tbuckley/cabot-search huggingface dataset:
Hypercholesterolemia Increases Colorectal Cancer Incidence by Reducing Production of NKT and γδ T Cells from Hematopoietic Stem Cells
Authors: Guodong Tie, Jinglian Yan, Lyne Khair, Julia A. Messina, April Deng, Joonsoo Kang, Thomas Fazzio, Louis M. Messina
Journal: Cancer Research (2017)

Obesity will soon surpass smoking as the most preventable cause of cancer. Hypercholesterolemia, a common comorbidity of obesity, has been shown to increase cancer risk, especially colorectal cancer. However, the mechanism by which hypercholesterolemia or any metabolic disorder increases cancer risk remains unknown. In this study, we show that hypercholesterolemia increases the incidence and pathologic severity of colorectal neoplasia in two independent mouse models. Hypocholesterolemia induced an oxidant stress-dependent increase in miR101c, which downregulated Tet1 in hematopoietic stem cells (HSC), resulting in reduced expression of genes critical to natural killer T cell (NKT) and γδ T-cell differentiation. These effects reduced the number and function of terminally differentiated NKT and γδ T cells in the thymus, the colon submucosa, and during early tumorigenesis. These results suggest a novel mechanism by which a metabolic disorder induces epigenetic changes to reduce lineage priming of HSC toward immune cells, thereby compromising immunosurveillance against cancer. Cancer Res; 77(9); 2351-62. ©2017 AACR.
Impact of adjuvant chemotherapy on clinical and biological ageing in older breast cancer patients
Authors: Barbara Brouwers, Sigrid Hatse, Lissandra Dal Lago, Patrick Neven, Peter Vuylsteke, Guy Debrock, Heidi Van den Bulck, Ann Smeets, Oliver Bechter, Evalien Swerts, Jithendra Kini Bailur, Cindy Kenis, Annouschka Laenen, Bruna Samia Dalmasso, Patrick Schöffski, Graham Pawelec, Hans Wildiers
Journal: Cancer Research (2015)
Targeting noncoding RNAs in disease
Authors: Brian D. Adams, Christine Parsons, Lisa Walker, Wen Cai Zhang, Frank J. Slack
Journal: Journal of Clinical Investigation (2017)

Many RNA species have been identified as important players in the development of chronic diseases, including cancer. Over the past decade, numerous studies have highlighted how regulatory RNAs such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play crucial roles in the development of a disease state. It is clear that the aberrant expression of miRNAs promotes tumor initiation and progression, is linked with cardiac dysfunction, allows for the improper physiological response in maintaining glucose and insulin levels, and can prevent the appropriate integration of neuronal networks, resulting in neurodegenerative disorders. Because of this, there has been a major effort to therapeutically target these noncoding RNAs. In just the past 5 years, over 100 antisense oligonucleotide–based therapies have been tested in phase I clinical trials, a quarter of which have reached phase II/III. Most notable are fomivirsen and mipomersen, which have received FDA approval to treat cytomegalovirus retinitis and high blood cholesterol, respectively. The continued improvement of innovative RNA modifications and delivery entities, such as nanoparticles, will aid in the development of future RNA-based therapeutics for a broader range of chronic diseases. Here we summarize the latest promises and challenges of targeting noncoding RNAs in disease.
