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ImportanceO6-methylguanine-DNA methyltransferase (MGMT [OMIM 156569]) promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy for glioblastomas and is routinely used to guide treatment decisions. However, the utility of MGMT promoter status for low-grade and anaplastic gliomas remains unclear due to molecular heterogeneity and the lack of sufficiently large data sets.ObjectiveTo evaluate the association of mMGMT for low-grade and anaplastic gliomas with chemotherapy response.Design, Setting, and ParticipantsThis cohort study aggregated grade II and III primary glioma data from 3 prospective cohort studies with patient data collected from August 13, 1995, to August 3, 2022, comprising 411 patients: MSK-IMPACT, EORTC (European Organization of Research and Treatment of Cancer) 26951, and Columbia University. Statistical analysis was performed from April 2022 to January 2023.ExposureMGMT promoter methylation status.Main Outcomes and MeasuresMultivariable Cox proportional hazards regression modeling was used to assess the association of mMGMT status with progression-free survival (PFS) and overall survival (OS) after adjusting for age, sex, molecular class, grade, chemotherapy, and radiotherapy. Subgroups were stratified by treatment status and World Health Organization 2016 molecular classification.ResultsA total of 411 patients (mean [SD] age, 44.1 [14.5] years; 283 men [58%]) met the inclusion criteria, 288 of whom received alkylating chemotherapy. MGMT promoter methylation was observed in 42% of isocitrate dehydrogenase (IDH)–wild-type gliomas (56 of 135), 53% of IDH-mutant and non-codeleted gliomas (79 of 149), and 74% of IDH-mutant and 1p/19q-codeleted gliomas (94 of 127). Among patients who received chemotherapy, mMGMT was associated with improved PFS (median, 68 months [95% CI, 54-132 months] vs 30 months [95% CI, 15-54 months]; log-rank P MGMT, 1.95 [95% CI, 1.39-2.75]; P P P = .01). After adjusting for clinical factors, MGMT promoter status was associated with chemotherapy response in IDH–wild-type gliomas (aHR for PFS, 2.15 [95% CI, 1.26-3.66]; P = .005; aHR for OS, 1.69 [95% CI, 0.98-2.91]; P = .06) and IDH-mutant and codeleted gliomas (aHR for PFS, 2.99 [95% CI, 1.44-6.21]; P = .003; aHR for OS, 4.21 [95% CI, 1.25-14.2]; P = .02), but not IDH-mutant and non-codeleted gliomas (aHR for PFS, 1.19 [95% CI, 0.67-2.12]; P = .56; aHR for OS, 1.07 [95% CI, 0.54-2.12]; P = .85). Among patients who did not receive chemotherapy, mMGMT status was not associated with PFS or OS.Conclusions and RelevanceThis study suggests that mMGMT is associated with response to alkylating chemotherapy for low-grade and anaplastic gliomas and may be considered as a stratification factor in future clinical trials of patients with IDH–wild-type and IDH-mutant and codeleted tumors.

Background Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody–drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. Methods In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. Results There were 639 randomized patients (median age 60, range 22–84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82–1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70–1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56–0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61–0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3–4), causing 12% to discontinue. Conclusions Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.

Infratentorial oligodendrogliomas, a rare pathological entity, are generally considered metastatic lesions from supratentorial primary tumors. Here, we report the case of a 23-year-old man presenting with a histopathologically confirmed right precentral gyrus grade 2 oligodendroglioma and a concurrent pontine grade 3 oligodendroglioma. The pontine lesion was biopsied approximately a year after the biopsy of the precentral lesion due to disease progression despite 4 cycles of procarbazine-CCNU-vincristine (PCV) chemotherapy and stable supratentorial disease. Histology and genetic analysis of the pontine biopsy were consistent with grade 3 oligodendroglioma, and comparison of the two lesions demonstrated common 1p/19q co-deletions and TERT promoter mutations but distinct IDH1 mutations, with a non-canonical IDH1 R132G mutation identified in the infratentorial lesion and a R132H mutation identified in the cortical lesion. Initiation of Temozolomide led to complete response of the supratentorial lesion and durable disease control, while Temozolomide with subsequent radiation therapy of 54 Gy in 30 fractions resulted in partial response of the pontine lesion. This case report supports possible distinct molecular pathogenesis in supratentorial and infratentorial oligodendrogliomas and raises questions about the role of different IDH1 mutant isoforms in explaining treatment resistance to different chemotherapy regimens. Importantly, this case suggests that biopsies of all radiographic lesions, when feasible and safe, should be considered in order to adequately guide management in multicentric oligodendrogliomas.

OBJECTIVE Genomic analysis in neurooncology has underscored the importance of understanding the patterns of survival in different molecular subtypes within gliomas and their responses to treatment. In particular, diffuse gliomas are now principally characterized by their mutation status (IDH1 and 1p/19q codeletion), yet there remains a paucity of information regarding the prognostic value of molecular markers and extent of resection (EOR) on survival. Furthermore, given the modern emphasis on molecular rather than histological diagnosis, it is important to examine the effect of maximal resection on survival in all gliomas with 1p/q19 codeletions, as these will now be classified as oligodendrogliomas under the new WHO guidelines. The objectives of the present study were twofold: 1) to assess the association between EOR and survival for patients with oligodendrogliomas in the National Cancer Database (NCDB), which includes information on mutation status, and 2) to demonstrate the same effect for all patients with 1p/19q codeleted gliomas in the NCDB. METHODS The NCDB was queried for all cases of oligodendroglioma between 2004 and 2014, with follow-up dates through 2016. The authors found 2514 cases of histologically confirmed oligodendrogliomas for the final analysis of the effect of EOR on survival. Upon further query, 1067 1p/19q-codeleted tumors were identified in the NCDB. Patients who received subtotal resection (STR) or gross-total resection (GTR) were compared to those who received no tumor debulking surgery. Univariable and multivariable analyses of both overall survival and cause-specific survival were performed. RESULTS EOR was associated with increased overall survival for both histologically confirmed oligodendrogliomas and all 1p/19q-codeleted–defined tumors (p < 0.001 and p = 0.002, respectively). Tumor grade, location, and size covaried predictably with EOR. When evaluating tumors by each classification system for predictors of overall survival, facility setting, age, comorbidity index, grade, location, chemotherapy, and radiation therapy were all shown to be significantly associated with overall survival. STR and GTR were independent predictors of improved survival in historically classified oligodendrogliomas (HR 0.83, p = 0.18; HR 0.69, p = 0.01, respectively) and in 1p/19q-codeleted tumors (HR 0.49, p < 0.01; HR 0.43, p < 0.01, respectively). CONCLUSIONS By using the NCDB, the authors have demonstrated a side-by-side comparison of the survival benefits of greater EOR in 1p/19q-codeleted gliomas.

