tbuckley/cabot-search huggingface dataset:
ENGINE: Phase III randomized study of enzastaurin/R-CHOP versus placebo/R-CHOP in frontline high-risk diffuse large B-cell lymphoma patients with novel genomic biomarker DGM1.
Authors: Stephen Smith, Jun Zhu, Owen A. O'Connor, Wen Luo, Ronald L. Shazer, Lei Zhang, Isabel Han, Manoj A. Jivani, Young Liu, Grzegorz S. Nowakowski
Journal: Journal of Clinical Oncology (2019)

TPS7569 Background: Progress in genome technology allows analysis of previously completed trials to identify patients subgroups potentially benefiting from therapy. Enzastaurin is a potent inhibitor of protein kinase C beta (PKC- b) and suppresses the phosphoinositide 3-kinase (PI3K)/AKT pathway. The safety and efficacy of Enzastaurin has been tested in more than 60 clinical trials including 2 major studies in DLBCL: (1) PRELUDE (A phase III maintenance trial of Enzastaurin vs Placebo, N=758) ( Crump, 2016), and (2) S028 (A randomized phase II study of Enzastaurin/R-CHOP vs R-CHOP in frontline intermediate/high-risk DLBCL, N=101) ( Hainsworth, 2016). DNA samples extracted from blood of patients from PRELUDE were retrospectively genotyped using whole genome SNP arrays. From the genome wide screening a novel genetic biomarker, DGM1, was identified showing high correlation with response to Enzastaurin treatment ( Luo, ASH 2018). Importantly, these findings were replicated in the phase II S028 study. In the S028 study the hazard ratio (HR) for OS in high-risk (IPI ≥ 3) DGM1 positive (+) patients who received Enzastaurin/R-CHOP was 0.28 (0.1-0.81) when compared to subjects who received R-CHOP, a benefit favoring Enzastaurin (p=0.018). These data suggest that addition of Enzastaurin to R-CHOP may significantly improve outcome in frontline high-risk DGM1 (+) DLBCL. The ENGINE study was initiated to validate this finding in a prospective study. Methods: Adult patients must have untreated CD20+ DLBCL, IPI ≥ 3. Patients are randomized 1:1 to Enzastaurin/R-CHOP or Placebo/R-CHOP for 6 cycles during combination phase. Each subject’s treatment assignment will be unblinded after response assessment at the end of the combination phase. Subjects randomized to the investigational arm who have a complete or partial response will have the option to continue in the single agent phase to receive Enzastaurin for up to 2 additional years. The study intends to enroll approximately 235 patients with primary endpoint of OS in DGM1 (+) patients. The study is ongoing with 51 sites open in the US and China. As of 22 Jan 2019, 70 patients have been randomized. Clinical trial information: NCT03263026.
Abstract 14151: Transthoracic Echocardiographic Assessment of Normal Left Ventricular Assist Device Function
Authors: yan topilsky, Jae K Oh, Fawn W Atchison, Dipesh K Shah, Barry Boilson, John A Schirger, Sudhir S Kushwaha, Brooks S Edwards, Naveen L Pereira, Soon J Park
Journal: Circulation (2010)

Continuous flow left ventricular assist devices (LVAD) are emerging to become the standard of care for the treatment of advanced heart failure. However, knowledge of normal values for transthoracic echocardiographic (TTE) examination and measurements in these patients are lacking. Methods: We retrospectively analyzed all TTE examinations in 63 consecutive patients, performed at 90 and 180 days after surgery with implantation of a HeartMate II continuous flow LVAD between February 2007 and January 2010. All patients had to be considered stable on LVAD therapy, without the need for inotropic support at the time of examination. Results: End diastolic and end systolic diameters, and left ventricle mass decreased considerably. Mitral inflow deceleration time prolonged, left atrial volume and E/e' ratio decreased, all consistent with decreased left ventricular filling pressure. Estimated right ventricular (RV), and right atrial pressure decreased significantly. Quantitatively estimated RV function and the right...
Abstract 1486: The immune atlas and chemokine profile of giant cell tumor of bone
Authors: Binghao Li, Zhan Wang, Zhaoming Ye
Journal: Cancer Research (2019)

