tbuckley/cabot-search huggingface dataset:
Abstract 19160: Impact of Correction for Immortal Time Bias on Mortality After Inferior Vena Cava Filter Placement for Venous Thromboembolic Disease and a Contraindication to Anticoagulation
Authors: Tyson E Turner, Mohammed J Saeed, Eric Novak, David L Brown
Journal: Circulation (2016)

Introduction: Inferior vena cava filters (IVCF) are recommended in patients with venous thromboembolic disease (VTE) and a contraindication to anticoagulation therapy. Observational studies of IVCF...
A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease
Authors: Mark R. Litzow, Xin V. Wang, Martin P. Carroll, Judith E. Karp, Rhett P. Ketterling, Yanming Zhang, Scott H. Kaufmann, Hillard M. Lazarus, Selina M. Luger, Elisabeth M. Paietta, Keith W. Pratz, Han Win Tun, Jessica K. Altman, Edward R. Broun, Witold B. Rybka, Jacob M. Rowe, Martin S. Tallman
Journal: American Journal of Hematology (2018)

To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re‐induction chemotherapy. They were randomized to the following regimens: carboplatin‐topotecan (CT), each by continuous infusion for 5 days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S‐MEC). The primary objective was attainment of a complete remission (CR). A Simon two‐stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared with 55 years for the CT arm and the S‐MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%‐35%), 28% in the FLAM arm (10/36, 90% CI, 16%‐43%), and 16% in the S‐MEC arm (3/19, 90% CI, 4%‐36%). There were nine treatment‐related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients.
Distinct Imaging Characteristics of Different Metastases From Primary Prostate Adenocarcinoma and Rectal Carcinoid Tumor on 18F-Fluciclovine and 68Ga-DOTATATE PET/CT
Authors: Andrew John Bosserman, Dong Dai, Yang Lu
Journal: Clinical Nuclear Medicine (2018)

A 71-year-old man with history of prostate cancer is evaluated for rising prostate-specific antigen. The patient also has a history of rectal well-differentiated neuroendocrine tumor. On F-fluciclovine PET/CT, 2 retroperitoneal lymph nodes exhibited intense fluciclovine avidity, whereas one enlarged perirectal lymph node only showed background uptake. On further Ga-DOTATATE PET/CT, the perirectal lymph node revealed intense DOTATATE avidity, whereas the 2 retroperitoneal lymph nodes only with similar to background DOTATATE avidity. Biopsy of the perirectal lymph node confirmed metastasis from neuroendocrine tumor. The distinct imaging characteristics of metastases from different primary malignancies correlated with their underlying different pathology.
Salvage Lymph Node Dissection for Nodal Recurrent Prostate Cancer: A Systematic Review
Authors: Guillaume Ploussard, Giorgio Gandaglia, Hendrik Borgmann, Pieter de Visschere, Isabel Heidegger, Alexander Kretschmer, Romain Mathieu, Cristian Surcel, Derya Tilki, Igor Tsaur, Massimo Valerio, Roderick van den Bergh, Piet Ost, Alberto Briganti
Journal: European Urology (2018)
GNAQ mutation in port-wine macrocheilia
Authors: G. Ma, Z. Yu, F. Liu, L. Wang, W. Yu, J. Zhu, H. Gu, Y. Liu, R. Cai, X. Lin
Journal: British Journal of Dermatology (2018)

Capillary malformations (CMs), also called port‐wine stains, are a type of birthmark which affect about 3 to 5 out of every 1000 newborn babies. Port‐wine macrocheilia (PWM) are CMs that also cause the lips to enlarge. It is known that port wine stains are caused by a mutation in a protein called GNAQ and this study by researchers in P.R. China aimed to figure out how often this mutation occurs in different tissues of PWM, such as skin, mucosa (e.g. the tissue inside the mouth and nose), gland, and muscle. The authors found that the mutation, called GNAQ(R183Q) mutation, was not present in gland samples, but it was detected in 90%, 95% and 95% of the skin, mucosa and muscle samples, respectively. The study also found a positive correlation between the GNAQ mutation frequency and clinical characteristics, meaning that the mutation was linked to symptoms, especially in mucosa. Thus, the authors hypothesize that GNAQ mutation in mucosa of the lips, with or without underlying port wine stain in the skin, may be used as a predictor for early‐stage PWM. The authors suggest that performing a biopsy of mucosa (testing a small skin sample) if doctors think the patient might have underlying port wine stain, could help detect PWM earlier and allow for earlier treatment. Biopsies are practical, convenient, heal rapidly and don't cause scarring.
Hyperpolarised xenon magnetic resonance spectroscopy for the longitudinal assessment of changes in gas diffusion in IPF
Authors: Nicholas D Weatherley, Neil J Stewart, Ho-Fung Chan, Matthew Austin, Laurie J Smith, Guilhem Collier, Madhwesha Rao, Helen Marshall, Graham Norquay, Stephen A Renshaw, Stephen Mark Bianchi, Jim M Wild
Journal: Thorax (2018)