PURPOSE Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation ( P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non–small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

Purpose: Few studies have evaluated the methodology by which radiation therapy (RT) for thyroid eye disease and compressive optic neuropathy is performed. The objective of this study was to retrospectively review our experience from a radiation planning standpoint and to determine whether current treatment methods provide adequate dose to target and collateral structures. Methods: A retrospective review of 52 patients (104 orbits) with bilateral thyroid eye disease and compressive optic neuropathy treated with RT (20 Gy in 10 fractions) at our institution. RT plans were analyzed for target volumes and doses. Visual fields, color plates, and visual acuity were assessed pretreatment and at last available follow-up post RT. A standardized, anatomic contour of the retro-orbital space was applied to these retrospective plans to determine dose to the entire space, rather than the self-selected target structure. Results: Compared with the anatomic retro-orbital space, the original contour overlapped by only 68%. Maximum and mean dose was 2134 cGy and 1910 cGy to the anatomic retro-orbital space. Consequently, 39.8% of the orbits had a mean dose 21 Gy 5%). There was no significant association of improvement in color plates (P = .07), visual fields (P = .77), and visual acuity (P = .62), based on these dose differences. When beam placement was retrospectively adjusted to include a space of 0.5 cm between the lens and the anterior beam edge, there was a 39.4% and 20.3% decrease in max and mean dose to the lens. Conclusions: Without a standardized protocol for contouring in thyroid eye disease, target delineation was found to be rather varied, even among the same practitioner. Differences in dose to the anatomic retro-orbital space did not affect outcomes in the follow-up period. Although precise contouring of the retro-orbital space may be of little clinical consequence overall, a >0.5 cm space from the lens may significantly reduce or delay cataractogenesis.

Background The American Radium Society (ARS) Appropriate Use Criteria brain malignancies panel systematically reviewed (PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses]) published literature on neurocognitive outcomes after stereotactic radiosurgery (SRS) for patients with multiple brain metastases (BM) to generate consensus guidelines. Methods The panel developed 4 key questions (KQs) to guide systematic review. From 11 614 original articles, 12 were selected. The panel developed model cases addressing KQs and potentially controversial scenarios not addressed in the systematic review (which might inform future ARS projects). Based upon quality of evidence, the panel confidentially voted on treatment options using a 9-point scale of appropriateness. Results The panel agreed that SRS alone is usually appropriate for those with good performance status and 2–10 asymptomatic BM, and usually not appropriate for >20 BM. For 11–15 and 16–20 BM there was (between 2 case variants) agreement that SRS alone may be appropriate or disagreement on the appropriateness of SRS alone. There was no scenario (among 6 case variants) in which conventional whole-brain radiotherapy (WBRT) was considered usually appropriate by most panelists. There were several areas of disagreement, including: hippocampal sparing WBRT for 2–4 asymptomatic BM; WBRT for resected BM amenable to SRS; fractionated versus single-fraction SRS for resected BM, larger targets, and/or brainstem metastases; optimal treatment (WBRT, hippocampal sparing WBRT, SRS alone to all or select lesions) for patients with progressive extracranial disease, poor performance status, and no systemic options. Conclusions For patients with 2–10 BM, SRS alone is an appropriate treatment option for well-selected patients with good performance status. Future study is needed for those scenarios in which there was disagreement among panelists.

Treatment of recurrent gliomas is especially challenging, as many of these patients have previously been treated with extensive surgery, radiation, or systemic therapy. Due to this, the optimum therapy for patients with recurrent glioma is controversial, with widely variable practice patterns. In this opinion piece, a multidisciplinary panel of experts provides rationale for their treatment approach in a patient with recurrent glioma following subtotal resection with adjuvant chemoradiation for an anaplastic astrocytoma. In summary, the consensus of the panel was to recommend re-resection if possible with hypofractionated radiotherapy schedules, with re-irradiation and systemic therapy as directed by a multidisciplinary team through repeat analysis of the tumor specimen for an updated mutational burden.

PurposeBrain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts.Methods and materialsA multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively.ResultsMedian survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01).ConclusionsMS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.

Management options for newly diagnosed vestibular schwannoma (VS) include observation, surgery, or radiation. There are no randomized trials to guide management of patients with VS. This article is a short review of the role of stereotactic radiosurgery in management of newly diagnosed VS.

Background Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). Methods A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. Results The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors—nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17–28 mo, P = 0.12; HER2, 15–19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27–18 mo, P = 0.02; HER2, 30–18 mo, P = 0.08). Conclusions Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. Key Points 1. Receptor discordance alters subtype in 32% of BCBM patients. 2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively. 3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

Introduction: Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) of the central nervous system (CNS) is a rare meningeal tumor. Given the absence of prospective or randomized data, there are no standard indications for radiotherapy. Recently, the NRG Oncology and EORTC cooperative groups successfully accrued and completed the first prospective trials evaluating risk-adapted adjuvant radiotherapy strategies for meningiomas. Using a similar framework, we sought to develop prognostic risk categories that may predict the survival benefit associated with radiotherapy, using two large national datasets. Methods: We queried the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) databases for all newly diagnosed cases of SFT/HPC within the CNS. Risk categories were created, as follows: low risk—grade 1, with any extent of resection (EOR) and grade 2, with gross–total resection; intermediate risk—grade 2, with biopsy/subtotal resection; high risk—grade 3 with any EOR. The Kaplan–Meier method and Cox proportional hazards regressions were used to determine the association of risk categories with overall and cause-specific survival. We then determined the association of radiotherapy with overall survival in the NCDB, stratified by risk group. Results: We identified 866 and 683 patients from the NCDB and SEER databases who were evaluated, respectively. In the NCDB, the 75% survival times for low- (n = 312), intermediate- (n = 239), and high-risk (n = 315) patients were not reached, 86 months (HR 1.60 (95% CI 1.01–2.55)), and 55 months (HR 2.56 (95% CI 1.68–3.89)), respectively. Our risk categories were validated for overall and cause-specific survival in the SEER dataset. Radiotherapy was associated with improved survival in the high- (HR 0.46 (0.29–0.74)) and intermediate-risk groups (HR 0.52 (0.27–0.99)) but not in the low-risk group (HR 1.26 (0.60–2.65)). The association of radiotherapy with overall survival remained significant in the multivariable analysis for the high-risk group (HR 0.55 (0.34–0.89)) but not for the intermediate-risk group (HR 0.74 (0.38–1.47)). Similar results were observed in a time-dependent landmark sensitivity analysis. Conclusion: Risk stratification based on grade and EOR is prognostic of overall and cause-specific survival for SFT/HPCs of the CNS and performs better than any individual clinical factor. These risk categories appear to predict the survival benefit from radiotherapy, which is limited to the high-risk group and, potentially, the intermediate-risk group. These data may serve as the basis for a prospective study evaluating the management of meningeal SFT/HPCs.

