tbuckley/cabot-search huggingface dataset:
Abstract CT075: Tumor mutation status will predict metabolic response to metformin in lung cancer treated with stereotactic body radiation therapy (SBRT)
Authors: Heath D. Skinner, Thomas Guerrero, Brian Hobbs, Laurence Court, Paige L. Nitsch, John Heymach
Journal: Cancer Research (2016)

Abstract At present, there are over 100 clinical trials examining the role of metformin in malignancy, either alone or in combination with chemotherapy. However, despite significant preclinical data, trials examining the role of metformin as a radiosensitizer are few. Moreover, the effects of endogenous tumor mutations on response to metformin are unknown, as some data suggests that certain mutations (eg. TP53, STK11) may confer sensitivity to this agent. Finally, the effects of metformin on FDG-uptake in solid tumors is far from clear, as this agent can actually lead to an increased uptake of FDG in normal bowel. Because of these questions, we have designed an imagining-guided trial of 70 patients, randomized 6:1 in favor of metformin treatment in patients with non-small cell lung cancer to be treated with stereotactic body radiotherapy (SBRT). Patients receive either placebo or metformin at a loading dose of 1,000 mg per day for one week followed by 1-2 weeks of metformin at 2,000 mg per day. Prior to study entry, an FDG-PET scan is performed which is then repeated after 2-3 weeks of metformin treatment. Metformin or placebo is maintained throughout SBRT and the standard daily cone-beam CTs are taken. Metformin or placebo stops at the end of SBRT followed by an additional FDG-PET scan 6 months after completion of therapy. All tumors with available tissue will be subjected to targeted sequencing. The primary outcome is FDG-PET response following initial metformin or placebo monotherapy as well as at 6 months. Secondary outcomes include the effect of common mutations (TP53, STK11, Kras) on metformin FDG-PET response. Currently, 14 patients have been registered for this trial. We anticipate that this study will provide a unique insight on how metformin affects FDG-PET response, if this response is affected by tumor mutation status, and provide preliminary data on the clinical efficacy of metformin in the setting of SBRT. Citation Format: Heath D. Skinner, Thomas Guerrero, Brian Hobbs, Laurence Court, Paige L. Nitsch, John Heymach. Tumor mutation status will predict metabolic response to metformin in lung cancer treated with stereotactic body radiation therapy (SBRT). [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 CT075.
OC-026 Joint endoscopic and laparoscopic approach as a salvage procedure for very large rectal lesions
Authors: G R Longcroft-Wheaton, R Mead, P Bhandari
Journal: Gut (2010)

<h3>Introduction</h3> Endoscopic mucosal resection (EMR) is an excellent technique for removing large lesions. It can also be used as an adjunct to surgery. Be describe a case where EMR was used to partially remove a large rectal adenoma, enabling a less radical surgical approach to be taken. <h3>Methods</h3> A 55-year-old woman with a previous history of an anterior resection for a sigmoid tumour was referred with a large 18-cm LST-G rectal adenoma, crossing the dentate line and involving the surgical anastomosis. It had been suggested that the only treatment option was an AP resection with permanent colostomy. On assessment of the lesion it was clear that a complete endoscopic resection was not possible due to the scar tissue from the previous surgery. However, it was decided that it would be possible to clear a 10-cm cuff to enable a low resection with primary anastomosis to be performed. <h3>Results</h3> A 10-cm cuff was cleared by piecemeal resection of the lesion using a conventional EMR technique. The patient was followed up after 8 weeks where a joint assessment by gastroenterologist and rectal surgeon was performed. It was felt that a sufficient margin had been created for a resection and primary anastomosis to be performed in. She subsequently underwent a successful laparoscopic surgical resection. <h3>Conclusion</h3> When a complete EMR is not viable it is important not to dismiss the potential benefit which can be gained by a combined endoscopic and laparoscopic surgical approach. This case illustrates how a permanent colostomy can be avoided in patients with low rectal lesions associated with scarring precluding a total endoscopic mucosal resection.
Abstract 1626: Krüppel-like factor 8 activates the transcription of C-X-C cytokine receptor type 4 to promote breast cancer cell invasion, transendothelial migration and metastasis
Authors: Debarati Mukherjee, Heng Lu, Lin Yu, Satadru K. Lahiri, Tianshu Li, Jihe Zhao
Journal: Cancer Research (2016)