Abstract Background and purpose: Giant cell tumor of bone (GCTB) is a locally aggressive tumor with metastatic potential. Given that GCTBs are composed of three major cell populations and the bone-resorption activity is attributed to the multinucleated giant cells which are conjectured to be recruited by “real” tumor cells, it is still elusive that how and what are these immune cells recruited. The purpose of this study is to present the immune landscape of GCTB, as well as to find out responsible chemokines during immune cell recruiting. Experimental procedures: We collected fresh GCTB tissues from surgical excisions. To identify immune cell composition within the tumor microenvironment, we performed mass cytometry (CyTOF) and conventional multicolor cytometry. Some fresh osteosarcoma and chondrosarcoma samples were also used to compare the immune atlas. For chemokine profiling, chemokine arrays were utilized. Further analysis on potential association between chemokines and immune cells were conducted. Results: For last updated, 47 GCTB fresh samples were collected, of which 12 cases received CyTOF analysis and the rest 35 samples were analyzed by multicolor cytometry. All GCTB samples were analyzed by chemokine array In-depth interrogation of the immune landscapes showed that compared with osteosarcoma and chondrosarcoma, GCTBs had some unique immune cell subgroups. Some CD163+ CD206+ macrophage clusters which expressed various immune suppressive markers were significantly enriched in GCTBs, while CD4+ CD25+ Treg cells were fewer in GCTB. In addition, some macrophage-like mononuclear cells (CD14- CD68+ CD163- CD206+ HLA-DR+) were only seen in GCTBs.Chemokine array revealed that higher levels of CXCL12, CCL22, and CCL7 might be associated with moremacrophage-like mononuclear cells in GCTBs. Conclusion: GCTB have very different immune features from other malignant bone tumors. Multiple chemokines may play important roles in recruiting “functional” monocytes. Such in-depth understanding has important implications in appropriate therapeutics for GCTB. Bigger sample size will further help in studying the immune and chemokine features of GCTB. Note: This abstract was not presented at the meeting. Citation Format: Binghao Li, Zhan Wang, Zhaoming Ye. The immune atlas and chemokine profile of giant cell tumor of bone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1486.
A milestone on the journey to a digital NHS
Authors: Talha Burki
Journal: The Lancet Digital Health (2019)

Digital health featured prominently in the 2019 NHS Long Term Plan. An entire chapter was devoted to outlining how “digitally-enabled primary and secondary care will go mainstream across the NHS”. Within the next five years, all patients in England will be entitled to online digital consultations with a general practitioner (GP), and women will be able to access their maternity notes, with their smartphone or other connected device. The long-term plan mentioned digital tools in connection with all kinds of conditions, including cancer, cardiovascular disease, chronic obstructive pulmonary disease, diabetes, mental health disorders, and musculoskeletal problems.
Parallel Evolution of HIV-1 in a Long-Term Experiment
Authors: Frederic Bertels, Christine Leemann, Karin J Metzner, Roland R Regoes
Journal: Molecular Biology and Evolution (2019)

Abstract One of the most intriguing puzzles in biology is the degree to which evolution is repeatable. The repeatability of evolution, or parallel evolution, has been studied in a variety of model systems, but has rarely been investigated with clinically relevant viruses. To investigate parallel evolution of HIV-1, we passaged two replicate HIV-1 populations for almost 1 year in each of two human T-cell lines. For each of the four evolution lines, we determined the genetic composition of the viral population at nine time points by deep sequencing the entire genome. Mutations that were carried by the majority of the viral population accumulated continuously over 1 year in each evolution line. Many majority mutations appeared in more than one evolution line, that is, our experiments showed an extreme degree of parallel evolution. In one of the evolution lines, 62% of the majority mutations also occur in another line. The parallelism impairs our ability to reconstruct the evolutionary history by phylogenetic methods. We show that one can infer the correct phylogenetic topology by including minority mutations in our analysis. We also find that mutation diversity at the beginning of the experiment is predictive of the frequency of majority mutations at the end of the experiment.
Abstract 4834: Effective treatment of squamous cell carcinoma of the head and neck (HNSCC) using a combined regimen of tipifarnib and cetuximab
Authors: Lihua Shu, Dongsheng Wang, Sreenivas Nannapaneni, Dong M. Shin, Nabil F. Saba, Georgia Z. Chen
Journal: Cancer Research (2019)

