Profiling the molecular and clinical landscape of glioblastoma utilizing the Oncology Research Information Exchange Network brain cancer database.

Background: Glioblastoma exhibits aggressive growth and poor outcomes despite treatment, and its marked variability renders therapeutic design and prognostication challenging. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling of 206 glioblastoma patients, providing opportunities to identify novel associations between molecular features and clinical outcomes. Methods: Survival analyses were performed using the Logrank test, and clinical features were evaluated using Wilcoxon and chi-squared tests with q-values derived via Benjamini-Hochberg correction. Mutational analyses utilized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test with Benjamini-Hochberg correction. Transcriptomic analyses utilized a student's t-test with Benjamini-Hochberg correction. Expression fold changes were processed with Ingenuity Pathway Analysis to determine pathway-level alterations between groups. Results: Key findings include an association of MUC17, SYNE1, and TENM1 mutations with prolonged overall survival (OS); decreased OS associated with higher epithelial growth factor receptor (EGFR) mRNA expression, but not with EGFR amplification or mutation; a 14-transcript signature associated with OS > 2 years; and 2 transcripts associated with OS < 1 year. Conclusions: Herein, we report the first clinical, genomic, and transcriptomic analysis of ORIEN glioblastoma cases, incorporating sample reclassification under updated 2021 diagnostic criteria. These findings create multiple avenues for further investigation and reinforce the value of multi-institutional consortia such as ORIEN in deepening our knowledge of intractable diseases such as glioblastoma.

Immunoprofiles and Oncologic Outcomes of 15 Patients with Androgen Receptor-Positive Salivary Duct Carcinoma.

BACKGROUND: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. METHODS: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan-Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). RESULTS: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8-6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. CONCLUSION: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients.

Scalp Irradiation with 3D-Milled Bolus: Initial Dosimetric and Clinical Experience.

BACKGROUND AND PURPOSE: A bolus is required when treating scalp lesions with photon radiation therapy. Traditional bolus materials face several issues, including air gaps and setup difficulty due to irregular, convex scalp geometry. A 3D-milled bolus is custom-formed to match individual patient anatomy, allowing improved dose coverage and homogeneity. Here, we describe the creation process of a 3D-milled bolus and report the outcomes for patients with scalp malignancies treated with Volumetric Modulated Arc Therapy (VMAT) utilizing a 3D-milled bolus. MATERIALS AND METHODS: Twenty-two patients treated from 2016 to 2022 using a 3D-milled bolus and VMAT were included. Histologies included squamous cell carcinoma (n = 14, 64%) and angiosarcoma (n = 8, 36%). A total of 7 (32%) patients were treated in the intact and 15 (68%) in the postoperative setting. The median prescription dose was 66.0 Gy (range: 60.0-69.96). RESULTS: The target included the entire scalp for 8 (36%) patients; in the remaining 14 (64%), the median ratio of planning target volume to scalp volume was 35% (range: 25-90%). The median dose homogeneity index was 1.07 (range: 1.03-1.15). Six (27%) patients experienced acute grade 3 dermatitis and one (5%) patient experienced late grade 3 skin ulceration. With a median follow-up of 21.4 months (range: 4.0-75.4), the 18-month rates of locoregional control and overall survival were 75% and 79%, respectively. CONCLUSIONS: To our knowledge, this is the first study to report the clinical outcomes for patients with scalp malignancies treated with the combination of VMAT and a 3D-milled bolus. This technique resulted in favorable clinical outcomes and an acceptable toxicity profile in comparison with historic controls and warrants further investigation in a larger prospective study.

Multi-phase failure modes and effects analysis for low dose bilateral whole lung irradiation of COVID-19 positive patients requiring respiratory ventilation.

