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Objective: Our purpose was to describe our initial institutional experience using dedicated brain [18F]-Fluoroestradiol (FES) PET/CT or PET/MRI in the management of patients with estrogen-receptor-positive (ER+) breast cancer brain metastases (BCBM), and compare to [18F]-Fluorodeoxyglucose (FDG) PET and MRI., Materials & Methods: Patients with biopsy-proven ER+ disease and MRI findings of suspected new, progressive, or recurrent BCBM were included in this retrospective study. Clinical and demographic data were collected. Dedicated brain FES PET/CT or PET/MRI was performed for clinical purposes. Maximum standardized uptake value (SUV) in MRI-defined target lesions and SUV ratio (SUVR, referencing normal-appearing parenchyma) were obtained. Pathology and/or clinical and MRI follow-up data were used as gold standard to classify viable neoplasm versus post-radiotherapy (RT) sequelae. Mann-Whitney tests were performed to compare subgroups., Results: Seven patients met inclusion criteria. 15/16 (94 %) lesions classified as neoplasm were FES-positive. 4/4 (100 %) lesions classified as RT sequelae were FES-negative. Median tumor FES-SUVR were higher than median RT-sequelae FES-SUVR (6.0 (2.8-9.1) versus 0.5 (0.3-0.7), p < 0.01), and similarly, median tumor FES-SUV were higher than median RT-sequelae FES-SUV (4.8 (2.8-9.1) versus 0.6 (0.3-0.8), p < 0.01). Lesion-based analysis of FDG-SUV and -SUVR demonstrated a trend for higher FDG avidity in lesions characterized as neoplasm; however, this did not reach statistical significance., Conclusion: Dedicated FES brain PET represents a promising adjunct modality, noting limitations of small sample size, retrospective nature of our study, and the possibility of ER expression heterogeneity. Our findings merit future prospective clinical trials incorporating dedicated brain FES PET/CT and PET/MRI in the management of patients with ER-positive disease and BCBM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Molecular profiles of renal cell carcinoma (RCC) brain metastases (BMs) are not well characterized. Effective management with locoregional therapies, including stereotactic radiosurgery (SRS), is critical as systemic therapy advancements have improved overall survival (OS)., Objective: To identify clinicogenomic features of RCC BMs treated with SRS in a large patient cohort., Design, Setting, and Participants: A single-institution retrospective analysis was conducted of all RCC BM patients treated with SRS from January 1, 2010 to March 31, 2021., Intervention: SRS for RCC BMs., Outcome Measurements and Statistical Analysis: Next-generation sequencing was performed to identify gene alterations more prevalent in BM patients. Clinical factors and genes altered in ≥10% of samples were assessed per patient using Cox proportional hazards models and per individual BM using clustered competing risks regression with competing risk of death., Results and Limitations: Ninety-one RCC BM patients underwent SRS to 212 BMs, with a median follow-up of 38.8 mo for patients who survived. The median intracranial progression-free survival and OS were 7.8 (interquartile range [IQR] 5.7-11) and 21 (IQR 16-32) mo, respectively. Durable local control of 83% was achieved at 12 mo after SRS, and 59% of lesions initially meeting the radiographic criteria for progression at 3-mo evaluation would be considered to represent pseudoprogression at 6-mo evaluation. A comparison of genomic alterations at both the gene and the pathway level for BM+ patients compared with BM- patients revealed phosphoinositide 3-kinase (PI3K) pathway alterations to be more prevalent in BM+ patients (43% vs 16%, p = 0.001, q = 0.01), with the majority being PTEN alterations (17% vs 2.7%, p = 0.003, q = 0.041)., Conclusions: To our knowledge, this is the largest study investigating genomic profiles of RCC BMs and the only such study with annotated intracranial outcomes. SRS provides durable in-field local control of BMs. Recognizing post-SRS pseudoprogression is crucial to ensure appropriate management. The incidence of PI3K pathway alterations is more prevalent in BM+ patients than in BM- patients and warrants further investigation in a prospective setting., Patient Summary: We examined the outcomes of radiotherapy for the treatment of brain metastases in kidney cancer patients at a single large referral center. We found that radiation provides good control of brain tumors, and certain genetic mutations may be found more commonly in patients with brain metastasis., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Malignant central nervous system (CNS) cancers include a group of heterogeneous dis-eases characterized by a relative resistance to treatments and distinguished as either primary tumors arising in the CNS or secondary tumors that spread from other organs into the brain. Despite therapeutic efforts, they often cause significant mortality and morbidity across all ages. Radiotherapy (RT) remains the main treatment for brain cancers, improving associated symptoms, improving tumor control, and inducing a cure in some. However, the ultimate goal of cancer treatment, to improve a patient's survival, remains elusive for many CNS cancers, especially primary tumors. Over the years, there have thus been many preclinical studies and clinical trials designed to identify and overcome mechanisms of resistance to improve outcomes after RT and other therapies. For example, immunotherapy delivered concurrent with RT, especially hypo-fractionated stereotactic RT, is synergistic and has revolutionized the clinical management and outcome of some brain tumors, in particular brain metastases (secondary brain tumors). However, its impact on gliomas, the most common primary malignant CNS tumors, remains limited. In this review, we provide an overview of radioresistance mechanisms, the emerging strategies to overcome radioresistance, the role of the tumor microenviroment (TME), and the selection of the most significant results of radiation-immuno-oncological investigations. We also identify novel therapeutic opportunities in primary and secondary brain tumors with the purpose of elucidating current knowledge and stimulating further research to improve tumor control and patients' survival.

The epigenetic landscape of cancer is regulated by many factors, but primarily it derives from the underlying genome sequence. Chromothripsis is a catastrophic localized genome shattering event that drives, and often initiates, cancer evolution. We characterized five esophageal adenocarcinoma organoids with chromothripsis using long-read sequencing and transcriptome and epigenome profiling. Complex structural variation and subclonal variants meant that haplotype-aware de novo methods were required to generate contiguous cancer genome assemblies. Chromosomes were assembled separately and scaffolded using haplotype-resolved Hi-C reads, producing accurate assemblies even with up to 900 structural rearrangements. There were widespread differences between the chromothriptic and wild-type copies of chromosomes in topologically associated domains, chromatin accessibility, histone modifications, and gene expression. Differential epigenome peaks were most enriched within 10 kb of chromothriptic structural variants. Alterations in transcriptome and higher-order chromosome organization frequently occurred near differential epigenetic marks. Overall, chromothripsis reshapes gene regulation, causing coordinated changes in epigenetic landscape, transcription, and chromosome conformation., Competing Interests: Declaration of interests P.J.C. is an academic co-founder, stockholder, and consultant for Quotient Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: Adjuvant stereotactic radiosurgery (SRS) enhances the local control of resected brain metastases (BrM). However, the risks of local failure (LF) and potential for posttreatment adverse radiation effects (PTRE) after early postoperative adjuvant SRS have not yet been established., Objective: To evaluate whether adjuvant SRS delivered within a median of 14 days after surgery is associated with improved LF without a concomitant increase in PTRE., Design, Setting, and Participants: This prospective cohort study examines a clinical workflow (RapidRT) that was implemented from 2019 to 2022 to deliver SRS to surgical patients within a median of 14 days, ensuring all patients were treated within 30 days postoperatively. This prospective cohort was compared with a historical cohort (StanRT) of patients with BrM resected between 2013 and 2019 to assess the association of the RapidRT workflow with LF and PTRE. The 2 cohorts were combined to identify optimal SRS timing, with a median follow-up of 3.3 years for survivors., Exposure: Timing of adjuvant SRS (14, 21, and 30 days postoperatively)., Main Outcomes and Measures: LF and PTRE, according to modified Response Assessment in Neuro-Oncology Brain Metastases criteria., Results: There were 438 patients (265 [60.5%] female patients; 23 [5.3%] Asian, 27 [6.2%] Black, and 364 [83.1%] White patients) with a mean (SD) age of 62 (13) years; 377 were in the StanRT cohort and 61 in the RapidRT cohort. LF and PTRE rates at 1 year were not significantly different between RapidRT and StanRT cohorts. Timing of SRS was associated with radiographic PTRE. Patients receiving radiation within 14 days had the highest 1-year PTRE rate (18.08%; 95% CI, 8.31%-30.86%), and patients receiving radiation between 22 and 30 days had the lowest 1-year PTRE rate (4.10%; 95% CI, 1.52%-8.73%; P = .03). LF rates were highest for patients receiving radiation more than 30 days from surgery (10.65%; 95% CI, 6.90%-15.32%) but comparable for patients receiving radiation within 14 days, between 15 and 21 days, and between 22 and 30 days (≤14 days: 5.12%; 95% CI, 0.86%-15.60%; 15 to ≤21 days: 3.21%; 95% CI, 0.59%-9.99%; 22 to ≤30 days: 6.58%; 95% CI, 3.06%-11.94%; P = .20)., Conclusions and Relevance: In this cohort study of adjuvant SRS timing following surgical resection of BrM, the optimal timing for adjuvant SRS appears to be within 22 to 30 days following surgery. The findings of this study suggest that this timing allows for a balanced approach that minimizes the risks associated with LF and PTRE.