Abstract Background: H-RAS driven carcinogenesis has been reported in many types of cancer including squamous cell carcinoma of the head and neck (HNSCC). The mutation rate of H-RAS in HNSCC is 4 - 8%. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). It is known that H-RAS, but not K-RAS and N-RAS, is delocalized into cytoplasm and inactivated by farnesyltransferase inhibitors (FTI), such as tipifarnib. Tipifarnib has demonstrated proof of concept activity in H-RAS mutant HNSCC in an ongoing clinical trial (NCT02383927). In this study, we examined H-RAS associated signaling pathway in HNSCC cell lines and PDX models to see if inhibition of wild-type HRAS signaling could re-sensitize cetuximab resistant cells and tumors to inhibition by cetuximab. UMSCC47 and SCC1-C are both H-RAS wild-type HNSCC cell lines, and SCC1-C is resistant to EGFR targeted therapy. Methods: In vitro cell growth with and without tipifarnib and/or cetuximab treatments were examined by Sulforhodamine B (SRB) and colony formation assay. Patient derived xenograft (PDX) models were then used to study the efficacy of the tipifarnib treatment as a single agent or in combination with cetuximab. Western blot analyses were performed to verify the effect of these treatments on EGFR/ERK/AKT signaling pathways. Results: Our results showed that tipifarnib could inhibit HNSCC growth, both in vitro and in the PDX model in a dose-dependent manner (control vs the low dose of tipifarnib, p = 0.02; control vs the high dose of tipifarnib, p = 0.001). However, the combined treatment with cetuximab significantly enhanced tipifarnib efficacy in the H-RAS wild type setting, particularly in the PDX model (control vs tipifarnib, p = 0.123; control vs cetuximab, p = 0.022; control vs the combination, p = 0.010). Western blot analyses showed that neither ERK nor AKT phosphorylation was effectively reduced after a prolonged treatment (48 hours) with tipifarnib alone. However, the addition of cetuximab reduced pERK. Conclusions: Our study demonstrates that cetuximab enhances the anti-tumor effect of tipifarnib in the H-RAS wild type setting through ERK inhibition. This study supports the rationale for combining tipifarnib with EGFR inhibitors as a possible effective therapeutic approach in HNSCC. Citation Format: Lihua Shu, Dongsheng Wang, Sreenivas Nannapaneni, Dong M. Shin, Nabil F. Saba, Georgia Z. Chen. Effective treatment of squamous cell carcinoma of the head and neck (HNSCC) using a combined regimen of tipifarnib and cetuximab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4834.
Abstract 2297: Anti-labyrinthin monoclonal antibody reduces human adenocarcinoma circulating tumor cells in the blood of patient-derived xenograft models and inhibits the growth of adenocarcinoma cell cultures
Authors: Natalia Saleev, Netta R. Blondheim-Shraga, Evgeny Solomonov, Shiran Shapira, Izhak Haviv, Solomon M. Stemmer, Hanoch Slor
Journal: Cancer Research (2019)

Abstract Labyrinthin is a 255-amino acid protein antigen that is expressed on the cell-surface of most adenocarcinoma tumors and is not expressed on the surface of most normal cells, which makes it an attractive candidate for targeted therapy. Originally, labyrinthin had been deduced to be a product of a large deletion in the gene coding for junctate. We found that the junctate gene in labyrinthin-expressing adenocarcinoma cells does not have any deletion, and we propose that the labyrinthin protein is a splice variant of the junctate gene. This study aimed to determine the effects of an anti-labyrinthin monoclonal antibody, on adenocarcinoma cells in vitro and on patient-derived xenograft (PDX) models in vivo. Lung, breast and colorectal adenocarcinoma cell lines, as well as a primary-cell culture of a colorectal adenocarcinoma patient, were assessed for cell surface expression of labyrinthin. The cells were then incubated in the presence of the anti-labyrinthin antibody and growth rate was monitored by live imaging methods. Untreated primary-cell cultures of the colorectal adenocarcinoma patient were also grafted to immunodeficient mice to produce PDX tumors. When establishment of palpable tumors was observed, the mice were injected with the antibody. Peripheral blood was sampled from the mice and circulating tumor cells (CTCs) were quantified by flow cytometry. A significant reduction of approximately 60% was detected in the number of CTCs in the peripheral blood of the antibody-treated PDX mice compared to untreated control PDX mice. Additionally, a significant reduction was measured in the growth-rate of cultured primary cells and in lung, breast and colorectal adenocarcinoma cell lines in the presence of the antibody. We conclude that the anti-labyrinthin antibody has an inhibitory effect on the formation of adenocarcinoma CTCs in vivo as well as on the growth rate of cultured adenocarcinoma tumor cells. Citation Format: Natalia Saleev, Netta R. Blondheim-Shraga, Evgeny Solomonov, Shiran Shapira, Izhak Haviv, Solomon M. Stemmer, Hanoch Slor. Anti-labyrinthin monoclonal antibody reduces human adenocarcinoma circulating tumor cells in the blood of patient-derived xenograft models and inhibits the growth of adenocarcinoma cell cultures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2297.
Abstract 3537: Targeted deep sequencing of driver mutations in airway epithelial cells from smokers
Authors: Daniel J. Craig, Thomas M. Blomquist, Erin L. Crawford, James C. Willey
Journal: Cancer Research (2019)

