tbuckley/cabot-search huggingface dataset:
Use of MRI-defined tumor distance from the anal verge to predict tumor response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.
Authors: Stanley Ka Tung Yu, Gina Brown, Diana M. Tait
Journal: Journal of Clinical Oncology (2012)

573 Background: Neoadjuvant Chemoradiotherapy (CRT) and surgical resection is the current standard management for patients with locally advanced rectal cancer (i.e. T3 or 4 N0/1 M0) (LARC). Tumour predictive factors for response to CRT in rectal cancer remain controversial. Staging investigations are not standardised and MRI has not been used consistently to approach this. The aim of this study is to investigate whether tumour distance from anal verge, as measured on MRI, is a predictive factor for response to CRT in LARC. Methods: This is a retrospective study. Patients with LARC or low T2 N0/1 M0 rectal cancer (i.e. ≤ 5cm from anal verge measured by MRI) treated with preoperative CRT in 2003- 2009 were included. Pelvic MRIs acquired before CRT and no less than 4 weeks post CRT were reviewed. Patients with ypT0-2 in the resected specimen were classified as responders because ypT0-2 has been shown with significant OS and DFS benefit (Valentini V et al. Int J Radiat Oncol Biol Phys. 2002; 53(3): 664-74). Downstage of mrT2 low rectal cancer was defined as ypT0-1 post CRT. Univariate binary logistic regression (UBLR) was used to analyse the predictor associated between responders and non-responders to CRT treated in the same period of time. Results: 281 patients with LARC who underwent CRT were included in the study. 96% patients in this study had T3/T4 LARC and 4% had T2 low rectal cancer. 114 (41%) were responders as defined above, 167 (59%) were non-responders to CRT. The mean MRI defined tumour distance from anal verge was significantly less in responders (6.4cm [Confidence Intervals (CI) = 5.7 -7.1]) when compared with non-responders (7.9cm [CI =7.3 – 8.6]) (P&lt;0.05). Conclusions: The UBLR analysis from our study indicated that an MRI measured tumour distance of ≤ 5cm from the anal verge independently predicted higher tumour downstaging rate (p &lt; 0.001) to CRT in LARC. Further investigation is recommended regarding tumour downstaging and sphincter preserving surgical resection rate in low rectal cancer post neoadjuvant CRT. [Table: see text]
Major Hematological Response Is the Main Factor for Achieving a Major Molecular Response in JAK2V617F-Positive Essential Thrombocythemia and Polycythemia Vera Patients Treated with Hydroxyurea
Authors: C. Besses, A Álvarez-Larrán, L Martínez-Avilés, R Longarón, S Serrano, B Bellosillo
Journal: Blood (2008)
664. Therapeutic Effect of Oncolytic Herpes Simplex Virus Type 1 (G47Δ) in Combination with Chemotherapy on Colorectal Cancer
Authors: Shinya Abe, Yasushi Ino, Hiroshi Fukuhara, Miwako Iwai, Toshiaki Watanabe, Tomoki Todo
Journal: Molecular Therapy (2016)

One of the reasons for the difficulty of curing unresectable advanced stage colorectal cancer is that cancer cells acquire resistance to anticancer drugs. Oncolytic virus therapy is a potent candidate for developing a new therapeutic approach that counteracts drug resistance, in which an oncolytic virus kills cancer cells in the course of tumor cell specific viral replication. G47Δ is a third-generation oncolytic herpes simplex virus type 1 with triple mutations in the γ34.5, ICP6, and α47 genes.
Abstract 1674: HER3 inhibition potentiates anti-tumor effects of PI3K inhibitors in pre-clinical models of HNSCC
Authors: Kara S. Davis, Nayel Khan, Carolyn Kemp, Sucheta Kulkarni, Diego Alvarado, Theresa LaVallee, Jennifer R. Grandis, Umamaheswar Duvvuri
Journal: Cancer Research (2015)