PP25. DISTRIBUTION OF IDH1 AND TERT MUTATIONS AND MGMT METHYLATION IN ADULT LOWER GRADE GLIOMA
Authors: Dr Anushree Singh, Dr Katherine Karakoula, Mrs Kate Ashton, Prof Tim Dawson, Prof Charles Davis, Mr Andrew Brodbelt, Mr Michael Jenkinson, Prof John Darling, Prof Tracy Warr
Journal: Neuro-Oncology (2017)

IDH1 encodes for isocitrate dehydrogenase which catalyzes the oxidative carboxylation of isocitrate to α-ketoglutarate. Mutations in IDH1 are heterozygous and affect only codon 132. IDH1 mutation results in global hypermethylation (G-CIMP phenotype) and is significantly associated with MGMT promoter methylation. Tumours exhibiting both TERT mutations and IDH1/2 mutations have been previously reported to be primarily of oligodendroglial histology. In this study, IDH1 mutation analysis was performed by direct sequencing using BigDye® Terminator v3.1 cycle sequencing kit and the ABI 3730 DNA analyser in a cohort of 135 lower grade glioma at first presentation, comprising 84 grade II and 51 grade III tumours of astrocytic, oligodendroglial and mixed histologies. The incidence of TERT mutation was also determined in 52 of these cases. MGMT methylation analysis was carried out using MS-PCR in 130 tumours. IDH1 and TERT mutation and MGMT methylation was correlated with overall survival for patients for whom data was available. The incidences of IDH1 R132H mutation, MGMT methylation and TERT mutation in the whole cohort were 57%, 55% and 36% respectively. IDH1 R132H mutations were significantly more common in grade II tumours compared to grade III tumours (67% vs 41%; p = 0.004). In contrast, there was no significant difference in the incidence of MGMT methylation or TERT mutation based on the histological grade (p = 0.855 and p = 0.559, respectively). In grade II tumours, IDH1 R132H mutations were present more frequently in oligodendroglioma (81%) and oligoastrocytoma (82%) compared to astrocytoma (51%) (p = 0.005). Similarly, MGMT was significantly methylated in grade II oligodendroglioma (69%) and oligoastrocytoma (75%) than astrocytoma (35%) (p = 0.001). There were no differences in the incidence of TERT mutation in histological subgroups. IDH1 R132H mutation was a positive prognostic indicator of overall survival independent of grade (p < 0.0001). However, presence of MGMT methylation was significantly associated with increased overall survival in grade III tumours only (p = 0.006).
Concomitant chemoradiotherapy using docetaxel and cisplatin for unresectable stage III lung squamous cell carcinoma.
Authors: Yaping Xu, Xiaojiang Sun, Yuanda Zheng, Qingren Lin, Xinmin Yu, Weimin Mao
Journal: Journal of Clinical Oncology (2014)

e18535 Background: Concomitant chemoradiotherapy is the standard treatment of unresectable stage III non-small cell lung cancer (NSCLC). However, the optimal chemotherapy regimen is still controversial, particularly in lung squamous cell carcinoma. We have conducted a phase II clinical trial in a Chinese population to evaluate concomitant treatment using docetaxel/cisplatin chemotherapy and thoracic radiotherapy followed by docetaxel/cisplatin consolidation chemotherapy in unresectable stage III lung squamous cell carcinoma. The purpose of this study was to evaluate the feasibility and activity, and also assess its impact on progression-free survival (PFS). Methods: A total of 32 patients were enrolled between January 2011 and January 2013. Patients received concomitant docetaxel 30mg/m2 on day 1 and day 8, cisplatin 25mg/m2 on day 1 to day 3 repeated every 3 weeks for 2 cycles and thoracic radiotherapy (60 Gy in 30 fractions, 5 days per week), followed by docetaxel/cisplatin for 2 cycles as consolidation therapy (docetaxel 60mg/m2 on day 1, cisplatin 25mg/m2on day 1 to day 3 repeated every 3 weeks). Results: Eight (25.0%) and 20 patients (62.5%) had a complete or partial response, respectively, while 3 patient’s disease remained stable and 1 patient had progression of the disease. The overall response rate (87.2%, 95% confidence interval (CI): 63–97%) exceeded the goal per study design. The median PFS was 11.0 months (95% CI: 5.6–16.4 months). This approach obtained better effects than history control group. Main toxicity (grade 3 or greater, %): neutropenia 10 (31.3%); thrombocytopenia 7 (21.9%); anaemia 8 (25.0%); nausea/vomiting 5 (15.6%); anorexia 7 (21.9%), dysphagia 4 (12.5%), radiation pneumonitis 3 (9.4%) and fatigue 4 (12.5%). Conclusions: This data suggests that concomitant treatment with docetaxel/cisplatin and thoracic radiotherapy was well tolerated, with promising activity in a Chinese population with unresectable stage III lung squamous cell carcinoma. Although the data presented herewith appears promising, this study is relatively small, and more data from randomized trials are needed to further validate this regimen.
