22 patients treated with conventional chemotherapy had similar changes. Additional findings in patients treated with BBBD included geographic retinal pigment epithelium atrophy, subretinal fluid, and in one case, choroidal neovascularization. Some cases of maculopathy resulted in reduced visual acuity. The presence of a pigmentary maculopathy was associated with a higher number of BBBD treatment sessions (20.1 vs 13.3, P = .016), but not vitreoretinal lymphoma involvement or intravitreal methotrexate injections., Conclusion: In this cohort, 58.3% of patients with primary CNS lymphoma treated with BBBD and chemotherapy were found to have a bilateral pigmentary maculopathy. This maculopathy can result in reduced visual acuity and is associated with the number of BBBD treatment sessions. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:S5-S12.]., (Copyright 2020, SLACK Incorporated.)

Purpose: The association between female reproductive factors and glioma risk is unclear, but most published studies have been limited by small sample size. We conducted a pooled multisite study of pre- and postmenopausal women, investigating the effect of female reproductive factors, including hormonal medications., Methods: Unconditional logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (95 % CIs) assessing the effects of female reproductive factors and female hormonal medications in glioma cases and unrelated controls., Results: Menarche over the age of 15 as compared to under 12 was associated with a statistically significant risk for glioma (OR 2.00, 95 % CI 1.47-2.71). Use of oral contraceptive pills (OCP) was inversely associated with risk of glioma (OR 0.61, 95 % CI 0.50-0.74), and there was an inverse trend with longer duration of OCP use (p for trend <0.0001). Use of hormone replacement therapy (HRT) was also inversely associated with risk of glioma (OR 0.55, 95 % CI 0.44-0.68), and there was an inverse trend with longer duration of use (p for trend <0.0001). Compared to those reporting neither OCP use nor HRT use, those who reported using both were less likely to have a diagnosis of glioma (OR 0.34, 95 % CI 0.24-0.48)., Conclusions: Female reproductive hormones may decrease the risk for glioma. The association appears to be strongest with greater length of use and use of both HRT and OCP.

Background: N-nitroso compounds (NOC) are found in processed meat and are formed endogenously from intake of nitrite and nitrate. Endogenous NOC formation is antagonized by nitrosation inhibitors in fruit and vegetables (e.g., vitamin C) and promoted by heme in red meat. It has been hypothesized that a diet resulting in high exposure to NOCs increases adult glioma risk., Methods: Using proportional hazards models, we tested this hypothesis among 545,770 participants in the prospective NIH-AARP Diet and Health Study, which assessed dietary intake at baseline (1995-1996) with a comprehensive food frequency questionnaire, and at ages 12 to 13 years with an abbreviated food frequency questionnaire., Results: During follow-up through 2003, 585 participants were diagnosed with glioma. We found no significant trends in glioma risk for consumption of processed or red meat, nitrate, or vitamin C or E. We found significant positive trends for nitrite intake from plant sources (hazard ratio for quintile 5 versus quintile 1, 1.59; 95% confidence interval, 1.20-2.10; P for trend = 0.028) and, unexpectedly, for fruit and vegetable intake (hazard ratio, 1.42; 95% confidence interval, 1.08-1.86; P for trend = 0.0081). Examination of interactions between dietary intakes (e.g., nitrite and vitamin C) and a limited analysis of diet at ages 12 to 13 years provided no support for the NOC hypothesis., Conclusions: Our results suggest that consumption of processed or red meat, nitrite, or nitrate does not increase adult glioma risk, and that consumption of fruit and vegetables, vitamin C, or vitamin E does not reduce risk., Impact: Our results, in agreement with the only previous prospective analysis, cast doubt on the NOC hypothesis in relation to dietary intake and adult glioma risk.

Magnetic resonance spectroscopy (MRS) offers a unique, noninvasive approach to assess pediatric neurological abnormalities at microscopic levels by quantifying cellular metabolites. The most widely available MRS method, proton ((1)H; hydrogen) spectroscopy, is FDA approved for general use and can be ordered by clinicians for pediatric neuroimaging studies if indicated. There are a multitude of both acquisition and post-processing methods that can be used in the implementation of MR spectroscopy. MRS in pediatric neuroimaging is challenging to interpret because of dramatic normal developmental changes that occur in metabolites, particularly in the first year of life. Still, MRS has been proven to provide additional clinically relevant information for several pediatric neurological disease processes such as brain tumors, infectious processes, white matter disorders, and neonatal injury. MRS can also be used as a powerful quantitative research tool. In this article, specific research applications using MRS will be demonstrated in relation to neonatal brain injury and pediatric brain tumor imaging.

To evaluate the NIH Image measured MIB-1 staining index (SI) as a useful tool for the determination of proliferative activity of gliomas, MIB-1 immunohistochemistry was performed on paraffin sections to estimate the proliferative activity of 50 gliomas. Five to eight RGB images at 200 magnifications were acquired per sample in a Macintosh computer using a RD-175 digital camera and Adope Photoshop program, followed by conversion of the RGB image to B (blue subtracted) and R (red subtracted) images and finally automatic cell counting of more than 1000 cells per sample by the NIH Image analysis program. The mean MIB-1 staining indices by both NIH count and visually assessed (manual) count respectively were 12.7% +/- 9.9% (mean +/- standard deviation) and 12.6% +/- 9.9% in all gliomas (n = 50), 2.9% +/- 0.6% and 2.3% +/- 0.6% in grade I and II astrocytomas (n = 9), 10.7% +/- 8.9% and 11.1% +/- 9.0% in grade III gliomas (n = 17), 16.1% +/- 9.1% and 16.3% +/- 9.1% in glioblastoma multiformes (n = 20), 26.0% +/- 4.9% and 24.5% +/- 2.6% in other glial tumors (n = 4). These paired values were assumed to be identical, since the p value obtained by paired t-test in all gliomas was 0.905. We conclude that the MIB-1 staining index measured by NIH Image is reliable and universal.