tbuckley/cabot-search huggingface dataset:
ACTR-38. A SINGLE CENTER STUDY: LONG-TERM OUTCOMES OF COMBINED CHEMORADIATION THERAPY WITH TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA IN KOREAN PATIENT
Authors: Kyeong-O Go, Ha Young Yang, Kihwan Hwang, Jung Ho Han, Hyoung Soo Choi, Yu Jung Kim, Chan Woo Wee, In Ah Kim, Gheeyoung Choe, Chae-Yong Kim
Journal: Neuro-Oncology (2019)

Abstract In newly diagnosed glioblastoma (GBM), Temozolomide (TMZ) during and after radiation therapy has become standard treatment. This study describes the long-term use and follow-up results of this therapy for GBM. From 2004 to 2013 in a single institute, 112 Korean patients with newly diagnosed GBM were analyzed retrospectively. The Kaplan-Meier method, the two-sided log-rank test and Cox’s regression analysis was used to determine survival and its affecting factors. The toxicities of TMZ were evaluated using CTCAE v5.0. During the median follow-up period of 18.8 months, median PFS and OS were 9.2 and 20.3 months, respectively. This better survival outcome than the Stupp’s original study might be probably a large treatment effect of a single institution, ethnicity, and associated genetic factors. The TMZ during radiation therapy was completed in 108 patients (96.4%) and TMZ after radiation therapy in 59 patients (52.7%). Eight patients presented with grade 3 or 4 hematologic toxic effects during the protocol. Sixty-six patients (58.9%) received salvage treatment because of the poor response to adjuvant treatment or progression of the disease who achieved completion of adjuvant treatment was shown significantly longer median OS (p= 0.007) and PFS (p&lt; 0.001). Age (&lt; 60 years), preoperative KPS score (≥ 90), the extent of resection (≥ 78% by volumetric measurement, gross total resection), and completion of the Stupp’s protocol were significant factors affecting better survival. Between the sexes, and ages over 65 years did not show any significant difference among their groups. With marginal significances, the mutated IDH-1 and the methylated MGMT promoter showed longer median PFS(p= 0.075 and 0.777, respectively) and OS (p= 0.085 and 0.131, respectively). TMZ during and after radiation therapy might be effective and safe for newly diagnosed Korean patients with GBM. Further studies about various clinical and genetic factors affecting better survival are mandatory.
IMMU-09. COMBINATION IMMUNE TREATMENT OF A HIGHLY AGGRESSIVE ORTHOTOPIC MURINE GLIOBLASTOMA WITH CHECKPOINT BLOCKADE AND MULTI-VALENT NEOANTIGEN VACCINATION
Authors: Connor Liu, Maximilian Schaettler, Jay Bowman-Kirigin, Dale Kobayashi, Chris Miller, Tanner Johanns, Gavin Dunn
Journal: Neuro-Oncology (2019)

Abstract Recent success using immunotherapies to treat a growing range of cancer types has reinvigorated efforts to identify effective immune-based treatments for glioblastoma (GBM). However, the limited clinical benefit observed in GBM patients treated with checkpoint blockade immunotherapy (CBI) has indicated a need for more rigorous approaches to augment host-immune recognition and killing of GBM. Of the myriad barriers to effective brain tumor immunotherapy, one potentially critical consideration is that a more systematic approach to tumor-specific antigen identification and targeting is necessary to potently stimulate and direct T cells to treat GBM. Therefore, in this study we set out to identify endogenous tumor neoantigens in the anti-PD-L1 resistant murine glioblastoma, CT2A, and assess the efficacy of neoantigen vaccination in combination with anti-PD-L1 treatment. In order to identify candidate CT2A neoantigens, we employed DNA whole exome sequencing, RNA sequencing, and in silico neoantigen prediction analyses. High-affinity H-2Kb and H-2Db candidate CT2A neoantigens were screened for immunogenicity by IFN-γ ELISPOT assays. Of the 30 top-ranking neoantigen candidates, 13 demonstrated immunogenic CD8+ T cell responses in the spleens of mice vaccinated with mutant peptides. Assessing for endogenous reactivity, we identified neoantigen specific CD8+ T cell responses in the intracranial TIL and draining lymph nodes to two H2-Kb restricted, Epb4H471L and Pomgnt1R497L, and one H2-Db restricted neoantigen, Plin2G332R. Survival studies showed that therapeutic neoantigen vaccination with Epb4H471L, Pomgnt1R497L, and Plin2G332R, in combination with anti-PD-L1 checkpoint blockade was superior to either neoantigen vaccination or anti-PD-L1 therapy alone. Thus, by applying a cancer immunogenomics approach to identify endogenous neoantigen reactivity in an aggressive and treatment resistant murine glioblastoma, we provide a preclinical framework to investigate the effects of multi-modality immunotherapeutic interventions in anti-glioma immunity.
oct-4 Is Essential for Aneuploidy/Polyploidy-Tolerance in Embryonic Stem (ES) Cells and the Fate of Tetraploid ES Cells during Early Differentiation.