Abstract Krüppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels, as determined by quantitative real-time PCR and immunoblotting. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of the cells towards the ligand CXCL12. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced CXCR4 expression associated with decreased cell migration, invasion and TEM towards CXCL12. Histological and database mining analyses of independent cohorts of patient tissue microarrays revealed a correlation of aberrant co-elevation of KLF8 and CXCR4 with metastatic potential. Promoter analysis indicated that KLF8 directly binds and activates the human CXCR4 gene promoter. Interestingly, a CXCR4-dependent activation of focal adhesion kinase (FAK), a known upregulator of KLF8, was highly induced by CXCL12 treatment in KLF8-overexpressing, but not KLF8 deficient cells. This activation of FAK in turns induced a further increase in KLF8 expression. Xenograft studies showed that overexpression of CXCR4, but not a dominant-negative mutant of it, in the MDA-MB-231 cells prevented the invasive growth of primary tumor and lung metastasis from inhibition by knockdown of KLF8. These results collectively suggest a critical role for a previously unidentified feed-forward signaling wheel made of KLF8, CXCR4 and FAK in promoting breast cancer metastasis and shed new light on potentially more effective anti-cancer strategies. Citation Format: Debarati Mukherjee, Heng Lu, Lin Yu, Satadru K. Lahiri, Tianshu Li, Jihe Zhao. Krüppel-like factor 8 activates the transcription of C-X-C cytokine receptor type 4 to promote breast cancer cell invasion, transendothelial migration and metastasis. [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 1626.
Pharmacological Approaches in the Treatment and Maintenance of Weight Loss
Authors: Luc Van Gaal, Eveline Dirinck
Journal: Diabetes Care (2016)

Obesity is a growing global health concern, associated with a number of important comorbid conditions. It increases the risk of diabetes and contributes to development of cardiovascular disease. While the benefits of weight loss are well established, weight reduction remains a difficult-to-reach goal in overweight and obese individuals due to several metabolic and psychological factors. For many patients, lifestyle intervention is insufficient to achieve long-term weight loss, and additional options, such as pharmacotherapy, need to be considered. Besides the challenging enterprise of weight reduction, weight maintenance remains an even more crucial and outcome-determining aspect of weight management. This article focuses on the potential of currently available pharmacological strategies to support weight loss and maintenance goals in individuals at risk. Two pharmacotherapy types are considered: those developed primarily to induce weight loss and those developed primarily for blood glucose control that have a favorable effect on body weight. Finally, the potential of very low- and low-calorie diets combined with pharmacotherapy and pharmacological combination therapies are discussed, as well as emerging approaches in development.
Graft-Versus-Tumor Effect In Patients with Graft-Versus-Host Disease Defined by NIH Consensus Criteria
Authors: Sung-Eun Lee, Byung-Sik Cho, Seung-Ah Yahng, Ki-Seong Eom, Yoo-Jin Kim, Hee-Je Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong-Wook Lee, Woo-Sung Min, Chong-Won Park
Journal: Blood (2010)
Abstract 4132: Multiple drug resistance-associated protein 4 (MRP4): Role in triple negative breast cancer
Authors: Tyler Kochel, Xinrong Ma, Namita Kundu, Jocelyn Reader, Olga Goloubeva, Amy M. Fulton
Journal: Cancer Research (2016)

