tbuckley/cabot-search huggingface dataset:
Abstract 2557: Germline mutations in renal cancer predisposing genes: Analysis of the Geisinger MyCode population
Authors: Heinric Williams, Raghu Metpally, Mahmoud Mohamed, Sarath Krishnamurthy, Sertac Kip, David J. Carey, Aris Baras, John Overton
Journal: Cancer Research (2016)

Abstract Renal cell cancer (RCC) is not a single disease but is made up of a number of cancers, each with a unique histology, biology, clinical course and response to therapy. Alterations in at least 16 hereditary genes have been attributed to the risk of developing RCC. In this study, we describe the prevalence and spectrum of germline variants among these genes and highlight correlations between germline genotype with tumor phenotype. Using the Geisinger MyCode cohort, we sequenced the whole exomes of 42,933 subjects. Subjects were divided into those with a renal cancer diagnosis, other cancer diagnosis and no cancer diagnosis. We analyzed the DNA sequences of 16 hereditary renal cancer genes from each of these groups. The damaging mutations was determined by following ACMG guidelines. Among the 42,933 subjects in the Geisinger MyCode cohort, 168 were diagnosed with RCC. None of these subjects had a family history of RCC. Clear cell RCC (ccRCC) was the most predominant histology (77%), followed by Type 1 papillary RCC (7%), chromophobe RCC (6%), and Type 2 papillary RCC (5%). Mutations in all the predisposing genes were identified in all the renal cancer subtypes but only a subset were deemed damaging. The top 2 ccRCC predisposing genes with damaging or likely damaging mutations were TSC2 (8%) and SDHD (4%). While TSC2 damaging variants were also found in the other histologies, novel TSC2 variants were differentially associated with high grade and metastatic disease in ccRCC as compared to those with low grade or non-metastatic disease. The genes harboring damaging or likely damaging variants in Type 1 and Type 2 papillary RCC were MET and FH respectively. Predisposing RCC germline mutations were found in a significant number of subjects with sporadic RCC. Family history was unhelpful in predicting the affected subjects. Knowledge of these mutations would be beneficial in counseling patients and their families as well as improving our understanding of the disease to direct patient care. Citation Format: Heinric Williams, Raghu Metpally, Mahmoud Mohamed, Sarath Krishnamurthy, Sertac Kip, David J. Carey, Aris Baras, John Overton. Germline mutations in renal cancer predisposing genes: Analysis of the Geisinger MyCode population. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2557.
P0265 : IGF2 is an oncogenic driver in HCC and emerges as a potential target for therapies
Authors: I. Martínez-Quetglas, R. Pinyol, D. Dauch, A. Portela, J. Peix, M. Higuera, J. Zucman-Rossi, M. Esteller, V. Mazzaferro, L. Zender, J.M. Llovet
Journal: Journal of Hepatology (2015)
Phase I-II trial of pentoxifylline for the prevention of transplant- related toxicities following bone marrow transplantation [published erratum appears in Blood 1992 Jun 15;79(12):3397] [see comments]
Authors: JA Bianco, FR Appelbaum, J Nemunaitis, J Almgren, F Andrews, P Kettner, A Shields, JW Singer
Journal: Blood (1991)
Does a Chronic Inflammatory Process Underlie Clonal Progression In Aplastic Anemia?- In Vitro and In Vivo Evidence That Inflammation Produces Aneuploidy for Chromosomes 7 and 8 In Replicating Cells
Authors: Elaine M Sloand, Kelsey Loeliger, Loretta Pfannes, Andrea Poon, Rodrigo Calado, Xingmin Feng, Hesed Padilla-Nash, Jichun Chen, Neal S. Young
Journal: Blood (2010)
Abstract CT125: A phase III randomized trial comparing FDA approved standard of care adjuvant therapy to one year of pembrolizumab in patients with high risk resected melanoma. SWOG 1404
Authors: Kenneth F. Grossmann, Vernon K. Sondak, Megan Othus, Ahmad Tarhini, Sapna Patel, John M. Kirkwood, Antoni Ribas, James Moon
Journal: Cancer Research (2016)

Abstract Background: Adjuvant therapy for melanoma has centered on high dose interferon for now almost 20 years. Recently, the FDA approved ipilimumab dosed at 10 mg/kg (10/kg ipi) for use in high risk resected melanoma. Though these two treatment options are available they still have limits in terms of efficacy with approximately 1 year of relapse free survival benefit (HDI and 10/kg ipi) and a modest overall survival benefit (HDI). Toxicity remains an issue as well with both therapies. S1404 is a Phase III, open label trial which seeks to compare currently available FDA approved treatments to one year of pembrolizumab in patients at high risk of relapse and death after surgery. Study Design: 1,378 patients will be randomized 1:1 to an FDA approved standard therapy, or pembrolizumab. Stratification factors include PD-L1 staining status, clinical stage, and pre-randomization selected standard treatment option. Patients: Patients must be 18 or older, and have Stage IIIA (n2), IIIB, IIIC or IV (M1a, b and c) resected melanoma to be eligible. Exclusion factors include brain metastases, ocular primary, and auto-immune disease. Prior therapy is not allowed, but radiation as adjuvant treatment is considered an option available to patients prior to treatment. Current status: As of January 2016, 30 sites are registered and 5 patients are randomized. An amendment to include 10 mg/kg ipilimumab as a treatment option is under review and will likely be finalized by the time of the meeting. Support: NIH/NCI NCTN grants CA180888, CA180819, CA180818, CA180826, CA180858, CA180820, CA180844 Citation Format: Kenneth F. Grossmann, Vernon K. Sondak, Megan Othus, Ahmad Tarhini, Sapna Patel, John M. Kirkwood, Antoni Ribas, James Moon. A phase III randomized trial comparing FDA approved standard of care adjuvant therapy to one year of pembrolizumab in patients with high risk resected melanoma. SWOG 1404. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT125.