Abstract Background: The phosphoinositide 3-kinase (PI3K) pathway is thought to be the most frequently mutated oncogenic pathway in head and neck squamous cell carcinoma (HNSCC). This pathway is often further activated by deregulated receptors such as the epidermal growth factor receptor family. HER3 has a direct phosphorylation site with the regulatory subunit of PIK3CA, and is being investigated as a potential co-target to increase anti-tumor effects of PI3K inhibition. In this investigation, we use blocking antibodies against HER3 and its ligand, neuregulin β-1, (KTN3379) and PIK3CA (BYL719) to investigate the effect of HER3 in modulating response to PI3K inhibition. Methods and Results: Treatment with neuregulin β-1 significantly increased phosphorylation of HER3, AKT, and S6 across HNSCC, regardless of baseline level of HER3 expression. HER3 inhibition (KTN3379) consistently abrogated these effects, and decreased baseline phosphorylation of HER3. Combined blockade of HER3 (KTN3379) and PI3K (BYL719) inhibits the growth of HNSCC cell lines more effectively than inhibition of a single receptor alone, in both cell proliferation and colony formation assays. Combined treatment decreases phosphorylation of AKT and S6 more effectively than inhibition with either drug in some HNSCC cell lines. Treatment with neuregulin β-1 diminishes the inhibitory effect of BYL719 on HNSCC cell growth. Furthermore, treatment of some HNSCC cell lines with BYL719 led to upregulation of the HER3 pathway in HNSCC cell lines by Western blotting analysis, suggesting a possible role of HER3 in PI3K resistance. Conclusion: HER3 interacts with PI3KCA, and the PI3K pathway in multiple HNSCC cell lines, and combined blockade leads to pronounced effects in pre-clinical models of HNSCC. These findings suggest that HER3 blockade, may be efficacious when combined with PI3K pathway inhibition. Citation Format: Kara S. Davis, Nayel Khan, Carolyn Kemp, Sucheta Kulkarni, Diego Alvarado, Theresa LaVallee, Jennifer R. Grandis, Umamaheswar Duvvuri. HER3 inhibition potentiates anti-tumor effects of PI3K inhibitors in pre-clinical models of HNSCC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1674. doi:10.1158/1538-7445.AM2015-1674
Fulminant B Hepatitis in a Hepatitis B Surface Antigen-Negative Patient after Rituximab Therapy for B-CLL.
Authors: Pasquale Niscola, Maria Ilaria Del Giudice, Luca Maurillo, Mariacarmela Solmone, Maria Rosaria Capobianchi, Fabrizio Carletti, Daniela Piccioni, Adriano Venditti, Sergio Amadori, Giovanni Del Poeta
Journal: Blood (2005)
Abstract 2996: Hypoxia pathway activation in HPV-associated OSCC
Authors: Jens P. Klussmann, JeJennifer Knuth, Steffen Wagner
Journal: Cancer Research (2015)

Abstract Introduction: HIF1A induces hypoxia dependent transcription of its target genes, resulting e.g. in increased glycolysis. However, increased glycolysis is found in a lot of tumors despite presence of oxygen, known as Warburg effect. Under normoxia HIF1A is hydroxylated by prolyl hydroxylases (PHDs) and degraded by the proteasome. According to literature, HIF1A protein level increase in the presence of HPV-oncoproteins. Nevertheless, HPV dependent induction of HIF1A and resulting downstream effects are still ambiguous for cervix carcinoma and even more for OSCC. We propose HPV-associated HIF1A induction in OSCC to be responsible for a Warburg-like effect, to gain nutrient resources for tumor growth and to be related to immune escape and metastasis. We investigated characteristic effects of HPV on the hypoxia signaling cascade and glycolysis for testing these hypotheses. Experimental Procedure: HPV-positive and -negative cell lines were cultured under normoxic and hypoxic conditions or in the presence or absence of hypoxia mimics. We analyzed components of the hypoxia signaling pathway with molecular- and cell biological methods. Furthermore we analyzed HIF1A and its target gene expression in a cohort of 40 HPV-positive and -negative OSCC by immunohistochemistry. Data: Immunoblot analysis showed 2.6 times higher HIF1A protein level (normalized relative expression) in normoxia and increased accumulation under hypoxic conditions in HPV-positive compared to HPV-negative (4.5 vs. 1.6 times more) cell lines. HPV-positive and -negative cell lines showed comparable PHD2 expression level under normoxia. Interestingly, PHD2 protein level increased more in HPV-positive than in HPV-negative cell lines (5.5 vs. 1.6 times) under hypoxia. Immunofluorescence also showed increased basal HIF1A expression and higher up-regulation after incubation with deferoxamine in HPV-positive vs. -negative cell lines. Immunohistochemistry of GLUT1 in HPV-associated OSCC showed a distinct “HPV-pattern” with a more evenly distributed expression compared to HPV-negative OSCC. Conclusion: Our findings suggest a difference between HPV-induced and HPV-unrelated carcinogenesis in OSCC referring to up-regulation of HIF1A and activation of its target genes under normoxia as well as under hypoxia. This was shown for HPV-positive cell lines in vitro and indicated for clinical samples. Current analyzes focus on HPV-oncoprotein interactions with cellular factors related to HIF1A protein degradation and stabilization. Citation Format: Jens P. Klussmann, JeJennifer Knuth, Steffen Wagner. Hypoxia pathway activation in HPV-associated OSCC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2996. doi:10.1158/1538-7445.AM2015-2996
MK-0457 Is a Novel Aurora Kinase and Janus Kinase 2 (JAK2) Inhibitor with Activity in Transformed JAK2-Positive Myeloproliferative Disease (MPD).
Authors: Francis Giles, Donald A. Bergstrom, Guillermo Garcia-Manero, Steven Kornblau, Michael Andreeff, Hagop Kantarjian, Dan Jones, Steven J. Freedman, Srdan Verstovsek
Journal: Blood (2006)
Abstract 561: Development of a highly specific Met antibody for screening Met overexpression in NSCLC
Authors: Caiwei Chen, Hsiangmin Emily Lu, Haitao Wei, Kehu Yuan, Donghui Ma, Wei-Wu He
Journal: Cancer Research (2015)

