Improved Dosimetry and Plan Quality for Accelerated Partial Breast Irradiation Using Online Adaptive Radiation Therapy: A Single Institutional Study.

Purpose: Accelerated partial breast irradiation (APBI) is an attractive treatment modality for eligible patients as it has been shown to result in similar local control and improved cosmetic outcomes compared with whole breast radiation therapy. The use of online adaptive radiation therapy (OART) for APBI is promising as it allows for a reduction of planning target volume margins because breast motion and lumpectomy cavity volume changes are accounted for in daily imaging. Here we present a retrospective, single-institution evaluation on the adequacy of kV-cone beam computed tomography (CBCT) OART for APBI treatments. Methods and Materials: Nineteen patients (21 treatment sites) were treated to 30 Gy in 5 fractions between January of 2022 and May of 2023. Time between simulation and treatment, change in gross tumor (ie, lumpectomy cavity) volume, and differences in dose volume histogram metrics with adaption were analyzed. The Wilcoxon paired, nonparametric test was used to test for dose volume histogram metric differences between the scheduled plans (initial plans recalculated on daily CBCT anatomy) and delivered plans, either the scheduled or adapted plan, which was reoptimized using daily anatomy. Results: Median (interquartile range) time from simulation to first treatment was 26 days (21-32 days). During this same time, median gross tumor volume reduction was 16.0% (7.3%-23.9%) relative to simulation volume. Adaptive treatments took 31.3 minutes (27.4-36.6 minutes) from start of CBCT to treatment session end. At treatment, the adaptive plan was selected for 86% (89/103) of evaluable fractions. In evaluating plan quality, 78% of delivered plans met all target, organs at risk, and conformity metrics evaluated, compared with 34% of scheduled plans. Conclusions: Use of OART for stereotactic linac-based APBI allowed for safe, high-quality treatments in this cohort of 21 treatment courses. Although treatment delivery times were longer than traditional stereotactic body treatments, there were notable improvements in plan quality for APBI using OART.

Single-cell sequencing reveals the landscape of the human brain metastatic microenvironment.

Brain metastases is the most common intracranial tumor and account for approximately 20% of all systematic cancer cases. It is a leading cause of death in advanced-stage cancer, resulting in a five-year overall survival rate below 10%. Therefore, there is a critical need to identify effective biomarkers that can support frequent surveillance and promote efficient drug guidance in brain metastasis. Recently, the remarkable breakthroughs in single-cell RNA-sequencing (scRNA-seq) technology have advanced our insights into the tumor microenvironment (TME) at single-cell resolution, which offers the potential to unravel the metastasis-related cellular crosstalk and provides the potential for improving therapeutic effects mediated by multifaceted cellular interactions within TME. In this study, we have applied scRNA-seq and profiled 10,896 cells collected from five brain tumor tissue samples originating from breast and lung cancers. Our analysis reveals the presence of various intratumoral components, including tumor cells, fibroblasts, myeloid cells, stromal cells expressing neural stem cell markers, as well as minor populations of oligodendrocytes and T cells. Interestingly, distinct cellular compositions are observed across different samples, indicating the influence of diverse cellular interactions on the infiltration patterns within the TME. Importantly, we identify tumor-associated fibroblasts in both our in-house dataset and external scRNA-seq datasets. These fibroblasts exhibit high expression of type I collagen genes, dominate cell-cell interactions within the TME via the type I collagen signaling axis, and facilitate the remodeling of the TME to a collagen-I-rich extracellular matrix similar to the original TME at primary sites. Additionally, we observe M1 activation in native microglial cells and infiltrated macrophages, which may contribute to a proinflammatory TME and the upregulation of collagen type I expression in fibroblasts. Furthermore, tumor cell-specific receptors exhibit a significant association with patient survival in both brain metastasis and native glioblastoma cases. Taken together, our comprehensive analyses identify type I collagen-secreting tumor-associated fibroblasts as key mediators in metastatic brain tumors and uncover tumor receptors that are potentially associated with patient survival. These discoveries provide potential biomarkers for effective therapeutic targets and intervention strategies.

