bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRLS-03. PHASE II TRIAL OF GDC-0084 IN COMBINATION WITH TRASTUZUMAB FOR PATIENTS WITH HER2-POSITIVE BREAST CANCER BRAIN METASTASES (BCBM)
Authors: Leone Jose Pablo , Trippa Lorenzo , Milisits Lindsey , Andrews Chelsea , Ligibel Jennifer , Parsons Heather , Bi Wenya , Zhao Jean , Winer Eric , Lin Nancy 
Published: August 2019

Abstract
BACKGROUND: The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. GDC-0084 is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS: This is a single-center, phase II study to evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha &lt; 10%. Cohort B will enroll 10 patients. The trial opened in February, 2019. NCT03765983.
THER-08. BRAIN METASTASES AS A FIRST SITE OF RECURRENCE IN PATIENTS RECEIVING CHEMOTHERAPY WITH CONTROLLED SYSTEMIC CANCER: A CRITICAL BUT UNDER-RECOGNIZED CLINICAL SCENARIO
Authors: O’Connell Kaelin , Romo Carlos , Grossman Stuart 
Published: August 2019

Abstract
BACKGROUND: As the treatment of non-central nervous system (CNS) malignancies has improved, brain metastases (BM) have been observed as a site of first recurrence in patients with controlled or responding systemic cancers. This suggests that while chemotherapy is effective for the systemic disease, drug concentrations in the CNS are likely subtherapeutic. These findings are in accord with data suggesting that over 98% of FDA-approved drugs are unable to penetrate the blood brain barrier (BBB). METHODS: A literature review was conducted to estimate the proportion of patients with non-small lung cancer (NSCLC), breast cancer, and melanoma with controlled systemic cancers who developed BM as initial site of recurrence. Only studies explicitly reporting BM with controlled extra-cranial (EC) disease or reporting the first site of recurrence after chemotherapy were included. RESULTS: Of 262 studies screened,13 contained adequate data regarding the status of systemic cancer and initial site of recurrence. These reported on 1,024 patients. Four studies in patients with NSCLC revealed that 11–43% developed BM as initial site of recurrence. Similar data was seen in patients with breast cancer (6 studies, 4–19%) and metastatic melanoma (3 studies, 4–25%). Approximately 15% of patients on chemotherapy with stable or responding systemic NSCLC, breast cancer, and melanoma developed isolated BM as initial site of relapse. CONCLUSIONS: This literature review included 1,024 patients with common and treatable metastatic cancers whose disease was controlled with chemotherapy. First recurrence in the brain was noted in 23% of those with NSCLC, 12% with breast cancer, and 12% with melanoma. These findings strongly suggest that, while systemic antineoplastic therapy controlled their systemic cancer, concentration of these drugs within the CNS was low, allowing disease progression in the CNS. Reducing the incidence of BM requires novel therapeutic approaches designed to facilitate drug entry through an intact BBB early in treatment.
THER-09. IMPACT OF KRAS MUTATION STATUS ON THE EFFICACY OF IMMUNOTHERAPY IN LUNG CANCER BRAIN METASTASES
Authors: Lauko Adam , Ali Assad , Sagar Soumya , Barnett Addison , Li Hong , Chao Samuel , Pennell Nathan , Stevens Glen , Peereboom David , Yu Jennifer , Murphy Erin , Angelov Lilyana , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet 
Published: August 2019