Sarcopenia has been shown to correlate with poor oncologic outcomes, but the optimal method to evaluate sarcopenia and its use as a prognostic tool in glioblastoma multiforme (GBM) remain unclear. We developed a method to reproducibly quantify sarcopenia using the temporalis muscle and correlated sarcopenia with overall survival (OS) in GBM patients. We measured the temporalis muscle width (TMW) on the postoperative radiotherapy CT simulation scan of 87 newly diagnosed GBM patients from 2011 to 2016. All patients successfully completed standard of care radiotherapy to a dose of 6000 cGy in 30 fractions with concurrent temozolomide without treatment breaks. TMW was measured bilaterally on four axial CT slices defined by bony orbit anatomy: orbit ceiling, superior quarter (equidistant between orbit and mid-orbit), mid-orbit, and inferior quarter (equidistant between mid-orbit and orbit floor). For analysis, TMW was dichotomized to either wide or narrow TMW by the median TMW and correlated with OS using Cox regression models. TMW at the orbit inferior quarter significantly correlated with OS. Median OS for wide TMW (> 1.583 cm) was greater than that of narrow TMW: 28.3 mo vs. 22.2 mo (HR (wide/narrow) = 0.42, 95% CI = (0.22, 0.82), p = 0.01), controlling for resection type and MGMT methylation. This effect was pronounced especially in the following patient subsets: females (HR (wide/narrow) = 0.26, 95% CI = (0.07, 0.92), p = 0.04) and patients without MGMT methylation (HR = 0.35, 95% CI = (0.15, 0.81), p = 0.01). Our results suggest sarcopenia and TMW correlate with GBM OS. Prospective validation of sarcopenia is needed to evaluate its potential in determining optimal patient treatment.

Practice patterns vary for adjuvant treatment of 1p/19q-codeleted oligodendroglioma patients. This study evaluates the outcomes of adjuvant (aRT) versus salvage radiation therapy (sRT) in a multi-institutional cohort. Oligodendroglioma patients with confirmed 1p/19q codeletion who were treated with RT with or without chemotherapy from 2000 to 2017 at four tertiary centers were retrospectively reviewed. Overall survival (OS), post-RT progression-free survival (PFS), freedom-from-RT (FFRT), and radiation necrosis (RN) rates were determined using Kaplan–Meier analyses. OS1/PFS1 were defined from the initial surgery. OS2/PFS2 were defined from the RT start-date. Multivariable analyses (MVAs) of prognostic factors for OS and PFS were performed with Cox regression. One hundred eighty-six patients were identified: 124(67%) received aRT and 62(33%) received sRT; of sRT patients, 58% were observed after surgery while 42% received chemotherapy without aRT. The median time from initial diagnosis to sRT was 61 months, and 74% had reoperations before sRT. sRT had longer OS1 than aRT (94% vs. 69% at 10 years, p = 0.03) and PFS1 (10-year PFS of 80% vs. 68%, p = 0.03), though sRT was not associated with significantly different OS1/PFS1 on MVAs. Chemotherapy did not delay sRT compared to observation and had worse PFS2 (42% vs. 79% at 5 years, p = 0.08). Higher RT dose was not associated with improved clinical outcomes but was associated with higher symptomatic RN rate (15% vs. 0% at 2 years, p = 0.003). Delaying RT for selected oligodendroglioma patients appears safe. Adjuvant chemotherapy does not delay sRT longer than observation and may be associated with worse PFS after RT.

Brain metastases (BrM) are a significant cause of morbidity and mortality, occurring in approximately 10% to 30% of cancer patients at one point in the course of their disease. In this chapter, the authors review the literature on the interplay between immunotherapy and stereotactic radiosurgery (SRS) for brain and spine metastases. In recent years, numerous investigators have explored the combination of immunotherapy and SRS in the management of patients with BrM in an effort to improve rates of local and distant intracranial control. When compared to traditional chemotherapeutic agents, immunotherapy drugs have a unique complement of adverse effects (AEs). Key to their mechanism of action, these agents upregulate the immune system, causing inflammatory AEs. Pseudoprogression, a phenomenon occasionally observed in tumors treated with immunotherapy, occurs when there is initial apparent tumor growth, followed by tumor regression. Pseudoprogression can be distinguished from true disease progression through biopsy or serial imaging.

Ocular melanocytosis has traditionally been associated with increased risk of developing uveal melanoma; however, rarely primary episcleral melanoma has been reported in the literature. Herein, we present the third case of primary episcleral melanoma treated by complete excision and cryotherapy. In contrast to previous cases, we obtained molecular genetic testing which revealed a GNA-11 mutation, and gene expression profiling resulted in a Class 2 PRAME positive tumor diagnosis. These two tests which have never been performed on previous cases, support lineage similar to uveal melanoma. In addition, we are the first case to report treatment of the surgical bed and surrounding orbital tissue with Gamma Knife stereotactic radiotherapy to both treat residual tissue and decrease risk of recurrence.

Highlights • Brain metastases in GI cancer patients are not uncommon. • Survival varies widely within this cohort. • New identified prognostic factors are incorporated in an updated prognostic index. • This index, the GI-GPA, will better estimate survival. • The GI-GPA is useful in treatment selection and stratification of clinical trials., 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.

National guidelines recommend maximal safe resection of low-grade and high-grade oligodendrogliomas. However, there is no level 1 evidence to support these guidelines, and recent retrospective studies on the topic have yielded mixed results. To assess the association between extent of resection (EOR) and survival for oligodendrogliomas in the general U.S. population. Cases diagnosed between 2004 and 2013 were selected from the Surveillance, Epidemiology, and End-Results (SEER) Program and retrospectively analyzed for treatment, prognostic factors, and survival times. Cases that did not undergo tumor de-bulking surgery (e.g. no surgery or biopsy alone) were compared to subtotal resection (resection) and gross-total resection (GTR). The primary end-points were overall survival (OS) and cause-specific survival (CSS). An external validation cohort with 1p/19q-codeleted tumors was creating using the TCGA and GSE16011 datasets. 3135 Cases were included in the final analysis. The 75% survival time (75ST) and 5-year survival rates were 47 months and 70.8%, respectively. Subtotal resection (STR, 75ST = 50 months) and GTR (75ST = 61 months) were associated with improved survival times compared to cases that did not undergo surgical debulking (75ST = 20 months, P