Benchmarking Automated Machine Learning-Enhanced Planning With Ethos Against Manual and Knowledge-Based Planning for Locally Advanced Lung Cancer.

Purpose: Currently, there is insufficient guidance for standard fractionation lung planning using the Varian Ethos adaptive treatment planning system and its unique intelligent optimization engine. Here, we address this gap in knowledge by developing a methodology to automatically generate high-quality Ethos treatment plans for locally advanced lung cancer. Methods and Materials: Fifty patients previously treated with manually generated Eclipse plans for inoperable stage IIIA-IIIC non-small cell lung cancer were included in this institutional review board-approved retrospective study. Fifteen patient plans were used to iteratively optimize a planning template for the Daily Adaptive vs Non-Adaptive External Beam Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Trial of an Individualized Approach for Toxicity Reduction (ARTIA-Lung); the remaining 35 patients were automatically replanned without intervention. Ethos plan quality was benchmarked against clinical plans and reoptimized knowledge-based RapidPlan (RP) plans, then judged using standard dose-volume histogram metrics, adherence to clinical trial objectives, and qualitative review. Results: Given equal prescription target coverage, Ethos-generated plans showed improved primary and nodal planning target volume V95% coverage (P < .001) and reduced lung gross tumor volume V5 Gy and esophagus D0.03 cc metrics (P ≤ .003) but increased mean esophagus and brachial plexus D0.03 cc metrics (P < .001) compared with RP plans. Eighty percent, 49%, and 51% of Ethos, clinical, and RP plans, respectively, were "per protocol" or met "variation acceptable" ARTIA-Lung planning metrics. Three radiation oncologists qualitatively scored Ethos plans, and 78% of plans were clinically acceptable to all reviewing physicians, with no plans receiving scores requiring major changes. Conclusions: A standard Ethos template produced lung radiation therapy plans with similar quality to RP plans, elucidating a viable approach for automated plan generation in the Ethos adaptive workspace.

Improving Communication of Peer-Review Conference Outcomes: A Practical Experience.

Purpose: The aim of this work was to describe the design and implementation of a more robust workflow for communicating outcomes from a peer-review chart rounds conference. We also provide information regarding cycle times, plan revisions, and other key metrics that we have observed since initial implementation. Methods and Materials: A multidisciplinary team of stakeholders including physicians, physicists, and dosimetrists developed a revised peer-review workflow that addressed key needs to improve the prior process. Consensus terminology was developed to reduce ambiguity regarding the priority of peer-review outcomes and to clarify expectations of the treating physician in response to peer-review outcomes. A custom workflow software tool was developed to facilitate both upstream and downstream processes from the chart rounds conference. The peer-review outcomes of the chart rounds conference and resulting plan changes for the first 18 months of implementation were summarized. Results: In the first 18 months after implementation of the revised processes, 2294 plans were reviewed, and feedback priority levels assigned. Across all cases with feedback, the median time for the treating attending physician to acknowledge conference comments was 1 day and was within 7 calendar days for 89.1% of cases. Conference feedback was acknowledged within 1 day for 74 of 115 (64.3%) cases with level 2 comments and for 18 of 21 (85.7%) cases with level 3 comments (P = .054). Contours were modified in 13 of 116 (11%) cases receiving level 2 feedback and 10 of 21 (48%) cases receiving level 3 feedback (P < .001). The treatment plan was revised in 18 of 116 (16%) cases receiving level 2 feedback and 13 of 21 (61%) cases receiving level 3 feedback (P < .001). Conclusions: We successfully implemented a workflow to improve upstream and downstream processes for a chart rounds conference. Standardizing how peer-review outcomes were communicated and recording physician responses allow for improved ability to monitor conference activities.

A roadmap for implementation of kV-CBCT online adaptive radiation therapy and initial first year experiences.