Abstract Approximately 5%-22% of non-small cell lung cancer (NSCLC) patients with secondary resistance to EGFR TKIs had evidence of amplification of the Met oncogene. This dysregulation of Met signaling was implicated in the proliferation and eventual metastasis of NSCLC, and therefore represents an attractive target for anticancer drug development. Currently, there are a number of clinical trials for Met targeted small molecule and monoclonal antibody therapies. Immunohistochemistry (IHC) analysis of the Met protein will be very important for these Met targeted therapies and requires a highly specific antibody to prevent false positives. To develop a highly specific monoclonal antibody against Met for IHC analysis in NSCLC, we generated 97 monoclonal antibodies. IHC evaluation showed that 8 of the antibodies had suitable performance in Met positive NSCLC patient tissues. The 8 Met monoclonal antibodies were further tested on a high density protein microarray chip containing 17,000 human proteins. The microarray analysis showed that clone 3G5 was highly specific as evidenced with it only reacting with Met on the microarray. This new 3G5 Met monoclonal antibody will be a promising candidate as a diagnostic reagent for detecting Met protein in NSCLC with minimal false positives. Citation Format: Caiwei Chen, Hsiangmin Emily Lu, Haitao Wei, Kehu Yuan, Donghui Ma, Wei-Wu He. Development of a highly specific Met antibody for screening Met overexpression in NSCLC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 561. doi:10.1158/1538-7445.AM2015-561
Abstract 1178: Loss of PHLPP expression promotes glycolysis in colon cancer cells
Authors: Xiaopeng Xiong, Yang-an Wen, Tianyan Gao
Journal: Cancer Research (2015)

Abstract Increased glycolysis is considered as one of the most important metabolic alterations adapted by cancer cells in order to generate high levels of glycolytic intermediates to support proliferation. PHLPP belongs to a novel family of Ser/Thr protein phosphatases. Our previous studies have shown that PHLPP serves as a tumor suppressor to inhibit cell proliferation, promote apoptosis and increase therapeutic sensitivity in colon cancer cells. Here, we further examined the role of PHLPP in regulating metabolic pathways in colon cancer. Our results showed that the rate of glucose consumption and lactate production was significantly increased in PHLPP knockdown colon cancer cells and in PHLPP knockout MEF cells. Metabolic analysis using Seahorse XF96 analyzer revealed that decreased PHLPP expression resulted in an increase in the extracellular acidification rate (ECAR) suggesting enhanced glycolysis. To determine the underlying molecular mechanism, we found that the Akt-mediated phosphorylation of HK2 was elevated in PHLPP knockdown colon cancer cells and the amount of mitochondria-associated hexokinase 2 (HK2) was increased. This is consistent with previous finding that Akt-mediated phosphorylation of HK2 increases its activity by promoting mitochondria translocation. Furthermore, PHLPP, Akt and HK2 were found in the same mitochondria fraction and PHLPP co-immunoprecipitated with HK2 in colon cancer cells. As HK2 is the key enzyme that determines the direction and magnitude of glucose flux, our studies identified PHLPP as a novel regulator of glucose metabolism by controlling Akt-mediated regulation of HK2 activity. Note: This abstract was not presented at the meeting. Citation Format: Xiaopeng Xiong, Yang-an Wen, Tianyan Gao. Loss of PHLPP expression promotes glycolysis in colon cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1178. doi:10.1158/1538-7445.AM2015-1178
Base-Position Error Rate Analysis of Next-Generation Sequencing Applied to Circulating Tumor DNA in Non-Small Cell Lung Cancer: A Prospective Study
Authors: Nicolas Pécuchet, Eleonora Zonta, Audrey Didelot, Pierre Combe, Constance Thibault, Laure Gibault, Camille Lours, Yves Rozenholc, Valérie Taly, Pierre Laurent-Puig, Hélène Blons, Elizabeth Fabre
Journal: PLoS Medicine (2016)