Site-specific integration (SSI) technology has emerged as an effective approach by the pharmaceutical industry for the development of recombinant Chinese hamster ovary (CHO) cell lines. While SSI systems have been demonstrated to be effective for the development of CHO cell lines, they can be limiting in terms of both transgene expression and in the case of multi-specifics, the ability to generate the correct product of interest. To maximize the performance of Pfizer's dual SSI expression system for expressing monoclonal and multi-specific antibodies, we used a novel approach to investigate the positional effect of transgenes within expression vectors by engineering nucleotide polymorphisms (NP)s to use as biomarkers to track the level of transcript output from each expression vector position. We observed differences in transcript level for two different transgenes across all four expression vector positions interrogated. We then applied these learnings to rationally design expression vectors for six different mAbs and a multi-specific antibody. We showed enhanced productivity and optimal product quality when compared to a conventional expression vector topology. The learnings gained here can potentially aid in the determination of optimal vector topologies for several IgG-like multi-specific formats., (© 2023 The Authors. Biotechnology Journal published by Wiley-VCH GmbH.)

Background and Purpose: Patients with brain metastases (BMs) are surviving longer and returning for multiple courses of stereotactic radiosurgery. BMs are monitored after radiation with follow-up magnetic resonance (MR) imaging every 2-3 months. This study investigated whether it is possible to automatically track BMs on longitudinal imaging and quantify the tumor response after radiotherapy., Methods: The METRO process (MEtastasis Tracking with Repeated Observations was developed to automatically process patient data and track BMs. A longitudinal intrapatient registration method for T1 MR post-Gd was conceived and validated on 20 patients. Detections and volumetric measurements of BMs were obtained from a deep learning model. BM tracking was validated on 32 separate patients by comparing results with manual measurements of BM response and radiologists' assessments of new BMs. Linear regression and residual analysis were used to assess accuracy in determining tumor response and size change., Results: A total of 123 irradiated BMs and 38 new BMs were successfully tracked. 66 irradiated BMs were visible on follow-up imaging 3-9 months after radiotherapy. Comparing their longest diameter changes measured manually vs. METRO, the Pearson correlation coefficient was 0.88 (p < 0.001); the mean residual error was -8 ± 17%. The mean registration error was 1.5 ± 0.2 mm., Conclusions: Automatic, longitudinal tracking of BMs using deep learning methods is feasible. In particular, the software system METRO fulfills a need to automatically track and quantify volumetric changes of BMs prior to, and in response to, radiation therapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Introduction: Highly effective brain-penetrant ALK-targeted tyrosine kinase inhibitors (TKIs) have been developed for the management of NSCLC patients with brain metastases (BM). Local therapy (LT) such as SRS or therapeutic craniotomy is increasingly being deferred for such patients. Herein we report detailed patient- and lesion-level intracranial outcomes and co-mutational genomic profiles from a cohort of NSCLC patients with BM treated with alectinib, with or without LT., Methods: We retrospectively reviewed ALK fusion-positive NSCLC patients with BMs who received alectinib at the diagnosis of BM from 1/2012 and 5/2021. Outcome variables included intracranial progression-free survival (iPFS), overall survival (OS), duration of TKI therapy, and CNS response rates. Genomic characteristics from tumor specimens were assessed with MSK-IMPACT, a next-generation sequencing (NGS)-based genomic profiling assay., Results: A total of 38 patients with 114 CNS lesions were included. Twelve of these patients also received contemporaneous LT (SRS, WBRT, or surgical resection). Maximal BM diameter in the TKI + LT group was greater (p < 0.003) but despite this difference, iPFS (TKI only, HR 1.21, 95 % CI 0.51-2.89; p = 0.66) and OS (TKI only, HR 5.99, 95 % CI 0.77-46.6; p = 0.052) were similar between groups and trended towards more favorable outcomes with the addition of LT. SMARCA4 co-alterations were associated with inferior OS (HR 8.76, 1.74-44.2; p = 0.009)., Conclusions: Our study demonstrated that patients with ALK fusion-positive NSCLC treated with TKI + LT had larger BM and higher likelihood of pre-treatment neurologic symptoms. Despite these differences, iPFS was similar between groups. Results should be interpreted with caution as our study was limited by an underpowered sample size. SMARCA4 co-alterations were associated with inferior OS and these findings warrant further investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Cystic postradiation degeneration has previously been described in the literature as a rare but potentially severe complication after central nervous system (CNS) irradiation for vascular malformations. Limited cases have been reported in the setting of brain metastases., Observations: Thirty-six total cases, including three reported here, of cystic postradiation degeneration are identified. Of 35 cases with complete clinical information, 34 (97.25%) of 35 were symptomatic from cystic changes at diagnosis. The average time between initial radiation dose and cyst development was 7.61 years (range 2-31 years). Although most patients were initially treated conservatively with medication, including steroids, 32 (88.9%) of 36 ultimately required surgical intervention. The most common interventions were craniotomy for cyst fenestration or resection (25 of 36; 69.4%) and Ommaya placement (8 of 36). After intervention, clinical improvement was seen in 10 (67%) of 15 cases, with persistent or worsening deficit or death seen in 5 (33%) of 15. Cysts were decompressed or obliterated on postoperative imaging in 20 (83.3%) of 24 cases, and recurrence was seen in 4 (16.7%) of 24., Lessons: Cystic degeneration is a rare and delayed sequela after radiation for brain metastases. This entity has the potential to cause significant and permanent neurological deficit if not properly recognized and addressed. Durable control can be achieved with a variety of surgical treatments, including cyst fenestration and Ommaya placement.

Purpose: Timely surgical cavity stereotactic radiosurgery (SRS) is an important adjuvant to brain metastasis resection, with earlier treatment associated with less frequent recurrence. The logistical complexity of treatment organization, however, has resulted in suboptimal start times postsurgically. We implemented a process improvement approach to reduce the time from surgery to adjuvant irradiation of resected brain metastases., Methods: A multidisciplinary working group used process mapping to identify opportunities to reduce visits and shorten treatment times. The care delivery process was modified to streamline perioperative SRS preparation with (1) early patient identification, (2) preoperative intrateam communication, and (3) consolidation of required steps. Plan-Do-Study-Act cycles were used for process improvement. The surgery-to-SRS initiation time interval was the primary outcome. Secondary outcomes included the number of associated patient encounters., Results: After implementation, the median (interquartile range) interval from surgery to SRS was reduced 48% from 27 (21-34) to 14 days (13-17; P < .001). The rate of surgical cavity SRS within 30 days increased from 64% (n = 63 of 98) to 97% (n = 60 of 62; P < .001). The median (interquartile range) number of CNS-associated encounters between resection and SRS decreased from 5 (4-6) to 4 (3-5; P < .001). The proportion of patients who had > 1 magnetic resonance imaging/computed tomography between surgery and SRS decreased from 45% (44 of 98) to 13% (8 of 62; P < .001). The time from surgery to systemic therapy resumption/initiation among patients treated within 90 days postoperatively decreased from 35 (24-48) to 32 days (23-40; P = .074). There were no wound complications in either group., Conclusion: Adjuvant SRS latency and treatment-associated encounters were significantly reduced after care-coordination implementation. This approach reduces patient and health care system burden and can be applied to other scenarios where early postoperative SRS administration is critical., Competing Interests: Nelson S. MossConsulting or Advisory Role: AstraZenecaResearch Funding: GT Medical Technologies (Inst) Samantha BrownResearch Funding: AACR (Inst) Justin ChenStock and Other Ownership Interests: MindMed, Moderna Therapeutics, Tonix Pharmaceuticals, Ocugen, Ocuphire Pharma, Innerscope Hearing Technologies, Heat Biologics Brandon S. ImberHonoraria: GT Medical Technologies Luke PikeStock and Other Ownership Interests: Clovis Oncology, Schrodinger, NovavaxConsulting or Advisory Role: Blackstone, Deerfield Management, Third Rock Ventures, Aviko, Monograph Capital, Roivant, Galera Therapeutics, Dynamo Therapeutics, Myst Therapeutics, Turnstone Bio, Best Doctors Inc Katherine S. PanageasStock and Other Ownership Interests: AstraZeneca, Pfizer, Sunesis Pharmaceuticals Cameron BrennanStock and Other Ownership Interests: AVEOPatents, Royalties, Other Intellectual Property: Co-inventor on patents licensed through Memorial Sloan Kettering to Elucida Oncology Viviane TabarStock and Other Ownership Interests: BlueRock Therapeutics (I)Honoraria: BlueRock Therapeutics (I)Consulting or Advisory Role: BlueRock Therapeutics (I)Research Funding: BlueRock Therapeutics (I)Patents, Royalties, Other Intellectual Property: BlueRock Therapeutics (I)Travel, Accommodations, Expenses: BlueRock Therapeutics (I) Kathryn BealStock and Other Ownership Interests: MMT (I)No other potential conflicts of interest were reported.