Prognosticating idiopathic pulmonary fibrosis (IPF) is challenging, in part due to a lack of sensitive biomarkers. A recent article in Thorax described how hyperpolarised xenon magnetic resonance spectroscopy may quantify regional gas exchange in IPF lungs. In a population of patients with IPF, we find that the xenon signal from red blood cells diminishes relative to the tissue/plasma signal over a 12-month time period, even when the diffusion factor for carbon monoxide is static over the same time period. We conclude that hyperpolarised 129Xe MR spectroscopy may be sensitive to short-term changes in interstitial gas diffusion in IPF.
THU0535 Title: safety and efficacy of platelet-rich plasma in treatment of carpal tunnel syndrome; a randomised controlled trial
Authors: L. Bagherzadeh, S.A. Raeissadat, A. Karimzadeh, M. Hashemi
Journal: Annals of the Rheumatic Diseases (2018)

Methods: 66 patients with chronic low back pain were enrolled in this study.The patients were randomised and divided into two groups.Lomber stabilisation exercises, TENS and Hotpack treatments were given to the first group (n: 28) while the second group (n: 37) were treated with only TENS and Hotpack.Patients' evaluations have been carried out before and after 8 weeks following the exercises.Visuel Analogue Scale (VAS) were used to determine the pain as a numeric scale during the rest and pyhsical activity.Modified Oswestry Questionnaire Survey and Roland Morris Scale were used to evaluate of functional disability.The Short Form-36 (SF36) applied to measure of quality of life.Tetrax device has been used to evaluation the body balance.7-15 MHZ Ultrasound has been used to evaluate the change of trophic changes of multifidus muscle's cross-sectional areas.Results: Except falling risk, in all parameters we have observed significant improvement in group 1. Cross-sectional area of the multifidus muscles, physical role of SF-36, mental health and energy/vitality sub parameters were found significantly better in group 1 when compared to the other group.There was no significant difference between the groups when the fall index, VAS scores, Roland Morris Questionnaire and Oswestry Disability Index were considered.Conclusions: As a result, lomber stabilisation exercises have positive effect on pain relief, improve the functional capacity and quality of life.Additionally the exercises also had benefit and increased cross-sectional areas of multifidus muscles.
SURG-11. PATHOLOGICAL INVESTIGATION OF NOVEL SPRAY-TYPE FLUORESCENT PROBES FOR BRAIN TUMORS
Authors: Shota Tanaka, Yosuke Kitagawa, Akira Ogasawara, Yugo Kuriki, Kyoko Yamamoto, Mako Kamiya, Yasuteru Urano
Journal: Neuro-Oncology (2018)

A fluorescent probe such as 5-aminolevulinic acid achieves greater extent of resection in glioma surgery and thus serves as a valuable surgical adjunct. However, its sensitivity and specificity are yet to be perfectly satisfactory. Our novel spray-type fluorescence system using green hydroxymethyl rhodamine green (HMRG) probes has been tested for brain tumors. In this study, we investigated on red dimethyl silicone rhodamine 600 (2MeSiR600) probes, which have a higher sensitivity for peptidase activity than HMRG probes. MATERIALS AND Fresh tumor tissues as well as fresh frozen tissues harvested from gliomas resected at our institutions were used in this study. The probe library included over 400 types with different combinations of amino acids attached to 2MeSiR600. Fluorescence intensity was measured over time after probes were applied to homogenized lysates made from fresh frozen tissues. Fluorescent probes which clearly discerned the tumor area from the peripheral area were selected, and then applied to fresh tumor tissues to confirm their selectivity. Tumor tissues were fixed with formalin and stained with hematoxylin and eosin. Immunohistochemistry staining was also performed. The correlation between fluorescence intensity and histopathology including cell density and MIB-1 labeling index was investigated. Probe screening demonstrated some 2MeSiR600 probes exhibited significantly higher fluorescence intensity in the peripheral area compared to the tumor area, which was confirmed when they were applied to fresh tumor tissues. 2MeSiR600 probes which selectively fluoresce the peripheral area may enable highly selective tumor recognition in conjunction with 5-aminolevulinic acid or our HMRG probes.
PATH-06. QUANTITATIVE ANALYSIS OF MGMT PROMOTER METHYLATION AND ITS PROGNOSTIC VALUE IN GLIOBLASTOMA MULTIFORME (GBM) PATIENTS TREATED WITH ALKYLATING CHEMOTHERAPY- PRELIMINARY REPORT
Authors: Samarjeet Bajwa, Lisa Flanagan, Stephania Hernandez, Dan Beverly Fu, Daniela Bota, Xiao-Tang Kong
Journal: Neuro-Oncology (2018)