Authors: Charlie R. Mantel, Ying Guo, Myung-Kwan Han, Sara Roharbaugh, Barbara Graham-Evans, Mervin C. Yoder, Robert A. Hromas, Hal E. Broxmeyer
Journal: Blood (2005)
MNGI-04. PATTERNS OF FAILURE AND FACTORS INFLUENCING LOCAL RECURRENCE OF MENINGIOMA TREATED WITH POSTOPERATIVE RADIATION THERAPY
Authors: Matthew Susko, Harish Vasudevan, Stephen Magill, Lucas Calixto-Hope, Javier Villanueva-Meyer, Jean Nakamura, Nancy Ann Oberheim-Bush, Philip Theodosopoulos, David Solomon, Steve Braunstein, Patricia Sneed, Michael McDermott, David Raleigh
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Factors associated with meningioma recurrence after postoperative radiotherapy are poorly understood, and the optimal postoperative radiotherapy target delineation for meningioma is unknown. The objective of this study was to identify factors influencing meningioma recurrence after postoperative radiotherapy to inform patient selection and treatment design. METHODS Medical records were retrospectively reviewed for patients who underwent meningioma resection at a single institution between 1991 and 2015. Patients with sufficient tumor tissue for histologic classification and who received postoperative radiation therapy with external beam radiotherapy (EBRT), stereotactic radiosurgery (SRS) or brachytherapy, were included. Local freedom from recurrence (LFFR) was analyzed according to tumor and treatment characteristics using the Kaplan Meier method. RESULTS We identified 86 patients with 96 meningiomas who met inclusion criteria. Nineteen meningiomas (20%) were WHO grade I, 56 (58%) were grade II and 21 (22%) were grade III. Forty-one meningiomas (43%) were recurrent, and 55 (57%) were de novo. The postoperative radiotherapy modality was EBRT for 58 patients (60%), SRS for 20 (21%) patients and brachytherapy for 18 (19%) patients. With a median follow up of 4.3 years (IQR 2.1–8.8 years), there were 48 (50%) local failures that occurred a median of 17 months after immediate prior resection (IQR 9–33 months). WHO grade II/III and recurrent meningiomas had worse LFFR (p&lt; 0.001). The 5-year LFFR was 53% after EBRT (95% CI 41–69%), 53% after SRS (95% CI 34–84%) and 15% after brachytherapy (95% CI 3–74%), although meningiomas that were treated with brachytherapy were significantly more likely to have received prior EBRT or SRS (86% versus 29%, p&lt; 0.001). CONCLUSIONS These data provide a foundation for understanding patterns of meningioma recurrence after postoperative radiotherapy. Ongoing analyses aim to quantify the relationships between postoperative radiotherapy dose, target delineation and local control of meningioma.
STEM-04. NICARDIPINE SENSITIZES APOPTOSIS OF GLIOMA STEM CELLS INDUCED BY TEMOZOLOMIDE THROUGH INHIBITING AUTOPHAGY
Authors: Jun Dong, Jia Shi
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioma stem cells (GSCs) play an important role in tumor progression and recurrence. Currently, treatments of glioma are limited mainly due to strong tolerance of GSCs against conventional chemotherapeutic drugs such as temozolomide. Nicardipine, a calcium antagonist, is commonly used in the therapy of hypertension, which is recently repurposed in the comprehensive strategies against gliomas in our previous studies. Here, we explored the cytotoxic sensitization effect of nicardipine combining temozolomide and the underlying mechanisms. METHODS Two human glioma stem cell lines were applied and treated with nicardipine, temozolomide, and combination of both, respectively. Cell viability was detected by CCK-8, cell apoptosis was analyzed by flow cytometry, and immunoblot was used to detect autophagic-releated proteins including p62, LC3 and mTOR. The mTOR agonists and inhibitors were applied to further evaluate whether nicardipine inhibits autophagy via mTOR pathway. RESULTS GSCs had strong tolerance against temozolomide while nicardipine could significantly inhibit the viaibility of GSCs and promote cell apoptosis when acting together with temozolomide, indicating that nicardipine could sensitize the toxicity of temozolomide. Furthermore, both temozolomide and nicardipine could inhibit autophagy, and the effects of nicardipine was more prominent, suggesting that nicardipine might enhance GSCs apoptosis induced by temozolomide through inhibiting autophagy. Further molecular studies showed that the cytotoxic sensitization effects of nicardipine was induced through activation of the phosphorylation level of mTOR, which was abolished with the treatment of rapamycin, a mTOR inhibitor. CONCLUSION Our results suggested that nicardipine could sensitize apoptosis of glioma stem cells induced by temozolomide through inhibiting autophagy, which was mediated by activation of mTOR activity.
