bluuebunny/crossref_metadata_2025_split huggingface dataset:
BSCI-27. MELATONIN REDUCES MALIGNANCY OF BREAST CANCER BRAIN METASTATIC CELLS
Authors: Gil Beatriz Fernandez , Rodriguez Katherine , Schiapparelli Paula , Ramos Carla Vazquez , Escames Germaine , Quinones-Hinojosa Alfredo , Sarabia-Estrada Rachel 
Published: August 2019

Abstract
Around fifteen to thirty percent of stage IV breast cancer metastasizes to the brain, severely decreasing the quality of life of these patients by causing neurological decline and eventually death. In metastatic cancers there is a small subset of cells in the primary tumor bulk called Metastatic Tumor Initiating Cells (MTICs) which are able to escape and produce a niche establishment at distal sites where they can quickly become resistant to surgery and radiation. Melatonin has shown an inhibitory role in the viability and invasiveness of breast cancer and in modulating the expression of proteins related to Breast Cancer Stem Cells (BCSCs). These findings suggest its potential anti-metastatic role in different breast cancer cell lines. In this study we aimed to evaluate the effects of melatonin treatment in vitro for breast cancer brain metastasis. The cell line MDA-BT was originally obtained from MDA-MB-231, passed through the rat’s heart and then isolated once engrafted as a tumor in the brain. After a dose response assay, cells were treated with melatonin at doses of 1500 and 3000 µM for 48hrs. Clonogenic assay, MTT, as well as a stem cell signature through RT-qPCR, including CD44, CD24 and ALDH1 markers, were performed to evaluate the malignancy of the MTICs. The results showed that melatonin at high doses impacts morphology, declines viability, reduces colony formation ability, and decreases stemness in MDA-BT cells. Therefore, our findings highlight melatonin as a relevant therapeutic candidate to target breast cancer brain metastases.
LPTO-01. LEPTOMENINGEAL METASTASIS FROM OVARIAN CARCINOMA TREATED WITH SYSTEMIC HIGH-DOSE METHOTREXATE
Authors: Coffee Elizabeth , Lobbous Mina , Nabors L Burt 
Published: August 2019

Abstract
BACKGROUND: Central nervous system metastasis in ovarian cancer is reported in approximately 1% of cases and typically localizes to the parenchyma. Leptomeningeal disease (LMD) is exceedingly rare. Prognosis is extremely poor with median survival of 60 days. Given the rarity of LMD in ovarian cancers, there is no consensus on the optimal treatment approach. High-dose systemic methotrexate (HD-MTX) has been studied in LMD. CASE REPORT: A 41-year-old Caucasian woman with a history of BRCA-positive stage IIIC ovarian carcinoma who was treated with cytoreduction and multiple rounds of intravenous and intraperitoneal chemotherapy presented to the emergency room with progressive headaches, vomiting and neck pain. Contrasted MRI of the brain showed nodular enhancement along the cerebellar folia, concerning for leptomeningeal disease. Cerebrospinal fluid cytology analysis was positive for malignancy and she was diagnosed with leptomeningeal metastasis 2.5 years after her diagnosis with ovarian carcinoma. Induction therapy with systemic HD-MTX was given every other week and complete response was achieved after two induction cycles. Serum CA-125 level decreased from 565.7 U/mL (prior to treatment) to 50.4 U/ML after the sixth induction cycle and she was transitioned to maintenance HD-MTX. Approximately 6 months after initiation of HD-MTX, contrasted MRI demonstrated LMD recurrence with corresponding rise in CA-125 to 395 U/mL. Whole body CT imaging did not show local disease recurrence. Temozolomide was added to the HD-MTX regimen and craniospinal radiation therapy was planned but her neurologic condition continued to decline. She died 8 months after her diagnosis of LMD. CONCLUSION: LMD has a dismal prognosis. HD-MTX may prolong the overall survival in patients with LMD secondary to ovarian carcinoma. In these patients, serum CA-125 level may serve as a biomarker for monitoring CNS disease burden. Due to the rarity of LMD, multi-institutional prospective studies are needed to explore novel therapeutics in LMD.
LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS
Authors: Deng Jiaojiao , Chernikova Sophia , Fischer Wolf-Nicolas , Koller Kerry , Jandeleit Bernd , Ringold Gordon , Gephart Melanie 
Published: August 2019