Abstract
BACKGROUND: Immunotherapy is increasingly used in patients with non-small cell lung cancer brain metastases (NSCLCBM). KRAS mutations are associated with worse prognosis and there is no FDA approved targeted therapy. KRAS mutations are associated with increased expression of PD-L1. We evaluated the outcomes of NSCLCBM with KRAS mutations treated with immune checkpoint inhibitors (ICI). METHODS: We reviewed 800 patients with NSCLCBM treated at our tertiary care center. 226 had known KRAS mutational status, 121 of which received immunotherapy. Overall survival (OS) was calculated from either the start of immunotherapy (when both groups received immunotherapy) or from the date of diagnosis of brain metastasis. Kaplan-Meier method and Cox Proportional hazard model were utilized to determine differences in OS and the Chi-square test was utilized to determine differences in PD-L1 expression. RESULTS: In 109 patients where both KRAS and PD-L1 status were known, KRAS mutations had greater PD-L1 expression (80.1% vs 61.9% positive, p=0.04). There was no difference in OS between KRAS mutant vs KRAS wild-type patients treated with immunotherapy. Median survival from the start of immunotherapy was 15.6 vs 15.5 months respectively (p=0.7), after adjusting for age, KPS, lesion number and extra-cranial metastasis (HR = .91, p=.7). Patients with KRAS mutations treated with immunotherapy versus those who received chemotherapy had a 1-year OS from the diagnosis of brain metastasis of 60.9% vs 38.7% respectively (trending towards significance, p=0.05). KRAS wild-type patients treated with immunotherapy versus those who did not receive immunotherapy had a 1-year OS from the diagnosis of brain metastasis of 61.9% vs 62.5% (p=0.85), respectively. DISCUSSION: KRAS mutations are associated with increased PD-L1 expression. Use of immunotherapy negates the poor outcomes seen traditionally in patients with NSCLCBM and KRAS mutations and it improves survival compared to use of chemotherapy. Our experience supports the use of immunotherapy in these patients.
THER-10. IMPACT OF BRAF MUTATIONAL STATUS ON THE EFFICACY OF IMMUNOTHERAPY FOR MELANOMA BRAIN METASTASES
Authors: Lauko Adam , Sagar Soumya , Barnett Addison , Wei Wei , Chao Samuel , Stevens Glen , Peereboom David , Yu Jennifer , Murphy Erin , Angelov Lilyana , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet 
Published: August 2019

Abstract
BACKGROUND: BRAF mutations occur in 50% of melanoma patients. Targeted agents – BRAF and MEK inhibitors and immunotherapy improve survival of melanoma patients with BRAF mutations. These agents have intracranial efficacy as shown in clinical trials. However, the efficacy of immunotherapies (immune checkpoint blockade) in melanoma brain metastases and the correlation with BRAF status is not as well characterized. METHODS: We reviewed 351 patients with melanoma brain metastases treated at our tertiary care center between 2000 and 2018, 75 of which received immunotherapy with known BRAF mutational status. Two-year, 5-year, and median overall survival (OS) was calculated from the start of immunotherapy to compare the efficacy of immunotherapy in BRAF mutant and BRAF wild type patients using the log-rank test. RESULTS: At the time of diagnosis of brain metastasis, the median age was 61 (23–87) years, median KPS was 80 (50–100), number of intracranial lesions was 2 (1–15), and 79% had extra-cranial metastases. Sixty-three patients were treated with stereotactic radiosurgery (SRS), 27 underwent whole brain radiation (WBRT) and 21 underwent surgery. When treated with immunotherapy, BRAF mutant and BRAF wild type median survival was 15.7 months (95% CI=9.4 – 42.4) and 6.9 (95% CI=4.1– 26.7) months (p-value=0.205), respectively. Two-year BRAF mutant and BRAF wild type survival was 35% (95% CI=21 – 58) and 28% (95% CI=16 – 51), and 5-year survival was 22% (95% CI=10 – 46) and 23% (95% CI=11 – 47), respectively. CONCLUSIONS: Twenty percent of patients with BRAF mutant and BRAF wild-type patients treated with immunotherapy derive a long-term benefit from immunotherapy and multimodality treatment and are alive 5 years from diagnosis of brain metastases. This was rarely seen in the pre-immunotherapy era in melanoma brain metastases. There was no difference in outcome based on the BRAF mutational status with use of immunotherapy in melanoma brain metastases.
THER-11. PEPTIDE-MEDIATED PERMEABILIZATION OF THE BLOOD-BRAIN BARRIER IMPROVES DRUG DELIVERY TO BRAIN METASTASIS
Authors: Aasen Synnøve Nymark , Espedal Heidi , Holte Christopher , Keunen Olivier , Karlsen Tine Veronika , Tenstad Olav , Maherally Zaynah , Miletic Hrvoje , Hoang Tuyen , Eikeland Anne Vaag , Baghirov Habib , Olberg Dag Erlend , Pilkington Geoffrey J , Sarkar Gobinda , Jenkins Robert , Sundstrøm Terje , Bjerkvig Rolf , Thorsen Frits 
Published: August 2019