To correlate the percentage of MGMT methylation with progression-free survival (PFS) and overall survival (OS) in GBM patients receiving alkylating chemotherapy. MGMT promoter methylation is a known favorable factor for patients with GBM to have better response to the treatment with alkylating chemotherapy and better survival outcome. However, in daily practice, patients with very high percentage of MGMT methylation sometimes were observed to have a shorter survival period. This study is to investigate if the strength of the positivity is correlated to the PFS and OS in GBM patients receiving alkylating chemotherapy. METHODS and PATIENTS: Quantitative MGMT methylation measurement was performed. 5% was defined as positive methylation. Seventeen patients with a diagnosis of GBM and methylated MGMT were reviewed retrospectively. Patients were placed into 3 categories based on their MGMT methylation percentages: 5–33%, 34–66%, and 67–100%. The average PFS and OS were calculated for each category. The 6 patients in the 5–33% methylation category had an average PFS of 14.8 months (range 9 to 32) and OS of 27.2 months (range 10 to 42). The 8 patients in the 34–66% methylation category had an average PFS of 23.9 months (range 0 to 73) and OS of 28.1 months (range 1 to 82). The 3 patients in the 67–100% methylation category had an average PFS of 9.6 months (range 2 to 21) and censored OS of 14.7 months (range 2 to 35) as 2 of the 3 are alive. Our sample size is too small to provide conclusions. Comparing the first two methylation categories, the extent of MGMT methylation appears positively correlates with PFS (14.8 versus 23.9 months) but not OS of patients (27.2 versus 28.1 months). Data from additional 15 MGMT methylated patients after follow-ups will be added for analysis.
IMMU-27. PREVENTING T-CELL S1P1 INTERNALIZATION OBVIATES BONE MARROW T CELL SEQUESTRATION AND IMPROVES IMMUNOTHERAPEUTIC EFFICACY IN GBM
Authors: Pakawat Chongsathidkiet, Karolina Woroniecka, Cosette Dechant, Hanna Kemeny, Xiuyu Cui, Daniel Wilkinson, Peter Fecci
Journal: Neuro-Oncology (2018)

INTRO: Glioblastoma (GBM) is among the most immunosuppressive of solid tumors, eliciting profound lymphopenia and T-cell dysfunction that limit immunotherapeutic success. This lymphopenia, as well as marked lymphoid organ contraction, is recapitulated in murine models of GBM. The bone marrow is the lone lymphoid organ not subject to T-cell loss, instead sequestering large numbers of naïve T-cells. We have previously shown that loss of the sphingosine-1-phosphate receptor type 1 (S1P1) from the T-cell surface plays a role in mediating this sequestration in both mice and patients with GBM. Here we show that stabilization of the receptor on T-cells reverses their sequestration and licenses T-cell activating therapies that were previously ineffective. Blood, bone marrow, and tumors were collected from mice bearing CT2A gliomas and analyzed by flow cytometry. T-cell S1P1 levels were assessed, as were T-cell counts in each compartment. S1P1 receptor stabilization was achieved with a knock-in model (S1P1KI) in which receptor internalization is inhibited. Adoptive transfer experiments utilized tail vein injections of 1x104 splenocytes. For treatment experiments, survival was assessed by Kaplan-Meier estimator. Sequestered T-cells in tumor-bearing mice show decreased surface S1P1 levels. Genetic stabilization of the S1P1 receptor through obviated internalization abrogates T-cell sequestration. Adoptively transferred T-cells with stabilized receptor resist sequestration when transferred into tumor bearing mice, and S1P1KI mice do not show T-cell sequestration following tumor implantation. S1P1KI mice also show increased numbers of activated tumor-infiltrating T-cells. While S1P1 stabilization alone does not extend survival, S1P1KI mice display enhanced survival when treated with 4-1BB agonist +/- anti-PD-1. S1P1-mediated bone marrow T-cell sequestration is a novel mode of cancer-induced T-cell dysfunction in GBM. Preventing receptor internalization abrogates T-cell sequestration and licenses T-cell activating therapies. Pharmacologic strategies to reverse sequestration and restore circulating T-cell counts are anticipated to improve immunotherapeutic efficacy for GBM.
EXTH-16. GOLPH3 SENSITIZES THE TUMOR SUPPRESSION EFFECT OF GEFITINIB ON GLIOMAS
Authors: Xu Wang, Zhaohao Wang, Yan Wang, Hao Zhang, Shao Xie, Peng Xie, Rutong Yu, Xiuping Zhou
Journal: Neuro-Oncology (2018)