PURPOSE: Online Adaptive Radiation Therapy (oART) follows a different treatment paradigm than conventional radiotherapy, and because of this, the resources, implementation, and workflows needed are unique. The purpose of this report is to outline our institution's experience establishing, organizing, and implementing an oART program using the Ethos therapy system. METHODS: We include resources used, operational models utilized, program creation timelines, and our institutional experiences with the implementation and operation of an oART program. Additionally, we provide a detailed summary of our first year's clinical experience where we delivered over 1000 daily adaptive fractions. For all treatments, the different stages of online adaption, primary patient set-up, initial kV-CBCT acquisition, contouring review and edit of influencer structures, target review and edits, plan evaluation and selection, Mobius3D 2nd check and adaptive QA, 2nd kV-CBCT for positional verification, treatment delivery, and patient leaving the room, were analyzed. RESULTS: We retrospectively analyzed data from 97 patients treated from August 2021-August 2022. One thousand six hundred seventy seven individual fractions were treated and analyzed, 632(38%) were non-adaptive and 1045(62%) were adaptive. Seventy four of the 97 patients (76%) were treated with standard fractionation and 23 (24%) received stereotactic treatments. For the adaptive treatments, the generated adaptive plan was selected in 92% of treatments. On average(±std), adaptive sessions took 34.52 ± 11.42 min from start to finish. The entire adaptive process (from start of contour generation to verification CBCT), performed by the physicist (and physician on select days), was 19.84 ± 8.21 min. CONCLUSION: We present our institution's experience commissioning an oART program using the Ethos therapy system. It took us 12 months from project inception to the treatment of our first patient and 12 months to treat 1000 adaptive fractions. Retrospective analysis of delivered fractions showed that the average overall treatment time was approximately 35 min and the average time for the adaptive component of treatment was approximately 20 min.

Leveraging intelligent optimization for automated, cardiac-sparing accelerated partial breast treatment planning.

Background: Accelerated partial breast irradiation (APBI) yields similar rates of recurrence and cosmetic outcomes as compared to whole breast radiation therapy (RT) when patients and treatment techniques are appropriately selected. APBI combined with stereotactic body radiation therapy (SBRT) is a promising technique for precisely delivering high levels of radiation while avoiding uninvolved breast tissue. Here we investigate the feasibility of automatically generating high quality APBI plans in the Ethos adaptive workspace with a specific emphasis on sparing the heart. Methods: Nine patients (10 target volumes) were utilized to iteratively tune an Ethos APBI planning template for automatic plan generation. Twenty patients previously treated on a TrueBeam Edge accelerator were then automatically replanned using this template without manual intervention or reoptimization. The unbiased validation cohort Ethos plans were benchmarked via adherence to planning objectives, a comparison of DVH and quality indices against the clinical Edge plans, and qualitative reviews by two board-certified radiation oncologists. Results: 85% (17/20) of automated validation cohort plans met all planning objectives; three plans did not achieve the contralateral lung V1.5Gy objective, but all other objectives were achieved. Compared to the Eclipse generated plans, the proposed Ethos template generated plans with greater evaluation planning target volume (PTV_Eval) V100% coverage (p = 0.01), significantly decreased heart V1.5Gy (p< 0.001), and increased contralateral breast V5Gy, skin D0.01cc, and RTOG conformity index (p = 0.03, p = 0.03, and p = 0.01, respectively). However, only the reduction in heart dose was significant after correcting for multiple testing. Physicist-selected plans were deemed clinically acceptable without modification for 75% and 90% of plans by physicians A and B, respectively. Physicians A and B scored at least one automatically generated plan as clinically acceptable for 100% and 95% of planning intents, respectively. Conclusions: Standard left- and right-sided planning templates automatically generated APBI plans of comparable quality to manually generated plans treated on a stereotactic linear accelerator, with a significant reduction in heart dose compared to Eclipse generated plans. The methods presented in this work elucidate an approach for generating automated, cardiac-sparing APBI treatment plans for daily adaptive RT with high efficiency.

Collagen deposition within brain metastases is associated with leptomeningeal failure after cavity-directed radiosurgery.