PURPOSE: To identify high-priority risks in a clinical trial investigating the use of radiation to alleviate COVID-19 pneumonia using a multi-phase failure modes and effects analysis (FMEA). METHODS: A comprehensive FMEA survey of 133 possible causes of failure was developed for the clinical trial workflow (Phase I). The occurrence, severity, and detection risk of each possible cause of failure was scored by three medical physicists. High-risk potential failure modes were identified using the risk priority number (RPN) and severity scores, which were re-scored by 13 participants in radiation oncology (Phase II). Phase II survey scores were evaluated to identify steps requiring possible intervention and examine risk perception patterns. The Phase II participants provided consensus scores as a group. RESULTS: Thirty high-priority failure modes were selected for the Phase II survey. Strong internal consistency was shown in both surveys using Cronbach's alpha (αc ≥ 0.85). The 10 failures with the largest median RPN values concerned SARS-CoV-2 transmission (N = 6), wrong treatment (N = 3), and patient injury (N = 1). The median RPN was larger for COVID-related failures than other failure types, primarily due to the perceived difficulty of failure detection. Group re-scoring retained 8/10 of the highest-priority risk steps that were identified in the Phase II process, and discussion revealed interpretation differences of process steps and risk evaluation. Participants who were directly involved with the trial working group had stronger agreement on severity scores than those who were not. CONCLUSIONS: The high ranking of failures concerning SARS-CoV-2 transmission suggest that these steps may require additional quality management intervention when treating critically ill COVID-19+ patients. The results also suggest that a multi-phase FMEA survey led by a facilitator may be a useful tool for assessing risks in radiation oncology procedures, supporting future efforts to adapt FMEA to clinical procedures.

miRNA-194-3p represses NF-κB in gliomas to attenuate iPSC genes and proneural to mesenchymal transition.

Severe tumor heterogeneity drives the aggressive and treatment refractory nature of glioblastomas (GBMs). While limiting GBM heterogeneity offers promising therapeutic potential, the underlying mechanisms that regulate GBM plasticity remain poorly understood. We utilized 14 patient-derived and four commercially available cell lines to uncover miR-194-3p as a key epigenetic determinant of stemness and transcriptional subtype in GBM. We demonstrate that miR-194-3p degrades TAB2, an important mediator of NF-κB activity, decreasing NF-κB transcriptional activity. The loss in NF-κB activity following miR-194-3p overexpression or TAB2 silencing decreased expression of induced pluripotent stem cell (iPSC) genes, inhibited the oncogenic IL-6/STAT3 signaling axis, suppressed the mesenchymal transcriptional subtype in relation to the proneural subtype, and induced differentiation from the glioma stem cell (GSC) to monolayer (ML) phenotype. miR-194-3p/TAB2/NF-κB signaling axis acts as an epigenetic switch that regulates GBM plasticity and targeting this signaling axis represents a potential strategy to limit transcriptional heterogeneity in GBMs.

Technical note: Commissioning of a linear accelerator producing ultra-high dose rate electrons.

BACKGROUND: Ultra-high dose rate radiation (UHDR) is being explored by researchers in promise of advancing radiation therapy treatments. PURPOSE: This work presents the commissioning of Varian's Flash Extension for research (FLEX) conversion of a Clinac to deliver UHDR electrons. METHODS: A Varian Clinac iX with the FLEX conversion was commissioned for non-clinical research use with 16 MeV UHDR (16H) energy. This involved addition of new hardware, optimizing the electron gun voltages, radiofrequency (RF) power, and steering coils in order to maximize the accelerated electron beam current, sending the beam through custom scattering foils to produce the UHDR with 16H beam. Profiles and percent depth dose (PDD) measurements for 16H were obtained using radiochromic film in a custom vertical film holder and were compared to 16 MeV conventional electrons (16C). Dose rate and dose per pulse (DPP) were calculated from measured dose in film. Linearity and stability were assessed using an Advanced Markus ionization chamber. RESULTS: Energies for 16H and 16C had similar beam quality based on PDD measurements. Measurements at the head of the machine (61.3 cm SSD) with jaws set to 10×10 cm2 showed the FWHM of the profile as 7.2 cm, with 3.4 Gy as the maximum DPP and instantaneous dose rate of 8.1E5 Gy/s. Measurements at 100 cm SSD with 10 cm standard cone showed the full width at half max (FWHM) of the profile as 10.5 cm, 1.08 Gy as the maximum DPP and instantaneous dose rate of 2.E5 Gy/s. Machine output with number of pulses was linear (R = 1) from 1 to 99 delivered pulses. Output stability was measured within ±1% within the same session and within ±2% for daily variations. CONCLUSIONS: The FLEX conversion of the Clinac is able to generate UHDR electron beams which are reproducible with beam properties similar to clinically used electrons at 16 MeV. Having a platform which can quickly transition between UHDR and conventional modes (<1 min) can be advantageous for future research applications.