Golgi phosphoprotein 3 (GOLPH3) is associated with worse prognosis of gliomas, but its role and mechanism in glioma progression remain largely unknown. We previously reported that GOLPH3 promotes glioma progression by inhibiting EGFR endocytosis and degradation, leading to EGFR accumulation and PI3K-AKT pathway over-activation. In the current study, we examine whether GOLPH3 affects the response of glioma cells to gefitinib, an EGFR selective inhibitor. We found that both the immortalized and primary glioma cells with GOLPH3 over-expression hold higher EGFR protein levels on the cell membrane and exhibited higher sensitivity to gefitinib. In addition, primary glioma cells with higher GOLPH3 level exhibited stronger proliferation behavior. Importantly, GOLPH3 enhanced the anti-tumor effect of gefitinib in vivo. Consistently, after gefitinib treatment, tumors derived from GOLPH3 over-expression cells exhibited lower Ki67 positive and higher cleaved caspase-3 positive cells than control tumors. Taken together, our results demonstrate that GOLPH3 increases the sensitivity of glioma cells to gefitinib. Our study provides foundation for further exploring whether GOLPH3 high gliomas will more sensitive to gefitinib treatment in clinic and give ideas for developing new possible treatments for gliomas.
IMMU-30. HIGH-DIMENSIONAL PHENOTYPING OF IMMUNE SUBSETS AND CHECKPOINTS IN THE MOUSE GLIOBLASTOMA MICROENVIRONMENT
Authors: Matheus Crommentuijn, Sjoerd Schetters, Sophie Dusoswa, Laura Kruijssen, Juan Garcia-Vallejo, Yvette van Kooyk
Journal: Neuro-Oncology (2018)

Recent clinical trials in glioblastoma have yet to show any benefit of immune checkpoint inhibitors and are mostly driven by the fact that these inhibitors have efficacy in other cancer types. For immunotherapy to succeed in glioblastoma patients, we need to understand the immunological subsets and phenotypes involved to target and manipulate them. To this end, we set up different glioblastoma mouse models and used multiparameter flow cytometry and t-SNE unsupervised clustering of immune subsets including co-expression of immune checkpoints and their ligands. When comparing the brain tumor microenvironment with immune cells present in the contralateral hemisphere and the systemic compartment, we identified unique immune subsets. Different populations of infiltrating CD4 T cells were characterized by expression of TIGIT, PD-1 and HVEM. PD-1 expression was also significantly increased on infiltrating CD8 T cells. Furthermore, analysis of myeloid subsets showed massive infiltration of macrophages in the brain tumor microenvironment, which is also apparent in clinical glioblastoma samples. Co-expression of PD-L1, CD155 and BTLA was observed on both infiltrating macrophages and brain-resident microglia. Together, these results suggest a glioblastoma-induced ‘tolerogenic’ microenvironment and, while T cells are present, myeloid cells might prove to be a better target for combination immunotherapy.
RARE-02. PRIMARY CNS POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE (PCNS-PTLD): RECOGNIZING THE ENTITY, MINIMIZING TREATMENT TOXICITY, AND DEVELOPMENT OF SURVEILLANCE TOOLS IN RENAL TRANSPLANT PATIENTS
Authors: Na Tosha Gatson, Jeffrey Summers, Gino Mongelluzzo, Erika Leese, Maria C. Bermudez, Joseph Vadakara
Journal: Neuro-Oncology (2018)