P1345 : A randomized, open-label study to evaluate efficacy and safety of ombitasvir/paritaprevir/ritonavir co-administered with ribavirin in adults with genotype 4 chronic hepatitis C infection and cirrhosis
Authors: T. Asselah, T. Hassanein, R.B. Qaqish, J.J. Feld, C. Hezode, S. Zeuzem, P. Ferenci, T. Pilot-Matias, Y. Yu, N. Mobashery
Journal: Journal of Hepatology (2015)
Abstract 3707: Semiconductor-based next-generation sequencing analysis of 409 cancer-related genes for mutations and copy-number variations in oral squamous cell carcinoma
Authors: Takafumi Nakagaki, Yasushi Sasaki, Masashi Idogawa, Ryota Koyama, Kenta Kobashi, Miyuki Tamura, Tomoko Ohashi, Kazuhiro Ogi, Hiroyoshi Hiratsuka, Takashi Tokino
Journal: Cancer Research (2016)

Abstract Somatic mutation analysis is standard of practice for human cancers in order to identify therapeutic sensitizing and resistance mutations. To better understand the molecular pathogenesis of oral squamous cell carcinoma (OSCC) patients, we performed comprehensive genomic analyses that use PCR target enrichment and next-generation sequencing on the Ion Torrent semiconductor sequencers (PGM and Proton). DNA (40 ng) was extracted from 45 human OSCC specimens and their corresponding non-cancerous tissues including FFPE samples. Using the Ion Ampliseq Comprehensive Cancer Panel, we sequenced 15992 loci from 409 tumor suppressor genes and oncogenes frequently cited and frequently mutated in human cancers (covered regions = 95.4% of total, 1.5 megabases of target sequence). We also detected copy number variations (CNVs) in which segments of the genome can be duplicated or deleted from sequencing data. Each sample underwent on average 5.9 million sequencing reads after quality filtering. The mean read depths were 367.8 x, and &amp;gt;95% of targeted bases were represented .The number of somatic mutations (SNVs and indels) in 45 patients with OSCC ranged from 1 to 36 with a median of 7.33 (6.40/Mb). The most frequent mutations were detected on TP53 (28 of 45; 62.2%). Many of the mutations on TP53 were detected in the DNA-binding domain (23 of 28; 82.1%). NOTCH1 mutations were identified in 10 cases (8 missense, 1 coding frameshift, and 1 essential splice site mutations). CDKN2A mutations were observed in 8 cases; and PIK3CA were mutated 3 cases. Although the most common mutations in OSCC were C/G&amp;gt;T/A transitions, which are consistent with previous reports on head and neck, lung and oesophageal SCCs, the second most frequent mutations were C/G&amp;gt;A/T transversions. We also identified a median of 100 significant CNVs (range of 0-481) per sample. Pathway assessment has shown that somatic aberrations within OSCC genomes are mainly involved in several important pathways, including cell cycle regulation (p53 pathway, 84.4%) and RTK-MAPK-PI3K (62.2%). This targeted next generation sequencing using low amounts of FFPE DNA is a valuable tool for high-throughput genetic testing in research and clinical settings. Citation Format: Takafumi Nakagaki, Yasushi Sasaki, Masashi Idogawa, Ryota Koyama, Kenta Kobashi, Miyuki Tamura, Tomoko Ohashi, Kazuhiro Ogi, Hiroyoshi Hiratsuka, Takashi Tokino. Semiconductor-based next-generation sequencing analysis of 409 cancer-related genes for mutations and copy-number variations in oral squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3707.