BACKGROUND: Prior studies have highlighted infratentorial tumor location as a prognostic factor for solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) of the central nervous system (CNS), and spinal location is considered a positive prognostic factor for other tumors of the CNS. While SFT/HPC of the CNS is known to frequently arise from the spinal meninges, there are no case series that report outcomes for spinally located CNS tumors, and their prognosis in relation to intracranial and other CNS-located tumors is unknown. OBJECTIVE: To investigate outcomes for patients with SFT/HPC of the spinal meninges. METHODS: The Surveillance, Epidemiology, and End-Results Program was used to identify patients with SFT/HPC within the CNS from 1993 – 2015. We retrospectively analyzed the relationship between tumor location (spinal vs. brain and other CNS) and survival. RESULTS: We identified 551 cases of CNS SFT/HPC, 64 (11.6%) of which were primary tumors of the spinal meninges. Spinal tumors were more likely than brain and other CNS tumors to be SFT vs. HPC (37.5 vs. 12%, p < 0.001), benign (42.2 vs. 20.3%, p < 0.001), and less than 5 cm (53.1 vs. 35.7%, p < 0.001). The 10-year survival rates for spinal and brain/other CNS tumors were 85 and 58%, respectively. Median survival time was significantly longer for spinal tumors (median survival not reached vs. 138 months, p = 0.03, HR = 0.41 [95% CI 0.18 – 0.94]). On multivariable analysis, spinal tumor location was associated with improved survival over tumors located in the brain and other CNS (HR = 0.36 [95% CI 0.15 – 0.89], p = 0.03). CONCLUSION: Spinal tumor location is associated with improved survival in patients with SFT/HPC of the CNS. Larger institutional studies are necessary to characterize the relationship between tumor location and other relevant factors such as presentation and amenability to gross-total resection and adjuvant radiotherapy. Future studies exploring optimal management of spinally located tumors are also needed.

INTRODUCTION: NRG protocols for glioblastoma allow for clinical target volume (CTV) reductions at natural barriers; however, literature examining CTV contouring and the relevant white matter pathways is lacking. This study proposes consensus CTV guidelines, with a focus on areas of controversy while highlighting common errors in glioblastoma target delineation. METHODS: Ten academic radiation oncologists specializing in brain tumor treatment contoured CTVs on 4 glioblastoma cases. CTV expansions were based on NRG trial guidelines. Contour consensus was assessed and summarized by kappa statistics. A meeting was held to discuss the mathematically averaged contours and form consensus contours and recommendations. RESULTS: Contours of the cavity plus enhancement (mean kappa 0.69) and T2-FLAIR signal (mean kappa 0.74) showed moderate to substantial agreement. Experts were asked to trim off anatomic barriers while respecting pathways of spread to develop their CTVs. Submitted CTV_4600 (mean kappa 0.80) and CTV_6000 (mean kappa 0.81) contours showed substantial to near perfect agreement. Simultaneous Truth and Performance Level Estimation (STAPLE) contours were then reviewed and modified by group consensus. Anatomic trimming reduced the amount of total brain tissue planned for radiation targeting by a 13.6% (range 8.7% - 17.9%) mean proportional reduction. Areas for close scrutiny of target delineation were described, with accompanying recommendations. CONCLUSIONS: Consensus contouring guidelines were established based on expert contours. Careful delineation of anatomic pathways and barriers to spread can spare radiation to uninvolved tissue without compromising target coverage. Further study is necessary to accurately define optimal target volumes beyond isometric expansion techniques for individual patients.

BACKGROUND: Whole-brain radiotherapy (WBRT) in patients with brain metastases (BM) is associated with neurocognitive decline. Given its crucial role in learning and memory, efforts to mitigate this toxicity have mostly focused on sparing radiation to the hippocampus. We hypothesized that BM are not evenly distributed across the brain and that several additional areas may be avoided in WBRT based on a low risk of developing BM. METHODS: We contoured 2757 lesions in a large, single-institution database of patients with newly diagnosed BM. BM centroids were mapped onto a standard brain atlas of 55 anatomic subunits and the observed percentage of BM was compared with what would be expected based on that region’s volume. A region of interest (ROI) analysis was performed in a validation cohort of patients from 2 independent institutions using equivalence and one-sample hypothesis tests. RESULTS: The brainstem and bilateral thalami, hippocampi, parahippocampal gyri, amygdala, and temporal poles had a cumulative risk of harboring a BM centroid of 4.83% in the initial cohort. This ROI was tested in 157 patients from the validation cohort and was found to have a 4.1% risk of developing BM, which was statistically equivalent between the 2 groups (P < 1 × 10(–6), upper bound). CONCLUSION: Several critical brain structures are at a low risk of developing BM. A risk-adapted approach to WBRT is worthy of further investigation and may mitigate the toxicities of conventional radiation.

Aminoacyl-tRNA synthetases (AARSs) charge their cognate tRNAs with corresponding amino acids, playing key roles in ribosomal protein synthesis. A series of proteomic studies have demonstrated that AARSs have levels of lysine acetylation much higher than those of other proteins in Escherichia coli. To study AARS acetylation, 25 site-specifically acetylated variants of four AARSs were generated by the genetic code expansion strategy. Kinetic analyses were performed to biochemically characterize the impact of site-specific acetylation on AARS functions, including amino acid activation, tRNA aminoacylation, and editing activities. The results showed that impacts of acetylation were different between class I and class II AARSs and also varied among the same class of AARSs. The results also showed that acetylation of threonyl-tRNA synthetase (ThrRS) could affect its editing function. Both in vivo and in vitro studies were further performed to explore the acetylation and deacetylation processes of ThrRS. Although nonenzymatic acetylation and CobB-dependent deacetylation were concluded, the results also indicated the existence of additional modifying enzymes or mechanisms for ThrRS acetylation and deacetylation.