Abstract Background: Inter-individual variation in risk for lung cancer is based on variation in both exposure to environmental factors and genetic predisposition. As such, it is reasonable to hypothesize that prevalence of mutations in the airway epithelium will vary based on the combined effects of these lung cancer risk factors. Genes most commonly mutated in non-small cell lung cancer were recently reported from The Cancer Genome Atlas (TCGA) project. The purpose of this study was to use targeted deep sequencing to assess the prevalence of these mutations in bronchial epithelial cells (BEC) of individuals at high demographic risk for lung cancer. Methods: We enrolled 19 individuals with varying demographic risk for lung cancer, who were undergoing standard-of-care bronchoscopy into an IRB-approved research study in which we collected 1-5 million BEC via bronchoscopic brush biopsy and extracted genomic DNA. 10 subjects were smokers with lung cancer, 6 subjects were smokers without lung cancer, and 3 subjects were non-smokers without lung cancer. For targeted deep sequencing, we prepared synthetic spike-in competitive internal standards for each of 12 gene loci commonly mutated in lung cancer based on TCGA results and combined them into an IS mixture (ISM). DNA aliquots from each patient were quantified and mixed with equivalent genome equivalents of ISM prior to library preparation to control for technical artifacts associated with library preparation and NGS platform-specific error. The DNA input varied depending on sample quantity; there were 5 samples with 50,000 genome copies loaded, 12 samples with 100,000 genome copies loaded, and 2 samples with 1 million genome copies loaded. This approach enabled reliable measurement of 95% confidence limits of variant allele frequency (VAF), controlled for technical sequencing error, and allowed confident call of variants at a VAF of 0.1% and lower. Libraries for specimens from each of the 19 subjects were first sequenced using the Illumina MiSeq platform to ensure equal coverage across targets and samples. Deeper sequencing was then obtained using the Illumina NextSeq platform. Results: Preliminary results showed that smokers harbored mutations up to 1.6% in gene loci associated with non-small cell lung cancer according to TCGA, while none were identified in non-smoking controls. Conclusion: Initial results suggest that airway epithelial cells in smokers acquire somatic mutations that gradually lead to malignant conversion. Deep sequencing replicate experiments are underway to expand these results. Citation Format: Daniel J. Craig, Thomas M. Blomquist, Erin L. Crawford, James C. Willey. Targeted deep sequencing of driver mutations in airway epithelial cells from smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3537.
Abstract 2203: WSD1227: A BBB penetrable VEGFR small molecule for the treatment of primary and metastatic brain tumors
Authors: Jinqiang Zhang, Wei Zhong, Zhihua Mu, Claire Sun
Journal: Cancer Research (2019)

Abstract Anti-angiogenesis has been proved to be a good strategy for cancer treatment (such as in GBM, NSCLC, mBC, CRC, OC, etc.) with satisfactory performance to extracranial lesions, but not in intracranial lesions. Insufficient penetration across BBB could be one of factors limiting intracranial activity for those approved anti-VEGF agents. There is a need to develop a BBB penetrable VEGFR inhibitor to clinic to assess the efficacy and safety. Here we report that WSD1227, a novel, selective VEGFR inhibitor, displays potent activity, excellent CNS penetration and preclinical safety and efficacy. The IC50 of WSD1227 against VEGFR1/2/3 at 0.69/0.35/0.41nM versus against other targets such as PDGFRα IC50 22.9nM, PDGFRβ IC50 19.4nM, cKit IC50 383nM, FLT3 IC50 555 nM and CSF1R IC50 1062nM. WSD1227 treatment resulted in significant anti-tumor activity in VEGF related extracranial and intracranial mice models, with superior efficacy than bevacizumab. There is no increased risk of CNS hemorrhage in intracranial tumor bearing mice treated with WSD1227. In addition, WSD1227 is predicted to be CNS penetrable with decent PK in human. Taken together, our data provide a good rationale for WSD1227 to be developed toward clinic to investigate anti-angiogenetic therapies for management of patients with primary or metastatic brain tumors. Citation Format: Jinqiang Zhang, Wei Zhong, Zhihua Mu, Claire Sun. WSD1227: A BBB penetrable VEGFR small molecule for the treatment of primary and metastatic brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2203.
Mortality After Breast Cancer Among Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
Authors: Chaya S. Moskowitz, Joanne F. Chou, Joseph P. Neglia, Ann H. Partridge, Rebecca M. Howell, Lisa R. Diller, Danielle Novetsky Friedman, Dana Barnea, Lindsay M. Morton, Lucie M. Turcotte, Michael A. Arnold, Wendy M. Leisenring, Gregory T. Armstrong, Leslie L. Robison, Kevin C. Oeffinger, Tara O. Henderson
Journal: Journal of Clinical Oncology (2019)

