tbuckley/cabot-search huggingface dataset:
EXTH-17. CDK7 IS A NOVEL THERAPEUTIC TARGET IN HIGH GRADE GLIOMA
Authors: Terrance Johns, Sameer Greenall
Journal: Neuro-Oncology (2016)

Cyclin dependent kinase 7 (CDK7), is a kinase that facilitates cell cycle progression and stabilises RNA polymerase II-based transcription. THZ1 is a novel irreversible inhibitor of CDK7 whose mechanism(s) of action are largely unknown. We now show that low nanomolar THZ1 has profound antitumor activity against high grade glioma (HGG) patient-derived cell lines and ex vivo HGG tissue slices. CDK7 appears indispensable for gliomagenesis as THZ1 perturbed the transcriptome and disabled CDK activation, leading to cell cycle arrest and DNA damage. THZ1 halted transcription of mitochondrial ribosomal genes, reducing mitochondrial translation and oxidative respiration. It also inhibited the expression of RTKs such EGFR and PDGFR, reducing signalling flux through downstream pathways. Finally, THZ1 disrupted nucleolar, Cajal-body and nuclear speckle formation resulting in reduced cytosolic translation and aberrant mRNA splicing. These studies validate CDK7 as a therapeutic target in HGG and provide new mechanistic insights into the antitumor activity of THZ1.
Clinical utility of the Revised International Staging System in unselected patients with newly diagnosed and relapsed multiple myeloma
Authors: N Tandon, S V Rajkumar, B LaPlant, A Pettinger, M Q Lacy, A Dispenzieri, F K Buadi, M A Gertz, S R Hayman, N Leung, R S Go, D Dingli, P Kapoor, Y Lin, Y L Hwa, A L Fonder, M A Hobbs, S R Zeldenrust, J A Lust, W I Gonsalves, S J Russell, S K Kumar
Journal: Blood Cancer Journal (2017)

Abstract We analyzed the utility of Revised International staging system (RISS) in an unselected cohort of newly diagnosed multiple myeloma (NDMM; cohort 1), and relapsed/refractory multiple myeloma (RRMM; cohort 2) patients. Cohort 1 included 1900 patients seen within 90 days of diagnosis, from 2005 to 2015, while cohort 2 had 887 patients enrolled in 23 clinical trials at Mayo Clinic. The overall survival (OS) and progression-free survival (PFS) was calculated from the time since diagnosis or trial registration. The median estimated follow up was 5 and 2.3 years for Cohorts 1 and 2, respectively. Among 1067 patients evaluable in Cohort 1, the median OS and PFS was 10 and 2.8 years for RISS stage I, 6 and 2.7 years for RISS stage II and 2.6 and 1.3 years for RISS stage III ( P &lt;0.0001). Among 456 patients evaluable in Cohort 2, the median OS and PFS was 4.3 and 1.1 years for RISS stage I, 2 and 0.5 years for RISS stage II and 0.8 and 0.2 years for RISS stage III ( P &lt;0.0001). In conclusions, RISS gives a better differentiation of NDMM as well as RRMM patients into three survival subgroups and should be used to stratify patients in future clinical trials.
<i>CHFR</i> promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer.
Authors: Manon van Engeland, Arjen Cleven, Sarah Derks, Muriel XG Draht, Kim M Smits, Veerle Melotte, Matty P Weijenberg, James Gordon Herman, Adriaan P de Bruïne, Wim Van Criekinge
Journal: Journal of Clinical Oncology (2013)

e14503 Background: Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here we examine the prognostic impact of promoter methylation in CRC patients treated with surgery alone in the context of microsatellite instability (MSI), BRAF- and KRAS mutations. Methods: 173 CRCs were analyzed for promoter methylation of 19 tumor suppressor- and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations. Results: Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 (CL1, 57% (98/173) of CRCs), cluster 2 (CL2, 25% (43/173) of CRCs) and cluster 3 (CL3, 18% (32/173) of CRCs). CL3 had the highest methylation index (0.25, 0.49 and 0.69 respectively, p=&lt;0.01) and was strongly associated with CIMP (p&lt;0.01). After stratification for tumor stage, MSI and BRAF status, no statistically significant differences in survival between CL1, CL2 and CL3 nor between CIMP and non-CIMP CRCs were detected. Analyzing genes separately revealed that CHFR promoter methylation was associated with a poor prognosis in stage II, MSS, BRAF wild-type CRCs: HR=3.89 (95% CI =1.58-9.60, p=0.003) and HR=2.21 (95% CI =1.09-4.48, p=0.03) in a second population-based study (n=151). Conclusions: CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF wild-type CRCs.