Circulating tumor DNA (ctDNA) is an approved noninvasive biomarker to test for the presence of EGFR mutations at diagnosis or recurrence of lung cancer. However, studies evaluating ctDNA as a noninvasive "real-time" biomarker to provide prognostic and predictive information in treatment monitoring have given inconsistent results, mainly due to methodological differences. We have recently validated a next-generation sequencing (NGS) approach to detect ctDNA. Using this new approach, we evaluated the clinical usefulness of ctDNA monitoring in a prospective observational series of patients with non-small cell lung cancer (NSCLC).We recruited 124 patients with newly diagnosed advanced NSCLC for ctDNA monitoring. The primary objective was to analyze the prognostic value of baseline ctDNA on overall survival. ctDNA was assessed by ultra-deep targeted NGS using our dedicated variant caller algorithm. Common mutations were validated by digital PCR. Out of the 109 patients with at least one follow-up marker mutation, plasma samples were contributive at baseline (n = 105), at first evaluation (n = 85), and at tumor progression (n = 66). We found that the presence of ctDNA at baseline was an independent marker of poor prognosis, with a median overall survival of 13.6 versus 21.5 mo (adjusted hazard ratio [HR] 1.82, 95% CI 1.01-3.55, p = 0.045) and a median progression-free survival of 4.9 versus 10.4 mo (adjusted HR 2.14, 95% CI 1.30-3.67, p = 0.002). It was also related to the presence of bone and liver metastasis. At first evaluation (E1) after treatment initiation, residual ctDNA was an early predictor of treatment benefit as judged by best radiological response and progression-free survival. Finally, negative ctDNA at E1 was associated with overall survival independently of Response Evaluation Criteria in Solid Tumors (RECIST) (HR 3.27, 95% CI 1.66-6.40, p < 0.001). Study population heterogeneity, over-representation of EGFR-mutated patients, and heterogeneous treatment types might limit the conclusions of this study, which require future validation in independent populations.In this study of patients with newly diagnosed NSCLC, we found that ctDNA detection using targeted NGS was associated with poor prognosis. The heterogeneity of lung cancer molecular alterations, particularly at time of progression, impairs the ability of individual gene testing to accurately detect ctDNA in unselected patients. Further investigations are needed to evaluate the clinical impact of earlier evaluation times at 1 or 2 wk. Supporting clinical decisions, such as early treatment switching based on ctDNA positivity at first evaluation, will require dedicated interventional studies.
Abstract 2589: Investigations of covalent binding efficiency for third-generation EGFR irreversible inhibitors AZD9291 and CO-1686
Authors: Zhen Qin, Xuebing Sun, Ye Liu, Yunguang Du, Miao Wang, Nan Hu, Jiye Zhang, Hao Peng, Lai Wang, Min Wei, Lusong Luo
Journal: Cancer Research (2015)