Purpose/Objective(s) Approximately one in eight women in the United States is diagnosed with breast cancer and eligible for mastectomy with implant reconstruction. Although it has been suggested that patients with breast cancer or those who are at high risk for breast cancer may have an increased risk of anaplastic large cell lymphoma (ALCL) after breast implantation, no studies have explored the association in this population. Our objective was to determine the relative and absolute risks of breast ALCL after post-mastectomy implant reconstruction for breast cancer compared with the general population. Materials/Methods This population-based study obtained incidence data on breast ALCL in the general population from the Surveillance, Epidemiology, and End Results (SEER) program from 2000 – 2017. Patients who underwent post-mastectomy implant reconstruction for primary breast cancer from 2000 – 2016 were identified and followed through 2017. Because breast implant-associated ALCL has been documented as early as 2 months after implantation, patients with less than two months of follow-up were excluded. Observed-to-expected ratios for breast ALCL were derived from multiple primary – standardized incidence ratios in the study population versus the general U.S. population after adjusting for age, sex, race, anatomical site, and year of diagnosis. For external validation, we compared the number of cases of breast ALCL diagnosed in SEER with the estimated number of FDA-reported cases over a similar time period. Results The incidence rate of breast ALCL in the general U.S. female population was 0.08 – 0.12 per 1,000,000 persons per year and was rising. 52,882 women were identified that received post-mastectomy implant reconstruction for primary breast cancer and were followed for a median of 69 months, including 10,979 patients with follow-up time greater than or equal to 10 years (range 2 – 215 months). After adjusting for demographical characteristics of the cohort, the expected incidence rate of breast ALCL was 0.25 – 0.34 per 1,000,000 persons per year versus an observed rate of 5.8 – 8.7 per 1,000,000 persons per year (standardized incidence ratio 23.4 [95% confidence interval 2.8 – 84.7]). These findings corresponded well with FDA-reported cases; 353 SEER versus 333 FDA cases, respectively. Conclusion Although breast cancer patients who receive post-mastectomy implant reconstruction are at increased risk of breast ALCL, the absolute risk remains extremely low. Furthermore, the risk does not appear to be increased compared to patients that receive implantation (for cosmesis or reconstruction) in previously reported literature.

Purpose/Objective(s) Standard therapy for patients with glioblastoma (GBM) consists of maximal safe surgical resection followed by concurrent chemotherapy and radiation (CRT) to the postoperative cavity and residual disease. After CRT, patients are standardly assessed at regular intervals of approximately 1-4 months with magnetic resonance imaging (MRI) of the brain to monitor for residual or recurrent tumor growth. At present, there are no accepted MRI methods or protocols to predict response either during or after CRT. Notably, GBM is associated with vascular dysregulation, manifesting radiographically as asynchrony on resting state BOLD fMRI. However, the impact of radiation therapy on BOLD asynchrony in glioblastoma remains unknown. In this study, we sought to collect radiographic data on a cohort of patients with recently resected glioblastoma prior to the start of CRT and again during the third week of therapy. The aim of this prospective pilot study was to determine the feasibility of collecting radiographic data to inform patient outcomes and ultimately predict the interval to disease progression of GBM using pre-treatment and mid-treatment MRI acquisitions. Materials/Methods Twelve patients with newly-diagnosed histologically proven GBM were enrolled in this institutional IRB approved prospective trial between 2015 and 2017. Patients underwent two resting-state BOLD fMRI scans: one immediately prior to starting standard six weeks of radiation and another during the third week of radiation. BOLD scans were processed and linearly registered to structural images. A BOLD asynchrony map was generated by comparing the time series in each voxel to the time series of the contralesional, radiographically normal brain, such that positive values denote synchrony with the contralateral hemisphere. The 60 Gy radiation dose maps were used for the purposes of determining the total radiation dose at each voxel. Results There were 8 males and 4 females included in the analysis with a median age at diagnosis of 63 years. We divided the brain into voxels that received lower total doses of radiation ( 24 Gy), and determined the mean change in the BOLD asynchrony before and during radiation for each group of voxels for each patient. The absolute change in BOLD asynchrony between the two scanning sessions was significantly higher in the regions that received higher doses of radiation (0.71 vs 0.04, P = 0.0007). Conclusion Here we show that radiation doses higher than 24 Gy change vascular regulation in glioblastoma patients, manifesting as altered asynchrony on resting-state BOLD fMRI. Further prospective evaluation is warranted to develop a non-invasive radiographic biomarker to predict and monitor responses to standard interventions for glioblastoma.

Purpose To implement Velocity-based image fusion and adaptive deformable registration to enable treatment planning for preclinical murine models of fractionated stereotactic radiosurgery (fSRS) using the small animal radiation research platform (SARRP). Methods and Materials C57BL6 mice underwent 3 unique cone beam computed tomography (CBCT) scans: 2 in the prone position and a third supine. A single T1-weighted post-contrast magnetic resonance imaging (MRI) series of a murine metastatic brain tumor model was selected for MRI-to-CBCT registration and gross tumor volume (GTV) identification. Two arms were compared: Arm 1, where we performed 3 individual MRI-to-CBCT fusions using rigid registration, contouring GTVs on each, and Arm 2, where the authors performed MRI-to-CBCT fusion and contoured GTV on the first CBCT followed by Velocity-based adaptive registration. The first CBCT and associated GTV were exported from MuriPlan (Xstrahl Life Sciences) into Velocity (Varian Medical Systems, Inc, Palo Alto, CA). In Arm 1, the second and third CBCTs were exported similarly along with associated GTVs (Arm 1), while in Arm 2, the first (prone) CBCT was fused separately to the second (prone) and third (supine) CBCTs, performing deformable registrations on initial CBCTs and applying resulting matrices to the contoured GTV. Resulting GTVs were compared between Arms 1 and 2. Results Comparing GTV overlays using repeated MRI fusion and GTV delineation (Arm 1) versus those of Velocity-based CBCT and GTV adaptive fusion (Arm 2), mean deviations ± standard deviation in the axial, sagittal, and coronal planes were 0.46 ± 0.16, 0.46 ± 0.22, and 0.37 ± 0.22 mm for prone-to-prone and 0.52 ± 0.27, 0.52 ± 0.36, and 0.68 ± 0.31 mm for prone-to-supine adaptive fusions, respectively. Conclusions Velocity-based adaptive fusion of CBCTs and contoured volumes allows for efficient fSRS planning using a single MRI-to-CBCT fusion. This technique is immediately implementable on current SARRP systems, facilitating advanced preclinical treatment paradigms using existing clinical treatment planning software.