Epigenetic <i>EGFR</i> Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas
Authors: Jaume Capdevila, Oriol Arqués, Jose Ramón Hernández Mora, Judit Matito, Ginevra Caratù, Francesco M. Mancuso, Stefania Landolfi, Jorge Barriuso, Paula Jimenez-Fonseca, Carlos Lopez Lopez, Rocio Garcia-Carbonero, Jorge Hernando, Ignacio Matos, Nuciforo Paolo, Javier Hernández-Losa, Manel Esteller, Anna Martínez-Cardús, Josep Tabernero, Ana Vivancos, Héctor G. Palmer
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The limited knowledge of the molecular alterations that characterize poorly differentiated neuroendocrine carcinomas has limited the clinical development of targeted agents directed to driver mutations. Here we aim to identify new molecular targets in colon neuroendocrine carcinomas (co-NEC) and proof the efficacy of matching drugs. Experimental Design: We performed a multi-omic analysis of co-NEC to identify genetic or epigenetic alterations that could be exploited as effective drug targets. We compared co-NEC samples with colorectal carcinomas (CRC) to identify neuroendocrine-specific traits. Patients with co-NEC and patient-derived xenografts were treated with a BRAFV600E-blocking drug to demonstrate sensitivity. Results: co-NEC and CRC are similar in their mutational repertoire, although co-NECs are particularly enriched in BRAFV600E mutations. We report for the first time that V600EBRAF-mutant co-NECs may benefit from BRAF inhibition in monotherapy and how EGFR status is essential to predict innate sensitivity and acquired resistance by a differential methylation of its gene regulatory regions. Conclusions: The identification of V600E BRAF mutations in high-grade co-NECs has allowed the description of radiological responses to combination therapy of BRAF and MEK inhibitors in basket clinical trials. However, the molecular rationale for this treatment combination was based on the presence of the BRAF mutation and the efficacy observed in other cancer types such as melanoma. Future drug development in this setting should test BRAF inhibitors upfront and the addition of anti-EGFR antibodies instead of MEK inhibitors for an efficient blockade of acquired resistance.
Attitudes of patients with chronic breathlessness towards treatment with opioids
Authors: Cornelia A. Verberkt, Marieke H.J. van den Beuken-van Everdingen, Emiel F.M. Wouters, Daisy J.A. Janssen
Journal: European Respiratory Journal (2019)

<b>Attitudes of patients towards opioid treatment for chronic breathlessness are mixed, with 37% of patients willing to use opioids, 25% unwilling and 38% of patients indecisive. Physicians are an important source of information for these patients.</b> http://bit.ly/2pvNtLJ
Facilitated Subcutaneous Immunoglobulin (fSCIG) Administration in Secondary Immune Deficiency (SID) Due to Hematological Malignancies. Efficacy and Safety Real-World Data from a Single-Center in Greece
Authors: Maria Dimou, Vasileios Pardalis, Theodoros Iliakis, Aikaterini Bitsani, Ioannis Grafakos, Sotiria Kalyva, Athanasios Markopoulos, Marie-Christine Kyrtsonis, Panayiotis Panayiotidis
Journal: Blood (2019)
Treatment of Ringworm of the Scalp
Authors: S. C. Shanks
Journal: BMJ (1949)

<h3>Background</h3> In patients with mild strokes the risk–benefit ratio of endovascular treatment (EVT) for tandem lesions has yet to be evaluated outside of current guideline recommendations. This study investigates the frequency as well as procedural and safety outcomes in daily clinical practice. <h3>Methods</h3> Using data from the German Stroke Registry-Endovascular Treatment (GSR-ET) we analyzed patients with anterior circulation stroke due to tandem-lesions and mild deficits. These patients were defined as ≤5 on the National Institutes of Health Stroke Scale (NIHSS). Recanalization was assessed with the modified Thrombolysis in Cerebral Infarction Scale (mTICI), t. Early neurological and long-term functional outcomes were assessed with the NIHSS change and modified Rankin scale (mRS), respectively. Safety assessment included periprocedural complications and the rate of symptomatic intracerebral hemorrhage (sICH). <h3>Results</h3> A total of 61 patients met the inclusion criteria and were treated endovascularly for tandem lesions. The median age was 68 (IQR:59–76) and 32.9% (20) were female. Patients were admitted to the hospital with a median NIHSS score of 4 (IQR:2–5) and a median Alberta Stroke Programme Early CT Score (ASPECTS) of 9 (IQR:8–10). Successful recanalization (mTICI 2b-3) was observed in 86.9% (53). NIHSS decreased non-significantly (p=0.382) from baseline to two points (IQR:1–9) at discharge. Excellent (mRS≤1) and favorable (mRS≤2) long-term functional outcome at 90-days was 55.8% (29) and 69.2% (36), respectively. Mortality rates at 90-days were 9.6% (5) and sICH occurred in 8.2% (5). <h3>Conclusions</h3> EVT for tandem lesions in patients with mild anterior circulation stroke appears to be feasible but may lead to increased rates of sICH. Further studies comparing endovascular with best medical treatment (BMT) especially investigating the risk of periprocedural hemorrhagic complications, are needed.