Abstract P6-01-06: Glutamine metabolism drives breast cancer invasion by providing a source of extracellular glutamate to activate the GRM3 metabotropic glutamate receptor
Authors: IR Macpherson, E Dornier, N Rabas, E Rainero, JC Norman
Journal: Cancer Research (2017)

Abstract Glutamine metabolism is well-established to contribute to cancer cell growth and proliferation by providing a source of nitrogen for nucleotide and amino acid biosynthesis as well as TCA cycle intermediates. There is also accumulating evidence that glutamine metabolism may contribute to metastasis although mechanistic links to tumour cell migration and invasion remain unclear. We have generated a number of highly invasive primary cell lines from the polyoma middle-T genetically engineered mouse model of breast cancer (MMTV-PyMT) and found that withdrawal of glutamine from these cells reduces not only their proliferation, but also their invasive migration into 'stroma-like' preparations of fibroblast-derived extracellular matrix. Our metabolomic analyses indicate that invasive MMTV-PyMT cells actively secrete glutamate, a product of glutamine metabolism, into the extracellular milieu. Moreover, addition of glutamate is sufficient to restore invasiveness (but not cell growth or proliferation) to glutamine-starved MMTV-PyMT cells. We have pursued these findings by investigating the role played by plasma membrane receptors for glutamate in cell migration and invasion in PyMT cells and in MDA-MB-231 triple negative breast cancer cells. We provide evidence that glutamate generated within the cell by deamidation of glutamine leaves the cell via the xCT antiporter to activate the GRM3 metabotropic glutamate receptor at the cell surface. This, in turn, suppresses adenylate cyclase activity to prevent protein kinase A activation and to drive an invasive programme. Indeed, knocking out GRM3 with CRISPR technology or inhibition using a selective GRM3 antagonist (LY341495) is sufficient to oppose invasiveness without compromising proliferation. Conversely, a specific GRM3 agonist (LY354740) drives invasiveness without increasing proliferation. Consistently, treatment with LY341495 was sufficient to abrogate lung colonisation following tail vein injection whilst tumour growth after orthotopic injection was unaffected. Our results provide a mechanistic link between glutamine metabolism and invasion and identify GRM3 as a potential therapeutic target in breast cancer. Citation Format: Macpherson IR, Dornier E, Rabas N, Rainero E, Norman JC. Glutamine metabolism drives breast cancer invasion by providing a source of extracellular glutamate to activate the GRM3 metabotropic glutamate receptor [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-01-06.
Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia
Authors: Yuka Yamashita, Masashi Sanada, Kenichi Yoshida, Hiroo Ueno, Hiroko Tanaka, Yuichi Shiraishi, Kenichi Chiba, Toshihiko Imamura, Satoru Miyano, Koji Kato, Seiji Kojima, Seishi Ogawa, Keizo Horibe
Journal: Blood (2015)
Suicide in European Hodgkin Lymphoma Patients
Authors: Austin I. Kim, Helen Goergen, Andreas Engert, Ann S. LaCasce, Louise Maranda, Bruce Barton, Sven Borchmann
Journal: HemaSphere (2019)

The purpose of this study was to determine whether there is an increased risk of suicide in European Hodgkin Lymphoma (HL) patients compared to the general European population. European HL patients enrolled in the German Hodgkin Study Group (GHSG) HD7 through HD15 studies were analyzed and standardized mortality ratio (SMR) was calculated using suicide mortality rates for the general European population. Case-control analysis was performed to identify characteristics associated with risk of death by suicide. Among 12,202 European HL patients observed for 94,972 person-years, 19 suicides (17 males and 2 females) were identified resulting in a SMR 1.63 (95% CI: 1.01-2.50, p = 0.046). The only characteristic associated with a statistically significant increased risk of suicide was male sex with an odds ratio (OR) 8.42 (95% CI = 1.04-67.85; p = 0.046) on multivariate analysis. These findings were confirmed in an independently analyzed Surveillance, Epidemiology, and End Results Program (SEER) validation dataset. European HL patients have a significantly increased incidence of suicide compared to the general European population. Male HL patients have a greater than 8-fold increased risk of suicide compared to female HL patients. Further study of social risk factors associated with an increased risk of suicide in HL patients is needed.