Abstract
BACKGROUND: Melanoma patients have a high risk of developing brain metastases, which is associated with a poor prognosis. The blood-brain barrier (BBB) inhibits sufficient drug delivery into metastatic lesions. We investigated the ability of a synthetic peptide (K16ApoE) to permeabilize the BBB for more effective drug treatment. METHODS: DCE-MRI was performed to study the therapeutic window of BBB opening facilitated by K16ApoE. In vivoand in vitroassays were used to determine K16ApoE toxicity and also to obtain mechanistic insight into its action on the BBB. The therapeutic impact of K16ApoE on melanoma metastases was determined together with dabrafenib, which is otherwise known not to cross an intact BBB. RESULTS: DCE-MRI exhibited an effective K16ApoE-mediated BBB opening for up to 1h. Mechanistic studies displayed a dose-dependent effect of K16ApoE caused by induction of endocytosis. At higher concentrations, the peptide also showed unspecific disturbances on plasma membranes. Combined treatment with K16ApoE and dabrafenib reduced the brain metastatic burden in mice compared to dabrafenib. We also showed by PET/CT that the peptide facilitated the delivery of compounds up to 150 kDa into the brain. CONCLUSIONS: We demonstrate a transient opening of the BBB, caused by K16ApoE, that facilitates improved drug-delivery into the brain. This improves the efficacy of drugs that otherwise do not cross the intact BBB.
MLTI-03. FIRST-LINE STEREOTACTIC RADIOSURGERY COMBINED WITH SYSTEMIC TARGETED AND IMMUNE CHECKPOINT INHIBITOR THERAPY IN MELANOMA PATIENTS WITH NEWLY DIAGNOSED BRAIN METASTASES
Authors: Heumann Thatcher , Ye Rebecca , Wu Peter , Habibi Akram , Sansosti Alexandra , Beaudreault Cameron , Kryger Marc , Bernstein Kenneth , Pavlick Anna , Kondziolka Douglas 
Published: August 2019

Abstract
BACKGROUND: Of solid tumors, melanoma has the highest propensity for CNS spread with historic median survivals of 5–8 months following brain metastasis diagnosis. We evaluated the impact of systemic BRAF targeted and immune checkpoint inhibitor (ICI) therapies on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM) and assessed patient treatment burden associated with prolonged survival. METHODS: We retrospectively reviewed the demographics, disease characteristics, therapeutic regimens, overall survival, and first-year cumulative incidence of comorbid disease for patients with de novo MBM treated between 2013 and 2017 at a major melanoma referral center. RESULTS: Among 123 newly diagnosed MBM patients: 65% were male, 24% were 50 years old or less, 50% were BRAF mutated, 63% had multiple intracranial lesions at diagnosis. Locally, 73% received SRS as first-line treatment. Systemically, 73% received ICI, 46% received BRAF targeted therapy, and 12% received neither. With a median follow up of 11 months (mo), total cohort median OS was 13.2 mo. Median OS for first-line SRS combined with ICI and BRAF targeted therapy was 31.0 mo (47% 3-year OS), 17.5 mo (31% 3-year OS) with ICI monotherapy, and 6.1 mo (22% 3-yr OS) alone. SRS and BRAF targeted therapy were associated with improved OS. At one-year follow-up, comorbid conditions with the greatest cumulative incidence were fatigue, nausea, intracranial hemorrhage, deep vein thrombosis, major depressive disorder, and pneumonia. Patients averaged one inpatient visit every 4.5 mo (1 week average length of stay), and 2 advanced imaging studies (MR/CT/PET-CT) per month following MBM diagnosis. CONCLUSIONS: In one of the largest reported MBM series, survival has improved markedly for patients receiving first-line SRS combined with targeted and immunotherapies. Simultaneously, longer life expectancy comes with increasing incidences of comorbid conditions reflecting an evolving complexity of and need for coordination of care for patients with MBM.
MLTI-08. AN EXCEPTIONAL INTRACRANIAL RESPONSE TO REPEAT RADIATION AND IMMUNOTHERAPY IN A PATIENT WITH METASTATIC, POORLY DIFFERENTIATED ADENOCARCINOMA OF THE LUNG
Authors: Sumrall Ashley , Burri Stuart , Asher Anthony 
Published: August 2019