Abstract 4978: T cell mediated immunity after combination therapy with intralesional PV-10 and co-inhibitory blockade in a melanoma model
Authors: Amy M. Weber, Hao Liu, Krithika N. Kodumudi, Amod A. Sarnaik, Shari Pilon-Thomas
Journal: Cancer Research (2016)

Abstract PV-10 is a 10% solution of Rose Bengal, a xanthene dye that was originally developed for ophthalmic use and later used in liver function studies. PV-10 was formulated for intralesional (IL) injection and is currently being investigated as a novel cancer therapeutic. In murine studies, we have previously shown that intralesional (IL) injection of PV-10 leads to a regression of both injected tumors and untreated bystander tumors. We have also shown that combination therapy of IL PV-10 with blockade of PD-1 and PDL-1 leads to increased anti-tumor immunity. In this study, we have examined the role played by specific immune cell populations in eliciting this response in a murine melanoma model. We first investigated the antigen specificity of CD8+ T cells in the spleens of mice treated with the combination therapy of IL PV-10 and systemic co-inhibitory blockade. We found that splenocytes from mice treated with the combination of IL PV-10 and anti PD-1 antibody have an increased mean percentage of OVA antigen-specific CD8+ T cells (5.77%) compared to single treatment with anti PD-1 antibody (3.8%) or IL PV-10 (3.60%) alone in OVA-expressing B16 tumor bearing mice. To investigate the role of T cell subsets in mediating an immune response, OVA-expressing B16 tumor bearing mice were treated with IL PV-10 followed by intraperitoneal injection of anti-PD-1 antibody. In addition, mice were given either 2.43 antibody to deplete CD8+ T cells, GK1.5 antibody to deplete CD4+ T cells, or PC61 to deplete regulatory T cells (Tregs). We found that depletion of CD4+ T cells in combination with IL PV-10 and anti-PD-1 antibody treatment resulted in an enhanced anti-tumor effect, with an average tumor size of 52.8 mm2 on day 25 compared to the control group (173.7 mm2), and depletion of Tregs resulted in an even greater anti-tumor effect, with an average tumor size of 1.2 mm2 on day 25 (p&amp;lt;0.05). In contrast, mice treated with the CD8+ depleting antibody exhibited diminished anti-tumor immunity compared to the control group, with an average tumor size of 200 mm2 on day 25. Together, these studies indicate that the effect of combination therapy with IL PV-10 and co-inhibitory blockade is mediated by CD8+ T cells, and that depletion of both CD4+ T cells and CD25+ Tregs significantly enhances anti-tumor immunity in a melanoma model. Citation Format: Amy M. Weber, Hao Liu, Krithika N. Kodumudi, Amod A. Sarnaik, Shari Pilon-Thomas. T cell mediated immunity after combination therapy with intralesional PV-10 and co-inhibitory blockade in a melanoma model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4978.
Abstract 4809: Combination therapy targeting ribosome biogenesis and mRNA translation provides a novel and potent therapeutic approach to treat MYC-driven malignancy
Authors: Jennifer R. Devlin, Richard J. Rebello, Katherine M. Hannan, Carleen Cullinane, Denis Drygin, Gail P. Risbridger, Luc Furic, Ross D. Hannan, Richard B. Pearson
Journal: Cancer Research (2016)

Abstract MYC-driven malignancies are associated with elevated rates of ribosome biogenesis and mTORC1/eIF4E-driven protein synthesis suggesting they may be vulnerable to therapeutic strategies that target the ribosome. We investigated the therapeutic efficacy of targeting multiple nodes of the network controlling the ribosome in mouse models of MYC-driven lymphoma (Eì-Myc) and prostate cancer (HI-MYC). Simultaneous inhibition of ribosomal RNA synthesis and repression of protein translation was achieved by utilizing the novel RNA polymerase I inhibitor CX-5461 and PI3K/AKT/mTORC1 and PIM 1 signaling inhibitors. Combined inhibition of ribosome biogenesis and function significantly improved therapeutic outcomes in lymphoma and prostate cancer models. CX-5461 and Everolimus (mTORC1 inhibitor) co-treatment more than doubled the survival of Eì-Myc lymphoma-bearing mice. While both classes of inhibitor suppress rDNA transcription, they treat MYC-driven malignancy through distinct molecular mechanisms facilitating their combinatorial effects. In contrast to CX-5461, PI3K/AKT/mTOR pathway inhibitors did not activate a nucleolar stress response and p53-dependent apoptosis but instead induce B-lymphoma cell death via the upregulation of the BH3-only protein BMF (Devlin et al Cancer Discovery 2015 Oct 21. pii: CD-14-0673. [Epub ahead of print]). PIM kinase has been shown to regulate eIF4Edriven protein synthesis on prostate cancer cell lines. Co-treatment of HI-MYC mice with CX-5461 and the PIM kinase inhibitor CX-6258 reverted highly invasive disease to low-grade prostate intraepithelial neoplasia. These findings demonstrate that MYC driven tumors are addicted to multiple regulatory steps associated with ribosome synthesis and function and coordinated targeting of these addictions provides an effective new therapeutic approach to treat MYC driven cancers. Citation Format: Jennifer R. Devlin, Richard J. Rebello, Katherine M. Hannan, Carleen Cullinane, Denis Drygin, Gail P. Risbridger, Luc Furic, Ross D. Hannan, Richard B. Pearson. Combination therapy targeting ribosome biogenesis and mRNA translation provides a novel and potent therapeutic approach to treat MYC-driven malignancy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4809.