Incidence of Hyperglycemia by 3 Years in Patients (Pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Nilotinib (NIL) or Imatinib (IM) in ENESTnd
Authors: Rea Delphine, Jean-francois Gautier, Massimo Breccia, Giuseppe Saglio, Timothy P. Hughes, Hagop M. Kantarjian, Charisse Kemp, Haitao Gao, Carmen Piccolo, Richard A. Larson, Andreas Hochhaus
Journal: Blood (2012)
EXTH-53. STEALTH LIPID NANO-ENCAPSULATION ENABLES EFFICACIOUS THERAPEUTIC RNA INTERFERENCE IN MALIGNANT GLIOMA
Authors: Peng Zhang, Dou Yu, Yu Han, Meijing Wu, Maciej Lesniak
Journal: Neuro-Oncology (2016)

Glioblastoma multiforme (GBM) is the most common and challenging primary brain malignancy in adults. A panel of miRNA has been recognized for effectively governing GBM progression, invasion, and stem-like traits, among which, miR-124 demonstrates a combinatorial role in repression of glioma malignancy, and is missing in glioma. Effective delivery of gene medicine to precisely regulate malignant glioma is an attractive approach, however, limitations of intratumoral oligonucleotide distribution are major hurdles for translatable therapeutic development. Lipid nano-encapsulation of GBM-targeting miRNA/siRNA represents a promising therapeutic strategy. We hypothesize that stealth lipid nano-encapsulation of miR-124 or siRNAs targeting miR-124 downstream targets maximizes translatable therapeutic efficacy for GBM. The stealth lipid nanovectors were fabricated through a thin-film rehydration and extrusion method, and surface engineered with a PEG corona to avoid premature clearance. A set of lipid components including cationic lipids and helper lipids were screened for maximal RNA payload encapsulation. The lipid vectors were then characterized via DLS and zeta-potential. The lipid vectors are uniform in size (< 90 nm in diameter), and show high RNA encapsulation efficiency. Flow cytometric analysis indicates rapid uptake of nano-encapsulated miR-124 or siRNAs into human glioma cells within 1 hour. In vitro luciferase assay demonstrated a 90% downregulation of luciferase expression by lipid encapsulated fluc siRNA; and cell viability assay indicated a significantly improved safety profile over Lipofectamine 2000. Significantly reduced luciferase activity was observed in mice treated with lipid nano-encapsulated fluc siRNA. Moreover, lipid nano-encapsulated miR-124 reduced gene expression of a panel of stemness promoting, therapy resistant, and tumor associated angiogenic genes in human glioma U87, U251, and patient derived GBM43 cells. This study establishes a versatile, safe, and efficacious translational strategy for nano-encapsulated RNA interference against GBM, with strong potential for multiplexed lipid nano-siRNA therapeutic actions that impede tumor growth and invasion.
Randomized phase II study of nimotuzumab, an anti-EGFR antibody, plus irinotecan in patients with 5-fluorouracil–based regimen-refractory advanced or recurrent gastric cancer in Korea and Japan: Preliminary results.