Objective: Cesium-131 brachytherapy is an adjunct for brain tumor treatment, offering potential clinical and radiation protection advantages over other isotopes including iodine-125. We present evidence-based radiation safety recommendations from an initial experience with Cs-131 brachytherapy in the resection cavities of recurrent, previously irradiated brain metastases., Methods: Twenty-two recurrent brain metastases in 18 patients were resected and treated with permanent Cs-131 brachytherapy implantation using commercially procured seed-impregnated collagen tiles (GammaTile, GT Medical Technologies). Exposure to intraoperative staff was monitored with NVLAP-accredited ring dosimeters. For patient release considerations, NCRP guidelines were used to develop an algorithm for modeling lifetime exposure to family and ancillary staff caring for patients based on measured dose rates., Results: A median of 16 Cs-131 seeds were implanted (range 6-46) with median cumulative strength of 58.72U (20.64-150.42). Resulting dose rates were 1.19 mSv/h (0.28-3.3) on contact, 0.08 mSv/h (0.01-0.35) at 30 cm, and 0.01 mSv/h (0.001-0.03) at 100 cm from the patient. Modeled total caregiver exposure was 0.91 mSv (0.16-3.26), and occupational exposure was 0.06 mSv (0.02-0.23) accounting for patient self-shielding via skull and soft tissue attenuation. Real-time dose rate measurements were grouped into brackets to provide close contact precautions for caregivers ranging from 1-3 weeks for adults and longer for pregnant women and children, including cases with multiple implantations., Conclusions: Radiological protection precautions were developed based on patient-specific emissions and accounted for multiple implantations of Cs-131, to maintain exposure to staff and the public in accordance with relevant regulatory dose constraints., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background: Salvage of recurrent previously irradiated brain metastases (rBrM) is a significant challenge. Resection without adjuvant re-irradiation is associated with a high local failure rate, while reirradiation only partially reduces failure but is associated with greater radiation necrosis risk. Salvage resection plus Cs131 brachytherapy may offer dosimetric and biologic advantages including improved local control versus observation, with reduced normal brain dose versus re-irradiation, however data are limited., Methods: A prospective registry of consecutive patients with post-stereotactic radiosurgery (SRS) rBrM undergoing resection plus implantation of collagen-matrix embedded Cs131 seeds (GammaTile, GT Medical Technologies) prescribed to 60 Gy at 5 mm from the cavity was analyzed., Results: Twenty patients underwent 24 operations with Cs131 implantation in 25 tumor cavities. Median maximum preoperative diameter was 3.0 cm (range 1.1-6.3). Gross- or near-total resection was achieved in 80% of lesions. A median of 16 Cs131 seeds (range 6-30), with a median air-kerma strength of 3.5 U/seed were implanted. There was one postoperative wound dehiscence. With median follow-up of 1.6 years for survivors, two tumors recurred (one in-field, one marginal) resulting in 8.4% 1-year progression incidence (95%CI = 0.0-19.9). Radiographic seed settling was identified in 7/25 cavities (28%) 1.9-11.7 months post-implantation, with 1 case of distant migration (4%), without clinical sequelae. There were 8 cases of radiation necrosis, of which 4 were symptomatic., Conclusions: With > 1.5 years of follow-up, intraoperative brachytherapy with commercially available Cs131 implants was associated with favorable local control and toxicity profiles. Weak correlation between preoperative tumor geometry and implanted tiles highlights a need to optimize planning criteria., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489., (© 2022 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Antibody-drug conjugates have transformed the treatment of HER2+ breast and other cancers. Unfortunately, the CNS remains a sanctuary site for many such patients in part due to poor macromolecule penetration across the blood-brain tumor barrier. Trastuzumab deruxtecan (T-DXd), a high-payload antibody-drug conjugate, was recently found to improve progression-free survival in HER2+ breast cancer patients versus prior-generation trastuzumab emtansine, prompting us to evaluate CNS activity in a woman with brain-only metastatic disease. T-DXd achieved complete response despite heavy pretreatment. Three persistent, previously-irradiated lesions were biopsy-proven to represent treatment effect. Subsequent recurrence occurred upon treatment holiday; partial response was observed with rechallenge. This case suggests T-DXd is active in HER2+ breast cancer brain metastases and supports further prospective evaluation.

Importance: Brain metastasis (BrM) in gastroesophageal adenocarcinoma (GEA) is a rare and poorly understood phenomenon associated with poor prognosis., Objectives: To examine the clinical and genomic features of patients with BrM from GEA and evaluate factors associated with survival., Design, Setting, and Participants: In this single-institution retrospective cohort study, 68 patients with BrM from GEA diagnosed between January 1, 2008, and December 31, 2020, were identified via review of billing codes and imaging reports from the electronic medical record with follow-up through November 3, 2021. Genomic data were derived from the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets clinical sequencing platform., Exposures: Treatment with BrM resection and/or radiotherapy., Main Outcomes and Measures: Overall survival after BrM diagnosis., Results: Sixty-eight patients (median age at diagnosis, 57.4 years [IQR, 49.8-66.4 years]; 59 [86.8%] male; 55 [85.9%] White) participated in the study. A total of 57 (83.8%) had primary tumors in the distal esophagus or gastroesophageal junction. Median time from initial diagnosis to BrM diagnosis was 16.9 months (IQR, 8.5-27.7 months). Median survival from BrM diagnosis was 8.7 months (95% CI, 5.5-11.5 months). Overall survival was 35% (95% CI, 25%-48%) at 1 year and 24% (95% CI, 16%-37%) at 2 years. In a multivariable analysis, an Eastern Cooperative Oncology Group performance status of 2 or greater (hazard ratio [HR], 4.66; 95% CI, 1.47-14.70; P = .009) and lack of surgical or radiotherapeutic intervention (HR, 7.71; 95% CI, 2.01-29.60; P = .003) were associated with increased risk of all-cause mortality, whereas 3 or more extracranial sites of disease (HR, 1.85; 95% CI, 0.64-5.29; P = .25) and 4 or more BrMs (HR, 2.15; 95% CI, 0.93-4.98; P = .07) were not statistically significant. A total of 31 patients (45.6%) had ERBB2 (formerly HER2 or HER2/neu)-positive tumors, and alterations in ERBB2 were enriched in BrM relative to primary tumors (8 [47.1%] vs 7 [20.6%], P = .05), as were alterations in PTPRT (7 [41.2%] vs 4 [11.8%], P = .03)., Conclusions and Relevance: This study suggests that that a notable proportion of patients with BrM from GEA achieve survival exceeding 1 and 2 years from BrM diagnosis, a more favorable prognosis than previously reported. Good performance status and treatment with combination surgery and radiotherapy were associated with the best outcomes. ERBB2 positivity and amplification as well as PTPRT alterations were enriched in BrM tissue compared with primary tumors; therefore, further study should be pursued to identify whether these variables represent genomic risk factors for BrM development.

Breast cancer brain metastases (BCBM) are a common and devastating complication of metastatic breast cancer with conventional systemic therapies demonstrating limited effectiveness. Consequently, radiotherapy (RT) ± surgery remains the cornerstone of BCBM management. Because preclinical and clinical evidence indicate that immune checkpoint blockade (ICB) may synergize with RT to promote systemic tumor regression, we explored the safety and efficacy of RT and concurrent tremelimumab-mediated cytotoxic T-lymphocyte associated protein 4 (CTLA-4) ICB with tremelimumab ± HER2-directed therapy with trastuzumab for BCBM. Eligible patients had BCBM indicated for brain RT. A Simon two-stage design was adopted to evaluate the efficacy of tremelimumab and RT in 20 patients with human epidermal growth factor receptor normal (HER2-) BCBM. The safety of concurrent RT, tremelimumab, and trastuzumab was evaluated in a cohort of 6 HER2+ patients. The primary endpoint was 12-week non-central nervous system (CNS) disease control rate (DCR). Secondary endpoints included safety, survival, and CNS response. Exploratory correlatives included characterization of peripheral blood immune responses among exceptional responders. Tremelimumab plus RT ± trastuzumab was tolerated with no treatment-related grade 4 adverse events reported. The 12-week non-CNS DCR was 10% (2/20) in the HER2- cohort and 33% (2/6) in the HER2+ cohort. One patient with HER2+ disease experienced a durable partial response with evidence of peripheral T-cell activation. Thus, tremelimumab and RT ± trastuzumab was tolerated. Although modest clinical activity was observed in the HER2- efficacy cohort, encouraging responses were observed in the HER2+ safety cohort. Consequently, a trial to determine efficacy in HER2+ BCBM is planned.Clinical Trial Registration Number: NCT02563925., (© 2022. The Author(s).)

