tbuckley/cabot-search huggingface dataset:
Development of combination chemotherapy regimens: What is the yield of published phase II trials?
Authors: C. Hudoba, M. L. Maitland, K. L. Snider, M. J. Ratain
Journal: Journal of Clinical Oncology (2009)

6510 Background: Although combination therapy presents an opportunity to advance cancer care, how well typical phase II development methods screen for regimens that improve care is not known. Since single arm phase II trials have fundamental flaws that could be magnified in combination treatment studies, we hypothesized that these phase II trials would have a low positive predictive value. Methods: We searched medline for phase II combination chemotherapy clinical trials published in 2001 and 2002, and selected for those which tested only systemic therapies in oncology patients, yielding 364 published trials. These studies were rated as positive, negative, or inconclusive based on review of abstract and text statements by the authors. The Web of Science Index (Thomson Reuters, NY, NY) was searched for all articles published between 2003 and October 2007 that cited at least one of these 364 source papers. Results: Of 364 published phase II combination chemotherapy trials (including 16,033 subjects), 262 were declared to be positive. The Web of Science search identified 3,764 unique subsequent citing papers. Of these, 20 reported randomized phase III trials testing the same combination in the same disease as the source paper, and 9 studies resulted in findings that improved standards of care. Based on these data, for any published, reported positive, phase II combination chemotherapy trial the likelihood that it will result in a published, confirmatory randomized trial demonstrating an improvement in standard of care within 5 years is 0.034 (95% confidence interval - 0.016, 0.064). Conclusions: For combination chemotherapy phase II trials performed by standards of published studies in 2001–02, the positive predictive value is low despite the participation of a large number of subjects. Historical approaches to the development of combination chemotherapy regimens have been an inefficient use of patient resources. Future phase II studies of combination regimens require better methods to screen for treatments most likely to improve standards of care. [Table: see text]
Impact of Bone Marrow Fibrosis Grade in Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis. a Study of the Mysec Group
Authors: Barbara Mora, Elisa Rumi, Paola Guglielmelli, Margherita Maffioli, Daniela Barraco, Alessandro Rambaldi, Marianna Caramella, Rami S. Komrokji, Jason Gotlib, Jean-Jacques Kiladjian, Francisco Cervantes, Timothy Devos, Francesca Palandri, Valerio De Stefano, Marco Ruggeri, Richard T. Silver, Giulia Benevolo, Francesco Albano, Chiara Cavalloni, Silvia Uccella, Claudia Siracusa, Tiziano Barbui, Alessandra Iurlo, Lorenza Bertù, Michele Merli, Mario Cazzola, Alessandro M. Vannucchi, Francesco Passamonti
Journal: Blood (2019)
EPID-13. IDENTIFICATION OF PROGNOSTIC MARKERS IN A COHORT OF CONSECUTIVE NON-SELECTED GLIOBLASTOMA PATIENTS RECEIVING STANDARD THERAPY
Authors: Signe Regner Michaelsen, Thomas Urup, Kirsten Grunnet, Ib Jarle Christensen, Ulrik Lassen, Hans Skovgaard Poulsen
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma is treated by standard with maximal surgical resection followed by radiation therapy with concomitant and adjuvant temozolomide. Still, median overall survival (OS) for glioblastoma is around 15 months, although the prognosis varies greatly. To improve the treatment, stratification of glioblastoma patients according to favorable and poor prognostic groups is needed. The aim of this study was to develop a prognostic model for glioblastoma patients treated with standard therapy outside clinical trials. The study included 680 consecutive, non-selected glioblastoma patients with WHO performance status (PS) 0–2 administered postoperative with standard first-line therapy between years 2005–2016 at the University Hospital of Copenhagen, Denmark. At disease recurrence, patients were mostly treated by reoperation and/or bevacizumab combination therapy. Patients were retrospectively evaluated by reviewing of medical records, histopathological descriptions and imaging analyses. The cohort had a median progression-free survival (PFS) of 7.5 months, median OS of 15.7 months and median OS from recurrence of 7.4 months. Comparative analyses of survival endpoints dependent on year of diagnosis did not reveal any statistically significant improvement from 2005 and forth. Factors significantly associated with worse prognosis in univariate and multivariate analyses were for OS, low extent of primary surgery, increased age, multifocal disease, increased PS and O6-methylguanine DNA methyltransferase (MGMT) tumor methylation. For PFS, multifocal disease, increased PS, and MGMT tumor methylation were significantly associated with worse prognosis. Gender, tumor location, tumor size, comorbidity score and site of tumor relapse were not significantly associated with any survival endpoints. Based on study results, a predictive model for survival will be generated able to calculate survival probability for the individual glioblastoma patient. Such a model could prove useful for stratification in clinical scientific protocols and for making glioblastoma treatment more individualized. Updated results will be presented.