PCNS-PTLD is a rare complication of solid organ transplantation (SOT) and is a distinct entity from primary CNS lymphoma (PCNSL). With fewer than 90 cases reported since 1970, there are no treatment standards. Existing data supports combining reduction of immunosuppression (RI), whole-brain radiotherapy, monoclonal antibody therapy, and systemic/IT chemotherapy. Treating kidney SOT PTLD is complicated by reduced renal clearance, contrast-dye restrictions, and nephrotoxicity. Treatment complications and allograft rejection cause early morbidity and mortality. Rapid identification of serum/CSF supporting diagnostic markers such as active EBV replication, elevated CSF protein, and positive cytology/flow cytometry is critical. We report three cases of B/T-cell PTLD in renal-SOT patients 1–27 years on immunosuppression (steroids, mycophenolate, tacrolimus/sirolimus) who presented with focal neurologic deficits and multifocal MRI lesions. After confirming CNS-isolated disease patients were treated with partial-RI, dexamethasone, and induction with rituximab weekly cycles. Patients had objective responses and underwent consolidative rituximab therapy q21-days with restaging. Residual enhancing lesions were treated by stereotactic radiosurgery and one year of temozolomide chemotherapy days 1–5 on a 28-day cycle. We monitored serum LD, drug levels, and serum EBV as indicators for progression/recurrence. Patients achieved complete responses and mOS has not been met. Long-term survival in PCNS-PTLD is one distinguishing feature from PCNSL. With multiple treatment obstacles in renal-SOT PT early recognition and minimally toxic regimens improve patient outcomes. This data challenges traditional paradigms in diagnosis and treatment of PTLD, specifically EBV+ disease occurring >6 years post SOT. We propose that the specialized CNS immune microenvironment permits EBV driving of neoplastic progression, which is exquisitely sensitive to B-cell targeting concurrent with partial restoration of host immunity. Furthermore, targeted radiotherapy, temozolomide, and partial immunosuppression maintains patient quality-of-life and reduce risk for allograft rejection.
DDIS-17. MULTI-LEVEL DRUG DEVELOPMENT PIPELINE FOR THE DISCOVERY OF TUMOR MICROTUBE TARGETING DRUGS
Authors: Erik Jung, Matthias Osswald, Philipp Koch, Wolfgang Wick, Frank Winkler
Journal: Neuro-Oncology (2018)

Tumor microtubes (TMs), which are ultra-thin and long cellular protrusions extended by glioma cells, have emerged as a novel mechanism of glioma cell growth, invasion and interconnection with consecutive therapy resistance. So far, few molecular drivers of TM formation and function (Gap43, Cx43, Ttyh1 and actin dynamics) have been identified and their downregulation strongly reduced therapy resistance and glioma cell dissemination in vivo. We implemented a multi-level screening pipeline which allows to test drugs for their anti-TM actions. Initially drugs are tested for their general actions on glioma cell growth in vitro before being evaluated by laser scanning microscopy for their impact on TM formation (number of TMs), morphometry (TM length and diameter) and functionality (calcium communication) in 2D models. These parameters as well as anti-invasive properties are further validated in a 3D matrix model, which has shown to correlate well with the phenotype observed in vivo. As a final step of the in vitro pipeline, we developed a brain organoid model with patient-derived glioma cells, which is used to confirm the observed effects of the most promising compounds in a more complex microenvironment. Effective drugs identified in the in vitro screen are then tested in our mouse model in vivo: tumor growth, TM formation (number, morphology, interconnection) and function (calcium communication, invasion, therapy resistance) are longitudinally followed on a single cell level using a chronic cranial window and intravital two photon microscopy. Finally, classical drug effectivity parameters such as survival and tumor size on 7-T MRI scans are measured. First results of compounds, which have demonstrated tumor microtube-inhibiting vs. -promoting effects in this pipeline will be presented. In summary, this novel pipeline enables the rapid development of anti-TM drugs to translate the growing evidence of the importance of TMs to glioma biology into clinical trials.
2008 Russell Ross Memorial Lectureship in Vascular Biology—Activating and Inhibitory Receptors in Blood and Vascular Cells
Authors: Peter Newman
Journal: Circulation (2008)

The activation state of circulating blood cells is a tightly controlled process that is continuously influenced by both stimulatory and inhibitory events, and proper integration of the signals transduced by physical and chemical mediators to which cells are exposed is crucial for maintaining homeostasis. Studies carried out over the past 20 years has led to the identification of numerous plasma membrane receptors linked to intracellular signaling pathways that regulate cellular activation, signal transmission, and later, adaptation. Human platelets are both a valuable and clinically relevant model system in which to study such activating and inhibitory processes at the molecular level, as their dysregulation can lead to bleeding, inflammation, thrombosis, and cardiovascular disease. Platelets express G protein-coupled receptors, kinase- and phosphatase-linked receptors, and a host of adhesion molecules, and there is growing recognition that these are intricately intertwined, making rational intervention to control platelet activation and platelet aggregation an increasingly approachable, albeit challenging, possibility. This lecture will highlight our recent understanding of the complex interplay between immunoreceptor tyrosine-based activation motif (ITAM)–bearing and immunoreceptor tyrosine-based inhibitory motif (ITIM)–bearing receptors that exists in platelets and other vascular cells, with an emphasis on the role that such receptors play in human health and the treatment of cardiovascular disease.