Purpose: The efficacy of salvage resection (SR) of recurrent brain metastases (rBrM) following stereotactic radiosurgery (SRS) is undefined. We sought to describe local recurrence (LR) and radiation necrosis (RN) rates in patients undergoing SR, with or without adjuvant post-salvage radiation therapy (PSRT)., Methods: A retrospective cohort study evaluated patients undergoing SR of post-SRS rBrM between 3/2003-2/2020 at an NCI-designated cancer center. Cases with histologically-viable malignancy were stratified by receipt of adjuvant PSRT within 60 days of SR. Clinical outcomes were described using cumulative incidences in the clustered competing-risks setting, competing risks regression, and Kaplan-Meier methodology., Results: One-hundred fifty-five rBrM in 135 patients were evaluated. The overall rate of LR was 40.2% (95% CI 34.3-47.2%) at 12 months. Thirty-nine (25.2%) rBrM treated with SR + PSRT trended towards lower 12-month LR versus SR alone [28.8% (95% CI 17.0-48.8%) versus 43.9% (95% CI 36.2-53.4%), p = .07 by multivariate analysis]. SR as re-operation (p = .03) and subtotal resection (p = .01) were independently associated with higher rates of LR. On univariate analysis, tumor size (p = .48), primary malignancy (p = .35), and PSRT technique (p = .43) bore no influence on LR. SR + PSRT was associated with an increased risk of radiographic RN at 12 months versus SR alone [13.4% (95% CI 5.5-32.7%) versus 3.5% (95% CI 1.5-8.0%), p = .02], though the percentage with symptomatic RN remained low (5.1% versus 0.9%, respectively). Median overall survival from SR was 13.4 months (95% CI 10.5-17.7)., Conclusion: In this largest-known series evaluating SR outcomes in histopathologically-confirmed rBrM, we identify a significant LR risk that may be reduced with adjuvant PSRT and with minimal symptomatic RN. Prospective analysis is warranted., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Stereotactic biopsy is increasingly performed on brain metastases (BrMs) as improving cancer outcomes drive aggressive multimodality treatment, including laser interstitial thermal therapy (LITT). However, the tract recurrence (TR) risk is poorly defined in an era defined by focused-irradiation paradigms. As such, the authors aimed to define indications and adjuvant therapies for this procedure and evaluate the BrM-biopsy TR rate., Methods: In a single-center retrospective review, the authors identified stereotactic BrM biopsies performed from 2002 to 2020. Surgical indications, radiographic characteristics, stereotactic planning, dosimetry, pre- and postoperative CNS-directed and systemic treatments, and clinical courses were collected. Recurrence was evaluated using RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases) criteria., Results: In total, 499 patients underwent stereotactic intracranial biopsy for any diagnosis, of whom 25 patients (5.0%) underwent biopsy for pathologically confirmed viable BrM, a proportion that increased over the time period studied. Twelve of the 25 BrM patients had ≥ 3 months of radiographic follow-up, of whom 6 patients (50%) developed new metastatic growth along the tract at a median of 5.0 months post-biopsy (range 2.3-17.1 months). All of the TR cases had undergone pre- or early post-biopsy stereotactic radiosurgery (SRS), and 3 had also undergone LITT at the time of initial biopsy. TRs were treated with resection, reirradiation, or observation/systemic therapy., Conclusions: In this study the authors identified a nontrivial, higher than previously described rate of BrM-biopsy tract recurrence, which often required additional surgery or radiation and justified close radiographic surveillance. As BrMs are commonly treated with SRS limited to enhancing tumor margins, consideration should be made, in cases lacking CNS-active systemic treatments, to include biopsy tracts in adjuvant radiation plans where feasible.

An increasing number of patients with multiple brain metastases are being treated with stereotactic radiosurgery (SRS). Manually identifying and contouring all metastatic lesions is difficult and time-consuming, and a potential source of variability. Hence, we developed a 3D deep learning approach for segmenting brain metastases on MR and CT images. Five-hundred eleven patients treated with SRS were retrospectively identified for this study. Prior to radiotherapy, the patients were imaged with 3D T1 spoiled-gradient MR post-Gd (T1 + C) and contrast-enhanced CT (CECT), which were co-registered by a treatment planner. The gross tumor volume contours, authored by the attending radiation oncologist, were taken as the ground truth. There were 3 ± 4 metastases per patient, with volume up to 57 ml. We produced a multi-stage model that automatically performs brain extraction, followed by detection and segmentation of brain metastases using co-registered T1 + C and CECT. Augmented data from 80% of these patients were used to train modified 3D V-Net convolutional neural networks for this task. We combined a normalized boundary loss function with soft Dice loss to improve the model optimization, and employed gradient accumulation to stabilize the training. The average Dice similarity coefficient (DSC) for brain extraction was 0.975 ± 0.002 (95% CI). The detection sensitivity per metastasis was 90% (329/367), with moderate dependence on metastasis size. Averaged across 102 test patients, our approach had metastasis detection sensitivity 95 ± 3%, 2.4 ± 0.5 false positives, DSC of 0.76 ± 0.03, and 95th-percentile Hausdorff distance of 2.5 ± 0.3 mm (95% CIs). The volumes of automatic and manual segmentations were strongly correlated for metastases of volume up to 20 ml (r=0.97,p<0.001). This work expounds a fully 3D deep learning approach capable of automatically detecting and segmenting brain metastases using co-registered T1 + C and CECT., (© 2021 Institute of Physics and Engineering in Medicine.)

Objective: Radiation therapy is a cornerstone of brain metastasis (BrM) management but carries the risk of radiation necrosis (RN), which can require resection for palliation or diagnosis. We sought to determine the relationship between extent of resection (EOR) of pathologically-confirmed RN and postoperative radiographic and symptomatic outcomes., Methods: A single-center retrospective review was performed at an NCI-designated Comprehensive Cancer Center to identify all surgically-resected, previously-irradiated necrotic BrM without admixed recurrent malignancy from 2003 to 2018. Clinical, pathologic and radiographic parameters were collected. Volumetric analysis determined EOR and longitudinally evaluated perilesional T2-FLAIR signal preoperatively, postoperatively, and at 3-, 6-, 12-, and 24-months postoperatively when available. Rates of time to 50% T2-FLAIR reduction was calculated using cumulative incidence in the competing risks setting with last follow-up and death as competing events. The Spearman method was used to calculate correlation coefficients, and continuous variables for T2-FLAIR signal change, including EOR, were compared across groups., Results: Forty-six patients were included. Most underwent prior stereotactic radiosurgery with or without whole-brain irradiation (N = 42, 91%). Twenty-seven operations resulted in gross-total resection (59%; GTR). For the full cohort, T2-FLAIR edema decreased by a mean of 78% by 6 months postoperatively that was durable to last follow-up (p < 0.05). EOR correlated with edema reduction at last follow-up, with significantly greater T2-FLAIR reduction with GTR versus subtotal resection (p < 0.05). Among surviving patients, a significant proportion were able to decrease their steroid use: steroid-dependency decreased from 54% preoperatively to 15% at 12 months postoperatively (p = 0.001)., Conclusions: RN resection conferred both durable T2-FLAIR reduction, which correlated with EOR; and reduced steroid dependency., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Sorafenib has demonstrated anti-tumor efficacy and radiosensitizing activity preclinically and in breast cancer. We examined sorafenib in combination with whole brain radiotherapy (WBRT) and explored the [18F] 3'deoxy-3'-fluorothymidine (FLT)-PET as a novel brain imaging modality in breast cancer brain metastases., Methods: A phase I trial of WBRT + sorafenib was conducted using a 3 + 3 design with safety-expansion cohort. Sorafenib was given daily at the start of WBRT for 21 days. The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). MacDonald Criteria were used for response assessment with a correlative serial FLT-PET imaging study., Results: 13 pts were evaluable for dose-limiting toxicity (DLT). DLTs were grade 4 increased lipase at 200 mg (n = 1) and grade 3 rash at 400 mg (n = 3). The MTD was 200 mg. The overall response rate was 71%. Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT + sorafenib and 5 WBRT) were enrolled in the FLT-PET study: baseline (n = 15), 7-10 days post WBRT (FU1, n = 14), and an additional 12 week (n = 9). A decline in average SUV max of ≥ 25% was seen in 9/10 (90%) of WBRT + sorafenib patients and 2/4 (50%) of WBRT only patients., Conclusions: Concurrent WBRT and sorafenib appear safe at 200 mg daily dose with clinical activity. CNS response was favorable compared to historical controls. This combination should be considered for further efficacy evaluation. FLT-PET may be useful as an early response imaging tool for brain metastases., Trial and Clinical Registry: Trial registration numbers and dates: NCT01724606 (November 12, 2012) and NCT01621906 (June 18, 2012).