Background: Leptomeningeal failure (LMF) represents a devastating progression of disease following resection of brain metastases (BrM). We sought to identify a biomarker at time of BrM resection that predicts for LMF using mass spectrometry-based proteomic analysis of resected BrM and to translate this finding with histochemical assays. Methods: We retrospectively reviewed 39 patients with proteomic data available from resected BrM. We performed an unsupervised analysis with false discovery rate adjustment (FDR) to compare proteomic signature of BrM from patients that developed LMF versus those that did not. Based on proteomic analysis, we applied trichrome stain to a total of 55 patients who specifically underwent resection and adjuvant radiosurgery. We used competing risks regression to assess predictors of LMF. Results: Of 39 patients with proteomic data, FDR revealed type I collagen-alpha-1 (COL1A1, P = .045) was associated with LMF. The degree of trichrome stain in each block correlated with COL1A1 expression (ß = 1.849, P = .001). In a cohort of 55 patients, a higher degree of trichrome staining was associated with an increased hazard of LMF in resected BrM (Hazard Ratio 1.58, 95% CI 1.11-2.26, P = .01). Conclusion: The degree of trichrome staining correlated with COL1A1 and portended a higher risk of LMF in patients with resected brain metastases treated with adjuvant radiosurgery. Collagen deposition and degree of fibrosis may be able to serve as a biomarker for LMF.

Efficacy and Survival after Palliative Radiotherapy for Malignant Pulmonary Obstruction.

Introduction: The purpose of this study was to determine the efficacy of palliative radiotherapy (PRT) for patients with pulmonary obstruction from advanced malignancy and identify factors associated with lung re-expansion and survival. Materials and Methods: We reviewed all patients treated with PRT for malignant pulmonary obstruction (n = 108) at our institution between 2010 and 2018. Radiographic evidence of lung re-expansion was determined through review of follow-up CT or chest X-ray. Cumulative incidence of re-expansion and overall survival (OS) were estimated using competing risk methodology. Clinical characteristics were evaluated for association with re-expansion, OS, and early mortality. Treatment time to remaining life ratio (TT:RL) was evaluated as a novel metric for palliative treatment. Results: Eighty-one percent of patients had collapse of an entire lung lobe, 46% had Eastern Cooperative Oncology Group (ECOG) performance status 3-4, and 64% were inpatient at consultation. Eighty-four patients had follow-up imaging available, and 25 (23%) of all patients had lung re-expansion at median time of 35 days. Rates of death without re-expansion were 38% and 65% at 30 and 90 days, respectively. Median OS was 56 days. Death within 30 days of PRT occurred in 38%. Inpatients and larger tumors trended toward lower rates of re-expansion. Notable factors associated with OS were re-expansion, nonlung histology, tumor size, and performance status. Median TT:RL was 0.11 and significantly higher for subgroups: ECOG 3-4 (0.19), inpatients (0.16), patients with larger tumors (0.14), those unfit for systemic therapy (0.17), and with 10-fraction PRT (0.14). Conclusion: One-fourth of patients experienced re-expansion after PRT for malignant pulmonary obstruction. Survival is poor and a significant proportion of remaining life may be spent on treatment. Careful consideration of these clinical factors is recommended when considering PRT fractionation.

Bloom where you are planted: Hemangioma or malignancy?

Vascular anomalies comprise a spectrum of disorders characterized by the abnormal development or growth of blood and lymphatic vessels. These growths have unique features and diverse behaviors, mandating a multidisciplinary approach in their evaluation, diagnosis, and management. Here we describe the case of a male toddler presenting with an abdominal mass, originally treated as a metastatic retroperitoneal tumor, but subsequently felt to represent a vascular anomaly.

Multiparametric radiomic tissue signature and machine learning for distinguishing radiation necrosis from tumor progression after stereotactic radiosurgery.