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma.

Background: A randomized, phase II, placebo-controlled, and blinded clinical trial (NCT01062425) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, versus placebo in combination with radiation and temozolomide in newly diagnosed glioblastoma. Methods: Patients with newly diagnosed glioblastoma were randomly assigned 2:1 to receive (1) cediranib (20 mg) in combination with radiation and temozolomide; (2) placebo in combination with radiation and temozolomide. The primary endpoint was 6-month progression-free survival (PFS) based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted MRI brain scans and was tested using a 1-sided Z test for 2 proportions. Adverse events (AEs) were evaluated per CTCAE version 4. Results: One hundred and fifty-eight patients were randomized, out of which 9 were ineligible and 12 were not evaluable for the primary endpoint, leaving 137 eligible and evaluable. 6-month PFS was 46.6% in the cediranib arm versus 24.5% in the placebo arm (P = .005). There was no significant difference in overall survival between the 2 arms. There was more grade ≥ 3 AEs in the cediranib arm than in the placebo arm (P = .02). Conclusions: This study met its primary endpoint of prolongation of 6-month PFS with cediranib in combination with radiation and temozolomide versus placebo in combination with radiation and temozolomide. There was no difference in overall survival between the 2 arms.

Vertebral Compression Fracture After Spine Stereotactic Body Radiotherapy: The Role of Vertebral Endplate Disruption.

BACKGROUND AND OBJECTIVES: Vertebral compression fracture (VCF) is a common, but serious toxicity of spinal stereotactic body radiotherapy (SBRT). Several variables that place patients at high risk of VCF have previously been identified, including advanced Spinal Instability Neoplastic Score (SINS), a widely adopted clinical decision criterion to assess spinal instability. We examine the role of tumoral endplate (EP) disruption in the risk of VCF and attempt to incorporate it into a simple risk stratification system. METHODS: This study was a retrospective cohort study from a single institution. Demographic and treatment information was collected for patients who received spinal SBRT between 2013 and 2019. EP disruption was noted on pre-SBRT computed tomography scan. The primary end point of 1-year cumulative incidence of VCF was assessed on follow-up MRI and computed tomography scans at 3-month intervals after treatment. RESULTS: A total of 111 patients were included. The median follow-up was 18 months. Approximately 48 patients (43%) had at least one EP disruption. Twenty patients (18%) experienced a VCF at a median of 5.2 months from SBRT. Patients with at least one EP disruption were more likely to experience VCF than those with no EP disruption (29% vs 6%, P < .001). A nomogram was created using the variables of EP disruption, a SINS of ≥7, and adverse histology. Patients were stratified into groups at low and high risk of VCF, which were associated with 2% and 38% risk of VCF (P < .001). CONCLUSION: EP disruption is a novel risk factor for VCF in patients who will undergo spinal SBRT. A simple nomogram incorporating EP disruption, adverse histology, and SINS score is effective for quickly assessing risk of VCF. These data require validation in prospective studies and could be helpful in counseling patients regarding VCF risk and referring for prophylactic interventions in high-risk populations.

TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways.

GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.

SREBP-1 upregulates lipophagy to maintain cholesterol homeostasis in brain tumor cells.