Prognostic significance of molecular classification of breast-invasive ductal carcinoma in a Brazilian outpatient cancer center.
Authors: F. M. Vieira, N. Teich, J. G. Musacchio, A. Boukai, A. O. Victorino, R. C. Helal, B. V. Silva, I. Á. Small, D. D. Corrêa, M. R. Schaum
Journal: Journal of Clinical Oncology (2010)

e12050 Background: In recent years, breast carcinoma classification has changed following application of molecular techniques, like immunohistochemistry. The aim of this work is to determine the prognostic influence of the molecular classification of breast carcinoma with immunohistochemistry. Methods: Between 1999 and 2009, we studied retrospectively 538 women with invasive ductal carcinoma diagnosed and treated in a private oncology clinic in Rio de Janeiro, Brazil. We have classified the cases in four tumor types according to the immunohistochemical expression of several markers, as luminal A tumors (estrogen and/or progesterone receptors [ER/PE] positive and HER2 negative); luminal B tumors (ER/PR positive and HER2 positive); HER2-positive tumors (ER/PR negative with HER2 positive); and triple negative phenotype (all markers negative). Results: In our series, 244 patients had tumors of luminal A type (61.2%); 51 (12.8%) were luminal type B; 46 (11.5%) were HER2 positive; and 58 (14.5%) were triple negative. The relapse rate was 5.8% for luminal type A tumors, 6% for luminal type B, 13.6% for HER2-positive and 15.5% for triple negative lesions. The progression free survival was 91.8%, 90.7%, 85.5% and 82.4% for luminal A and B, HER2 and triple-negative lesions, respectively. The mean overall survival for these groups was not reached. Conclusions: In our series, 244 patients had tumors of luminal A type (61.2%); 51 (12.8%) were luminal type B; 46 (11.5%) were HER2-positive; and 58 (14.5%) were triple negative. The relapse rate was 5.8% for luminal type A tumors, 6% for luminal type B, 13.6% for HER2-positive and 15.5% for triple-negative lesions. The progression-free survival was 91.8%, 90.7%, 85.5% and 82.4% for luminal A and B, HER2 and triple-negative lesions, respectively. The mean overall survival for these groups was not reached. No significant financial relationships to disclose.
Abstract 4399: Hypoxia as a driver of myeloid-derived suppressor cell recruitment in hepatocellular carcinoma via CCL26/CX3CR1
Authors: David Kung-Chun Chiu, Iris Ming-Jing Xu, Robin Kit-Ho Lai, Aki Pui-Wah Tse, Larry Lai Wei, Hui-Yu Koh, Regina Cheuk-Lam Lo, Chun-Ming Wong, Irene Oi-Lin Ng, Carmen Chak-Lui Wong.