BACKGROUND: Treatment paradigms for large cell neuroendocrine carcinoma (LCNEC) of the lung are based largely upon small retrospective studies and smaller prospective trials. It is unclear if these tumors behave like non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). Data are lacking with regard to the role of radiotherapy (RT). U. S. guidelines recommend that LCNEC be treated as a NSCLC. We sought to perform a cross-sectional study of LCNEC cases to understand treatment paradigms and outcomes in this disease. METHODS: The Surveillance, Epidemiology and End Results database was queried for cases of stage I–III pulmonary LCNEC diagnosed 2004–2013. Treatment groups were defined as no surgery, RT alone, surgery alone, and surgery + RT. The Cox-proportional hazards regression model was used to compare overall survival and cause-specific survival (OS/CSS), stratified by AJCC 6th Staging. Factors that were significant on univariable analysis were included in multivariable analysis. RESULTS: We identified 1,523 cases of LCNEC, with 748, 177, and 598 cases of stage I, II, and III disease, respectively. In stage I and II disease, RT was associated with improved survival for non-surgical patients, but not for those who underwent surgery. In stage I disease, the adjusted hazard ratios for OS for RT alone, surgery, and surgery + RT were 0.39, 0.21, and 0.22, respectively (P

BackgroundCancer patients’ treatment is often dispersed across multiple physician communities that may not exchange information. We measured the association between this type of discoordinated care and healthcare utilization, cost, and mortality in stage IV non-small cell lung cancer (NSCLC).MethodsStage IV NSCLC patients ≥65 years were identified from the Surveillance, Epidemiology, and End Results database attached to Medicare claims. A discoordinated care subgroup was selected using a novel index that approximated how many physician communities each patient encountered. Communities were defined by (1) using claims data to create a nationwide social network of healthcare providers and then (2) dividing that network into communities using cluster label propagation. Associations between discoordinated care and overall survival (OS), cancer-specific survival (CSS), hospitalizations, the burden of diagnostic imaging, and cost were assessed.ResultsOf the 11,417 patients in our cohort, 5,855 received discoordinated care. Discoordination was associated with younger age, higher socioeconomic status, higher physician density, and lack of a home health aide. Discoordinated care was associated with improved OS and CSS (HR = 0.92, 95% CI 0.88 - 0.95 for OS). However, discoordinated patients also received 32% more MRIs (p = 0.007) and paid $494.02 more for imaging (p = 0.004). There was no association with other kinds of imaging, rates of hospitalization, or other healthcare costs, including total cost.ConclusionsDiscoordinated care was associated with additional MRIs, but also improved survival. The reason is unclear, but discoordinated patients may be seeking the best care at the expense of continuity.Key PointsQuestionHow does dispersing healthcare across multiple physician communities impact healthcare utilization and survival in patients with advanced stage non-small cell lung cancer?FindingsIn this retrospective cohort study, we found that discoordinated care was associated with increased utilization of MRIs and total cost of imaging. Surprisingly, it was also associated with improved survival.MeaningCancer patients with dispersed healthcare may be seeking care through a tertiary care center or clinical trial. This may lead to increased healthcare utilization but also improved survival.

Background High-frequency image-guided radiotherapy (hfIGRT) is ubiquitous but its benefits are unproven. We examined the cost effectiveness of hfIGRT in stage III non-small-cell lung cancer (NSCLC). Methods We selected stage III NSCLC patients ≥66 years old who received definitive radiation therapy from the Surveillance, Epidemiology, and End-Results-Medicare database. Patients were stratified by use of hfIGRT using Medicare claims. Predictors for hfIGRT were calculated using a logistic model. The impact of hfIGRT on lung toxicity free survival (LTFS), esophageal toxicity free survival (ETFS), cancer-specific survival (CSS), overall survival (OS), and cost of treatment was calculated using Cox regressions, propensity score matching, and bootstrap methods. Results Of the 4,430 patients in our cohort, 963 (22%) received hfIGRT and 3,468 (78%) did not. By 2011, 49% of patients were receiving hfIGRT. Predictors of hfIGRT use included treatment with intensity-modulated radiotherapy (IMRT) (OR = 7.5, p < 0.01), recent diagnosis (OR = 51 in 2011 versus 2006, p < 0.01), and residence in regions where the Medicare intermediary allowed IMRT (OR = 1.50, p < 0.01). hfIGRT had no impact on LTFS (HR 0.97; 95% CI 0.86–1.09), ETFS (HR 1.05; 95% CI 0.93–1.18), CSS (HR 0.94; 95% CI 0.84–1.04), or OS (HR 0.95; 95% CI 0.87–1.04). Mean radiotherapy and total medical costs six months after diagnosis were $17,330 versus $15,024 (p < 0.01) and $71,569 versus $69,693 (p = 0.49), respectively. Conclusion hfIGRT did not affect clinical outcomes in elderly patients with stage III NSCLC but did increase radiation cost. hfIGRT deserves further scrutiny through a randomized controlled trial.

BackgroundImmune checkpoint inhibitors (ICIs) are important new therapeutic options for the treatment of malignancy. Existing data on the relative safety of ICI treatment in patients with pre-existing autoimmune disease (AID) are limited.MethodsIn this retrospective study utilizing an oncology medical claims database, we determined the rates of treatment with immunosuppressive agents and hospitalization within 180 days of treatment with ICIs (pembrolizumab, nivolumab, and ipilimumab) in patients both with and without AID. Patients had diagnoses of either malignant melanoma or lung cancer. Immunosuppressive agents evaluated included oral prednisone and intravenous methylprednisolone.Results124 cancer patients with AID and 1896 cancer patients without AID met inclusion criteria for oral prednisone analysis, while 284 patients with AID and 3230 patients without AID met inclusion criteria for all other analyzes. Following treatment with PD-1 inhibitors, rates of treatment with both oral prednisone and intravenous methylprednisolone within 180 days of ICI treatment were significantly increased in the AID group relative to the control group (oral prednisone: 16.7% treatment in AID vs 8.3% in non-AID, p=0.0048; intravenous methylprednisolone: 8.4% treatment in AID vs 3.7% in non-AID, p=0.0012). Rates of hospitalization were significantly increased in melanoma patients with AID relative to melanoma patients without AID following treatment with PD-1 inhibitors (24.1% in AID vs 5.8% in non-AID, pConclusionCancer patients with AID have higher rates of hospitalization and treatment with immunosuppressive agents following treatment with ICI therapy compared with patients with no AID. This suggests that patients with AID may have increased toxicity risk while being treated with checkpoint inhibitor therapy. Further prospective clinical trials are needed to determine safety.