Cholesterol is a structural component of cell membranes. How rapidly growing tumor cells maintain membrane cholesterol homeostasis is poorly understood. Here, we found that glioblastoma (GBM), the most lethal brain tumor, maintains normal levels of membrane cholesterol but with an abundant presence of cholesteryl esters (CEs) in its lipid droplets (LDs). Mechanistically, SREBP-1 (sterol regulatory element-binding protein 1), a master transcription factor that is activated upon cholesterol depletion, upregulates critical autophagic genes, including ATG9B, ATG4A, and LC3B, as well as lysosome cholesterol transporter NPC2. This upregulation promotes LD lipophagy, resulting in the hydrolysis of CEs and the liberation of cholesterol from the lysosomes, thus maintaining plasma membrane cholesterol homeostasis. When this pathway is blocked, GBM cells become quite sensitive to cholesterol deficiency with poor growth in vitro. Our study unravels an SREBP-1-autophagy-LD-CE hydrolysis pathway that plays an important role in maintaining membrane cholesterol homeostasis while providing a potential therapeutic avenue for GBM.

Association of partial T2-FLAIR mismatch sign and isocitrate dehydrogenase mutation in WHO grade 4 gliomas: results from the ReSPOND consortium.

PURPOSE: While the T2-FLAIR mismatch sign is highly specific for isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted astrocytomas among lower-grade gliomas, its utility in WHO grade 4 gliomas is not well-studied. We derived the partial T2-FLAIR mismatch sign as an imaging biomarker for IDH mutation in WHO grade 4 gliomas. METHODS: Preoperative MRI scans of adult WHO grade 4 glioma patients (n = 2165) from the multi-institutional ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium were analyzed. Diagnostic performance of the partial T2-FLAIR mismatch sign was evaluated. Subset analyses were performed to assess associations of imaging markers with overall survival (OS). RESULTS: One hundred twenty-one (5.6%) of 2165 grade 4 gliomas were IDH-mutant. Partial T2-FLAIR mismatch was present in 40 (1.8%) cases, 32 of which were IDH-mutant, yielding 26.4% sensitivity, 99.6% specificity, 80.0% positive predictive value, and 95.8% negative predictive value. Multivariate logistic regression demonstrated IDH mutation was significantly associated with partial T2-FLAIR mismatch (odds ratio [OR] 5.715, 95% CI [1.896, 17.221], p = 0.002), younger age (OR 0.911 [0.895, 0.927], p < 0.001), tumor centered in frontal lobe (OR 3.842, [2.361, 6.251], p < 0.001), absence of multicentricity (OR 0.173, [0.049, 0.612], p = 0.007), and presence of cystic (OR 6.596, [3.023, 14.391], p < 0.001) or non-enhancing solid components (OR 6.069, [3.371, 10.928], p < 0.001). Multivariate Cox analysis demonstrated cystic components (p = 0.024) and non-enhancing solid components (p = 0.003) were associated with longer OS, while older age (p < 0.001), frontal lobe center (p = 0.008), multifocality (p < 0.001), and multicentricity (p < 0.001) were associated with shorter OS. CONCLUSION: Partial T2-FLAIR mismatch sign is highly specific for IDH mutation in WHO grade 4 gliomas.

Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas.

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.

Comparison of Gonadal Toxicity of Single-Fraction Ultra-High Dose Rate and Conventional Radiation in Mice.

Purpose: Increasing evidence suggests that ultra-high-dose-rate (UHDR) radiation could result in similar tumor control as conventional (CONV) radiation therapy (RT) while reducing toxicity to surrounding healthy tissues. Considering that radiation toxicity to gonadal tissues can cause hormone disturbances and infertility in young patients with cancer, the purpose of this study was to assess the possible role of UHDR-RT in reducing toxicity to healthy gonads in mice compared with CONV-RT. Methods and Materials: Radiation was delivered to the abdomen or pelvis of female (8 or 16 Gy) and male (5 Gy) C57BL/6J mice, respectively, at conventional (∼0.4 Gy/s) or ultrahigh (>100 Gy/s) dose rates using an IntraOp Mobetron linear accelerator. Organ weights along with histopathology and immunostaining of irradiated gonads were used to compare toxicity between radiation modalities. Results: CONV-RT and UHDR-RT induced a similar decrease in uterine weights at both studied doses (∼50% of controls), which indicated similarly reduced ovarian follicular activity. Histologically, ovaries of CONV- and UHDR-irradiated mice exhibited a comparable lack of follicles. Weights of CONV- and UHDR-irradiated testes were reduced to ∼30% of controls, and the percentage of degenerate seminiferous tubules was also similar between radiation modalities (∼80% above controls). Pairwise comparisons of all quantitative data indicated statistical significance between irradiated (CONV or UHDR) and control groups (from P ≤ .01 to P ≤ .0001) but not between radiation modalities. Conclusions: The data presented here suggest that the short-term effects of UHDR-RT on the mouse gonads are comparable to those of CONV-RT.