Authors: Y. H. Kim, Y. Sasaki, K. H. Lee, S. Y. Rha, S. Park, N. Boku, Y. Komatsu, T. Kim, S. Kim, Y. Sakata
Journal: Journal of Clinical Oncology (2011)

87 Background: Nimotuzumab is a humanized IgG1 anti-EGFR monoclonal antibody. In previous studies, nimotuzumab has demonstrated efficacy associated with an absence of severe skin toxicity, commonly caused by other EGFR-targeting therapies. Methods: This is a Korea and Japan collaborative, multi-center, randomized, open-label study of nimotuzumab (400 mg, IV q1 week) plus irinotecan (150 mg/m 2 IV q2 weeks) (N+I) versus irinotecan (I) in patients with advanced or metastatic gastric cancer refractory to 5-fluorouracil-based regimen. The primary endpoint was PFS with an external review and the secondary endpoints included safety, ORR, OS, PK, and a biomarker. Results: Eighty-two eligible patients (ECOG PS 0-1, one prior regimen) were treated with N+I (n = 40) or I (n = 42). Baseline characteristics were balanced between both arms. Archival tumor tissues collected from 48 patients (N+I arm: 26, I arm: 22) were analyzed for EGFR and K-ras. EGFR status, 0/1+/2+/3+, examined by immunohistochemistry was 44%/25%/13%/17%, respectively. Two patients in N+I arm had a K-ras mutation in codon 12 or 13. The efficacy analysis was conducted 6 months after completion of randomization with median follow-up period of 197 days. Median PFS was 73.0 days in N+I arm compared with 85.0 days in I arm (HR 0.860; 95% CI, 0.516, 1.435). MST was 293.0 days in N+I arm compared with 227.0 days in I arm (HR 0.717; 95% CI, 0.420, 1.224). In the sub-analysis, the hazard ratio in PFS for patients with EGFR +1/2+/3+ was 0.463 (95%CI, 0.177, 1.212) and that of EGFR 2+/3+ was 0.341 (95% CI, 0.080, 1.457) and the hazard ratio in OS was 0.584 (95% CI, 0.242, 1.409) and 0.295 (95% CI, 0.077, 1.129), respectively. The incidence of adverse events was similar between both arms. No adverse events of grade 3 skin rash or grade 3 infusion-related reaction were reported. Conclusions: These results didn't demonstrate clear benefit at this sample size. However, EGFR-positive patients treated nimotuzumab showed a potential improvement of PFS and OS. This study supports the selection of gastric cancer patients by molecular status for future study of nimotuzumab. [Table: see text]
Safety and Efficacy of Low Dose CD19 Targeted Chimeric Antigen Receptor T (CAR-T) Cell Immunotherapy in 47 Cases with Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia (B-ALL)
Authors: Biping Deng, Alex Hongsheng Chang, Junfang Yang, Jing Pan, Xian Zhang, Yuehui Lin, Yanan Wu, Zhenling Deng, Peihua Lu, Tong Wu, Zhaoli Liu, Yu'e Zhang, Chunrong Tong
Journal: Blood (2016)
Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial
Authors: Mark A. Exley, Phillip Friedlander, Nadia Alatrakchi, Lianne Vriend, Simon Yue, Tetsuro Sasada, Wanyong Zeng, Yo Mizukami, Justice Clark, David Nemer, Kenneth LeClair, Christine Canning, Heather Daley, Glenn Dranoff, Anita Giobbie-Hurder, F. Stephen Hodi, Jerome Ritz, Steven P. Balk
Journal: Clinical Cancer Research (2017)

Purpose: Invariant NKT cells (iNKT) are innate-like CD1d-restricted T cells with immunoregulatory activity in diseases including cancer. iNKT from advanced cancer patients can have reversible defects including IFNγ production, and iNKT IFNγ production may stratify for survival. Previous clinical trials using iNKT cell activating ligand α-galactosylceramide have shown clinical responses. Therefore, a phase I clinical trial was performed of autologous in vitro expanded iNKT cells in stage IIIB-IV melanoma.Experimental Design: Residual iNKT cells [<0.05% of patient peripheral blood mononuclear cell (PBMC)] were purified from autologous leukapheresis product using an antibody against the iNKT cell receptor linked to magnetic microbeads. iNKT cells were then expanded with CD3 mAb and IL2 in vitro to obtain up to approximately 109 cells.Results: Expanded iNKT cells produced IFNγ, but limited or undetectable IL4 or IL10. Three iNKT infusions each were completed on 9 patients, and produced only grade 1-2 toxicities. The 4th patient onward received systemic GM-CSF with their second and third infusions. Increased numbers of iNKT cells were seen in PBMCs after some infusions, particularly when GM-CSF was also given. IFNγ responses to α-galactosylceramide were increased in PBMCs from some patients after infusions, and delayed-type hypersensitivity responses to Candida increased in 5 of 8 evaluated patients. Three patients have died, three were progression-free at 53, 60, and 65 months, three received further treatment and were alive at 61, 81, and 85 months. There was no clear correlation between outcome and immune parameters.Conclusions: Autologous in vitro expanded iNKT cells are a feasible and safe therapy, producing Th1-like responses with antitumor potential. Clin Cancer Res; 23(14); 3510-9. ©2017 AACR.