BACKGROUND: Stereotactic radiosurgery (SRS) may cause radiation necrosis (RN) that is difficult to distinguish from tumor progression (TP) by conventional MRI. We hypothesize that MRI-based multiparametric radiomics (mpRad) and machine learning (ML) can differentiate TP from RN in a multi-institutional cohort. METHODS: Patients with growing brain metastases after SRS at 2 institutions underwent surgery, and RN or TP were confirmed by histopathology. A radiomic tissue signature (RTS) was selected from mpRad, as well as single T1 post-contrast (T1c) and T2 fluid-attenuated inversion recovery (T2-FLAIR) radiomic features. Feature selection and supervised ML were performed in a randomly selected training cohort (N = 95) and validated in the remaining cases (N = 40) using surgical pathology as the gold standard. RESULTS: One hundred and thirty-five discrete lesions (37 RN, 98 TP) from 109 patients were included. Radiographic diagnoses by an experienced neuroradiologist were concordant with histopathology in 67% of cases (sensitivity 69%, specificity 59% for TP). Radiomic analysis indicated institutional origin as a significant confounding factor for diagnosis. A random forest model incorporating 1 mpRad, 4 T1c, and 4 T2-FLAIR features had an AUC of 0.77 (95% confidence interval [CI]: 0.66-0.88), sensitivity of 67% and specificity of 86% in the training cohort, and AUC of 0.71 (95% CI: 0.51-0.91), sensitivity of 52% and specificity of 90% in the validation cohort. CONCLUSIONS: MRI-based mpRad and ML can distinguish TP from RN with high specificity, which may facilitate the triage of patients with growing brain metastases after SRS for repeat radiation versus surgical intervention.

Bulk and Single-Cell Profiling of Breast Tumors Identifies TREM-1 as a Dominant Immune Suppressive Marker Associated With Poor Outcomes.

BACKGROUND: Triggering receptor expressed on myeloid cells (TREM)-1 is a key mediator of innate immunity previously associated with the severity of inflammatory disorders, and more recently, the inferior survival of lung and liver cancer patients. Here, we investigated the prognostic impact and immunological correlates of TREM1 expression in breast tumors. METHODS: Breast tumor microarray and RNAseq expression profiles (n=4,364 tumors) were analyzed for associations between gene expression, tumor immune subtypes, distant metastasis-free survival (DMFS) and clinical response to neoadjuvant chemotherapy (NAC). Single-cell (sc)RNAseq was performed using the 10X Genomics platform. Statistical associations were assessed by logistic regression, Cox regression, Kaplan-Meier analysis, Spearman correlation, Student's t-test and Chi-square test. RESULTS: In pre-treatment biopsies, TREM1 and known TREM-1 inducible cytokines (IL1B, IL8) were discovered by a statistical ranking procedure as top genes for which high expression was associated with reduced response to NAC, but only in the context of immunologically "hot" tumors otherwise associated with a high NAC response rate. In surgical specimens, TREM1 expression varied among tumor molecular subtypes, with highest expression in the more aggressive subtypes (Basal-like, HER2-E). High TREM1 significantly and reproducibly associated with inferior distant metastasis-free survival (DMFS), independent of conventional prognostic markers. Notably, the association between high TREM1 and inferior DMFS was most prominent in the subset of immunogenic tumors that exhibited the immunologically hot phenotype and otherwise associated with superior DMFS. Further observations from bulk and single-cell RNAseq analyses indicated that TREM1 expression was significantly enriched in polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and M2-like macrophages, and correlated with downstream transcriptional targets of TREM-1 (IL8, IL-1B, IL6, MCP-1, SPP1, IL1RN, INHBA) which have been previously associated with pro-tumorigenic and immunosuppressive functions. CONCLUSIONS: Together, these findings indicate that increased TREM1 expression is prognostic of inferior breast cancer outcomes and may contribute to myeloid-mediated breast cancer progression and immune suppression.

Stereotactic body radiotherapy for synchronous early stage non-small cell lung cancer.