Abstract
We report an unusual case of a long-term survivor of metastatic, poorly differentiated adenocarcinoma of the lung (EGFR- ALK-) who developed intracranial disease after definitive treatment of a stage IIIB lung cancer. He received a complex course of RT which began with SRS to his intracranial disease in 2012 and included: brainstem (pontine) mass, left parietal mass, left frontal, left lateral temporal, and left insular lesions. The left temporal mass progressed and was resected. Subsequently, SRS was given to a right anterior frontal lesion. Additional SRS was given to progressive right superior frontal mass & left temporal tumor bed was given fractionated RT to the left temporal tumor bed. Later, he developed bilateral cerebellar masses and right-sided progression. More SRS was given to right frontal area, and then to bilateral cerebellar lesions. Surprisingly, he did well neurologically until seizures developed. His repeat biopsy was sent for NGS and noted to be PDL1+, APC mutated, and KRAS mutated. This gentleman was started on pembrolizumab in May 2016. Due to colitis, his therapy stopped in January 2017. His colitis progressed such that immunotherapy could not be restarted. Now, after observation only for the past 2.5 years. his disease has disappeared. He is doing well neurologically. We propose that the use of radiation and immunotherapy worked to produce an exceptional, durable response.
MLTI-17. DIFFERENTIATION OF RADIATION INJURY FROM RECURRENT BRAIN METASTASIS USING COMBINED FET PET/MRI RADIOMICS
Authors: Lohmann Philipp , Kocher Martin , Ceccon Garry , Bauer Elena , Stoffels Gabriele , Viswanathan Shivakumar , Ruge Maximilian , Neumaier Bernd , Shah Nadim , Fink Gereon , Langen Karl-Josef , Galldiks Norbert 
Published: August 2019

Abstract
BACKGROUND: The aim of this study was to investigate the potential of combined radiomics textural feature analysis of contrast-enhanced MRI (CE MRI) and static O-(2-[18F]fluoroethyl)-L-tyrosine(FET) PET for the differentiation of recurrent brain metastasis from radiation injury. PATIENTS AND METHODS: Fifty-two patients with newly diagnosed or progressive contrast-enhancing brain lesions on MRI after radiotherapy (predominantly radiosurgery, 84% of patients) of brain metastases were additionally investigated using FET PET. Based on histology (n=19) or clinicoradiological follow-up (n=33), local recurrent brain metastases were diagnosed in 21 patients (40%) and radiation injury in 31 patients (60%). Forty-two features (shape-based, first and second order features) were calculated on both unfiltered and filtered CE MRI and summed FET PET images (20–40 min p.i). After feature selection, logistic regression models using a maximum of five features to avoid overfitting were calculated for each imaging modality separately and for the combined FET PET/MRI features. The resulting models were validated using cross-validation. Diagnostic accuracies were calculated for each imaging modality separately as well as for the combined model. RESULTS: For differentiation between radiation injury and brain metastasis recurrence, textural features extracted from CE MRI had a diagnostic accuracy of 81%. FET PET textural features revealed a slightly higher diagnostic accuracy of 83%. However, the highest diagnostic accuracy was obtained when combining CE MRI and FET PET features (accuracy, 89%). CONCLUSION: Our findings suggest that combined FET PET/MRI radiomics using textural feature analysis offers a great potential to contribute significantly to the management of patients with brain metastases. SUPPORT: This work was supported by the Wilhelm-Sander Stiftung, Germany
OTHR-01. USING COGNITION TO PREDICT RISK OF MEDICAL DECISION-MAKING IMPAIRMENT IN BRAIN CANCER
Authors: Gerstenecker Adam , Triebel Kristen 
Published: August 2019