Abstract Patients with non-small cell lung cancer with activating EGFR mutations initially respond to first-generation and second-generation EGFR inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR T790M mutation. In addition, patients oftentimes experience severe side effects including rash and diarrhea due to the inhibition profile against wild-type EGFR. AZD9291 and CO-1686 are the leading third-generation irreversible EGFR inhibitors in clinical development. They selectively inhibit T790M EGFR, while sparing wild-type EGFR. In this study, we investigated the covalent binding efficiency of these two irreversible EGFR inhibitors using biochemical and cellular assays. We discovered that these two inhibitors had dramatic difference in covalent binding efficiencies in WT and mutant EGFR binding at biochemical and cellular levels. In pEGFR cellular assay, AZD9291 displayed much prolonged inhibition of pEGFR than CO-1686. In CO-1686 treated cells, recovery of pEGFR had reached 50% of control levels only after 4 hours. In the meantime, pEGFR in AZD9291 treated cells had no recovery even after 24 hours. These data may suggest different covalent bond formation efficiency and reversibility between different types of irreversible EGFR inhibitors. This may be one of the important factors for consideration when develop third-generation EGFR inhibitors. Citation Format: Zhen Qin, Xuebing Sun, Ye Liu, Yunguang Du, Miao Wang, Nan Hu, Jiye Zhang, Hao Peng, Lai Wang, Min Wei, Lusong Luo. Investigations of covalent binding efficiency for third-generation EGFR irreversible inhibitors AZD9291 and CO-1686. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2589. doi:10.1158/1538-7445.AM2015-2589
A comparison of two exponential models of the time constant during left ventricular isovolumic pressure decay in coronary artery disease.
Authors: Motoshi Takeuchi, Kazuhiro Fujitani, Kenji Kurogane, Bai Tai, Chuichi Toda, Tohru Yamasaki, Shinji Takano, Hisashi Fukuzaki
Journal: Circulation (1985)
Cytokine Gene Expression in Peripheral Blood Mononuclear Cells Points to Interleukin-10 as an Inhibitor of Alloreactivity Following Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning.
Authors: Soren L. Petersen, Hans O. Madsen, Lars P. Ryder, Arne Svejgaard, Ebbe Dickmeiss, Lars Vindelov
Journal: Blood (2005)
Evaluation of Differences in Medical Costs Associated with Venous Thromboembolism Prophylaxis with Desirudin Vs. Low Molecular Weight Heparin Among Patients Undergoing Total Hip Replacement Surgery
Authors: Steven Deitelzweig, Edith A Nutescu, James Meyer, Jay Lin, Melissa Lingohr-Smith, Alpesh N Amin
Journal: Blood (2014)
Paclitaxel with bevacizumab (PB) as first-line therapy for metastatic breast cancer: Our experience.
Authors: N. Salesi, M. Colonna, B. Di Cocco, M. Moscato, A. Calogero, L. Pacini, E. Veltri
Journal: Journal of Clinical Oncology (2011)

e11013 Background: In a clinical trial of 722 patients (pts) with locally recurrent metastatic breast cancer (MBC) solvent-based paclitaxel 90 mg/m2 was administered intravenously (IV) over 1 hr weekly for 3 weeks (wPac) followed by a week of rest (q3/4w) alone or in combination with bevacizumab (Bev) 10 mg/kg every 2 weeks (q2w) (E2100 Trial). As compared with single agent, the combination had a greater median progression-free survival (PFS; 11.4 months (mo) vs. 6.11 mo, p < 0.0001) and overall response rate (ORR; 30% vs. 14%, p < 0.0001). Methods: We reviewed data for 16 patients: pts ≥20 years with HER2-negative measurable MBC, ECOG PS≤1 and no prior chemotherapy for MBC received Bev 10 mg/kg d 1 and 15 with wPac 90 mg/m2, d 1, 8, and 15 q4w, as in E2100 trial. Coprimary endpoints were time to progression (TTP) and safety. Secondary endpoints included ORR (RECIST v1) and overall survival (OS). Results: A total of 16 patients were registered and evaluated between June 2009 and September 2010. Median age: 68 (32-76); postmenopausal: 80%; baseline ECOG<2 100% of patients. Metastatic sites were lung (45%), nodes (60%), liver (47%), pleura (35%), bone (47%). Two patients (12.5%) achieved CR, 6 (37.5%) PR (ORR 50.0%) and 8 (50.0%) SD; the median follow up was 9 mo (range, 2.5-16.0), the median time to progression 9.6 mo. The median survival was 20.3 mo and the probability of 1-year survival 71.3%. Main grade 3-4 toxicity was neutropenia (31.5%). A total of 115 cycles were administered (median: 6 cycles/patient). Conclusions: The Bev-wPac combination in our experience showed high activity, similar to that seen in E2100 trial. No new safety signals were seen in this population.
Insight into Risk Factors for Pulmonary Hypertension in Thalassemia: Abnormal Platelet, Hemolysis and Vascular Markers.
Authors: Sylvia T. Singer, Frans Kuypers, Fineman Jeffrey, Larkin Sandy, Harmon Cynthia, Rosenfeld Howard, Lui Ann, Nugent Diane, Vichinsky Elliott
Journal: Blood (2007)
Mechanisms of Co-Operation of DNMT3A Mutations with JAK2 V617F Through Histone H4 Arginine 3 Provides New Insights in MPN Disease Pathogenesis
Authors: Nisha Rao, Carolyn M Butcher, Petra J Neufing, Sarah Bray, Chris N Hahn, Hamish S Scott, Junia V. Melo, David Ross, Ian D Lewis, Peter Bardy, Richard J D'Andrea
Journal: Blood (2011)