INTRODUCTION: In patients with non-small cell lung cancer (NSCLC) who present with multiple pulmonary nodules, it is often difficult to distinguish metastatic disease from synchronous primary lung cancers (SPLC). We sought to evaluate clinical outcomes after stereotactic body radiotherapy (SBRT) alone to synchronous primary lesions. MATERIAL AND METHODS: Patients with synchronous AJCC 8th Edition Stage IA-IIA NSCLC and treated with stereotactic body radiation therapy (SBRT) to all lesions between 2009-2018 were reviewed. SPLC was defined as patients having received two courses of SBRT within 180 days for treatment of separate early stage tumors. In total, 36 patients with 73 lesions were included. Overall survival (OS), progression-free survival (PFS), cumulative incidence of local failure (LF), and regional/distant failure (R/DF) were estimated and compared with a control cohort of solitary early stage NSCLC patients. RESULTS: Median PFS was 38.8 months (95% CI 14.3-not reached [NR]); 3-year PFS rates were 50.6% (35.6-72.1). Median OS was 45.9 months (95% CI: 35.9-NR); 3-year OS was 63.0% (47.4-83.8). Three-year cumulative incidence of LF and R/DF was 6.6% (3.7-13.9) and 35.7% (19.3-52.1), respectively. Patients with SPLC were compared to a control group (n = 272) of patients treated for a solitary early stage NSCLC. There was no statistically significant difference in PFS (p = .91) or OS (p = .43). Evaluation of the patterns of failure showed a trend for worse cumulative incidence of R/DF in SPLC patients as compared to solitary early stage NSCLC (p = .06). CONCLUSION: SBRT alone to multiple lung tumors with SPLC results in comparable PFS, OS, and LF rates to a cohort of patients treated for solitary early stage NSCLC. Those with SPLC had non-significantly higher R/DF. Patients with SPLC should be followed closely for failure and possible salvage therapy.

Cisplatin/5-Fluorouracil (5-FU) Versus Carboplatin/Paclitaxel Chemoradiotherapy as Definitive or Pre-Operative Treatment of Esophageal Cancer.

Purpose To determine the efficacy and toxicity of two standard chemotherapy regimens used concurrent with radiation for the treatment of esophageal cancer: cisplatin/5-fluorouracil (5-FU) and carboplatin/paclitaxel. Materials and methods We prospectively reviewed records of 364 patients with histologically confirmed stage I to IVA esophageal cancer receiving chemoradiotherapy (CRT) with or without resection. All patients received surgical evaluation and imaging at presentation as well as following completion of their course of CRT. Treatment and prognostic variables were compared across the two chemotherapy regimens. Results We identified 261 patients treated with concurrent carboplatin/paclitaxel (n = 133) or cisplatin/5-FU (n = 128). Weight loss during CRT was lower in patients receiving carboplatin/paclitaxel (median: 7.0 pounds; 4.1% body weight) vs. cisplatin/5-FU (median: 11.0 pounds; 6.5% body weight) (p < 0.01). In 117 patients receiving trimodality therapy, post-operative death rates within one month of resection were similar. Pathologic complete response was better with carboplatin/paclitaxel vs. cisplatin/5-FU, 29.6% vs. 21.8% (p = 0.03), respectively. In the multivariable analysis, there was no association between chemotherapy regimen and overall survival (OS) or progression-free survival (PFS), though there was a trend toward improved OS with carboplatin/paclitaxel with a HR = 0.75 (p = 0.08). Further analysis revealed that trimodality therapy and stage were predictors for improved OS and PFS while female gender and grade predicted for improved PFS. Conclusions Carboplatin/paclitaxel was associated with decreased weight loss and improved pathologic response for trimodality patients when compared to cisplatin/5-FU. We observed no differences in OS, PFS, or post-operative death by chemotherapy regimen for both the entire cohort and trimodality patients.

Five- Versus Ten-Fraction Regimens of Stereotactic Body Radiation Therapy for Primary and Metastatic NSCLC.