Female survivors of childhood cancer have a high risk of subsequent breast cancer. We describe the ensuing risk for mortality and additional breast cancers.Female participants in the Childhood Cancer Survivor Study, a cohort of 5-year survivors of cancer diagnosed between 1970 and 1986 before age 21 years, and subsequently diagnosed with breast cancer (n = 274; median age at breast cancer diagnosis, 38 years; range, 20 to 58 years) were matched to a control group (n = 1,095) with de novo breast cancer. Hazard ratios (HRs) and 95% CIs were estimated from cause-specific proportional hazards models.Ninety-two childhood cancer survivors died, 49 as a result of breast cancer. Overall survival after breast cancer was 73% by 10 years. Subsequent risk of death as a result of any cause was higher among childhood cancer survivors than among controls (HR, 2.2; 95% CI, 1.7 to 3.0) and remained elevated after adjusting for breast cancer treatment (HR, 2.4; 95% CI, 1.7 to 3.2). Although breast cancer-specific mortality was modestly elevated among childhood cancer survivors (HR, 1.3; 95% CI, 0.9 to 2.0), survivors were five times more likely to die as a result of other health-related causes, including other subsequent malignant neoplasms and cardiovascular or pulmonary disease (HR, 5.5; 95% CI, 3.4 to 9.0). The cumulative incidence of a second asynchronous breast cancer also was elevated significantly compared with controls (P < .001).Mortality after breast cancer was higher in childhood cancer survivors than in women with de novo breast cancer. This increased mortality reflects the burden of comorbidity and highlights the need for risk-reducing interventions.
Validation, clinical utility and limitations of the Amsterdam-Oxford model for primary sclerosing cholangitis
Authors: Jorn C. Goet, Annarosa Floreani, Xavier Verhelst, Nora Cazzagon, Lisa Perini, Willem J. Lammers, Annemarie C. de Vries, Adriaan J. van der Meer, Henk R. van Buuren, Bettina E. Hansen
Journal: Journal of Hepatology (2019)
Lung cancer-derived EGFR mutations affect responses to tyrosine kinase inhibitors, but not to monoclonal antibodies
Authors: M. Dechant, M. Peipp, T. Schneider-Merck, T. Beyer, J. J. Lammerts van Bueren, W. K. Bleeker, P. W. Parren, J. G. van de Winkel, T. Valerius
Journal: Journal of Clinical Oncology (2007)

3044 Background: The epidermal growth factor receptor (EGFR) serves as a molecular target for novel cancer therapeutic approaches. Two groups of anti-EGFR agents are clinically most advanced: tyrosine kinase inhibitors (TKI) and EGFR antibodies. Recently, somatic mutations in the EGFR kinase domain were identified in tumors from lung cancer patients, which affected EGFR signaling and which correlated with responses to TKI therapy. Since interference with tumor cell signaling is also considered an important mechanism of action for therapeutic antibodies, we investigated the influence of these intracellular EGFR mutations on cell killing by EGFR antibodies, in comparison to TKI. Methods: For this purpose, we established an EGF-responsive, non-transformed cell line model for the three most common lung cancer-derived intracellular EGFR mutations L858R, G719S and delE746-A750. EGFR phosphorylation status was analyzed by Western Blots. MTT assays were performed to compare TKI gefitinib and erlotinib with antibodies C225 and 2F8 in their capacity to inhibit cell growth of wild type and mutated EGFR-transfectants. Impact of intracellular EGFR mutations on immune cell-mediated killing by EGFR antibodies was measured in classical 3 hours 51-chromium-release assays. Results: Mutated EGFR transfected cells were growth factor- responsive, and significantly more sensitive to both gefitinib and erlotinib than wild type (WT) EGFR expressing cells. However, anti-tumor effector functions of both EGFR-directed IgG1 antibodies—chimeric C225 and fully human 2F8—were not affected by the mutations. Conclusions: Intracellular mutations of EGFR may, therefore, be less relevant for EGFR antibodies than for TKI. No significant financial relationships to disclose.