Fusion Cell Vaccination in Conjunction with Stem Cell Transplantation Is Well Tolerated, Induces Anti-Tumor Immunity and Is Associated with Responses in Patients with Multiple Myeloma
Authors: Davi D Avigan, Jacalyn Rosenblatt, Baldev Vasir, Zekui Wu, Adam Bissonnette, Poorvi Somaiya, Claire MacNamara, Lynne Uhl, Irit Avivi, Tami Katz, Corrine Zarwan, Robin Joyce, James D. Levine, Vassiliki Boussiotis, Dimitrios Tzachanis, Karen Lowe, Dilani Dombagoda, Nancy Giallombardo, Jamie Mortellite, Katharine Conway, Donna Fitzgerald, Paul Richardson, Kenneth Anderson, Nikhil C. Munshi, Michal Tsumer, Lina Bisharat, Jacob Rowe, Donald Kufe
Journal: Blood (2008)
Methylguanine Methyltransferase-Based In Vivo Selection Results in Only Transient Improvement in Long-Term Marking after Autologous Transplantation of Transduced Hematopoietic Stem Cells in Rhesus Macaques.
Authors: Andre Larochelle, Uimook Choi, Nora Naumann, Josh R. Clevenger, Harry L. Malech, Cynthia E. Dunbar
Journal: Blood (2006)
Phosphodiesterase-4 Inhibition Reduces Ischemic/Reperfusion Liver Injury in a Mouse Model for Sickle Cell Disease.
Authors: Alida Filippini, Giorgio Malpeli, Anne Janin, Orah S Platt, Christhope Leboeuf, Aldo Scarpa, Yves Beuzard, Lucia De Franceschi
Journal: Blood (2008)
Ruxolitinib Remains Effective in Myelofibrosis after the Necessary Dose Reductions: Real-Life Data from a Multi-Center Observational Study
Authors: Damianos Sotiropoulos, Vassilios Papadopoulos, Maria Dimou, Despoina Kyriakou, George Papaioannou, George Karavalakis, Chara Giatra, Alexandra Kourakli, Polyxeni Lampropoulou, Maria Palasopoulou, Anastasia Banti, Nora-Athina Viniou, Theodoros Marinakis, Eleftheria Hatzimichael, Evdoxia Hatjiharissi, Diamantina Vasilatou, Emmanuel Papadakis, George Vassilopoulos, Panagiotis Repousis, Taxiarchis Kourelis, Nikolaos Harhalakis, Argiris S. Symeonidis, Panayiotis Panayiotidis, Achilles Anagnostopoulos
Journal: Blood (2016)
Rothman index as a predictor for type of discharge and readmission rates in a cancer hospital: The Yale experience.