INTRODUCTION: At our institution, stereotactic body radiotherapy (SBRT) has commonly been prescribed with 50 Gy in 5 fractions and in select cases, 50 Gy in 10 fractions. We sought to evaluate the impact of these 2 fractionation schedules on local control and survival outcomes. METHODS: We reviewed patients treated with SBRT with 50 Gy/5 fraction or 50 Gy/10 fraction for early-stage non-small cell lung cancer (NSCLC) and metastatic NSCLC. Cumulative incidence of local failure (LF) was estimated using competing risk methodology. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method only for patients with stage I disease. RESULTS: Of the 353 lesions, 300 (85%) were treated with 50 Gy in 5 fractions and 53 (15%) with 10 fractions. LFs at 3 years were 6.5% and 23.9% and Kaplan-Meier estimate of median time to LF was 17.5 months and 26.2 months, respectively. Multivariable analysis revealed increasing planning target volume (hazard ratio 1.01, P = .04) as an independent predictor of increased LF, but tumor size, ultracentral location, and 10 fractions were not. Among patients with stage I NSCLC (n = 298), overall median PFS was 35.6 months and median OS was 42.4 months. There was no difference in PFS or OS between the 2 treatment regimens for patients with stage I NSCLC. Low rates of grade 3+ toxicity were observed, with 1 patient experiencing grade 3 pneumonitis after a 5-fraction regimen of SBRT. CONCLUSION: Dose-fractionation schemes with BED10 ≥ 100 Gy provide superior local control and should be offered when meeting commonly accepted constraints. If those regimens appear unsafe, 50 Gy in 10 fractions may provide acceptable compromise between tumor control and safety with relatively durable control, and minimal negative impact on long-term survival.

Attenuating hypoxia driven malignant behavior in glioblastoma with a novel hypoxia-inducible factor 2 alpha inhibitor.

Hypoxia inducible factor (HIFs) signaling contributes to malignant cell behavior in glioblastoma (GBM). We investigated a novel HIF2α inhibitor, PT2385, both in vitro, with low-passage patient-derived cell lines, and in vivo, using orthotopic models of glioblastoma. We focused on analysis of HIF2α expression in situ, cell survival/proliferation, and survival in brain tumor-bearing mice treated with PT2385 alone and in combination with standard of care chemoradiotherapy. HIF2α expression increased with glioma grade, with over half of GBM specimens HIF2α positive. Staining clustered in perivascular and perinecrotic tumor regions. Cellular phenotype including proliferation, viability, migration/invasion, and also gene expression were not altered after PT2385 treatment. In the animal model, PT2385 single-agent treatment did improve median overall survival compared to placebo (p = 0.04, n = 21) without a bioluminescence correlate (t = 0.67, p = 0.52). No difference in animal survival was seen in combination treatment with radiation (RT)/temozolomide (TMZ)/PT2385 (p = 0.44, n = 10) or mean tumor bioluminescence (t 1.13, p = 0.32). We conclude that HIF2α is a reasonable novel therapeutic target as expressed in the majority of glioblastomas in our cohort. PT2385 as a single-agent was efficacious in vivo, however, an increase in animal survival was not seen with PT2385 in combination with RT/TMZ. Further study for targeting HIF2α as a therapeutic approach in GBM is warranted.

Impact of brain metastasis velocity on neurologic death for brain metastasis patients experiencing distant brain failure after initial stereotactic radiosurgery.

PURPOSE: Patients with high rates of developing new brain metastases have an increased likelihood of dying of neurologic death. It is unclear, however, whether this risk is affected by treatment choice following failure of primary stereotactic radiosurgery (SRS). METHODS: From July 2000 to March 2017, 440 patients with brain metastasis were treated with SRS and progressed to have a distant brain failure (DBF). Eighty-seven patients were treated within the immunotherapy era. Brain metastasis velocity (BMV) was calculated for each patient. In general, the institutional philosophy for use of salvage SRS vs whole brain radiotherapy (WBRT) was to postpone the use of WBRT for as long as possible and to treat with salvage SRS when feasible. No further treatment was reserved for patients with poor life expectancy and who were not expected to benefit from salvage treatment. RESULTS: Two hundred and eighty-five patients were treated with repeat SRS, 91 patients were treated with salvage WBRT, and 64 patients received no salvage radiation therapy. One-year cumulative incidence of neurologic death after salvage SRS vs WBRT was 15% vs 23% for the low- (p = 0.06), 30% vs 37% for the intermediate- (p < 0.01), and 31% vs 48% (p < 0.01) for the high-BMV group. Salvage WBRT was associated with increased incidence of neurologic death on multivariate analysis (HR 1.64, 95% CI 1.13-2.39, p = 0.01) when compared to repeat SRS. One-year cumulative incidence of neurologic death for patients treated within the immunotherapy era was 9%, 38%, and 38% for low-, intermediate-, and high-BMV groups, respectively (p = 0.01). CONCLUSION: Intermediate and high risk BMV groups are predictive of neurologic death. The association between BMV and neurologic death remains strong for patients treated within the immunotherapy era.