Abstract
Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43
LPTO-08. INTRATHECAL TRASTUZUMAB PLUS/MINUS IT TOPOTECAN FOR PATIENTS WITH HER2+ BREAST CANCER AND LEPTOMENINGEAL METASTASIS
Authors: Trevino Christopher R , Murthy Rashmi K , Raghavendra Akshara Singareeka , Loghin Monica , Seligman Christa , Ferguson Sherise , Kamiya-Matsuoka Carlos , Harrison Rebecca , Sinicrope Kaylyn D , Valero Vicente , Tummala Sudhakar , Hess Kenneth , Tripathy Debu , de Groot John , O’Brien Barbara 
Published: August 2019

Abstract
BACKGROUND: Leptomeningeal metastasis (LM) is an aggressive complication of cancer. No standard therapies exist, although at our institution we commonly use IT topotecan in good-risk patients. We report our experience in patients with HER2+ breast cancer (BC) LM treated with intrathecal (IT) trastuzumab +/- IT topotecan. METHODS: We retrospectively reviewed records of patients managed with IT trastuzumab at MD Anderson Cancer Center from 2016–2019. Demographics, clinical course, and outcomes data (Kaplan-Meier) were collected and analyzed. RESULTS: 14 female patients (median age 49, range 33–67) with HER2+ BC (29% hormone receptor (HR) positive, 71% negative) were treated with IT trastuzumab (titrated to 40 mg -100 mg/week); 8 (57%) received concurrent IT topotecan. LM diagnosis was made in 64% by MRI alone, and 36% by both MRI and CSF cytology; 79% had brain metastases (BM), and of those, 55% (6/11) had active BM at LM diagnosis; 57% received WBRT prior to initiation of IT therapy. Median KPS was 90 (range, 60–100). Of those with initially positive cytology, 50% (4/8) converted to negative during treatment. MRI findings improved in 79%; 79% were symptomatic at diagnosis (most commonly ataxia, cranial neuropathy, headache); 70% (7/10) had symptom improvement on IT therapy. The only IT-associated symptom reported was mild nausea that occurred in 29%. Median time from diagnosis of metastatic BC was 10.7 mos. (range 0–83 mos); 36% had active extra-CNS disease and 86% received concurrent systemic therapy; 57% underwent change in systemic therapy during IT treatment; 91% were progression-free at 6 months, 32% at 24 months. Median overall survival from LM diagnosis was 24.7 months (95% CI 10.7, NR). CONCLUSIONS: IT trastuzumab is a safe and promising therapy for patients with HER2+ BC and LM. Dual IT therapy with trastuzumab and topotecan was well-tolerated and warrants further investigation in a larger study.
TRLS-04. NEAR INFRARED FLUORESCENT DYE LOCALIZES BRAIN METASTASIS PRIOR TO DURAL OPENING AND IS MORE SENSITIVE THAN WHITE LIGHT IN BRAIN METASTASIS SURGERY
Authors: Buch Love , Cho Steve , Salinas Ryan , Hussain Jasmin , Lee John 
Published: August 2019

Abstract
INTRODUCTION: To improve surgical resection of brain tumors, our lab has pioneered a novel fluorescent dye technique, Second-Window Indocyanine-Green (SWIG), that relies on passive delivery and accumulation of indocyanine-green (ICG) in neoplastic tissue via the enhanced permeability and retention effect. We hypothesize that SWIG can provide early localization of brain metastasis prior to dural opening and can improve identification of surgical margins. METHODS: Subjects were prospectively enrolled in clinical trial after informed consent. Approximately 24 hours prior surgery, subjects were infused intravenously with 2.5mg/kg or 5mg/kg of ICG. Intraoperatively, a dedicated near-infrared (NIR) camera was used to detect ICG signal. After bone flap removal, the NIR imaging system was positioned above the presumed location of tumor. Additional NIR images were obtained after dural opening, corticectomy, and after conventional white-light surgical resection. RESULTS: We enrolled 50 patients with 51 total intraparenchymal brain metastases (23 lung, 7 breast, 8 GU/GI, 4 melanoma, and 7 others). Prior to dural opening, NIR signal was identified in 35 patients at an average depth of 4.3mm with SBR = 5.3 + 3.7. In the seven patients where NIR signal could not be identified prior to dural opening, tumor depth was an average of 8.4mm from cortical surface. Upon dural opening and tumor identification, all 51 tumors demonstrated strong NIR signal with SBR = 6.2 + 2.8. With white light alone, sensitivity/specificity/PPV/NPV for tumor detection was 83%, 94%, 98%, 57%. With NIR, sensitivity/specificity/PPV/NPV for tumor detection was 100%, 29%, 85%, 100%. DISCUSSION: NIR fluorophores are superior to visible light fluorophores in their depth of penetration. All contrast-enhancing brain metastasis accumulate ICG using our SWIG technique, and NIR fluorescence could be used to localize brain metastasis prior to dural opening. NIR fluorophores are likely to represent the next phase in tumor visualization given the rapid growth of fluorophores targeted to systemic cancers.
TRLS-05. EARLY RESULTS FROM A PROSPECTIVE PHASE I/II DOSE ESCALATION STUDY OF NEOADJUVANT RADIOSURGERY FOR BRAIN METASTASES
Authors: Murphy Erin , Yang Kailin , Suh John , Yu Jennifer , Schilero Cathy , Mohammadi Alireza , Stevens Glen , Angelov Lilyana , Vogelbaum Michael , Barnett Gene , Ahluwalia Manmeet , Neyman Gennady , Chao Samuel 
Published: August 2019