Neoadjuvant Arterial Embolization of Spine Metastases Associated With Improved Local Control in Patients Receiving Surgical Decompression and Stereotactic Body Radiotherapy.

BACKGROUND: Spine metastases often cause significant pain, instability, and/or neurological morbidity. Local control (LC) of spine metastases has been augmented with advances in systemic therapies, radiation, and surgical technique. Prior reports suggest an association between preoperative arterial embolization and improved LC and palliative pain control. OBJECTIVE: To further elucidate the role of neoadjuvant embolization on LC of spine metastases and the potential for improved pain control in patients receiving surgery and stereotactic body radiotherapy (SBRT). METHOD: A retrospective single-center review between 2012 and 2020 identified 117 patients with spinal metastases from various solid tumor malignancies managed with surgery and adjuvant SBRT with or without preoperative spinal arterial embolization. Demographic information, radiographic studies, treatment characteristics, Karnofsky Performance Score, Defensive Veterans Pain Rating Scale, and mean daily doses of analgesic medications were reviewed. LC was assessed using magnetic resonance imaging obtained at a median 3-month interval and defined as progression at the surgically treated vertebral level. RESULTS: Of 117 patients, 47 (40.2%) underwent preoperative embolization, followed by surgery and SBRT and 70 (59.8%) underwent surgery and SBRT alone. Within the embolization cohort, the median LC was 14.2 months compared with 6.3 months among the nonembolization cohort ( P = .0434). Receiver operating characteristic analysis suggests ≥82.5% embolization predicted significantly improved LC (area under the curve = 0.808; P < .0001). Defensive Veterans Pain Rating Scale mean and maximum scores significantly decreased immediately after embolization ( P < .001). CONCLUSION: Preoperative embolization was associated with improved LC and pain control suggesting a novel role for its use. Additional prospective study is warranted.

Caregiver survey in glioblastoma focused on cognitive dysfunction: development and results from a multicenter study.

Aim: To develop a cognitive dysfunction (CD) focused questionnaire to evaluate caregiver burden in glioblastoma. Materials & methods: The survey was developed from stakeholder consultations and a pilot study, and disseminated at eight US academic cancer centers. Caregivers self-reported caring for an adult with glioblastoma and CD. Results: The 89-item survey covered demographics, CD symptoms and caregiver burden domains. Among 185 caregivers, most were white, educated females and reported memory problems as the most common CD symptom. An exposure-effect was observed, with increase in number of CD symptoms significantly associated with greater caregiver burden. Conclusion: This questionnaire could guide caregiver interventions and be adapted for use longitudinally, in community cancer settings, and in patients with brain metastases.

Glioblastoma (GBM) is a very aggressive brain cancer. People who have GBM have trouble remembering things and are unable to do things they used to do. These changes can be very hard. Researchers are trying to better understand what it is like for people who take care of people with GBM (or caregivers). In this study, researchers created a new survey for caregivers. The survey included questions about what caregivers see happening in their loved one with GBM. Caregivers said that memory problems were common. Also, when the patient had more problems the caregiver had a harder time, too. Researchers hope to improve the survey and use it in the future for more studies.

Exposure to radon and heavy particulate pollution and incidence of brain tumors.