Simple Summary Brain metastases are the most common cause of cancerous brain tumors in adults. Large brain metastases are an especially difficult clinical scenario as patients often have debilitating symptoms from these tumors, and large tumors are more difficult to control with traditional single treatment radiation regimens alone or after surgery. Hypofractionated stereotactic radiotherapy is a novel way to deliver the higher doses of radiation to control large tumors either after surgery (most common), alone (common), or potentially before surgery (uncommon). Herein, we describe how delivering high doses over three or five treatments may improve tumor control and decrease complication rates compared to more traditional single treatment regimens for brain metastases larger than 2 cm in maximum dimension. Abstract Brain metastases are the most common intracranial malignant tumor in adults and are a cause of significant morbidity and mortality for cancer patients. Large brain metastases, defined as tumors with a maximum dimension >2 cm, present a unique clinical challenge for the delivery of stereotactic radiosurgery (SRS) as patients often present with neurologic symptoms that require expeditious treatment that must also be balanced against the potential consequences of surgery and radiation therapy—namely, leptomeningeal disease (LMD) and radionecrosis (RN). Hypofractionated stereotactic radiotherapy (HSRT) and pre-operative SRS have emerged as novel treatment techniques to help improve local control rates and reduce rates of RN and LMD for this patient population commonly managed with post-operative SRS. Recent literature suggests that pre-operative SRS can potentially half the risk of LMD compared to post-operative SRS and that HSRT can improve risk of RN to less than 10% while improving local control when meeting the appropriate goals for biologically effective dose (BED) and dose-volume constraints. We recommend a 3- or 5-fraction regimen in lieu of SRS delivering 15 Gy or less for large metastases or resection cavities. We provide a table comparing the BED of commonly used SRS and HSRT regimens, and provide an algorithm to help guide the management of these challenging clinical scenarios.

Background Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with limited treatment options and poor survival. The delivery of systemic therapies in this disease is severely limited by the blood-brain barrier (BBB). Focused ultrasound combined with intravenous microbubbles (FUS+MB) can effectively open the BBB permitting the entry of drugs across the cerebrovasculature. Etoposide is a chemotherapy frequently used in pediatric oncology with well-established anti-tumor effects but limited efficacy when administered systemically in DIPG. Given that FUS+MB in DIPG is not well studied, our goal was to determine the feasibility of ultrasound-mediated BBB opening and etoposide delivery in a preclinical murine pontine glioma model. Methods A syngeneic, orthotopic model was established by stereotactic injection of PDGF-B+PTEN-/-p53-/- murine glioma cells into the pons of B6 albino mice. Mice were randomly divided into control (n=6) or FUS+MB groups (n=6). A single-element, spherical-segment FUS transducer (center frequency=1.5MHz) driven by a function generator through a power amplifier was used with concurrent microbubble injection to sonicate the tumor and its margins on post-injection day 14. Immediately after treatment, 5 mg/kg of intraperitoneal etoposide was administered to all 12 mice. All animals underwent cardiac puncture and blood sampling, followed by transcardiac perfusion and brain harvesting. Liquid chromatography-mass spectometry was performed on both serum and tumor tissue to measure etoposide levels. Results Contrast-enhanced MRI demonstrated successful BBB opening in all FUS+MB mice. Compared to control (mean=20.98ng/g), etoposide concentration in the sonicated tumor tissue (mean=164.77ng/g) was nearly eight times greater. Lastly, the mean brain tumor–to-serum ratio was more than fivefold higher in the treated mice (1.50%) compared with the control mice (0.28%) (P Conclusions FUS+MB is hereby shown successful in BBB opening and enhanced delivery of etoposide in a preclinical pontine glioma model.

Purpose Glioblastoma (GBM) is a devastating disease. With the current treatment of surgery followed by chemoradiation, outcomes remain poor, with median survival of only 15 months and a 5-year survival rate of 6.8%. A challenge in treating GBM is the heterogeneous integrity of the blood-brain barrier (BBB), which limits the bioavailability of systemic therapies to the brain. There is a growing interest in enhancing drug delivery by opening the BBB with the use of focused ultrasound (FUS). We hypothesize that an FUS-mediated BBB opening can enhance the delivery of etoposide for a therapeutic benefit in GBM. Methods and Materials A murine glioma cell line (Pdgf+, Pten-/-, P53-/-) was orthotopically injected into B6(Cg)-Tyrc-2J/J mice to establish the syngeneic GBM model for this study. Animals were treated with FUS and microbubbles to open the BBB to enhance the delivery of systemic etoposide. Magnetic resonance (MR) imaging was used to evaluate the BBB opening and tumor progression. Liquid chromatography tandem mass spectrometry was used to measure etoposide concentrations in the intracranial tumors. Results The murine glioma cell line is sensitive to etoposide in vitro. MR imaging and passive cavitation detection demonstrate the safe and successful BBB opening with FUS. The combined treatment of an FUS-mediated BBB opening and etoposide decreased tumor growth by 45% and prolonged median overall survival by 6 days: an approximately 30% increase. The FUS-mediated BBB opening increased the brain tumor-to-serum ratio of etoposide by 3.5-fold and increased the etoposide concentration in brain tumor tissue by 8-fold compared with treatment without ultrasound. Conclusions The current study demonstrates that BBB opening with FUS increases intratumoral delivery of etoposide in the brain, resulting in local control and overall survival benefits.

Objective: Recent studies of primary central nervous system lymphoma (PCNSL) have found a positive association between cytoreductive surgery and survival, challenging the traditional notion that surgery is not beneficial and potentially harmful. However, no studies have examined the potential added benefits of adjuvant treatment in the post-operative setting. Here, we investigate survival in PCNSL patients treated with surgery plus radiation therapy (RT). Methods: The Surveillance, Epidemiology, and End-Results Program was used to identify patients with PCNSL from 1995–2013. We retrospectively analyzed the relationship between treatment, prognostic factors, and survival using case-control design. Treatment categories were compared to biopsy alone. Results: We identified 5417 cases. Median survival times for biopsy alone (n = 1824, 34%), biopsy + RT (n = 1460, 27%), surgery alone (n = 1222, 27%), and surgery + RT (n = 911, 17%) were 7, 8, 20, and 27 months, respectively. On multivariable analysis, surgery + RT was associated with improved survival over surgery alone (hazard ratio [HR] = 0.58 [95% confidence interval = 0.53–0.64] vs. HR = 0.71 [0.65–0.77]). Adjuvant RT was associated with improved survival, regardless of the extent of resection. HR’s for subtotal resection, gross-total resection, subtotal resection + RT, and gross-total resection + RT were 0.77 (0.66–0.89), 0.66 (0.57–0.76), 0.62 (0.52–0.72), and 0.54 (0.46–0.63), respectively. Survival improved after adjuvant RT in patients under and over 60 years old. All findings were confirmed by multivariable analysis of cause-specific survival. Conclusion: Adjuvant RT was associated with improved survival in PCNSL patients who underwent surgery. Although these data are hypothesis-generating, additional information on neurotoxicity, dosing, and concurrent chemotherapy will be necessary to validate these findings. Cytoreductive surgery for PCNSL is common in the general population, and more studies are needed to assess optimal treatment in the post-operative setting.

Brain metastasis (BM) is the most common intracranial malignancy, and most patients present with multiple brain metastases at time of diagnosis. Whole brain radiation therapy (WBRT) has been the standard of care for multiple BM; however, recent studies have shown that stereotactic radiosurgery (SRS) may have similar outcomes and better toxicity profile than WBRT in the setting of multiple BM.