Background and Purpose: To determine the ability of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict long-term response of brain metastases prior to and within 72 hours of stereotactic radiosurgery (SRS)., Methods: In this prospective pilot study, multiple b-value DWI and T1-weighted DCE-MRI were performed in patients with brain metastases before and within 72 hours following SRS. Diffusion-weighted images were analyzed using the monoexponential and intravoxel incoherent motion (IVIM) models. DCE-MRI data were analyzed using the extended Tofts pharmacokinetic model. The parameters obtained with these methods were correlated with brain metastasis outcomes according to modified Response Assessment in Neuro-Oncology Brain Metastases criteria., Results: We included 25 lesions from 16 patients; 16 patients underwent pre-SRS MRI and 12 of 16 patients underwent both pre- and early (within 72 hours) post-SRS MRI. The perfusion fraction (f) derived from IVIM early post-SRS was higher in lesions demonstrating progressive disease than in lesions demonstrating stable disease, partial response, or complete response (q = .041). Pre-SRS extracellular extravascular volume fraction, v e , and volume transfer coefficient, K trans , derived from DCE-MRI were higher in nonresponders versus responders (q = .041)., Conclusions: Quantitative DWI and DCE-MRI are feasible imaging methods in the pre- and early (within 72 hours) post-SRS evaluation of brain metastases. DWI- and DCE-MRI-derived parameters demonstrated physiologic changes (tumor cellularity and vascularity) and offer potentially useful biomarkers that can predict treatment response. This allows for initiation of alternate therapies within an effective time window that may help prevent disease progression., (© 2020 American Society of Neuroimaging.)

Background: Adjuvant stereotactic radiosurgery (SRS) improves the local control of resected brain metastases (BrM). However, the dependency of long-term outcomes on SRS timing relative to surgery remains unclear., Methods: Retrospective analysis of patients treated with metastasectomy-plus-adjuvant SRS at Memorial Sloan Kettering Cancer Center (MSK) between 2013 and 2016 was conducted. Kaplan-Meier methodology was used to describe overall survival (OS) and cumulative incidence rates were estimated by type of recurrence, accounting for death as a competing event. Recursive partitioning analysis (RPA) and competing risks regression modeling assessed prognostic variables and associated events of interest., Results: Two hundred and eighty-two patients with BrM had a median OS of 1.5 years (95% CI: 1.2-2.1) from adjuvant SRS with median follow-up of 49.8 months for survivors. Local surgical recurrence, other simultaneously SRS-irradiated site recurrence, and distant central nervous system (CNS) progression rates were 14.3% (95% CI: 10.1-18.5), 4.9% (95% CI: 2.3-7.5), and 47.5% (95% CI: 41.4-53.6) at 5 years, respectively. Median time-to-adjuvant SRS (TT-SRS) was 34 days (IQR: 27-39). TT-SRS was significantly associated with surgical site recurrence rate ( P = 0.0008). SRS delivered within 1 month resulted in surgical site recurrence rate of 6.1% (95% CI: 1.3-10.9) at 1-year, compared to 9.2% (95% CI: 4.9-13.6) if delivered between 1 and 2 months, or 27.3% (95% CI: 0.0-55.5) if delivered >2 months after surgery. OS was significantly lower for patients with TT-SRS >~2 months. Postoperative length of stay, discharge to a rehabilitation facility, urgent care visits, and/or disease recurrence between surgery and adjuvant SRS associated with increased TT-SRS., Conclusions: Adjuvant SRS provides durable local control. However, delays in initiation of postoperative SRS can decrease its efficacy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Persistent radiation-induced alopecia (pRIA) and its management have not been systematically described., Objective: To characterize pRIA in patients with primary central nervous system (CNS) tumors or head and neck sarcoma., Design, Setting, and Participants: A retrospective cohort study of patients from January 1, 2011, to January 30, 2019, was conducted at 2 large tertiary care hospitals and comprehensive cancer centers. Seventy-one children and adults diagnosed with primary CNS tumors or head and neck sarcomas were evaluated for pRIA., Main Outcomes and Measures: The clinical and trichoscopic features, scalp radiation dose-response relationship, and response to topical minoxidil were assessed using standardized clinical photographs of the scalp, trichoscopic images, and radiotherapy treatment plans., Results: Of the 71 patients included (median [range] age, 27 [4-75] years; 51 female [72%]), 64 (90%) had a CNS tumor and 7 (10%) had head and neck sarcoma. Alopecia severity was grade 1 in 40 of 70 patients (56%), with localized (29 of 54 [54%]), diffuse (13 of 54 [24%]), or mixed (12 of 54 [22%]) patterns. The median (range) estimated scalp radiation dose was 39.6 (15.1-50.0) Gy; higher dose (odds ratio [OR], 1.15; 95% CI, 1.04-1.28) and proton irradiation (OR, 5.7; 95% CI, 1.05-30.8) were associated with greater alopecia severity (P < .001), and the dose at which 50% of patients were estimated to have severe (grade 2) alopecia was 36.1 Gy (95% CI, 33.7-39.6 Gy). Predominant trichoscopic features included white patches (16 of 28 [57%]); in 15 patients, hair-shaft caliber negatively correlated with scalp dose (correlation coefficient, -0.624; P = .01). The association between hair density and scalp radiation dose was not statistically significant (-0.381; P = .16). Twenty-eight of 34 patients (82%) responded to topical minoxidil, 5% (median follow-up, 61 [interquartile range, 21-105] weeks); 4 of 25 (16%) topical minoxidil recipients with clinical images improved in severity grade. Two patients responded to hair transplantation and 1 patient responded to plastic surgical reconstruction., Conclusions and Relevance: Persistent radiation-induced alopecia among patients with primary CNS tumors or head and neck sarcomas represents a dose-dependent phenomenon that has distinctive clinical and trichoscopic features. The findings of this study suggest that topical minoxidil and procedural interventions may have benefit in the treatment of pRIA.

Purpose: Radiographic changes of brain metastases after stereotactic radiosurgery (SRS) can signify tumor recurrence and/or radiation necrosis (RN); however, standard imaging modalities cannot easily distinguish between these two entities. We investigated whether 18 F-Fluorocholine uptake in surgical samples of the resected lesions correlates with pathologic evidence of recurrent tumor and PET imaging., Methods: About 14 patients previously treated with SRS that developed radiographic changes were included. All patients underwent a preoperative 40-min dynamic PET/CT concurrent with 392 ± 11 MBq bolus injection of 18 F-Fluorocholine. 18 F-Fluorocholine pharmacokinetics were evaluated by standardized uptake value (SUV), graphical analysis (Patlak plot; K i P ) and an irreversible two-compartment model (K 1 , k 2 , k 3 , and K i ). 12 out of 14 patients were administered an additional 72 ± 14 MBq injection of 18 F-Fluorocholine 95 ± 26 minutes prior to surgical resection. About 113 resected samples from 12 patients were blindly reviewed by a neuropathologist to assess the viable tumor and necrotic content, microvascular proliferation, reactive gliosis, and mono- and polymorphonuclear inflammatory infiltrates. Correlation between these metrics 18 F-Fluorocholine SUV was investigated with a linear mixed model. Comparison of survival distributions of two groups of patients (population median split of PET SUV max ) was performed with the log-rank test., Results: Exactly 10 out of 12 patients for which surgical samples were acquired exhibited pathologic recurrence. Strong correlation was observed between SUV max as measured from a surgically removed sample with highest uptake and by PET (Pearson's r = 0.66). Patients with 18 F-Fluorocholine PET SUV max > 6 experienced poor survival. Surgical samples with viable tumor had higher 18 F-fluorocholine uptake (SUV) than those without tumor (4.5 ± 3.7 and 2.6 ± 3.0; p = 0.01). 18 F-fluorocholine count data from surgical samples is driven not only by the percentage viable tumor but also by the degree of inflammation and reactive gliosis (p ≤ 0.02; multivariate regression)., Conclusions: 18 F-Fluorocholine accumulation is increased in viable tumor; however, inflammation and gliosis may also lead to elevated uptake. Higher 18 F-Fluorocholine PET uptake portends worse prognosis. Kinetic analysis of dynamic 18 F-Fluorocholine PET imaging supports the adequacy of the simpler static SUV metric.