Impact of sFLC Ratio on Outcome in Patients with MM: Validating the Utility of sFLC in Response Definition
Authors: Nadine Abdallah, S. Vincent Rajkumar, Dragan Jevremovic, Prashant Kapoor, Angela Dispenzieri, Morie A. Gertz, Martha Q. Lacy, Francis K. Buadi, Suzanne R. Hayman, David Dingli, Eli Muchtar, Wilson I Gonsalves, Taxiarchis Kourelis, Rahma M Warsame, Mustaqeem A. Siddiqui, Ronald S. Go, Nelson Leung, Yi L. Hwa, Miriam A. Hobbs, Amie Fonder, Robert A. Kyle, Shaji K. Kumar
Journal: Blood (2019)
Ex-Vivo Expanded NK Cell Therapy Combined with Elotuzumab for MRD after Autologous Stem Cell Transplantation: A Phase I/ II Clinical Trial in Progress
Authors: Shotaro Hagiwara, Yan-Hua Wang, Hirohito Kobayashi, Yutaka Kato, Norina Tanaka, Yuki Iizuka, Aya Watanabe, Midori Ishiyama, Akihito Shinohara, Hiroshi Kazama, Kentaro Yoshinaga, Masayuki Shiseki, Hitoshi Kanno, Junji Tanaka
Journal: Blood (2019)
ACTR-52. PHASE 1 STUDY OF FT-2102, AN INHIBITOR OF MUTANT IDH1, IN PATIENTS WITH RELAPSED/REFRACTORY IDH1 MUTANT GLIOMAS: PRELIMINARY SAFETY AND CLINICAL ACTIVITY
Authors: Macarena I De la Fuente, Howard Colman, Mark Rosenthal, Brian A Van Tine, Ekokobe Fonkem, Tobias Walbert, Mohammed Milhem, Kate Lipford, Sanjeev Forsyth, Sylvie Guichard, Julie Brevard, Yelena Mikhailov, Blythe Thomson, Varun Monga
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Isocitrate dehydrogenase mutations (mIDH1) are present in &gt; 70% of patients with Grade II/III gliomas resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. FT-2102 is a potent, brain penetrant (Kpuu=0.4 in intact rodent) and selective inhibitor of mIDH1. METHODS Patients with advanced relapsed/refractory mIDH1 gliomas received FT-2102 150mg BID, orally. Following a dose confirmation 3 + 3 Phase 1b, 20 pts enrolled in a Simon 2 stage Phase 2 study (NCT: 03684811). RESULTS As of 01-May-2019, 23 with glioma (Grade at enrollment: II/III/IV; n=4, n=12 &amp; n=7 respectively) were treated with FT-2102 monotherapy. The patient’s median age was 46 years (range: 23–64) &amp; 61% were male. Median number of prior treatments was 2 (range 1–5) and 78% had received prior temozolomide. mIDH1 status was locally determined (IHC, NGS or PCR): R132H, R132L, R132C &amp; unspecified (n=15, n=2, n=1 &amp; n=5). Median duration of FT-2102 treatment to date was 40 days (range: 26–177), with 1 patient discontinuing (disease progression). Treatment emergent adverse events (all grades, regardless of attribution) that occurred in &gt;10% of were: fatigue (22%), nausea (17%), diarrhea (17%), ALT increase (13%), headache (13%) and AST increase (13%), none leading to treatment discontinuation. None experienced an adverse event of QTcF prolongation or skin hyperpigmentation. There were no protocol-defined DLT’s. To date, six had at least 1 evaluable post-baseline response assessment, with best response of 1 PR (unconfirmed as of data cutoff), 3 SD and 2 PD. Responses of patients remaining on FT-2102 will be updated as available. Evaluations of serum/CSF pharmacokinetics and selected pharmacodynamics will be provided. CONCLUSION FT-2102 at 150 mg BID demonstrates acceptable safety and tolerability with potential clinical activity in with gliomas. The Phase 2 study is ongoing, evaluating both single agent, FT-2102 and in combination with azacitidine.