Abstract
OBJECTIVES: Single-session stereotacic radiosurgery (SRS) alone for brain metastases larger than 2cm in maximal dimension results in local control of only 50%. Surgical resection followed by SRS to the resection cavity can result in leptomeningeal failure (LMD). This Phase I/II study aims to determine the safety and local control of neoadjuvant SRS at escalating doses followed by surgical resection of brain metastases greater than 2 cm. METHODS: Radiosurgery dose was escalated at 3 Gy increments from currently accepted RTOG standard. If no dose-limiting toxicities (DLT) were observed, the dose was escalated. Patients underwent surgical resection of brain metastases within 2 weeks and were followed with brain MRIs and neurologic evaluations every 3 months. RESULTS: 27 patients were enrolled. For tumor size &gt;2.0–3.0 cm, 2 patients completed treatment at 18 Gy and 3 patients at 21Gy. For tumor size &gt;3.0–4.0 cm, 4 patients were treated at 15 Gy and 9 patients were treated at 18 Gy and 1 patient at 21 Gy. For tumor size &gt;4.0–5.0 cm, 1 patient was treated at 12 Gy and 7 patients at 15 Gy. No DLT have occurred. With a mean follow-up of 13.1 months, the 6 and 12 month local control was 93.8% and 72.3%, respectively. Six and 12 month distant brain control was 38.6% and 25.8%. Overall survival at 12 months was 53.5%. One patient developed LMD 5 months following SRS. 4 patients (15%) had acute grade 1/2 toxicity, and no grade 3/4 toxicity was observed. CONCLUSIONS: Neoadjuvant SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm results in local control comparable to postoperative SRS or WBRT, and demonstrates acceptable acute toxicity. A low rate of LMD failure was found. The Phase II portion of the trial will be conducted at the maximum tolerated SRS doses.
TRLS-08. CNS PENETRATION AND PRELIMINARY EFFICACY OF SACUTIZUMAB GOVITECAN IN BREAST BRAIN METASTASIS AND GLIOBLASTOMA: A SURGICAL STUDY
Authors: Brenner Andrew , Floyd John , Surapaneni Prathiba , Madhusudanan-Kunnuparampil Vinu , Tiziani Stefano 
Published: August 2019

Abstract
Sacituzumab govitecan (SG) is an antibody drug conjugate (ADC) that targets Trop-2 for the selective delivery of SN-38 to tumors. SG carries SN-38, a topoisomerase inhibitor active in the nanomolar range for most cells (including TNBC and GBM) and freely cross the blood brain barrier. SN-38 is conjugated to SG by a linker designated CL2A which is sensitive to acidic conditions. SG has since been granted priority review designation by the FDA, with approval anticipated for triple negative breast cancer. Brain metastases is a significant concern in this patient population, but whether this agent is able to target the CNS through the blood brain barrier is unknown. Based upon the characteristics of this specific ADC, including the use of a pH labile linker and a payload with good CNS penetration, it is our specific hypothesis that the SG can achieve intratumoral concentrations of SN-38 sufficient to achieve therapeutic benefit in patients with neoplastic involvement of the brain. We further hypothesize that while total concentration of SN-38 will correlate with expression of trop2, free SN-38 will correlate more strongly with intratumoral hypoxia. To address this, we are performing a non-randomized, prospective study of SG in subjects with CNS involvement and planned surgical resection. SG is given as single dose at 10mg/kg pre-operatively on Day-1. Surgery will be followed by post-operative treatment with sacituzumab govitecan given intravenously with standard dose of 10 mg/kg on day1 and day 8 of 21-day cycle, until disease progression. Approximately 20 patients, 2 cohorts of 10 patients each with GBM and breast brain tumors, will be enrolled. Tumors will be analyzed for total antibody, free SN-38, and total SN-38 (free SN-38 + Antibody-SN38) concentrations in tumor tissue. Correlations will be made to Trop2 expression and hypoxia. Interim results will be presented.
TRLS-09. RTOG1119: PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY / STEREOTACTIC RADIOSURGERY IN COMBINATION WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN METASTASIS FROM HER2-POSITIVE BREAST CANCER
Authors: Kim In Ah , Winter Kathryn , Peereboom David , Sperduto Paul , De Los Santos Jennifer , Ogunleye Tomi , Boulter Daniel , White Julia , Mehta Minesh 
Published: August 2019