Background: Early imaging-based treatment response assessment of brain metastases following stereotactic radiosurgery (SRS) remains challenging. The aim of this study is to determine whether early (within 12 weeks) intratumoral changes in interstitial fluid pressure (IFP) and velocity (IFV) estimated from computational fluid modeling (CFM) using dynamic contrast-enhanced (DCE) MRI can predict long-term outcomes of lung cancer brain metastases (LCBMs) treated with SRS. Methods: Pre- and post-treatment T 1 -weighted DCE-MRI data were obtained in 41 patients treated with SRS for intact LCBMs. The imaging response was assessed using RANO-BM criteria. For each lesion, extravasation of contrast agent measured from Extended Tofts pharmacokinetic Model (volume transfer constant, K trans ) was incorporated into a computational fluid model to estimate tumor IFP and IFV. Estimates of mean IFP and IFV and heterogeneity (skewness and kurtosis) were calculated for each lesion from pre- and post-SRS imaging. The Wilcoxon rank-sum test was utilized to assess for significant differences in IFP, IFV, and IFP/IFV change (Δ) between response groups. Results: Fifty-three lesions from 41 patients were included. Median follow-up time after SRS was 11 months. The objective response (OR) rate (partial or complete response) was 79%, with 21% demonstrating stable disease (SD) or progressive disease (PD). There were significant response group differences for multiple posttreatment and Δ CFM parameters: post-SRS IFP skewness (mean -0.405 vs. -0.691, p = 0.022), IFP kurtosis (mean 2.88 vs. 3.51, p = 0.024), and IFV mean (5.75e-09 vs. 4.19e-09 m/s, p = 0.027); and Δ IFP kurtosis (mean -2.26 vs. -0.0156, p = 0.017) and IFV mean (1.91e-09 vs. 2.38e-10 m/s, p = 0.013). Posttreatment and Δ thresholds predicted non-OR with high sensitivity (sens): post-SRS IFP skewness (-0.432, sens 84%), kurtosis (2.89, sens 84%), and IFV mean (4.93e-09 m/s, sens 79%); and Δ IFP kurtosis (-0.469, sens 74%) and IFV mean (9.90e-10 m/s, sens 74%). Conclusions: Objective response was associated with lower post-treatment tumor heterogeneity, as represented by reductions in IFP skewness and kurtosis. These results suggest that early post-treatment assessment of IFP and IFV can be used to predict long-term response of lung cancer brain metastases to SRS, allowing a timelier treatment modification., (Copyright © 2020 Swinburne, LoCastro, Paudyal, Oh, Taunk, Shah, Beal, Vachha, Young, Holodny, Shukla-Dave and Hatzoglou.)

Palliation of metastatic disease compromises a significant portion of radiation treatments in the United States. These patients present a unique challenge in resource-limited settings, as expeditious treatment is often required to prevent serious morbidity. In order to reduce the risk of infection with severe acute respiratory syndrome coronavirus-2 and maximize the benefit to patients, we present evidence-based recommendations for radiation in patients with oncologic emergencies. Radiation oncologists with expertise in the treatment of metastatic disease at a high-volume comprehensive cancer center reviewed the available evidence and recommended best practices for the treatment of common oncologic emergencies, with attention to balancing the risk of infection with severe acute respiratory syndrome coronavirus-2 and the potential morbidity of delaying treatment. Many prospective trials and national guidelines support the use of abbreviated courses of radiotherapy for patients with oncologic emergencies. As such, in the setting of the current coronavirus disease 2019 pandemic, the use of hypofractionated radiation therapy for patients requiring palliation for oncologic emergencies achieves desirable functional outcomes without compromising care., (© 2020 The Author(s).)

The reprogramming of cellular metabolism is a hallmark of cancer diagnosis and prognosis. Proton magnetic resonance spectroscopic imaging (MRSI) is a non-invasive diagnostic technique for investigating brain metabolism to establish cancer diagnosis and IDH gene mutation diagnosis as well as facilitate pre-operative planning and treatment response monitoring. By allowing tissue metabolism to be quantified, MRSI provides added value to conventional MRI. MRSI can generate metabolite maps from a single volume or multiple volume elements within the whole brain. Metabolites such as NAA, Cho and Cr, as well as their ratios Cho:NAA ratio and Cho:Cr ratio, have been used to provide tumor diagnosis and aid in radiation therapy planning as well as treatment assessment. In addition to these common metabolites, 2-hydroxygluterate (2HG) has also been quantified using MRSI following the recent discovery of IDH mutations in gliomas. This has opened up targeted drug development to inhibit the mutant IDH pathway. This review provides guidance on MRSI in brain gliomas, including its acquisition, analysis methods, and evolving clinical applications., (© 2020 The Authors. Published by the British Institute of Radiology.)

Tobacco smoking causes lung cancer 1-3 , a process that is driven by more than 60 carcinogens in cigarette smoke that directly damage and mutate DNA 4,5 . The profound effects of tobacco on the genome of lung cancer cells are well-documented 6-10 , but equivalent data for normal bronchial cells are lacking. Here we sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking was the major influence on mutational burden, typically adding from 1,000 to 10,000 mutations per cell; massively increasing the variance both within and between subjects; and generating several distinct mutational signatures of substitutions and of insertions and deletions. A population of cells in individuals with a history of smoking had mutational burdens that were equivalent to those expected for people who had never smoked: these cells had less damage from tobacco-specific mutational processes, were fourfold more frequent in ex-smokers than current smokers and had considerably longer telomeres than their more-mutated counterparts. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged subjects who had never smoked. In current smokers, at least 25% of cells carried driver mutations and 0-6% of cells had two or even three drivers. Thus, tobacco smoking increases mutational burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of the bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.

Purpose: It can be challenging to differentiate pseudoprogression from progression. We assessed the ability of dynamic contrast enhanced T1 MRI (DCE-MRI) perfusion to identify pseudoprogression in melanoma brain metastases., Methods: Patients with melanoma brain metastases who underwent immunotherapy and DCE-MRI were identified. Enhancing lesions ≥  5mm in diameter on DCE-MRI and that were new or increased in size between a week from beginning the treatment, and a month after completing the treatment were included in the analysis. The 90th percentiles of rVp and rKtrans and the presence or absence of hemorrhage were recorded. Histopathology served as the reference standard for pseudoprogression. If not available, pseudoprogression was defined as neurological and radiographic stability or improvement without any new treatment for ≥ 2 months., Results: Forty-four patients were identified; 64% received ipilimumab monotherapy for a median duration of 9 weeks (range, 1-138). Sixty-four lesions in 44 patients were included in the study. Of these, nine lesions in eight patients were determined to be pseudoprogression and seven lesions were previously irradiated. Forty-four progression lesions and eight pseudoprogression lesions were hemorrhagic. Median lesion volume for pseudoprogression and progression were not significantly different, at 2.3 cm 3 and 3.2 cm 3 , respectively (p = 0.82). The rVp 90 was smaller in pseudoprogression versus progression, at 2.2 and 5.3, respectively (p = 0.02), and remained significant after false discovery rate adjustment (p = 0.04)., Conclusions: Pseudoprogression exhibited significantly lower rVp 90 on DCE-MRI compared with progression. This knowledge can be useful for managing growing lesions in patients with melanoma brain metastases who are receiving immunotherapy.

Background: Mutations in human epidermal growth factor receptor 2 (HER2; also known as ERBB2) are found in approximately 2% of lung adenocarcinomas. The frequency and clinical course of brain metastases in this oncogenic subset are ill defined., Methods: Baseline and subsequent development of brain metastases was evaluated in consecutive patients with HER2-mutant (n = 98), epidermal growth factor receptor (EGFR)-mutant (n = 200), and KRAS-mutant lung cancers (n = 200)., Results: At metastatic diagnosis, the odds ratio (ORs) for brain metastases was similar for patients whose tumors harbored HER2 mutations (19%) in comparison with patients with KRAS mutations (24%; OR for HER2 vs KRAS, 0.7; P = .33) but lower compared to patients with EGFR mutations (31%; OR for HER2 vs EGFR, 0.5; P = .03). Patients with lung cancer and HER2 mutations developed more brain metastases on treatment than patients with KRAS mutations (28% vs 8%; hazard ratio [HR], 5.2; P < .001) and trended more than patients with EGFR mutations (28% vs 16%; HR, 1.7; P = .06). Patients with HER2 YVMA mutations also developed more brain metastases on treatment than patients with KRAS mutations (HR, 5.9; P < .001). The median overall survival (OS) was shorter for patients with HER2-mutant (1.6 years; P < .001) or KRAS-mutant lung cancers (1.1 years; P < .001) than patients with EGFR-mutant lung cancers (3.0 years). Brain metastases occurred in 47% of patients with HER2-mutant lung cancers, which imparted shorter OS (HR, 2.7; P < .001)., Conclusions: These data provide a framework for brain imaging surveillance in patients with HER2-mutant lung cancers and underpin the need to develop HER2-targeted agents with central nervous system activity., (© 2019 American Cancer Society.)

Purpose: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood. Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes., Results: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF -mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context., Conclusions: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma., (©2019 American Association for Cancer Research.)