BACKGROUND: Global incidence for brain tumors varies substantially without explanation. Studies correlating radon exposure and incidence are inconclusive. Particulate pollution has been linked to increased tumor incidence. Particulates may disrupt the blood-brain barrier allowing intracranial exposure to oncogenic radon. We investigated the relationship between exposure to residential radon, particulate pollution, and brain tumor incidence in the United States (US). METHODS: County-level median radon testing results and annual air quality index values were obtained and divided into tertiles. Counties without both values were excluded. Four groups of counties were generated: high particulate/high radon (high/high), high/low, low/high, and low/low. Using incidence data from the Central Brain Tumor Registry of the US (provided by CDC's National Program of Cancer Registries and NCI's SEER), annual age-adjusted incidence rates (AAAIRs) by group were generated by behavior. Incidence rate ratios were calculated to examine for significant differences (α = .05). Poisson regression accounting for possible confounders was conducted. RESULTS: Counties with available data included 83% of the US population. High/high exposure was significantly associated with increased AAAIR of all non-malignant tumors (up to 26% higher, including most meningiomas) even after accounting for potential confounders. An increased AAAIR was noted for all malignant tumors (up to 10% higher), including glioblastoma, but was negated after accounting for demographic/socioeconomic differences. CONCLUSIONS: We present the first report suggesting increased non-malignant brain tumor incidence in regions with high particulate and radon exposure. These findings provide insight into unexplained variation in tumor incidence. Future studies are needed to validate these findings in other populations.

Safety of Nivolumab Added to Chemoradiation Therapy Platforms for Intermediate and High-Risk Locoregionally Advanced Head and Neck Squamous Cell Carcinoma: RTOG Foundation 3504.

PURPOSE: Programmed death-1 immune checkpoint blockade improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed patients with HNSCC remain unknown. METHODS AND MATERIALS: We evaluated the safety of nivolumab concomitant with 70 Gy intensity modulated radiation therapy and weekly cisplatin (arm 1), every 3-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4) in newly diagnosed intermediate- or high-risk locoregionally advanced HNSCC. Patients received nivolumab from 2 weeks prior to radiation therapy until 3 months post-radiation therapy. The primary endpoint was dose-limiting toxicity (DLT). If ≤2 of the first 8 evaluable patients experienced a DLT, an arm was considered safe. Secondary endpoints included toxicity and feasibility of adjuvant nivolumab to 1 year, defined as all 7 additional doses received by ≥4 of the first 8 evaluable patients across arms. RESULTS: Of 39 patients (10 in arms 1, 3, 4 and 9 in arm 2), 72% had T3-4 tumors, 85% had N2-3 nodal disease, and 67% had >10 pack-years of smoking. There were no DLTs in arms 1 and 2, 1 in arm 3 (mucositis), and 2 in arm 4 (lipase elevation and mucositis in 1 and fatigue in another). The most common grade ≥3 nivolumab-related adverse events were lipase increase, mucositis, diarrhea, lymphopenia, hyponatremia, leukopenia, fatigue, and serum amylase increase. Adjuvant nivolumab was feasible as defined in the protocol. CONCLUSIONS: Concomitant nivolumab with the 4 tested regimens was safe for patients with intermediate- and high-risk HNSCC, and subsequent adjuvant nivolumab was feasible as defined (NCT02764593).

Stereotactic Radiosurgery for Women Older than 65 with Breast Cancer Brain Metastases.