Multi-Omics Analysis of Brain Metastasis Outcomes Following Craniotomy.

BACKGROUND: The incidence of brain metastasis continues to increase as therapeutic strategies have improved for a number of solid tumors. The presence of brain metastasis is associated with worse prognosis but it is unclear if distinctive biomarkers can separate patients at risk for CNS related death. METHODS: We executed a single institution retrospective collection of brain metastasis from patients who were diagnosed with lung, breast, and other primary tumors. The brain metastatic samples were sent for RNA sequencing, proteomic and metabolomic analysis of brain metastasis. The primary outcome was distant brain failure after definitive therapies that included craniotomy resection and radiation to surgical bed. Novel prognostic subtypes were discovered using transcriptomic data and sparse non-negative matrix factorization. RESULTS: We discovered two molecular subtypes showing statistically significant differential prognosis irrespective of tumor subtype. The median survival time of the good and the poor prognostic subtypes were 7.89 and 42.27 months, respectively. Further integrated characterization and analysis of these two distinctive prognostic subtypes using transcriptomic, proteomic, and metabolomic molecular profiles of patients identified key pathways and metabolites. The analysis suggested that immune microenvironment landscape as well as proliferation and migration signaling pathways may be responsible to the observed survival difference. CONCLUSION: A multi-omics approach to characterization of brain metastasis provides an opportunity to identify clinically impactful biomarkers and associated prognostic subtypes and generate provocative integrative understanding of disease.

Multi-institutional validation of brain metastasis velocity, a recently defined predictor of outcomes following stereotactic radiosurgery.

INTRODUCTION: Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radiosurgery (SRS). We have previously risk stratified patients into high, intermediate, and low-risk BMV groups, which correlates with overall survival (OS). We sought to externally validate BMV in a multi-institutional setting. METHODS: Patients from nine academic centers were treated with upfront SRS; the validation cohort consisted of data from eight institutions not previously used to define BMV. Patients were classified by BMV into low (<4 BMV), intermediate (4-13 BMV), and high-risk groups (>13 BMV). Time-to-event outcomes were estimated using the Kaplan-Meier method. Cox proportional hazards methods were used to estimate the effect of BMV and salvage modality on OS. RESULTS: Of 2829 patients, 2092 patients were included in the validation dataset. Of these, 921 (44.0%) experienced distant brain failure (DBF). Median OS from initial SRS was 11.2 mo. Median OS for BMV < 4, BMV 4-13, and BMV > 13 were 12.5 mo, 7.0 mo, and 4.6 mo (p < 0.0001). After multivariate regression modeling, melanoma histology (ß: 10.10, SE: 1.89, p < 0.0001) and number of initial brain metastases (ß: 1.52, SE: 0.34, p < 0.0001) remained predictive of BMV (adjusted R2 = 0.06). CONCLUSIONS: This multi-institutional dataset validates BMV as a predictor of OS following initial SRS. BMV is being utilized in upcoming multi-institutional randomized controlled trials as a stratification variable for salvage whole brain radiation versus salvage SRS after DBF.

Stereotactic body radiotherapy for an isolated splenic metastasis from ovarian carcinoma.

Splenic metastases from oligometastatic ovarian carcinoma are a rare occurrence. Usual treatment for splenic metastases includes splenectomy, but some patients are either unable or unwilling to undergo surgery. Stereotactic body radiotherapy (SBRT) is an effective ablative modality for treating metastatic disease. SBRT to abdominopelvic tumors has been shown to be safe and effective for properly-selected patients and is particularly attractive in the oligometastatic setting as an alternative to radical resection. In this case study, we report a patient with an isolated splenic metastasis from ovarian carcinoma treated with 50 Gy in 10 fractions.