Context: Pituitary adenomas (PA) are often irregularly shaped, particularly posttreatment. There are no standardized radiographic criteria for assessing treatment response, substantially complicating interpretation of prospective outcome data. Existing imaging frameworks for intracranial tumors assume perfectly spherical targets and may be suboptimal., Objective: To compare a three-dimensional (3D) volumetric approach against accepted surrogate measurements to assess PA posttreatment response (PTR)., Design: Retrospective review of patients with available pre- and postradiotherapy (RT) imaging. A neuroradiologist determined tumor sizes in one dimensional (1D) per Response Evaluation in Solid Tumors (RECIST) criteria, two dimensional (2D) per Response Assessment in Neuro-Oncology (RANO) criteria, and 3D estimates assuming a perfect sphere or perfect ellipsoid. Each tumor was manually segmented for 3D volumetric measurements. The Hakon Wadell method was used to calculate sphericity., Setting: Tertiary cancer center., Patients or Other Participants: Patients (n = 34, median age = 50 years; 50% male) with PA and MRI scans before and after sellar RT., Interventions: Patients received sellar RT for intact or surgically resected lesions., Main Outcome Measures: Radiographic PTR, defined as percent tumor size change., Results: Using 3D volumetrics, mean sphericity = 0.63 pre-RT and 0.60 post-RT. With all approaches, most patients had stable disease on post-RT scan. PTR for 1D, 2D, and 3D spherical measurements were moderately well correlated with 3D volumetrics ( e.g., for 1D: 0.66, P < 0.0001) and were superior to 3D ellipsoid. Intraclass correlation coefficient demonstrated moderate to good reliability for 1D, 2D, and 3D sphere ( P < 0.001); 3D ellipsoid was inferior ( P = 0.009). 3D volumetrics identified more potential partially responding and progressive lesions., Conclusions: Although PAs are irregularly shaped, 1D and 2D approaches are adequately correlated with volumetric assessment., Competing Interests: Disclosure Summary: The authors declare that there are no relevant conflicts of interest for this study. E.B.G. has no relevant conflicts but has served as the principal investigator of research grants to MSKCC from Novartis, Strongbridge, Chiasma, and IONIS and has received occasional consulting honoraria from Strongbridge, Corcept, and Pfizer.The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Objective: To evaluate clinical outcomes of patients with BRCA-associated ovarian cancer who developed brain metastases (BM)., Methods: Patients with epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC) and BM, treated at a single institution from 1/1/2008-7/1/2018, were identified from two institutional databases. Charts and medical records were retrospectively reviewed for clinical characteristics and germline BRCA mutation status. Appropriate statistics were used., Results: Of 3649 patients with EOC, 91 had BM (2.5%). Germline mutation status was available for 63 (69%) cases; 21 (35%) of these harbored a BRCA1/2 mutation (15 BRCA1, 6 BRCA2). Clinical characteristics were similar between groups. BM were diagnosed at a median of 31 months (95% CI, 22.6-39.4) in BRCA-mutated (mBRCA) and 32 months (95% CI, 23.7-40.3) in wild-type BRCA (wtBRCA) (p = 0.78) patients. Brain metastases were the only evidence of disease at time of BM diagnoses in 48% (n = 10) mBRCA and 19% (n = 8) wtBRCA (p = 0.02) patients. There was no difference in treatment of BM by mutation status (p = 0.84). Survival from time of BM diagnosis was 29 months (95%CI, 15.5-42.5) in mBRCA and 9 months (95% CI, 5.5-12.5) in wtBRCA patients, with an adjusted hazard ratio (HR) of 0.53, p = 0.09; 95% CI, 0.25-1.11. HR was adjusted for presence of systemic disease at time of BM diagnosis., Conclusion: This is the largest study to date comparing outcomes in patients with EOC and BM by mutation status. mBRCA patients were more likely to have isolated BM, which may be a factor in their long survival. This supports the pursuit of aggressive treatment for mBRCA EOC patients with BM. Additional studies examining the correlation of BRCA mutational status with BM are warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Patients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985-2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database., Methods: An IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA., Results: Median survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0-1, 1.5-2, 2.5-3.0 and 3.5-4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0)., Conclusions: Brain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com., Competing Interests: None of the authors have a conflict of interest related to this work. The following authors have no relationships to report: PWS, PF, JL, WB, PDB, DC, JBY, VC, SJ, LEG, SM, SB, PS, BC, A Attia, JKM, CCW, JP, JMB, RS, DDT, DS, MC, HS, HA, LM. The following authors have relationships to report, but again none are related to this work: A Aizer (Astra Zeneca), AS (Elekta, Varian, Accuray), TJCW (Merck, Astra-Zeneca, Doximity, Novocure, Elekta, Wolters Kluwer), EL (Novocure, Nomocan Pharmaceuticals), JPK (Varian), HAS (Genentech), DR (Varian, Siemens, Accuray, BrainLab, Elekta, Pfizer, EMD Serono), MPM (Agenus, Insys, Remedy, IBA, Varian, Oncoceutics, Astra-Zeneca, Monteris.

The literature describing the prognosis of patients with gastrointestinal (GI) cancers and brain metastases (BM) is sparse. Our group previously published a prognostic index, the Graded Prognostic Assessment (GPA) for GI cancer patients with BM, based on 209 patients diagnosed from 1985-2005. The purpose of this analysis is to identify prognostic factors for GI cancer patients with newly diagnosed BM in a larger contemporary cohort. A multi-institutional retrospective IRB-approved database of 792 GI cancer patients with new BM diagnosed from 1/1/2006 to 12/31/2016 was created. Demographic data, clinical parameters, and treatment were correlated with survival and time from primary diagnosis to BM (TPDBM). Kaplan-Meier median survival (MS) estimates were calculated and compared with log-rank tests. The MS from time of first treatment for BM for the prior and current cohorts were 5 and 8 months, respectively (P < 0.001). Eight prognostic factors (age, stage, primary site, resection of primary tumor, Karnofsky Performance Status (KPS), extracranial metastases, number of BM and Hgb were found to be significant for survival, in contrast to only one (KPS) in the prior cohort. In this cohort, the most common primary sites were rectum (24%) and esophagus (23%). Median TPDBM was 22 months. Notably, 37% (267/716) presented with poor prognosis (GPA 0-1.0). Although little improvement in overall survival in this cohort has been achieved in recent decades, survival varies widely and multiple new prognostic factors were identified. Future work will translate these factors into a prognostic index to facilitate clinical decision-making and stratification of future clinical trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The presence of brain metastases (BM) in patients with non-seminomatous germ cell tumor (NSGCT) is associated with poor prognosis. While radiation therapy (RT) is an important treatment for patients with NSGCT BM, there is a paucity of data on the optimal regimen. We sought to investigate the impact of RT on clinical outcomes in patients with NSGCT BM., Methods: Patients with NSGCT BM who received RT at our institution from 2002 to 2017 were included. Sixty-three consecutive patients were identified. Clinical factors associated with intracranial control (ICC) and overall survival (OS) were evaluated using cox regression analysis and Kaplan Meier method., Results: Median age was 31 years and number of BM was three. Fifteen patients presented with BM at diagnosis, while 48 developed BM at a median time of 8.4 months from diagnosis. At a median follow-up of 3.6 years, ICC and OS were 39.7% and 30.1%. On multivariate analysis, ICC (hazard ratio [HR] = 0.93, p = 0.03) and OS (HR = 0.93, p = 0.005) were both significantly associated with biologically effective dose (BED) of RT. The 4-year OS of patients who received BED < 39Gy, 39 Gy, 40-50 Gy, and ≥ 50 Gy were 0%, 14.7%, 34.1%, and 70.0%, respectively. Patients who achieved ICC after RT were able to achieve long-term survival (4-year OS 68.1% vs. 0%, p < 0.0001)., Conclusions: Our data supports that a higher BED is required for durable ICC, and that ICC is needed for patients with NSGCT to achieve long-term survival. Prospective studies evaluating radiation dose-escalation for the treatment of NSGCT BM should be considered.

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Purpose: Spatial and temporal patterns of response of human glioblastoma to fractionated chemoradiation are described by changes in the bioscales of residual tumor volume (RTV), tumor cell volume fraction (CVF), and tumor cell kill (TCK), as derived from tissue sodium concentration (TSC) measured by quantitative sodium MRI at 3 Tesla. These near real-time patterns during treatment are compared with overall survival., Experimental Design: Bioscales were mapped during fractionated chemoradiation therapy in patients with glioblastomas ( n = 20) using TSC obtained from serial quantitative sodium MRI at 3 Tesla and a two-compartment model of tissue sodium distribution. The responses of these parameters in newly diagnosed human glioblastomas undergoing treatment were compared with time-to-disease progression and survival., Results: RTV following tumor resection showed decreased CVF due to disruption of normal cell packing by edema and infiltrating tumor cells. CVF showed either increases back toward normal as infiltrating tumor cells were killed, or decreases as cancer cells continued to infiltrate and extend tumor margins. These highly variable tumor responses showed no correlation with time-to-progression or overall survival., Conclusions: These bioscales indicate that fractionated chemoradiotherapy of glioblastomas produces variable responses with low cell killing efficiency. These parameters are sensitive to real-time changes within the treatment volume while remaining stable elsewhere, highlighting the potential to individualize therapy earlier in management, should alternative strategies be available., (©2018 American Association for Cancer Research.)