Proteomic research in sarcomas – current status and future opportunities
Authors: Jessica Burns, Christopher P Wilding, Robin L Jones, Paul H Huang
Journal: Seminars in Cancer Biology (2019)

Sarcomas are a rare group of mesenchymal cancers comprising over 70 different histological subtypes. For the majority of these diseases, the molecular understanding of the basis of their initiation and progression remains unclear. As such, limited clinical progress in prognosis or therapeutic regimens have been made over the past few decades. Proteomics techniques are being increasingly utilised in the field of sarcoma research. Proteomic research efforts have thus far focused on histological subtype characterisation for the improvement of biological understanding, as well as for the identification of candidate diagnostic, predictive, and prognostic biomarkers for use in clinic. However, the field itself is in its infancy, and none of these proteomic research findings have been translated into the clinic. In this review, we provide a brief overview of the proteomic strategies that have been employed in sarcoma research. We evaluate key proteomic studies concerning several rare and ultra-rare sarcoma subtypes including, gastrointestinal stromal tumours, osteosarcoma, liposarcoma, leiomyosarcoma, malignant rhabdoid tumours, Ewing sarcoma, myxofibrosarcoma, and alveolar soft part sarcoma. Consequently, we illustrate how routine implementation of proteomics within sarcoma research, integration of proteomics with other molecular profiling data, and incorporation of proteomics into clinical trial studies has the potential to propel the biological and clinical understanding of this group of complex rare cancers moving forward.
Acute Dilatation of the Stomach
Authors: C. Ll. Lander
Journal: BMJ (1945)

On March 9 he appeared quite well, but stated that he had been having attacks of paroxysmal tachycardia, especially at night, each lasting about an hour.His pulse was 110.Second Admission.-OnMarch 14 the patient was readmitted, complaining of pain, stiffness, and swelling in his right arm of four days' duration.The first symptom noticed was tenderness of the muscles, beginning with the 'right biceps but later spreading to the forearm and shoulder muscles.This was followed shortlyby increasing swelling of the muscles, with accompanying pain and stiffness.On examination he did not look ill, but his face was flushed and his skin hot and moist.There was marked brawny swelling of the right forearm and arm, most pronounced in the biceps region.The whole arm was very tender, and movement of the limb caused great pain.There was some tenderness, though very little swelling, of the shoulder muscles.A blood count on March 15 revealed 11,000 leucocytes per c.mm.-neutrophils 8,910, eosinophils 110, basophils 0, lymphocytes 1,430, and monocytes 550; Hb 87%.
Oral Contraceptives and Liver Damage
Authors: I. P. Palva, O. O. Mustala
Journal: BMJ (1964)

complication which I find fairly frequently -namely, pain in the right subcostal area.I feel certain that it is a manifestation of change in the biliary system, but it is not a colic, the pain being dull and steady with tenderness in the same area.One patient had an area of paraesthesia in addition.It tends to continue intermittently throughout the prenatal course and disappears after delivery.To date I have found no good explanation for it, or method of relieving it, other than by using analgesics.-Iam, etc.,
Scared to Death?
Authors: A. R. Elkington, P. R. Steele, D. D. Yun
Journal: BMJ (1965)

Total faecal calcium is then given by f=(d+s) (1-a)+s' ................... (1) The discussion is simplified by taking s+s'=287 mg./day, the value found by Dr.Rose and his colleagues, and s'=40 mg./day, the value derived by Heaney.' Equation ( 1) then reduces to f=(d+247) (1-a)+40 or, a.d=(d-f)-247.a+287............ (2) Equation (2) is plotted for various values of a and d in the Figure.At constant a values a.d on (d-f) is a family of straight lines with gradient unity.The line degenerates to a point, V, at a = 0. XY and UT represent the lines for a=1 and a =0.5 At constant d values a.d on d -f is a family of straight lines radiating from V (a = 0).VW and VY represent the lines for diets of 300 and 1,01)0 mg./day and os values from 0 to 1. T * ~~~~~~~~~~z 0X $U, -SO-2W630-4:L O 0 1000 NET ABSORPTION d-f mq./4..As the figure shows, a.d on d -f, when both a and d vary, represents an area, not a single line.This area shrinks to a straight line if s is independent of a.The line then obtained is VZ, the regression line of Dr. Rose and his colleagues.a.