Authors: Daniel Morgensztern, Bing Xia, Chryssanthi S. Kournioti, Erin Wysong Hofstatter, Maureen Raucci, Ashley Keyes, Alienne Morrione, Elizabeth Blasiak, Elizabeth Rosenberg, Joan Rimar, Michael J Rothman, Rogerio Lilenbaum
Journal: Journal of Clinical Oncology (2013)

6635 Background: There is limited data on predictors of discharge (DC) and readmission (RA) for oncology inpatients. The Rothman index (RI) is a single score calculated from 26 parameters including nursing assessments, vital signs, and laboratory tests, integrated with the hospital’s electronic medical record and automatically updated when new data are entered. Scores are inversely related to patient impairment. We evaluated the role of RI in the prediction of DC types and RA rates at the Smilow Cancer Hospital at Yale. Methods: Patients (pts) with solid tumors, length of stay longer than 24 hours, admitted between 6/1/11 and 12/31/11 were enrolled. Elective admissions were excluded. DC types were classified as home without hospice (Hm), nursing home (NH), hospice (Hp) and death (D). The RI at the time of DC was evaluated as a predictor for RA at 7 or 30 days and the type of DC. Analysis of variance (ANOVA) was used to determine whether there were statistically significant differences between RI means and DC categories, followed by pair-wise contrast using the Tukey method. Results: Among the 476 admissions from 331 pts, the median age was 63 (range 21-92, 23% age 70 or older), and 55% males. The most common tumors were lung (24%) and breast (8%). The number of DCs were 313 Hm (66%), 75 NH (16%), 55 Hp (11%) and 33 D (7%). RI at DC for H, NH, Hp and D were 74, 62, 47 and 23. All comparisons among RI at DC and type of DC were significant (p &lt; 0.05). Among the Hm pts, the rates of RA at 7 days were significantly higher for RI &lt; 50 (45%) and 50-60 (32%) compared to 81-90 (13%) and &gt; 90 (7%) (Table). RA rates at 30 days were also related to RI at DC, ranging from 65% in RI &lt; 50 to 33% in RI &gt; 90. Conclusions: RI is a useful tool in the evaluation of inpatients by providing an objective metric at the time of DC. The high correlation between RI scores and both DC type and RA rate underscores the need for a more consistent and reproducible evaluation at the time of DC and may be used by health care providers to guide disposition planning. A prospective study is being planned at our institution. [Table: see text]
Why has mortality in England and Wales been increasing? An iterative demographic analysis
Authors: Lucinda Hiam, Danny Dorling, Dominic Harrison, Martin McKee
Journal: Journal of the Royal Society of Medicine (2017)

Objectives To understand why mortality increased in England and Wales in 2015. Design Iterative demographic analysis. Setting England and Wales Participants Population of England and Wales. Main outcome measures Causes and ages at death contributing to life expectancy changes between 2013 and 2015. Results The long-term decline in age-standardised mortality in England and Wales was reversed in 2011. Although there was a small fall in mortality rates between 2013 and 2014, in 2015 we then saw one of the largest increases in deaths in the post-war period. Nonetheless, mortality in 2015 was higher than in any year since 2008. A small decline in life expectancy at birth between 2013 and 2015 was not significant but declines in life expectancy at ages over 60 were. The largest contributors to the observed changes in life expectancy were in those aged over 85 years, with dementias making the greatest contributions in both sexes. However, changes in coding practices and diagnosis of dementia demands caution in interpreting this finding. Conclusions The long-term decline in mortality in England and Wales has reversed, with approximately 30,000 extra deaths compared to what would be expected if the average age-specific death rates in 2006-2014 had continued. These excess deaths are largely in the older population, who are most dependent on health and social care. The major contributor, based on reported causes of death, was dementia but caution was advised in this interpretation. The role of the health and social care system is explored in an accompanying paper.