Amino acid sequence variation in protein therapeutics requires close monitoring during cell line and cell culture process development. A cross-functional team of Pfizer colleagues from the Analytical and Bioprocess Development departments worked closely together for over 6 years to formulate and communicate a practical, reliable sequence variant (SV) testing strategy with state-of-the-art techniques that did not necessitate more resources or lengthen project timelines. The final Pfizer SV screening strategy relies on next-generation sequencing (NGS) and amino acid analysis (AAA) as frontline techniques to identify mammalian cell clones with genetic mutations and recognize cell culture process media/feed conditions that induce misincorporations, respectively. Mass spectrometry (MS)-based techniques had previously been used to monitor secreted therapeutic products for SVs, but we found NGS and AAA to be equally informative, faster, less cumbersome screening approaches. MS resources could then be used for other purposes, such as the in-depth characterization of product quality in the final stages of commercial-ready cell line and culture process development. Once an industry-wide challenge, sequence variation is now routinely monitored and controlled at Pfizer (and other biopharmaceutical companies) through increased awareness, dedicated cross-line efforts, smart comprehensive strategies, and advances in instrumentation/software, resulting in even higher product quality standards for biopharmaceutical products.

Background: Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985-2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors., Methods: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively., Results: The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0-1.0, 1.5-2.0, 2.5-3, and 3.5-4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively., Conclusion: The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.

Background: Although brain metastases (BM) are associated with poor prognosis, patients with human epidermal growth factor receptor 2 (HER2) overexpressing (HER2 + ) breast cancer (BC) with BM who are treated with anti-HER2 therapy have a relatively longer survival after BM diagnosis compared with other subtypes and HER2 + patients previously untreated with anti-HER2 therapy. It is unclear if previously reported prognostic factors are applicable to patients with HER2 + BC in the era of HER2-targeted therapy., Patients and Methods: We evaluated 100 consecutive patients with HER2 + BC with BM who underwent radiation therapy as primary BM treatment from January 2001 to December 2011 at Memorial Sloan Kettering Cancer Center by retrospective review. Patient characteristics at the time of BM diagnosis and their associations with time from BM to death were evaluated by Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models., Results: Significantly better survival from BM was noted for patients with higher performance status, fewer BM lesions, continued use of HER2-targeted therapy after BM diagnosis, and better controlled extracranial metastatic disease. Absence of neurologic symptoms at BM diagnosis was significantly associated with fewer lesions, decreased use of whole brain radiotherapy, and longer survival in univariate and multivariate analysis (multivariate hazard ratio, 3.69; 95% confidence interval, 1.69-8.07)., Conclusion: Our finding supports the continued use of HER2-targeted therapy after BM diagnosis. In addition, future research on the clinical impact of detecting asymptomatic BM in patients with HER2 + BC, in terms of improving prognosis, quality of life, and avoidance of whole brain radiotherapy, is warranted., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To determine whether phosphatidylinositol-3-kinase (PI3K) mutations confer suboptimal local control after radiation therapy (RT) for brain metastases., Methods and Materials: We retrospectively reviewed 259 patients with brain metastases treated with RT during the period 2004 to 2017 for whom tumor genetic data (MSK-IMPACT) were available for primary or metastatic lesions. Associations between clinical factors, PI3K mutations status, and local failure (LF) were evaluated with univariate and multivariate competing risks regression., Results: A total of 112 patients received whole brain radiation therapy (WBRT) to a median dose of 30 Gy in 10 fractions, and 147 patients received stereotactic radiosurgery (SRS) to 338 lesions; 276 lesions were treated with single fraction SRS (median dose 21 Gy) and 76 lesions over 3 to 5 fractions SRS (median dose 30 Gy). PI3K mutations were present in 36 WBRT patients (32%) and 44 SRS patients (30%). For WBRT, patients with PI3K mutations (hazard ratio 2.67, P < .001) were found to be at higher risk for LF on multivariable analysis, and the 1-year cumulative incidence of LF was 50% (95% confidence interval [CI] 32%-65%) for patients with PI3K mutations versus 26% (95% CI 17%-37%) for patients without PI3K mutations. For SRS lesions, while PI3K mutations positivity was not statistically significantly associated with LF, higher rate of LF was observed: 1-year LF cumulative incidence of 11% (95% CI 6%-17%) for patients with PI3K mutations versus 5% (95% CI 3%-9%) for patients without PI3K mutations., Conclusion: Patients with PI3K mutations are at higher risk for LF for brain metastases after RT. Novel therapeutic strategies to improve treatment outcomes in these patients should be considered., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To identify prognostic factors, define evolving patterns of care, and the effect of targeted therapies in a larger contemporary cohort of renal cell carcinoma (RCC) patients with new brain metastases (BM)., Methods and Materials: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new BM diagnosed from January 1, 2006, to December 31, 2015, was created. Clinical parameters and treatment were correlated with median survival and time from primary diagnosis to BM. Multivariable analyses were performed., Results: The median survival for the prior/present cohorts was 9.6/12 months, respectively (P < .01). Four prognostic factors (Karnofsky performance status, extracranial metastases, number of BM, and hemoglobin b) were significant for survival after the diagnosis of BM. Of the 6 drug types studied, only cytokine use after BM was associated with improved survival. The use of whole-brain radiation therapy declined from 50% to 22%, and the use of stereotactic radiosurgery alone increased from 46% to 58%. Nonneurologic causes of death were twice as common as neurologic causes., Conclusions: Additional prognostic factors refine prognostication in this larger contemporary cohort. Patterns of care have changed, and survival of RCC patients with BM has improved over time. The reasons for this improvement in survival remain unknown but may relate to more aggressive use of local brain metastasis therapy and a wider array of systemic treatment options for those patients with progressive extracranial tumor., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m 2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m 2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m 2 /d once daily) with radiotherapy and TMZ 75 mg/m 2 /d, followed by TMZ 150 mg to 200 mg/m 2 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic concentrations were achieved in tumor and brain. No dose-limiting toxicities were observed; the recommended phase II dose was 600 mg/d flat dose. Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O 6 -methylguanine-DNA methyltransferase unmethylated and bevacizumab-refractory tumors. In cohort 2 (n = 15), median progression-free survival was 15 months and median overall survival was not reached (median follow-up, 28 months; 2-year overall survival, 62%). Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors ( P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population.

Purpose: To assess clinical characteristics of patients with metastatic pancreas ductal adenocarcinoma (PDAC) and brain metastases (BM), and to assess somatic and germ-line molecular profiles where performed., Patients and Methods: Patients with PDAC and BM between January 1990 and January 2016 were identified. Molecular characteristics of somatic and germ-line testing where performed in the subset of patients who had provided informed consent. Somatic alterations were assessed by either MSK-IMPACT testing (>340 key cancer genes) or Sequenom testing (8-gene panel). Overall survival was calculated from date of diagnosis to either date of last follow-up or death. Survival after BM was calculated from date of diagnosis of BM by radiology or pathology to either date of last follow-up or death., Results: From a total of 5824 patients with PDAC identified from January 2000 to January 2016, twenty-five patients (0.4%) had BM. Median age at PDAC diagnosis was 58 years. Median time to the development of BM from initial PDAC diagnosis was 17 months (range, 0-79 months). Median overall survival after BM diagnosis was 1.5 months (range, 1-31 months). Overall survival for patients who had craniotomy (n = 4) was 11 months (range, 1-31 months), with 2 long-term survivors at 21 and 31 months, respectively. Four patients had leptomeningeal disease. Six of 25 patients had germ-line testing, and 3 had BRCA mutations (2 BRCA1 and 1 BRCA2). Somatic profiling identified KRAS mutations in 100% (4 G12D, 2 G12V, and 1 Q61K)., Conclusion: BM from PDAC is a rare event. We identified a speculative association of germ-line BRCA1/2 alterations with BM in PDAC, which requires corroboration. Survival after BM development is poor; prolonged survival occurred in selected patients via a multidisciplinary approach., (Copyright © 2018 Elsevier Inc. All rights reserved.)

During development of a cell line intended to support production of an IgG2 monoclonal antibody, a sequence variant caused by a genetic mutation was identified in the bulk drug substance. Gene copy number analysis together with the level of the observed variant in genomic DNA indicated that the master cell bank was a mixed population of cells; some harboring the variant copy and some mutation free. Since the cell bank had been single-cell cloned, this variant could be used as a biomarker to demonstrate either that the bank was not derived from a single cell, or that the variant was a result of a post-cloning genetic event, leading to a mixed population of cells. The sequence variant was only present in a small percentage of subclones, confirming the hypothesis that the cell bank was indeed a mixed population. Interrogation of subclones via Southern blot analysis revealed that almost all subclones had very similar transgene integrant structures, suggesting that the cell bank was likely derived from a single cell, and the cellular event that yielded the sequence variant was a post-cloning event. Further, there were likely several other post-cloning events that impacted transgene loci, leading to a population of related, yet genetically distinct cells comprising the cell bank. Despite this, the heterogeneous bank performed consistently in a bioprocess across generational age with comparable product quality. These results experimentally demonstrate the heterogeneity of a cell bank derived from a single cell, and its relationship to process consistency. © 2018 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers Biotechnol. Prog., 34:602-612, 2018., (© 2018 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers.)