Abstract
BACKGROUND: Medical decision-making capacity refers to the ability to make informed decisions about medical treatment. Understanding is the most cognitively demanding aspect of medical decision-making and requires the ability to comprehend medically-related information and then use that information to make decisions about diagnosis, prognosis, and treatment options. In previous papers, we have shown that knowledge about specific cognitive abilities that affect understanding in brain cancer could be used to construct actuarial equations designed to help clinicians identify persons with brain cancer or brain metastases at risk of understanding impairment. METHODS: In total, 184 participants (67 with brain metastasis, 41 with non-brain metastasis, 29 with malignant glioma, and 47 healthy controls) were recruited. All participants were administered a neuropsychological battery that included a performance-based measure of medical decision-making capacity. Impairment cutoffs were calculated from control group performance. Using the cognitive scores that were most highly associated with understanding, logistic and linear regression models were used to construct actuarial equations designed to predict intact/impaired understanding and understanding scores, respectively. RESULTS: As expected, both brain cancer groups had poorer understanding than controls and approximately 50% of both brain cancer groups exhibited impaired understanding. Over 24% of the non-brain metastasis group exhibited impaired understanding. Significant associations were found between understanding and all administered cognitive variables, with the strongest correlations noted as between understanding and measures of executive function, verbal memory, and verbal fluency. Using these cognitive variables, we were able to construct predictive equations that showed strong psychometric properties. CONCLUSIONS: These data demonstrate how cognitive measures can estimate medical understanding in persons with cancer. Clinically, these findings suggest that poor verbal memory, executive function, and/or phonemic fluency function could serve as “red flags” for reduced consent capacity in this patient population, and thus signal that a more comprehensive medical decision-making capacity evaluation is warranted.
OTHR-04. INCIDENCE AND SURVIVAL OUTCOMES IN UROTHELIAL CARCINOMA BRAIN METASTASES
Authors: Kavouridis Vasileios , Harary Maya , Smith Timothy , Braun David , Iorgulescu Bryan 
Published: August 2019

Abstract
INTRODUCTION: Urothelial carcinoma is a common malignancy with ~79,000 new cases diagnosed annually. However, urothelial brain metastases (UBM) are encountered uncommonly. Herein we evaluate their national prevalence, predictors, and treatment outcomes in the contemporary era. METHODS: The characteristics, management, and overall survival (OS) of UBM patients (2010–2015) were evaluated using the National Cancer Database, which comprises &gt;70% of all newly diagnosed cancers in the U.S. OS was analyzed with Kaplan-Meier methods and log-rank tests. National outcomes were compared to our institutional cohort of UBMs. RESULTS: Out of 208,600 patients diagnosed with urothelial carcinoma, 8.4% presented with stage IV disease--of these only 216 (1.2%) had BMs at the time of diagnosis. Patients presenting with bone, liver, or lung metastases were more likely to present with synchronous BMs. Brain involvement demonstrated significantly worse median OS (3.9mos, 95%CI: 3.1–4.9) than non-BM stage IV disease (10.9mos, 95%CI: 10.6–11.2, p&lt; 0.001). Compared to non-BM stage IV disease, UBMs were more likely to have surgery for metastatic disease and receive radiotherapy (p&lt; 0.001); but were less likely to have primary resection or chemotherapy. In multivariable analysis of stage IV urothelial cancer, BMs demonstrated significantly worse OS (HR 1.43, 95%CI: 1.20–1.72, p&lt; 0.001). In our institutional data, 10 urothelial cancer patients developed BMs; of which 7 were male, median age and KPS at diagnosis were 64.9yo (IQR 56.4–72.0) and 85 (IQR 75–100). Four patients had synchronous metastases; the median number of BM lesions was 2 (IQR 1–2), with a median size of 2.6cm (IQR 1.6–3.3). All 10 underwent GTR, 3 also with SRS and 7 with WBRT, associated with a median OS of 16.5mos. CONCLUSION: Our results confirm the rarity of UBMs and suggest that BM screening may only be indicated in stage IV patients with neurological symptoms. Systemic therapies demonstrate improved OS in these patients.