BACKGROUND: Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of older breast cancer patients ≥65 years old with BM compared to younger patients at our institution. METHODS: An IRB-approved single-institutional retrospective review of biopsy-proven breast cancer patients with BM treated with 1- to 5-fraction stereotactic radiation therapy (SRS) from 2015 to 2020 was performed. Primary endpoint was intracranial progression-free survival (PFS) defined as the time interval between the end of SRS to the date of the first CNS progression. Secondary endpoints were overall survival (OS) from the end of SRS and radiation treatment patterns. Kaplan-Meier estimates and Cox proportional hazard regression method were used for survival analyses. RESULTS: A total of 112 metastatic breast cancer patients with BMs were included of which 24 were ≥65 years old and 88 were <65 years old. Median age at RT was 72 years (range 65-84) compared to 52 years (31-64) in younger patients. There were significantly higher number of older women with ER/PR positive disease (75% vs. 49%, p = 0.036), while younger patients were more frequently triple negative (32% vs. 12%, p = 0.074) and HER2 positive (42% vs. 29%, p = 0.3). Treatment-related adverse events were similar in both groups. Overall, 14.3% patients had any grade radiation necrosis (RN) (older vs. young: 8.3% vs. 16%, p = 0.5) while 5.4% had grade 3 or higher RN (0% vs. 6.8%, p = 0.7). Median OS after RT was poorer in older patients compared to younger patients (9.5 months vs. 14.5 months, p = 0.037), while intracranial PFS from RT was similar between the two groups (9.7 months vs. 7.1 months, p = 0.580). On univariate analysis, significant predictors of OS were age ≥65 years old (hazard risk, HR = 1.70, p = 0.048), KPS ≤ 80 (HR = 2.24, p < 0.001), HER2 positive disease (HR = 0.46, p < 0.001), isolated CNS metastatic disease (HR = 0.29, p < 0.001), number of brain metastases treated with RT (HR = 1.06, p = 0.028), and fractionated SRS (HR = 0.53, p = 0.013). On multivariable analysis, KPS ≤ 80, HER2 negativity and higher number of brain metastases predicted for poorer survival, while age was not a significant factor for OS after adjusting for other variables. Patients who received systemic therapy after SRS had a significantly improved OS on univariate and multivariable analysis (HR = 0.32, p < 0.001). Number of brain metastases treated was the only factor predictive of worse PFS (HR = 1.06, p = 0.041), which implies a 6% additive risk of progression for every additional metastasis treated. CONCLUSIONS: Although older women had poorer OS than younger women, OS was similar after adjusting for KPS, extracranial progression, and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths, and LMD in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and that outcomes for breast cancer patients with BMs and personalized decision-making including other clinical factors should be considered. Future studies are warranted to assess neurocognitive outcomes and other radiation treatment toxicities in older patients.

Feasibility, safety, and efficacy of circumferential spine stereotactic body radiotherapy.

Background: With advances in systemic therapy translating to improved survival in metastatic malignancies, spine metastases have become an increasingly common source of morbidity. Achieving durable local control (LC) for patients with circumferential epidural disease can be particularly challenging. Circumferential stereotactic body radiotherapy (SBRT) may offer improved LC for circumferential vertebral and/or epidural metastatic spinal disease, but prospective (and retrospective) data are extremely limited. We sought to evaluate the feasibility, toxicity, and cancer control outcomes with this novel approach to circumferential spinal disease. Methods: We retrospectively identified all circumferential SBRT courses delivered between 2013 and 2019 at a tertiary care institution for post-operative or intact spine metastases. Radiotherapy was delivered to 14-27.5 Gy in one to five fractions. Feasibility was assessed by determining the proportion of plans for which ≥95% planning target volume (PTV) was coverable by ≥95% prescription dose. The primary endpoint was 1-year LC. Factors associated with increased likelihood of local failure (LF) were explored. Acute and chronic toxicity were assessed. Detailed dosimetric data were collected. Results: Fifty-eight patients receiving 64 circumferential SBRT courses were identified (median age 61, KPS ≥70, 57% men). With a median follow-up of 15 months, the 12-month local control was 85% (eight events). Five and three recurrences were in the epidural space and bone, respectively. On multivariate analysis, increased PTV and uncontrolled systemic disease were significantly associated with an increased likelihood of LF; ≥95% PTV was covered by ≥95% prescription dose in 94% of the cases. The rate of new or progressive vertebral compression fracture was 8%. There were no myelitis events or any grade 3+ acute or late toxicities. Conclusions: For patients with circumferential disease, circumferential spine SBRT is feasible and may offer excellent LC without significant toxicity. A prospective evaluation of this approach is warranted.