Abstract P6-16-03: Phase 2 trial of everolimus and/or trastuzumab in hormone refractory, hormone receptor (HR)-positive, HER2-normal metastatic breast cancer (MBC)
Authors: E Paplomata, K Gogineni, J Meisel, C Santa-Maria, L Yuan, J Kramer, X Bill Li, A Zelnak, S Pakkala, V Kaklamani, R O'Regan
Journal: Cancer Research (2017)

Abstract Background: Increased signaling through growth factor pathways including PI3K/Akt/mTOR and HER2 have been implicated in hormone resistance. Everolimus (EVE) improves outcomes when added to endocrine therapy for patients with HR-positive MBC. This study evaluated the efficacy of everolimus (EVE) and trastuzumab (TRAS) in hormone refractory HER2-normal metastatic breast cancer. Methods: Eligible patients had HR-positive, HER2/neu-negative (IHC +1 or +2, HER2-non-amplified) MBC that had progressed within 6 months of the most recent endocrine therapy. Patients continued on the most recent endocrine therapy they received and were randomized to receive EVE 10 mg oral daily or TRAS IV (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks). At progression, the other agent was added (TRAS in the EVE arm and EVE in the TRAS arm). Patients were followed until disease progression or death. Results: 54 eligible patients were included in the analysis, and were randomized to EVE (n=30) or TRAS (n=24). 33% of patients were on fulvestrant, 31% exemestane, 22% tamoxifen and 7% letrozole, which were continued. The median PFS was 5.7 months for EVE vs. 2 months for TRAS until first progression or death with hazard ratio of 0.45 (95% CI 0.25-0.81, p=0.008). Among 48 patients who had disease progression, EVE was added to 16 patients who were originally treated by TRAS, and TRAS was added to 12 patients who were originally treated by EVE; the median time to the second progression was 6.3 months for the arm where EVE was added vs. 3.1 months in the arm where TRAS was added. Three patients were taken off study due to decrease in ejection fraction. Conclusions: This trial demonstrates the efficacy of EVE alone or in combination with TRAS in patients with hormone refractory HR-positive, HER2-negative metastatic breast cancer, who remained on the endocrine therapy they had experienced disease progression on. This suggests that mTOR inhibition has the potential of restoring sensitivity to endocrine therapy and potentially allows the re-use of endocrine agents. Updated results and correlative studies will be presented. Clinical trial information: NCT00912340. Citation Format: Paplomata E, Gogineni K, Meisel J, Santa-Maria C, Yuan L, Kramer J, Bill Li X, Zelnak A, Pakkala S, Kaklamani V, O'Regan R. Phase 2 trial of everolimus and/or trastuzumab in hormone refractory, hormone receptor (HR)-positive, HER2-normal metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-16-03.