Abstract
The addition of trastuzumab to cytotoxic chemotherapy has improved outcomes for patients with HER2 positive breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of trastuzumab may contribute to the increased incidence of brain metastasis in these patients. Half of these patients die of intracranial disease progression rather than extracranial disease. Therefore, strategies to improve survival must include increased CNS disease control in these patients. Lapatinib crosses the BBB and demonstrates modest activity against intracranial metastases. Based upon preclinical data and results of a phase I study, we hypothesized that lapatinib plus WBRT /SRS can improve the intracranial disease control compared to WBRT / SRS alone. A randomized phase II trial of WBRT (37.5 Gy/3 weeks) or SRS plus or minus concurrent lapatinib (daily 1000 mg for 6 weeks) was initiated. CNS penetrating HER2 targeted therapy is permitted throughout the study, but patients not on trastuzumab, pertuzumab or any other breast cancer therapy at study entry are not permitted to begin this therapy while on protocol treatment, but may begin it 24 hours after completion of protocol treatment. Eligibility includes HER2+ breast cancer with at least one measurable, unirradiated parenchymal brain metastasis. The two populations targeted for accrual include patients with 1) newly diagnosed, multiple brain metastases or 2) progressive brain metastases after stereotactic radiosurgery (SRS) or surgical resection of 1–3 metastases. Prior lapatinib is allowed. Patients are stratified by breast-specific graded prognostic assessment; use of non-CNS penetrating HER2 targeted therapy; and prior SRS or surgical resection. The primary endpoint is complete response rate in the brain 12 weeks after WBRT. Secondary endpoints include objective response rate, lesion-specific response rate, CNS progression-free survival, and overall survival. 140 of 143 target accrual have enrolled (4/22/2019).
THER-01. PRECLINICAL DEVELOPMENT OF EO1001, A NOVEL IRREVERSIBLE BRAIN PENETRATING PAN-ErbB INHIBITOR
Authors: Shen Wang , Bacha Jeffrey , Brown Dennis , Kanekal Sarath , Sankar Neil , Wang ZhenZhong , Pedersen Harry , Butowski Nicholas , Nicolaides Theodore , Sarkaria Jann , James C David , Giles Francis 
Published: August 2019

Abstract
Dysregulation of ErbB-mediated signaling is observed in up to 90% of solid tumors. ErbB family cross-talk is implicated in the development of resistance and metastasis, including CNS metastases. Inhibition of multiple ErbB receptors may result in improved patient outcomes. EO1001 is a novel, patented, oral, brain-penetrating, irreversible pan-ErbB inhibitor targeting EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4). METHODS: (1) In vitro testing. EO1001 demonstrates high specificity for the ErbB family of receptors with excellent, balanced equipotent activity against EGFR, HER2 and HER4 (0.4 to 7.4 nM). EO1001 inhibits signaling downstream of wild type EGFR, mutant EGFR (T790M, L858R and d746-750) and HER2. (2) PK and toxicity. In rodent studies in vivo, EO1001 exhibited a half-life of 16–20 hours. EO1001 rapidly enters the CNS and penetrates tumor tissue at higher concentrations relative to plasma. Safety of EO1001 was evaluated by repeat-dosing studies in SD rats and beagle dogs. Toxicities typical of the ErbB inhibitor class, including gastro-intestinal effects, weight loss and decreased activity were observed at higher dose groups in both species. Mortality was observed in SD rats at higher dose groups. (3) In vivo efficacy studies. EO1001 was studied following oral administration in several erbB-positive mouse xenograft models including N87 (Her2+), H1975 (EGFR/T790M), GBM12 (EGFR+), GBM39 (EGVRvIII+). Following oral administration, treatment with EO1001 resulted in a statistically significant improvement in outcomes compared to positive and negative controls in both CNS and systemic tumor models. EO1001 was well-tolerated with no gastrointestinal side effects observed at efficacious doses in these models. CONCLUSION: Based on research to date, EO1001 has the potential to be a best-in-class CNS-penetrating pan-ErbB inhibitor with a safety and pharmacokinetic profile amenable for use as a single agent and in combination with other agents. EO1001 is poised to enter phase 1-2a clinical testing in the second-half of 2019.
THER-04. THE USE OF AN ADENOSINE A2 AGONIST TO IMPROVE THE PREVENTION AND TREATMENT OF BRAIN METASTASES
Authors: Grossman Stuart , Romo Carlos , O’Connell Kaelin 
Published: August 2019