Abstract Introduction: MRP4 is responsible for the active export of prostaglandin E2 (PGE2) from cells. PGE2, derived from cyclooxygenase-2-mediated synthesis, contributes to tumor growth and metastasis of many epithelial tumors; however, the role of MRP4 in breast cancer has not been investigated. Methods: We employed publicly available breast cancer gene expression datasets and a panel of breast cancer cell lines to examine the expression and function of MRP4 as well as other members of the PGE2 pathway. In contrast to the export function of MRP4, the prostaglandin transporter PGT/SLCO2A1 imports PGE2 into the cell where 15-prostaglandin dehydrogenase (5-PGDH/HPGD) metabolizes PGE2 to terminate ligand-mediated activation of the prostaglandin E (EP) receptors. Results: We found that ABCC4, which encodes the MRP4 protein, is widely expressed in breast cancer but breast cancer subtypes have different expression profiles of PGE2 pathway members. ABCC4/MRP4 is elevated more frequently in basal breast tumors than in apocrine or luminal tumors. This is the first report that elevated expression of MRP4 is found in breast cancer subtypes (basal, HER2-enriched) with the worst prognoses. ABCC4 expression was also higher in breast cancer-associated stroma compared to healthy mammary tissue. Basal-type tumors also expressed the highest levels of PTGS2/COX-2 while the genes responsible for PGE2 metabolism (HPGD and SLCO2A1) are negatively correlated with TNBC. The same pattern was observed in breast cancer cell lines, where basal-type and HER2-enriched cell lines highly express MRP4 but luminal breast cancers do not. HPGD was decreased in most cancer cell lines compared to MCF10A immortalized cells, consistent with the known tumor suppressor role of HPGD/15PGDH. MRP4 exports PGE2 which was reduced in the presence of MRP4 small m.w. inhibitors or by MRP4 gene silencing. Lastly, expression of shMRP4 in highly metastatic, basal-type MDA-MB-231 human breast cancer cells reduced the ability of these cells to spontaneously metastasize to the lungs of NOD/SCID mice but did not affect the tumor growth properties of tumor cells implanted proximal to the mammary gland. Conclusions: Elevated MRP4 is a characteristic of aggressive breast cancer subtypes and is partially responsible for the high levels of PGE2 in the tumor microenvironment. Silencing of MRP4 reduces spontaneous metastasis in a xenograft model of TNBC. Further investigation of MRP4 as a potential therapeutic target is warranted. Citation Format: Tyler Kochel, Xinrong Ma, Namita Kundu, Jocelyn Reader, Olga Goloubeva, Amy M. Fulton. Multiple drug resistance-associated protein 4 (MRP4): Role in triple negative breast cancer. [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 4132.
Can nipple-sparing mastectomy serve as an alternative to mastectomy for early-stage breast cancer without radiotherapy? Over 20-year experience at a Japanese institution.
Authors: Teruhisa Sakurai, Takaomi Suzuma, Goro Yoshimura, Eri Jinta, Teiji Umemura, Hirokazu Tanino, Koji Yamashita, Takeo Sakurai
Journal: Journal of Clinical Oncology (2014)

e12030 Background: A cosmetic outcome is one of the most important goals of surgical treatment of breast cancer. We began performing nipple-sparing mastectomy (NSM) in 1978. NSM is a controversial procedure because of its association with surgical complications and recurrence. We herein review the safety of the NSM surgical technique, compare the recurrence and prognosis of NSM with those of standard mastectomy (MT) and breast-conserving surgery (BCS), and compare the recurrence and prognosis of NSM with and without reconstruction. Methods: We retrospectively analyzed 723 patients with early-stage breast cancer who underwent NSM, including 93 patients who underwent reconstruction and 630 patients who did not undergo reconstruction, from 1985 to 2007. Our surgical method of NSM involved creation of a thick skin flap to avoid surgical complications including nipple necrosis. We compared the outcome of NSM with that of 100 patients who underwent MT and 259 patients who underwent BCS. No patients who underwent NSM or MT received radiotherapy. We compared the local recurrence rate (LRR), disease-free survival (DFS), and overall survival (OS) among all patients who underwent NSM, MT, and BCS. Results: (1) In the NSM group, the numbers of patients with stage 0, 1, 2A, and 2B cancer were 21, 320, 253, and 129, respectively. No nipple necrosis occurred during the 114-month follow-up period. In total, 6.7% of patients in the NSM group developed local recurrence, including 3.3% at the nipple and 3.4% at the skin flap. There were no significant differences among the NSM, MT, and BCS groups in LLR (6.7%, 4.0%, and 4.2%, respectively), 10-year DFS (88%, 90%, and 87%, respectively), or 10-year OS (92%, 91%, and 97%, respectively). (3) There were also no significant differences between patients with and without reconstruction in LLR (7.5% and 6.5%, respectively), 10-year DFS (91% and 88%, respectively), or 10-year OS (95% and 92%, respectively). Conclusions: Our data show that NSM without radiotherapy may be considered as an alternative option for mastectomy when BCS is inapplicable in patients with early-stage breast cancer.
Australian doctors condemn “horrific” treatment of children in juvenile detention
Authors: Paul Smith
Journal: BMJ (2016)

Doctors in Australia have condemned the treatment of children in juvenile detention after film footage showing detainees being tear gassed, hooded, and stripped naked was broadcast on national television.

The country’s prime minister, Malcolm Turnbull, has ordered a royal commission into the treatment of young people in detention across the Northern Territory after the footage was shown by the Australian Broadcast Corporation on 25 July.