PP20. CHILDHOOD LEUKAEMIA TREATED WITH CRANIAL RADIATION AND DELAYED PRESENTATION OF MENINGIOMAS IN ADULTHOOD
Authors: Mr Craig Robson, Mr Masood Hussain, Mr chittoor rajaraman, Mr Gerry O’reilly, Mr Nicholas Mcconnell, Mr Shailendra Achawal, Dr Alhafidz Hamdan, Mr Daniel Brown
Journal: Neuro-Oncology (2017)

AbstractAIM: Individuals with a history of childhood cancers treated with cranial radiotherapy are suggested to be at subsequent increased risk of intracranial meningiomas. When the childhood cancer is leukaemia these children are not routinely followed up in “late-effects” clinics with surveillance MR imaging. METHODS: We report our experience of patients with a history of childhood leukaemia treated with cranial radiotherapy and subsequently went on to develop intracranial meningiomas in adulthoood. RESULTS: All patients had a belated presentation and all underwent surgical resection. CONCLUSION: Considering the causal relationship between exposure of the cranium to ionising radiation and subsequent development of meningiomas is now recognised, there should be an expectation that affected individuals are followed up in regional “late-effects” clinics with surveillance MR imaging from mid-teenage years. It is our experience that childhood leukaemic patients in contrast to paediatric brain tumour patients both of which receive cranial radiotherpay are not routinely followed up. There should be clinician and patient/parent awareness of such complications and any concern on imaging should result in early involvement of the loco-regional neuro-oncology service.
Effect of Timing and Duration of Maintenance Lenalidomide in Myeloma Patients after Autologous Stem Cell Transplantations
Authors: Idrees Mian, Denai Milton, Uday R. Popat, Nina Shah, Yago Nieto, Partow Kebriaei, Simrit Parmar, Sairah Ahmed, Jatin J. Shah, Robert Z. Orlowski, Muzaffar H. Qazilbash, Qaiser Bashir, Richard E. Champlin
Journal: Blood (2014)
Phase II study of irinotecan plus capecitabine in patients with anthracycline and taxane pretreated metastatic breast cancer
Authors: K. S. Lee, J. Ro, I. H. Park, E. A. Kim, B. Nam
Journal: Journal of Clinical Oncology (2009)

1093 Background: Irinotecan (I) and capecitabine (X) have demonstrated single agent activity against breast cancer by different antitumor mechanism without cross-resistance. To assess the objective response rate (RR) of IX combination in metastatic breast cancer (MBC) patients (pts) was the primary end point. Methods: Anthracycline- and taxane-pretreated pts with measurable disease, age ≥ 18 years, adequate organ functions, and ECOG performance score (PS) 0–2 were eligible. Sample size of 36 was calculated with Simon's two stage minimax design. Pts received I 80 mg/m 2 intravenously on days 1 and 8 and X 1,000 mg/m 2 orally twice daily on days 1–14 of every 21-day cycle. Results: Between September 2006 and April 2008, 36 pts with median age of 50 years (range, 28–71) were enrolled. Median follow-up was 17 months (range, 8.3+ - 27.7+). Among 35 evaluable pts excluding 1-consent withdrawal, 86% received at least one prior chemotherapy for MBC; 20% had stage IV disease with 66% lung/37% liver metastases; 80% had PS 0–1; 77% had hormone receptor (HR) positive tumors, 20% triple negative disease and 3% HER-2 positive tumors. Overall RR was 60% (95% CI, 43.5–74.5) with median response duration of 6.3 months (range, 1.0+-17.1+); 2 CR (6%), 19 PR (54%), 8 SD (23%), and 6 PD (17%) with similar RR between HR+ (63%) versus triple negative disease (57%). Median survival was not reached with 76% estimated survival at 1-year, and median progression free survival (PFS) was 7.3 months (range, 0.7–21.1+). Pts received a median of 8 cycles of treatment (range, 1–26+). G1, G2, and G3 hand-foot syndrome were observed in 34%, 17%, and 0%, respectively. NCI grade ≥ 3 adverse events were: neutropenia (60%); asthenia, diarrhea, and vomiting (9%, each); transaminase elevation and febrile neutropenia (6%, each); abdominal pain, anorexia, fatigue, myalgia, and nausea (3%, each). Conclusions: I and X combination by this schedule and doses is highly efficacious in anthracyline- and taxane-pretreated MBC pts with manageable toxicities. Further investigation of this combination in phase III trials is warranted. No significant financial relationships to disclose.