Multiple Time-Point 68Ga-PSMA I&amp;T PET/CT for Characterization of Primary Prostate Cancer
Authors: Sebastian Schmuck, Martin Mamach, Florian Wilke, Christoph A. von Klot, Christoph Henkenberens, James T. Thackeray, Jan M. Sohns, Lilli Geworski, Tobias L. Ross, Hans-Juergen Wester, Hans Christiansen, Frank M. Bengel, Thorsten Derlin
Journal: Clinical Nuclear Medicine (2017)

Purpose The aims of this study were to gain mechanistic insights into prostate cancer biology using dynamic imaging and to evaluate the usefulness of multiple time-point 68Ga–prostate-specific membrane antigen (PSMA) I&T PET/CT for the assessment of primary prostate cancer before prostatectomy. Methods Twenty patients with prostate cancer underwent 68Ga-PSMA I&T PET/CT before prostatectomy. The PET protocol consisted of early dynamic pelvic imaging, followed by static scans at 60 and 180 minutes postinjection (p.i.). SUVs, time-activity curves, quantitative analysis based on a 2-tissue compartment model, Patlak analysis, histopathology, and Gleason grading were compared between prostate cancer and benign prostate gland. Results Primary tumors were identified on both early dynamic and delayed imaging in 95% of patients. Tracer uptake was significantly higher in prostate cancer compared with benign prostate tissue at any time point (P ≤ 0.0003) and increased over time. Consequently, the tumor-to-nontumor ratio within the prostate gland improved over time (2.8 at 10 minutes vs 17.1 at 180 minutes p.i.). Tracer uptake at both 60 and 180 minutes p.i. was significantly higher in patients with higher Gleason scores (P < 0.01). The influx rate (Ki) was higher in prostate cancer than in reference prostate gland (0.055 [r = 0.998] vs 0.017 [r = 0.996]). Conclusions Primary prostate cancer is readily identified on early dynamic and static delayed 68Ga-PSMA ligand PET images. The tumor-to-nontumor ratio in the prostate gland improves over time, supporting a role of delayed imaging for optimal visualization of prostate cancer.
BMET-12. IS CISTERNAL PUNCTURE UNDERUTILIZED?
Authors: Yoshie Umemura, Katherine Panageas
Journal: Neuro-Oncology (2016)

To investigate the utility of cisternal puncture (CP) in current neuro-oncologic clinical practice. CSF examination is indicated in various neurological disorders including infection, inflammation, and malignancy. Suspicion of leptomeningeal disease (LMD) may require multiple lumbar punctures (LPs) before a definitive diagnosis is reached. Despite multiple LPs, a diagnosis oftentimes remains elusive. Evidence for the utility of CP after non-diagnostic LP remains lacking. We undertook a retrospective review of CPs performed at Memorial Sloan Kettering Cancer Center from 12/2009 to 1/2016. The records of 50 patients were included for analysis. Cancer diagnoses included primary brain tumors (N=11), systemic solid cancers (N=15), systemic hematologic malignancies (N=15), and some had no cancer (N=9). LPs were non-diagnostic in 34 patients prior to CPs. In 16 patients, no prior LP was done for the presenting problem; LP was contraindicated (N=10) or CP was presumed to have a higher diagnostic yield (N=6). Diagnostic CPs were undertaken in 48 patients to evaluate suspected LMD (N=21), both LMD and parenchymal disease in a surgically unfavorable location (N=13), parenchymal disease only (N=11), and CNS infection (N=3). Findings from these CPs altered clinical management in 15 patients (32%): 10 began chemotherapy, 1 received IVIG for confirmed paraneoplastic syndrome, infection was ruled out in 2 patients; 2 others were treated for confirmed CNS infections. In 5 patients with prior non-diagnostic LPs, LMD was diagnosed by subsequent CPs. Therapeutic palliative CPs in 2 patients to remove CSF improved LMD symptoms in both patients. There were no immediate or delayed complications related to the CP procedure. CP is diagnostically and therapeutically useful in both malignancy and non-malignant CNS disease. The procedure is well-tolerated and can change clinical management. CP should be considered in patients for whom LP is contraindicated or non-diagnostic.