Journal: Cancer Research (2016)

Abstract Background and Objective: Myeloid-derived suppressor cells (MDSCs) accumulate in tumors and highly pro-tumorigenic. These MDSCs exhibit inhibitory functions against effector T cells and natural killer cells in tumor sites, as well as secrete pro-angiogenic factors or differentiate to endothelial cells to promote angiogenesis and metastasis. While it is appreciated that depletion of MDSCs could bring tumoricidal effects, there are significant gaps in knowledge about the underlying mechanisms responsible for MDSC recruitment to tumor sites. Hypoxia, O2 deprivation, is an important factor in the tumor microenvironment of HCC that modifies the stromal components. Using hepatocellular carcinoma (HCC) as a model, we investigated whether hypoxia is a driver of MDSC recruitment in HCC. Experimental Procedures: Gene profiling of HCC cells exposed to hypoxia and normoxia were analyzed by transcriptome sequencing to identify potential hypoxia-induced chemokines for MDSC recruitment. MDSCs were isolated from HCC-bearing mice by magnetic bead sorting for different functional assays. Boyden chambers were used to evaluate the invasive ability of MDSCs. Flow cytometry was used to detect the frequencies of tumor-associated MDSCs in orthotopic HCC mouse models. Results: We observed that MDSCs preferentially infiltrated into hypoxic regions in human HCC tissues and hypoxia-induced MDSC infiltration was dependent on hypoxia-inducible factors (HIFs). HIFs activated the transcription of chemokine (C-C motif) ligand 26 (CCL26) in HCC cells to recruit chemokine (C-X3-C motif) receptor 1 (CX3CR1)-expressing MDSCs to the primary tumor. Knockdown of CCL26 in HCC cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth. Therapeutically, blockade of CCL26 production in HCC cells by HIF inhibitor, digoxin, or blockade of CX3CR1 in MDSCs by CX3CR1 neutralizing antibody could substantially suppress MDSC recruitment and tumor growth. Conclusion: This study unprecedentedly reveals a novel molecular mechanism by which HCC cells direct MDSC homing to primary tumor and suggests that targeting MDSC recruitment represents an attractive therapeutic approach against HCC. Citation Format: David Kung-Chun Chiu, Iris Ming-Jing Xu, Robin Kit-Ho Lai, Aki Pui-Wah Tse, Larry Lai Wei, Hui-Yu Koh, Regina Cheuk-Lam Lo, Chun-Ming Wong, Irene Oi-Lin Ng, Carmen Chak-Lui Wong. Hypoxia as a driver of myeloid-derived suppressor cell recruitment in hepatocellular carcinoma via CCL26/CX3CR1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4399.
Phase II randomised placebo controlled neoadjuvant chemotherapy study of nintedanib with gemcitabine and cisplatin in locally advanced muscle invasive bladder cancer.
Authors: Syed A. Hussain, Richard Jackson, Alice Shields, Lynne Dickinson, Philip Cornford, Robert J. Jones, Jason Francis Lester, John D. Chester, Alison J. Birtle, Thomas Powles, Simon J. Crabb, Danish Mazhar, Robert Anthony Huddart, Andrew Protheroe, Faisal Azam, Naveen Vasudev, Mohammad Butt, Nicholas David James
Journal: Journal of Clinical Oncology (2015)

TPS4574 Background: The triple angiokinase inhibitor nintedanib (nin) has shown reduced proliferation and elevated apoptosis to a greater extent than chemotherapy alone in animal models. We aim to compare the effectiveness of nin vs placebo in combination with gemcitabine (gem) and cisplatin (cis) in muscle invasive bladder cancer (MIBC) patients prior to radical treatment. A safety sub-study will run in parallel with the main study to establish the maximum tolerated dose (MTD) of nin for patients with impaired glomerular filtration rate (GFR). Methods: The study opened in September 2014 and has recruited 4 patients to date (3 to main study, 1 to sub-study). 14 UK sites are planned. All patients must have localised muscle invasive carcinoma with no evidence of metastatic disease, ECOG performance status grade 0 – 1 and adequate haematological and hepatic function. Linked-in tissue collection and translational samples are built into the protocol. Main Study Patients will be stratified by centre and baseline GFR and randomised to receive 4 x 21 day cycles of gem 1000 mg/m2 and cis 70mg/m2 with 200mg BD nin or placebo. The primary outcome measure is cystoscopic and pathological complete response rate, with secondary outcome measures of progression free survival and toxicity. Overall survival is not assessed in order to facilitate seamless expansion into a phase III study. 120 patients (60 per arm) will provide 80% power to detect a 20% response difference, p < 0.01. Initially patients’ GFR must be > 60ml/min. After sub-study data analysis and determination of MTD in patients with GFR 40 – 60 ml/min, these patients may be included in the main study with split dose cis. Sub-study A 3+3 design is followed with an initial cohort of 3 patients with GFR 40 – 60 ml/min receiving 4 x 21 day cycles of gem 1000mg/m2 and split dose cis 35mg/m2 on day 1 and day 8 with 150mg BD nin. Nin dose-escalation/de-escalation for future cohorts of 3 – 6 patients will occur based on the no. of dose limiting toxicities, with a max. 12 patients recruited. The primary outcome measure is the MTD and safety of nin in combination with gem and split dose cis in patients with impaired renal function. Clinical trial information: 56349930.