Leading doctors condemned the behaviour and warned of the potential psychological and physical harms faced by children in detention.

The footage was taken at the Don Dale Youth Detention Centre in Darwin in August 2014.

One clip showed guards laughing and calling one 14 year old inmate a “fucking idiot” following an attempted escape.

“I’ll pulverise the little fucker, grab the fucking gas, and fucking gas them through,” another guard added.

The footage then showed the child and five other teenagers who …
Abstract 491: Salvage MET amplification detection and therapy through cell-free DNA NGS in a progressing lung cancer patient
Authors: Nir Peled, Anna Belilovski, Lior Soussan-Gutman, Richard B. Lanman, AmirAli Talasaz
Journal: Cancer Research (2016)

Abstract Background: Mutational analysis has become standard of care in lung cancer. However, many patients do not have tissue available due to lack of tissue, or more commonly due to tissue exhaustion by previous tissue analysis. Next generation sequencing of circulating cell-free DNA (cfDNA) provides a non-invasive alternative. EGFR point mutations and indels are well reported in this manner, however gene copy number amplification is more challenging. Here we present a cases where MET amplification has been detected and guided highly efficient therapy in advanced lung cancer patient. Methods: Guardant360TM is a targeted cfDNA NGS panel using hybrid capture and complete exon sequencing exons for single nucleotide variant detection in 68 genes, copy number amplifications (CNA) in 16 genes, and selected indels and fusions. CNA has been validated against cell lines with known amplifications. Results: A 70 y old former light smoker (15 PY) with pulmonary fibrosis and moderate pulmonary hypertension was diagnosed with a 30 mm RMB lung adenocarcinoma that was treated by stereotactic beam radiotherapy due to poor pulmonary reserve. After 5 months, mediastinal, liver and multiple bone metastases were diagnosed. Genomic analysis of the primary tissue biopsy yielded a rare EGFR mutation (I744F) and afatinib therapy was started to cover uncommon EGFR mutations. However, 2 months later, a significant progression has occurred and the patient had severe local progression with respiratory near-failure. The patient was not a candidate for chemotherapy and there was no further tissue available for molecular testing. Therefore cfDNA testing was performed finding no residual EGFR mutation in the blood but a MET amplification reported above the 90th percentile for the Guardant Health laboratory with copy number of 53.6 in the blood. Upon this result, crizotinib 250 mg BID was started with immediate clinical improvement, followed with a dramatic imaging response on CT/PET scans. Currently, the patient is in PS-0 and free of any symptoms, 3 months since treatment has been started. Conclusion: cfDNA detection of MET amplification as a key resistance mechanism after EGFR TKI therapy is feasible in patients where tissue is not accessible or was undergenotyped and may be accompanied by a fast and dramatic clinical improvement. Citation Format: Nir Peled, Anna Belilovski, Lior Soussan-Gutman, Richard B. Lanman, AmirAli Talasaz. Salvage MET amplification detection and therapy through cell-free DNA NGS in a progressing lung cancer patient. [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 491.
Clinical Course and Significance of the Novel FLT3-Y842C Mutation in a Patient with AML Treated with PKC412 Monotherapy.
Authors: T. Kindler, F. Breitenbuecher, S. Kasper, E. Estey, F. Giles, E. Feldman, G. Ehninger, G. Schiller, V. Klimek, S. D. Nimer, A. Gratwohl, C. Choudhary, C. Mueller-Tidow, H. Serve, H. Gschaidmeier, P. S. Cohen, C. Huber, T. Fischer
Journal: Blood (2004)
Abstract 1646: A glioblastoma methylation assay (GaMA) developedfrom genomic analysis of glioma spheroid cultures predicts response toradiation therapy in patients with glioblastoma
Authors: Qianghu Wang, Ravesanker Ezhilarasan, Eskil Eskilsson, Joy Gumin, Jie Yang, Mona Jaffari, Ming Tang, Kenneth D. Aldape, Frederick F. Lang, Roel G.W. Verhaak, Erik P. Sulman
Journal: Cancer Research (2016)