IMMU-14. ONCOLYTIC VIRUS EXPRESSING A POSITIVE IMMUNE CHECKPOINT MODULATOR AS A THERAPEUTIC APPROACH FOR DIPG
Authors: Virginia Laspidea, Montse Puigdelloses, Ignacio Iñigo-Marco, Marc Garcia-Moure, Iker Ausejo, Jaime Gallego, Juan Fueyo, Candelaria Gomez-Manzano, Marta M Alonso
Journal: Neuro-Oncology (2019)

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor, being the leading cause of pediatric death caused by cancer. We previously showed that administration of the oncolytic virus Delta-24-RGD to DIPG murine models was safe and led to an increase in the median survival of these animals. However, not all the animals responded, underscoring the need to improve this therapy. In order to increase the antitumoral effect of the virus, we have engineered Delta-24-RGD with the costimulatory ligand 4-1BBL (Delta24-ACT). 4-1BB is a costimulatory receptor that promotes the survival and expansion of activated T cells, and the generation and maintenance of memory CD8+ T cells. In this project, we evaluated the oncolytic effect of Delta24-ACT and the antitumor immune response in DIPG murine models. In vitro, Delta24-ACT was able to infect and induce cell death in a dose-dependent manner in murine DIPG cell lines. In addition, Delta24-ACT was able to replicate in these tumor cells and to express viral proteins. Moreover, infected cells expressed 41BBL in their membranes. Delta24-ACT could induce immunogenic cell death due to an increased secretion of ATP and calreticulin translocation to the membrane of infected cells (in no-infected cells it located in the ER), DAMPs that can trigger the immune response activation. In vivo, Delta24-ACT demonstrated to be safe in all the tested doses and was able to induce a significant increase in the median survival of the treated animals. Moreover, long-term survivors display immunological memory. Delta24-ACT treatment led to antitumoral effect in DIPG murine cell lines in vitro. Of significance, we have demonstrated that in vivo administration of Delta24-ACT is safe and results in an enhanced antitumor effect. Future in vivo studies will explore the underlying immune mechanism of the virus.
Evolving Selection of Unrelated Donor for Hematopoietic Stem Cell Transplantation for Patients with β Thalassemia
Authors: Wanxia Tan, Yuelin He, Xiaoqin Feng, Xuedong Wu, Chunfu Li, Jianyun Liao, Xuan Liu, Xiaoting Liu, Yongsheng Ruan, Jianyun Wen, Yuqiong Ren, Fuyu Pei, Qiujun Liu
Journal: Blood (2019)
Anticoagulant Therapy in Acute Myocardial Infarction
Authors: Tage Hilden, Kurt Iversen, Flemming Raaschou, Michael Schwartz
Journal: JAMA (1963)

<h3>To the Editor:</h3> —In a Special Communication (<i>JAMA</i><b>180:</b>307, 1962) Dr. Friedberg has given some critical remarks on our paper "Anticoagulants in Acute Myocardial Infarction" (<i>Lancet</i><b>2:</b>327, 1961). Dr. Friedberg seems to mean that our material is biased because we did not use the method of random selection (alternate case method). We used the method of treating with anticoagulants all patients admitted with acute myocardial infarction to two of the four participating medical departments in Copenhagen for 2 yr, after which time we changed over, so that the treating departments stopped treatment and the two others took up treatment for 2 yr. The four participating departments belong to the Municipality of Copenhagen and all admissions are effected through a Central Office for Admissions, and it must be emphasized that neither the referring physicians in Copenhagen nor the Central Office for Admissions were aware that this clinical trial was
Hypoxia-tropic nanozymes as oxygen generators for tumor-favoring theranostics
Authors: Fangli Gao, Jin Wu, Heqi Gao, Xueyan Hu, Lihua Liu, Adam C. Midgley, Qiqi Liu, Zhiyuan Sun, Yijin Liu, Dan Ding, Yanming Wang, Deling Kong, Xinglu Huang