Pediatric Hematologist/Oncologists' Beliefs about Hematopoietic Stem Cell Transplant for Children with Sickle Cell Disease: A Sickle Cell Transplant Advocacy and Research Alliance (STAR) Study
Authors: Emily Riehm Meier, Allistair Abraham, Alexander I. Ngwube, Isaac Janson, Gregory M.T. Guilcher, John T. Horan, Kimberly A. Kasow
Journal: Blood (2019)
CBMT-21. TERT PROMOTER-MUTANT GLIOBLASTOMAS EXHIBIT DEPENDENCY ON TELOMERASE
Authors: Elisa Aquilanti, Duncan Baird, Jacqueline Watson, Matthew Meyerson
Journal: Neuro-Oncology (2019)

Abstract TERT promoter mutations are among the most common somatic alterations in cancer and they occur in about 80% of IDH-wildtype glioblastomas. TERT promoter mutations were found to reactivate telomerase by providing a novel binding site for the GABP transcription factor. While the effects of telomerase ablation are well understood in mice and somatic human cells, these effects in cancer are yet to be fully elucidated. In this study, we used a genetic approach with CRISPR-interference to knock down telomerase in TERT promoter-mutant glioblastoma cell lines. We show that this leads to a gradual and significant reduction in proliferation. This phenotype ultimately culminates in telomere crisis, with telomere shortening, activation of the DNA damage response pathway and formation of chromatin bridges. These data suggest that anti-telomerase therapy is a potential effective approach for glioblastoma tumors.
Sulphamerazine for Pneumonia in Adults
Authors: H. Joules, S. D. V. Weller
Journal: BMJ (1947)

Estradiol is protective in experimental cerebral ischemia, but the precise mechanisms remain unknown. Signal transducer and activator of transcription-3 (STAT3) is a transcription factor that is activated by estrogen, translocates to the nucleus, and induces the transcription of neuroprotective genes, such as <i>bcl-2</i>. We determined whether estradiol increases STAT3 activation in female rat brain after focal cerebral ischemia and whether STAT3 activation contributes to estradiol-mediated neuroprotection against ischemic brain injury. Ovariectomized (OVX) female rats with and without estradiol replacement were subjected to 2 h of middle cerebral artery occlusion (MCAO), and phosphorylated STAT3 (P-STAT3) and total STAT3 (T-STAT3) were quantified by Western blot analysis at 3 and 22 h of reperfusion. STAT3 activation was colocalized with neuronal and survival markers microtubule-associated protein 2 (MAP2) and Bcl-2 using immunohistochemistry. Infarct size was measured at 22 h after MCAO in estradiol-treated OVX animals in the presence and absence of STAT3 inhibitor cucurbitacin I (JSI-124) using 2,3,5-triphenyltetrazolium chloride staining. Estradiol increased P-STAT3 in the ischemic cortex cytosolic fraction at 3 h after MCAO without affecting T-STAT3. This was associated with increased P-STAT3 in the nuclear fraction, which remained elevated at 22 h after MCAO. The nuclear P-STAT3 colocalized with MAP2 and Bcl-2 within the peri-infarct zone. The P-STAT3 inhibitor JSI-124 abolished the protective effect of estradiol without affecting infarct size in untreated OVX rats. We conclude that estradiol increases STAT3 phosphorylation in neurons after MCAO and that STAT3 activation plays an important role in estradiol-mediated neuroprotection.