Abstract Radiation therapy (RT) remains one of the most effective treatments for patients with GBM and has been repeatedly demonstrated to improve survival; yet response to RT is variable. We explored the relationship between methylation status and radiation response to develop a predictor of RT response using the epigenetic data of glioma sphere-forming cells (GSCs). The DNA methylomes of 42 GSCs were profiled using Illumina Infinium 450K methylation bead arrays. 15 GSCs were irradiated with 2-, 4-, and 6-Gy RT and response determined using clonogenic assays. We discovered 168 CpG probes capable of distinguishing sensitive from resistant GSCs. To validate, we analyzed 362 TCGA GBM samples, 272 that received standard 60Gy RT and 90 treated with low or no RT. Using the glioblastoma methylation assay (GaMA) signature, we classified the samples as either RT sensitive or resistant. Survival was significantly different between the predicted sensitive vs resistant patients for those treated with standard RT (median 21.0m vs 14.7m, p&amp;lt;0.005). GaMA did not predict a survival difference among patients receiving no/low-dose RT, suggesting a predictive, but not prognostic, role for the signature. Using the ENCODE ChIP-Seq Significance Tool, we observed that the transcription factor EZH2 was significantly associated with the radiation resistant promoters in the GaMA signature. Among the hypermethylated genes with EZH2 binding sites, the NR2F2 promoter had the greatest number of hypermethylated CpG sites correlated to RT resistance. NR2F2 has previously been identified as negatively associated with activation of the wnt/β-catenin, a pathway associated with RT resistance of mammary progenitor cells. Expression of WNT1 in TCGA GBM cohort was negatively associated with NR2F2 expression. Our GSC RT response-based methylome analysis corroborates this association and provides a rationale for the methylation signature as a predictive biomarker of radiation response. Citation Format: Qianghu Wang, Ravesanker Ezhilarasan, Eskil Eskilsson, Joy Gumin, Jie Yang, Mona Jaffari, Ming Tang, Kenneth D. Aldape, Frederick F. Lang, Roel G.W. Verhaak, Erik P. Sulman. A glioblastoma methylation assay (GaMA) developedfrom genomic analysis of glioma spheroid cultures predicts response toradiation therapy in patients with glioblastoma. [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 1646.
Abstract 3545: Gallotannin induces senescence and autophagy leading to cell death via SIRT1 inhibition and AMPK activation in hepatocellular carcinoma cells
Authors: Hee Young Kwon, Sung-hoon Kim
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC) is one of the most fatal malignancies with high mortality rate worldwide. In the present study, the underlying antitumor mechanism of gallotannin, a hydrolysable tannic acid, was elucidated in HepG2 and SKHep1 HCC cells. Gallotannin suppressed growth and colony formation and also induced senescence via upregulation of p21, G0 / G1 arrest and higher senescence-associated β-galactosidase (SA-β-gal) activity within 24 h culture in HepG2 and SKHep1 cells. Of note, gallotannin also induced autophagy by increasing the number of protein-cytosol-associated protein light chain 3 (LC3) punctae, LC3B-II conversion and SQSTM1/p62, autophagic vacuoles (AVOs) by transmission electron microscopy (TEM) and decreasing the of Beclin1 in HepG2 and SKHep1 cells. A tandem fluorescent-tagged LC3 reporter plasmid (GFP-mRFP-LC3) transfection revealed that gallotannin increased the number of yellow colored LC3 punctae through the co-localization of GFP and mRFP punctae and yellow colored LC3 punctae were increased by CQ or NH4Cl with accumulation of autophagosomes, LC3B-II and SQSTM1/p62 in HepG2 and SKHep1 cells. Additionally, gallotannin attenuated the of sirtuin1 (SIRT1) and mTOR and activated the phosphorylation of 5′-AMP activated protein kinase (AMPK) in two HCC cells. Furthermore, AMPK activator AICAR significantly enhanced SA-β-gal activity and antiproliferation induced by gallotannin, while AMPK inhibitor compound C did not in two HCC cells. Of note, gallotannin time dependently activated caspase 8 / 3 and time/concentration dependently increased sub G1 portion along with weak cleavages of PARP in two HCC cells. Collectively, gallotannin induces senescence and inhibits late autophagy flux, finally leading to apoptotic cell death in HepG2 and SKHep1 cells via inhibition of SIRT1 and activation of p-AMPK as a potent antitumor agent for HCC treatment. Citation Format: Hee Young Kwon, Sung-hoon Kim. Gallotannin induces senescence and autophagy leading to cell death via SIRT1 inhibition and AMPK activation in hepatocellular carcinoma cells. [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 3545.