Journal: Biomaterials (2019)
PDTM-20. THE HISTONE MUTATION H3.3-G34R ENCOUNTERED IN PEDIATRIC HIGH GRADE GLIOMA MODIFIES THE TUMOR IMMUNE MICROENVIRONMENT RENDERING IT MORE PERMISSIVE FOR IMMUNE MEDIATED THERAPIES
Authors: Maria B Garcia-Fabiani, Padma Kadiyala, Santiago Haase, Mahmoud Alghamri, Andrea Comba, Felipe Nunez, Matthew Whalen, Pedro Lowenstein, Maria Castro
Journal: Neuro-Oncology (2019)

Abstract Pediatric high grade gliomas (pHGGs) have a median survival (MS) of 9–15 months and are the most common malignant brain tumors in children. No significant improvement in the MS of these patients has been registered in decades. Thus, a representative in vivo model to study these tumors is critical. Recurrent mutations in genes encoding histones H3.3 and H3.1 have been described, which are distinctive of pHGGs. To stablish a mouse model for pHGG harboring the mutation H3.3-G34R, which co-occurs with inactivating mutations in ATRX and TP53, we used the Sleeping Beauty transposase system (H3.3-G34R group). The MS of mice harboring H3.3-G34R mutation was significantly longer than the MS of the WT-H3.3 control group (p&lt; 0.0001). We performed RNA-Sequencing of these tumors which yielded 233 differentially expressed genes between these two groups (p&lt; 0.05). Gene set enrichment analysis of the upregulated genes in H3.3-G34R group showed significant GOs related to immune response activation and response to IFNγ. Thus, we next studied the tumor microenvironment (TME) to determine the distinctive immune cell populations, at the phenotypic and functional level. We observed that the H3.3-G34R TME exhibited less frequency of Gr-1+/CD11b+ cells (myeloid-derived suppressor cells: MDSC). MDSC are immature myeloid cells that impair T cell functions and the adaptive immune response. Moreover, the H3.3-G34R TME had increased numbers of total macrophages (p&lt; 0.05), a higher proportion of M1 anti-tumor macrophages, and higher levels of CD8+ T cells (p&lt; 0.01). Also, the H3.3-G34R renders glioma cells more sensitive to IFNγ regulation as it induced a higher pSTAT1/STAT1 ratio in H3.3-G34R cells. These results shed light on the interaction between the immune system and the H3.3-G34R glioma cells and how this could be harnessed to develop immune mediated therapies specific for pHGG harboring the H3.3-G34R mutation.
High Complete Response Rate Observed with Second-Line Chemo-Immunotherapy with Pembrolizumab and GVD (Gemcitabine, Vinorelbine, and Liposomal Doxorubicin) in Relapsed and Refractory Classical Hodgkin Lymphoma
Authors: Alison J. Moskowitz, Gunjan L. Shah, Heiko Schoder, Helen Hancock, Theresa Davey, Christopher Joong, Lauren Pomerantz, Christine Jarjies, Anita Kumar, Oscar B Lahoud, Connie Lee Batlevi, Paul A. Hamlin, David J. Straus, Ildefonso Rodriguez-Rivera, Colette Owens, Philip Caron, Donald Steven Colbourn, Andrew M. Intlekofer, Audrey Hamilton, Steven M. Horwitz, Erel Joffe, M. Lia Palomba, Ariela Noy, Matthew J Matasar, Santosha Vardhana, Gottfried R. von Keudell, Joachim Yahalom, Anas Younes, Andrew D. Zelenetz, Craig H. Moskowitz
Journal: Blood (2019)
Results from a First-in-Human, Proof-of-Concept Phase 1 Trial in Pretreated B-Cell Malignancies for Loxo-305, a Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor
Authors: Anthony R. Mato, Ian W. Flinn, John M. Pagel, Jennifer R. Brown, Chan Y. Cheah, Catherine C. Coombs, Manish R. Patel, S. Michael Rothenberg, Donald E. Tsai, Nora C. Ku, Michael L. Wang
Journal: Blood (2019)
Superior Efficacy of CAR-T Cells Using Marrow-Infiltrating Lymphocytes (MILsTM) As Compared to Peripheral Blood Lymphocytes (PBLs)
Authors: Eric R. Lutz, Srikanta Jana, Lakshmi Rudraraju, Elizabeth DeOliveira, Jing Zhou, Sean Mackay, Ivan M. Borrello, Kimberly Noonan
Journal: Blood (2019)
Cryptococcal meningoencephalitis.