JAK-2-Positive Latent Myeloproliferative Neoplasms with Splanchnic Vein Thrombosis- from the Hematopathology Perspective
Authors: Dina Sameh Soliman, Aliaa Amer, Firyal Ibrahim, Ahmad Al-Sabbagh, Halima El-Omri, Mohamed A Yassin, Susanna Jane Akiki
Journal: Blood (2019)
Efficacy of Nivolumab plus Ipilimumab According to Number of IMDC Risk Factors in CheckMate 214
Authors: Bernard Escudier, Robert J. Motzer, Nizar M. Tannir, Camillo Porta, Yoshihiko Tomita, Matthew A. Maurer, M. Brent McHenry, Brian I. Rini
Journal: European Urology (2019)
Sixty seconds on . . . valuing GPs
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Yes, but this isn’t about money. GPs Sam Finnikin and Margaret McCartney, Royal College of General Practitioners clinical support fellows for values and evidence, have started a campaign called Value GP. They are asking 100 GPs and 100 patients to produce short videos describing what they value about their work or their GP.

The plan, with help …
A Phase 2 Open-Label Study of Danicopan (ACH-0144471) in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to Eculizumab Monotherapy
Authors: Austin Kulasekararaj, Antonio M. Risitano, Jaroslaw P. Maciejewski, Rosario Notaro, Peter Browett, Jong-Wook Lee, Mingjun Huang, Michael Geffner, Robert A. Brodsky
Journal: Blood (2019)
Phase 1 Results of CNCT19: CD19 CAR Constructed of a New Anti-CD19 Chimeric Antigen Receptor in Relapsed or Refractory Acute Lymphoblastic Leukemia
Authors: Runxia Gu, Fang Liu, Dehui Zou, Bingcheng Liu, Wei Liu, Xiaojuan Chen, Kaiqi Liu, Ye Guo, Xiaoyuan Gong, Rui Lv, Xia Chen, Chunlin Zhou, Mengjun Zhong, Yingxi Xu, Huijun Wang, Hui Wei, Yingchang Mi, Lugui Qiu, Lulu Lv, Min Wang, Ying Wang, Xiaofan Zhu, Jianxiang Wang
Journal: Blood (2019)
Recovery of the Gut Microbiota after Antibiotics Depends on Host Diet, Community Context, and Environmental Reservoirs
Authors: Katharine Michelle Ng, Andrés Aranda-Díaz, Carolina Tropini, Matthew Ryan Frankel, William Van Treuren, Colleen T. O’Loughlin, Bryan Douglas Merrill, Feiqiao Brian Yu, Kali M. Pruss, Rita Almeida Oliveira, Steven Kyle Higginbottom, Norma F. Neff, Michael Andrew Fischbach, Karina Bivar Xavier, Justin Laine Sonnenburg, Kerwyn Casey Huang
Journal: Cell Host & Microbe (2019)

Antibiotics alter microbiota composition and increase infection susceptibility. However, the generalizable effects of antibiotics on and the contribution of environmental variables to gut commensals remain unclear. To address this, we tracked microbiota dynamics with high temporal and taxonomic resolution during antibiotic treatment in a controlled murine system by isolating variables such as diet, treatment history, and housing co-inhabitants. Human microbiotas were remarkably resilient and recovered during antibiotic treatment, with transient dominance of resistant Bacteroides and taxa-asymmetric diversity reduction. In certain cases, in vitro sensitivities were not predictive of in vivo responses, underscoring the significance of host and community context. A fiber-deficient diet exacerbated microbiota collapse and delayed recovery. Species replacement through cross housing after ciprofloxacin treatment established resilience to a second treatment. Single housing drastically disrupted recovery, highlighting the importance of environmental reservoirs. Our findings highlight deterministic microbiota adaptations to perturbations and the translational potential for modulating diet, sanitation, and microbiota composition during antibiotics.
Tandem Autologous-Autologous Vs. Autologous-Allogeneic Transplantation for Newly Diagnosed Multiple Myeloma: Pooled Analysis of 1,338 Patients from Four Trials with Long-Term Follow up
Authors: Luciano J. Costa, Simona Iacobelli, Marcelo C. Pasquini, Riddhi Modi, Luisa Giaccone, Joan Bladé, Stefan Schonland, Andrea Evangelista, Jose A. Perez-Simon, Parameswaran Hari, Elizabeth E. Brown, Sergio A Giralt, Francesca Patriarca, Edward A. Stadtmauer, Laura Rosinol, Amrita Y. Krishnan, Goesta Gahrton, Benedetto Bruno
Journal: Blood (2019)