MYC Translocation Partner Gene Determines Survival in Large B-Cell Lymphoma with MYC- or Double Hit MYC/BCL2 Translocation
Authors: Mette Ølgod Pedersen, Anne Ortved Gang, Tim Svenstrup Poulsen, Helle Knudsen, Anne M Falensteen Lauritzen, Signe Ledou Nielsen, Tobias Wirenfeldt Klausen, Peter H. Nørgaard
Journal: Blood (2012)
Genome-Wide Epigenetic Analysis of Cancer Stem Cells (CSCs) In Acute Myeloid Leukemia.
Authors: Jumpei Yamazaki, Marcos R Estecio, Jaroslav Jelinek, David Graber, Yue Lu, Louis Ramagli, Shoudan Liang, Steven M. Kornblau, Jean-Pierre Issa
Journal: Blood (2010)
Effectiveness of a Strategy to Proceed to Allogeneic Stem Cell Transplantation in All Elderly AML Patients Treated with Intensive Chemotherapy: Only Patients in Complete Remission After First Induction Show Long Term Survival.
Authors: Peter A. Von Dem Borne, Constantijn J.M. Halkes, Erik W.A. Marijt, Sabina Kersting, J.H. Frederik Falkenburg, J.Hendrik Veelken
Journal: Blood (2012)
Abstract P2-01-15: Clinical application of multimodal fluorescent-radioactive system in advanced breast cancer patients with neoadjuvant therapy; interim analysis for 65 patients
Authors: S Lee, S-Y Jung, S-K Kim, ES Lee, MH Lee, SJ Park, H-S Kang, KS Lee, IH Park, SH Sim, Y Kim, Y Kwon, J Joo, SH Kang
Journal: Cancer Research (2017)

Abstract Purpose This study aimed to evaluated the identification rate and operation time of sentinel lymph node biopsy (SLNB) by a multimodal fluorescent-radioactive system (MFS) using a mixture of indocyanine green (ICG), radioisotope (RI) compared with the RI alone in advanced breast cancer patients with neoadjuvant therapy. Methods In this phase II randomized study, we enrolled 65 patients with advanced breast cancer with neoadjuvant therapy. Then, they received SLNB with either MFS or RI. We compared the identification rate, operation time of SLNB and number of sentinel lymph nodes. We also evaluated the safety. We analyzed the data of 65 patients for interim analysis. Results The mean age of the MFS group and RI group was 51.7 and 45.9 years (p=0.024), respectively. There were no differences in histopathological characteristics, including tumor size, node positivity, and hormone receptor status between two groups. The radiologic study showed the clinically complete response in axillary lymph nodes after neoadjuvant therapy. In MFS group, sentinel lymph nodes (SLNs) were identified in 30 patients and we could not identify the SLNs in one patient. In RI group, we identified the SLNs in 33 patients and also could not identify them in one patient. (p=0.947). The average numbers of SLNs in the MFS and RI group were similar. (2.32±1.10 vs. 2.18 ± 1.57, respectively; p=0.668) The operation time of SLNB was similar in the each group (11.65 ± 6.49 vs. 9.47 ± 6.26, respectively, p= 0.174) There were no complication, including allergic reactions, skin staining or necrosis. Conclusions This study is the randomized trial that compared MFS using ICG and RI and the conventional RI method for SLNB in the advanced breast cancer with neoadjuvant therapy. The multimodal fluorescent-radioactive system is a feasible and safe method for SLNB for the breast cancer patients with neoadjuvant therapy. We will evaluate the 130 patients for final analysis. Citation Format: Lee S, Jung S-Y, Kim S-K, Lee ES, Lee MH, Park SJ, Kang H-S, Lee KS, Park IH, Sim SH, Kim Y, Kwon Y, Joo J, Kang SH. Clinical application of multimodal fluorescent-radioactive system in advanced breast cancer patients with neoadjuvant therapy; interim analysis for 65 patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-15.