Authors: R A Martin, D Bates, D A Shaw
Journal: BMJ (1975)

A patient was admitted to hospital with an apparent psychiatric disturbance. When she became stuporous the cerebrospinal fluid was cultured but proved sterile. The latex test showed that serum was positive for cryptococcal antigens, and cryptococcal meningoencephalitis was diagnosed. Amphotericin B was given but when she developed a toxic reaction it was replaced by flucytosine. She responded well to flucytosine alone and no side effects appeared on continued treatment. Cryptococcal meningitis may present as a psychiatric disturbance, and serological tests are invaluable aids to diagnosis.
Aberrant RNA Splicing Contributes to the Pathogenesis of EVI-Rearranged Myeloid Leukemias
Authors: Daichi Inoue, Stanley C Lee, Akihide Yoshimi, Justin Taylor, Lillian E Bitner, Atsushi Tanaka, Yasutaka Hayashi, Hana Cho, Chie Fukui, Ruth Saganty, Alexander V Penson, Omar Abdel-Wahab
Journal: Blood (2019)
High-fat diet exacerbates SIV pathogenesis and accelerates disease progression
Authors: Tianyu He, Cuiling Xu, Noah Krampe, Stephanie M. Dillon, Paola Sette, Elizabeth Falwell, George S. Haret-Richter, Tiffany Butterfield, Tammy L. Dunsmore, William M. McFadden, Kathryn J. Martin, Benjamin B. Policicchio, Kevin D. Raehtz, Ellen P. Penn, Russell P. Tracy, Ruy M. Ribeiro, Daniel N. Frank, Cara C. Wilson, Alan L. Landay, Cristian Apetrei, Ivona Pandrea
Journal: Journal of Clinical Investigation (2019)

Consuming a high-fat diet (HFD) is a risk factor for obesity and diabetes; both of these diseases are also associated with systemic inflammation, similar to HIV infection. A HFD induces intestinal dysbiosis and impairs liver function and coagulation, with a potential negative impact on HIV/SIV pathogenesis. We administered a HFD rich in saturated fats and cholesterol to nonpathogenic (African green monkeys) and pathogenic (pigtailed macaques) SIV hosts. The HFD had a negative impact on SIV disease progression in both species. Thus, increased cell-associated SIV DNA and RNA occurred in the HFD-receiving nonhuman primates, indicating a potential reservoir expansion. The HFD induced prominent immune cell infiltration in the adipose tissue, an important SIV reservoir, and heightened systemic immune activation and inflammation, altering the intestinal immune environment and triggering gut damage and microbial translocation. Furthermore, HFD altered lipid metabolism and HDL oxidation and also induced liver steatosis and fibrosis. These metabolic disturbances triggered incipient atherosclerosis and heightened cardiovascular risk in the SIV-infected HFD-receiving nonhuman primates. Our study demonstrates that dietary intake has a discernable impact on the natural history of HIV/SIV infections and suggests that dietary changes can be used as adjuvant approaches for HIV-infected subjects, to reduce inflammation and the risk of non-AIDS comorbidities and possibly other infectious diseases.
IPO11 Is Upregulated in Relapsed AML and Supports Survival of Leukemic Stem Cells
Authors: Boaz Nachmias, Veronique Voisin, Rose Hurren, Xioaming Wang, Neil Maclean, G. Wei Xu, Ayesh K Seneviratne, Changjiang Xu, Gary D Bader, Liran I. Shlush, Aaron D Schimmer
Journal: Blood (2019)