Abstract
As systemic therapies for cancer become increasingly effective, there is generally a rise in the incidence of brain metastases as a site of first recurrence. This occurs because most antineoplastic agents do not reach the brain in therapeutic concentrations. Many approaches have been studied to improve drug distribution to the central nervous system (CNS) such as intra-arterial administration, osmotic blood-brain barrier (BBB) disruption, focused ultrasound, convection-enhanced delivery, development of CNS penetrant pro-drugs, and the use of vasoactive peptides to transiently disrupt the BBB. However, none of these has improved the prevention or treatment of CNS metastases. Regadenoson is an adenosine A2 agonist that is FDA approved for use in cardiac stress tests. In animals, it has been shown to transiently increase BBB permeability allowing high molecular weight dextran and chemotherapy to enter brain in higher concentrations. A clinical study designed to determine if regadenoson will perform similarly in humans has been CTEP approved and will soon be accruing patients through the Adult Brain Tumor Consortium. If the results are encouraging, future studies will focus on administering regadenoson concurrently with systemically administered chemotherapy in an effort to reduce the incidence of CNS metastases and to improve CNS drug delivery in patients with known brain metastases. This presentation will focus on the available pre-clinical and clinical data supporting this approach and the potential advantages and risks associated with transient BBB disruption in this setting.
THER-05. SOLITARY CEREBRAL METASTASIS FROM TRANSITIONAL CELL CARCINOMA OF THE BLADDER
Authors: Jimenez Lissette , Hanefeld-Fox Liliana , Huang Bryan , Andryka Michael 
Published: August 2019

Abstract
INTRODUCTION: Brain metastasis is the most common neurological neoplasia seen in adults. They typically metastasize from primary lung or breast but very seldom is bladder cancer the culprit. Transitional cell carcinoma (TCC) of the bladder accounts for less than 1% of brain metastasis and few cases have been reported in literature. Here we present a rare case of TCC presenting with signs of neurological impairment. CASE DESCRIPTION: A 75-year-old male with history of TCC presented to the emergency department with right upper extremity hemiparesis and dysarthria of 5 hours duration. He had undergone cystoscopy with resection of tumor 3 years prior followed by gemcitabine chemotherapy and combination radiotherapy/immunotherapy. CT imaging revealed a hyperdense 3.3 cm mass in the left frontoparietal region with internal hemorrhage measuring 1.4 cm and surrounding vasogenic edema. He was immediately treated with high dose corticosteroids and antiepileptics which did not result in improvement of his symptoms. Metastatic workup which included contrast enhanced CT of chest, abdomen and pelvis revealed no evidence of local or metastatic recurrence. Due to rapid worsening of his status, respiratory failure and encephalopathy, family did not want to pursue additional treatment and decided on inpatient hospice. The patient died 3 weeks later due to rapid neurological decline. DISCUSSION: According to literature, CNS involvement of disseminated TCC varies from 0.6% - 8%, and bladder carcinoma accounts for 0.5% of all intracranial metastases. Incidence of CNS involvement without evidence of recurrence or disseminated disease is extremely uncommon. Aggressive multitherapeutic regimens, which include gemcitabine, have been favored for its penetration of the blood-brain barrier but even with its use disease may present years later with an unfavorable prognosis. Although metastasis from TCC of the bladder is rare any decline in neurological status should warrant further investigation in these patients.