Radiation therapy has been a mainstay of managing brain metastases for decades. In the past, clinicians have relied on whole brain radiotherapy (WBRT) and in some instances partial brain radiation therapy to deliver conformal radiation dose distributions using MRI and CT-guidance to plan treatment. The dose limitations of various critical structures of the brain and treatment-induced neurocognitive side effects made intracranial treatment challenging. However, the development and popularization of stereotactic radiosurgery (SRS), including Gamma Knife stereotactic radiosurgery (GKRS) and linear accelerator (LINAC)-based SRS, has had a profound impact on the field of neuro-oncology. As the name suggests, SRS typically uses a method of immobilization to maintain a particular patient position for the duration of treatment. While this method of immobilization has traditionally been an invasive, rigid frame placed onto a patient’s head, with newer technical advances, frameless treatments with masks have become feasible without sacrificing accuracy. In this chapter, we outline seven particularly interesting applications in which SRS was used to increase the likelihood of achieving local control in patients with a variety of brain metastatic lesions.

In the Clinical Reasoning piece “Transient speech deficits in a patient with history of medulloblastoma” by Schulte et al.,1 the byline is missing degrees for two authors. The author list should have included “Tony J.C. Wang, MD” and “Angela Lignelli, MD.” The authors regret the error.

BACKGROUND Approximately 50% of nGBMs harbor EGFR-amp. Depatuxizumab mafodotin (depatux-m) is an antibody drug conjugate: a monoclonal antibody that binds activated EGFR (wild-type and EGFRvIII mutant) linked to a microtubule-inhibitor toxin. Pre-clinical and earlier clinical trials suggested efficacy. METHODS RTOGF 3508/AbbVie M13-813 (INTELLANCE-1, NCT02573324) was a phase 3 academic-industry collaboration (RTOG-Foundation, AbbVie). Eligible adults (KPS ≥ 70, EGFR-amp nGBM, centrally confirmed histology and biomarkers) were randomized 1:1 to radiotherapy (RT) and temozolomide and either depatux-m (2.0 mg/kg during RT, 1.25 mg/kg thereafter, q 14 days) or placebo, stratified by region of world, RPA class, MGMT methylation, and EGFRvIII mutation. Primary endpoint was overall survival (OS), with 640 patients planned for randomization; 441 events yielded 85% power to detect 25% reduction in hazard of death (HR 0.75), one-sided 2.5% level of significance by stratified weighted log-rank. RESULTS 2229 patients were screened and 639 (median age 60, range 22–84; 394 men, 62%) randomized. Pre-specified interim analysis after 346 events (≥ 75% required) found no OS improvement for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.01, 95% CI 0.82–1.25, one-sided p= 0.63). Progression-free survival (PFS) trended toward depatux-m (median 8.0 vs. 6.3 months; HR 0.84, 95% CI 0.70–1.02), particularly among the ~50% with EGFRvIII mutation (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56–0.93) but without an OS improvement (median 19.8 vs. 18.2, HR=0.95, 95% CI 0.71–1.27). Ocular side effects (grade ≥ 1) occurred in 95% of depatux-m treated patients, 61% grade 3–4, causing 12% to discontinue, and were the most common treatment related adverse events. CONCLUSION Interim analysis demonstrated no OS benefit for treating EGFR-amp nGBM with depatux-m. PFS trended toward favoring depatux-m, particularly in the EGFRvIII harboring subgroup. No new important safety risks were identified. The trial was stopped for futility. Active patients are permitted to continue treatment.

The Radiation Therapy Committee of SWOG periodically evaluates its strategic plan in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2017 Strategic Planning Workshop included leaders in cancer basic sciences, molecular theragnostics, pharmaceutical and technology industries, clinical trial design, oncology practice, and statistical analysis. The committee discussed high-priority research areas, such as optimization of combined modality therapy, radiation oncology–specific drug design, identification of molecular profiles predictive of radiation-induced local or distant tumor responses, and methods for normal tissue-specific mitigation of radiation toxicity. The following concepts emerged as dominant questions ready for national testing: (i) what is the role of radiotherapy in the treatment of oligometastatic, oligorecurrent, and oligoprogressive disease? (ii) How can combined modality therapy be used to enhance systemic and local response? (iii) Can we validate and optimize liquid biopsy and other biomarkers (such as novel imaging) to supplement current response criteria to guide therapy and clinical trial design endpoints? (iv) How can we overcome deficiencies of randomized survival endpoint trials in an era of increasing molecular stratification factors? And (v) how can we mitigate treatment-related side effects and maximize quality of life in cancer survivors? The committee concluded that many aspects of these questions are ready for clinical evaluation and example protocol concepts are provided that could improve rates of cancer cure and quality of survival. Clin Cancer Res; 24(15); 3500–9. ©2018 AACR.

Tufted angioma (TA) is a rare, slow-growing, vascular lesion that commonly presents as a solitary macule, papule, or nodule arising in the soft tissues of the torso, extremities, and head and neck in children and young adults. Adult-onset cases have been infrequently reported. While typically benign, TAs may be locally aggressive. Complete physical examination and hematological workup are recommended in patients with TA to exclude the presence of Kasabach-Merritt phenomenon (KMP). The authors describe the case of a 69-year-old man with a contrast-enhancing frontal lobe lesion, with surrounding vasogenic edema, which was treated by gross-total resection. Characteristic histological features of a TA were demonstrated, with multiple cannonball-like tufts of densely packed capillaries emanating from intraparenchymal vessels in cerebral cortex and adjacent white matter. Tumor recurrence was detected after 4 months and treated with adjuvant Gamma Knife radiosurgery. To the extent of the authors' knowledge, this case illustrates the first report of TA presenting in an adult as an intracranial intraaxial tumor without associated KMP. The fairly rapid regrowth of this tumor, requiring adjuvant treatment after resection, is consistent with a potential for locally aggressive growth in a TA occurring in the brain.

Aim: The number of breast cancer brain metastases is a prognostic clinical variable in the modified graded prognostic assessment (GPA) Index for breast cancer. Patients & methods: We retrospectively gathered data from 127 breast cancer patients who underwent radiation therapy for brain metastasis. Patients were stratified by both breast GPA and modified breast GPA scores, and survival was determined using the Kaplan–Meier curves and Cox proportional hazards model. Results & Conclusion: The Kaplan–Meier curve for patients under the breast GPA classification were not significant, but were significant under the modified breast GPA classification. The inclusion of number of brain metastases into the modified breast GPA index improved prognosis, thus validating the use of the modified breast GPA in prognosticating patient outcome.