tbuckley/cabot-search huggingface dataset:
Abstract 4939: Evaluating a novel biomarkers set for postoperative outcome in patients with gastrointestinal cancer
Authors: Kunizaki Masaki, Shigekazu Hidaka, Tetsurou Tominaga, Yoichi Furukawa, Takeshi Nagayasu
Journal: Cancer Research (2016)

Abstract Gastrointestinal cancer is the leading cause of cancer deaths in developed countries. The incidence of gastroinetestinal cancer has been increasing dramatically in Japan and has attracted worldwide attention. Despite the introduction of new postoperative chemotherapy regimens and the progress in endoscopic surgery techniques, overall survival is still poor for most advanced gastrointestinal cancer patients. The prognosis of gastrointestinal cancer patients is based on the presence of lymph node metastasis and the depth of tumour cell invasion. Usually, these parameters can be determined by microscopic examination of tissue sections from the primary neoplasm and lymph nodes. However, it is not always possible to establish a prognosis based only on the histopathological examination of cancer specimens. Therefore, there is continuing interest in prognostic factors that can permit more accurate patient stratification, improve clinical decision-making and possibly contribute to more rational study analysis. In the past few years, much progress has been made towards a better understanding of the molecular mechanisms of gastrointestinal cancer. Mutations and overexpression of p53 are common characteristics of various solid tumors. The overexpression of mutant p53 protein has been found to induce the formation of serum p53 IgG antibodies in gastrointestinal cancer patients. In addition, recent studies have revealed that the inflammation-based scoring is a useful tool for predicting postoperative outcome in gastrointestinal cancer patients. Therefore, in this study, we retrospectively reviewed a database of patients who had undergone elective surgery for gastrointestinal cancer at the Division of Surgical Oncology, Nagasaki University Hospital, and that was conducted to evaluate the usefulness of the combination of such biomarkers (CEA, CA19-9, GPS, s-p53ab etc.) for prediction of postoperative mortality in gastroinetestinal cancer patients. Citation Format: Kunizaki Masaki, Shigekazu Hidaka, Tetsurou Tominaga, Yoichi Furukawa, Takeshi Nagayasu. Evaluating a novel biomarkers set for postoperative outcome in patients with gastrointestinal 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 4939.
Twin randomized studies of daratumumab (DARA; D) plus standard of care (lenalidomide/dexamethasone or bortezomib/dexamethasone [DRd or DVd]) versus Rd or Vd alone in relapsed or refractory multiple myeloma (MM): 54767414MMY3003 (Pollux) and 54767414MMY3004 (Castor).
Authors: Antonio Palumbo, Meletios A. Dimopoulos, Donna Ellen Reece, Pieter Sonneveld, Andrew Spencer, Asher Alban Akmal Chanan-Khan, Hartmut Goldschmidt, Howard Yeh, Jordan Mark Schecter, Xiang Qin, Himal Amin, Mary E. Guckert, Tahamtan Ahmadi, Robert Z. Orlowski
Journal: Journal of Clinical Oncology (2015)

TPS8609 Background: Lenalidomide or bortezomib plus low-dose dexamethasone are considered standard of care for relapsed/refractory MM patients. DARA is a human anti-CD38 IgG1κ monoclonal antibody. In ongoing phase I/II studies, DARA (16 mg/kg) has shown promising efficacy and safety as a single agent (overall response rate (ORR) 35%; Lokhorst HM et al. ASCO 2014), in combination with Rd (ORR 87%; Plesner T et al. ASH 2014), as well as in combination with Vd (ORR 100 %; Moreau P et al. ASH 2014). Methods: MMY3003 and MMY3004 are phase III randomized, open-label, multicenter studies for patients with relapsed/refractory MM. For both studies, the main inclusion criteria are documented MM after one or more prior line of therapy, and documented evidence of progressive disease. In MMY3003, approximately 560 patients will be randomized in a 1:1 ratio to DRd (DARA 16 mg/kg IV weekly x 8 wk, every 2 wk x 16 wk, every 4 wk thereafter; lenalidomide 25 mg PO Days 1-21 of each 28-day cycle; dexamethasone 40 mg weekly) or Rd and stratified by International Staging System (ISS), number of prior lines (1 vs 2 or 3 vs > 3), and prior lenalidomide exposure. In MMY3004, approximately 480 subjects will be randomized in a 1:1 ratio to DVd (DARA 16 mg/kg IV weekly x 3 cycles, Day 1 of Cycles 4-9, every 4 wk thereafter; bortezomib 1.3 mg/m2 SC Days 1, 4, 8, and 11 of each 21-day cycle; dexamethasone 80 mg weekly) or Vd and stratified by ISS, number of prior lines (1 vs 2 or 3 vs > 3), and prior bortezomib exposure. The primary endpoints for MMY3003 and MMY3004 are progression-free survival (PFS). An Independent Data Monitoring Committee (IDMC) will review data every 6 months for safety and at 2 predetermined interim analyses for both studies. First patients were dosed June/September 2014 (MMY3003/MMY3004). The primary analysis in each study will occur after 295 PFS events have been observed. Clinical trial information: NCT02076009 and NCT02136134.
ASTER 70s: Benefit of adjuvant chemotherapy for estrogen receptor-positive HER2-negative breast cancer in women over 70 according to genomic grade—A French GERICO/UCBG UNICANCER multicenter phase III trial.
Authors: Etienne Brain, Veronique Girre, Florence Rollot, Franck Bonnetain, Marc Debled, Magali Lacroix, Sandrine Baffert, Aurelien Latouche, Claire Falandry, Helene P. Peyro Saint Paul, Christine Orsini, Fabrice Andre, Herve R. Bonnefoi
Journal: Journal of Clinical Oncology (2012)

TPS667 Background: The benefit of adjuvant chemotherapy (CT) is highly controversial for elderly breast cancer (BC) women presenting with an oestrogen receptor-positive (ER+) HER2-negative (HER2-) phenotype. Conversely to hormonal treatment (HT) that remains the cornerstone of adjuvant treatment for such luminal tumours, CT may severely decompensate comorbidities and alter quality of life in elderly patients. As disappointing as it is in drug development, elderly have been constantly excluded from trials evaluating new modern prognosis classifiers. This prospective multicentre trial funded by a French national grant (PHRC 2011) is the first phase III trial to investigate the impact on overall survival (OS) of adjuvant CT in elderly ER+ HER2- BC patients selected with a modern prognosis classifier and taking into account competing risks for mortality (EudraCT 2011-004744-22). Methods: Following surgery, 2,000 women 70+ with ER+ HER2- BC (any pT/pN), will have a genomic grade (GG, derived from frozen MapQuantDx™, Ipsogen) centrally assessed on formalin-fixed paraffin-embedded samples. Only those with a high GG (estimation~700) will be randomized between HT alone vs CT followed by HT. CT regimen is left to the choice of investigators amongst 3 regimen of same duration [4 q3w cycles, docetaxel+cyclophosphamide, doxorubicin or non pegylated liposomal doxorubicin (Myocet)+cyclophosphamide, all with G-CSF], as well as HT (aromatase inhibitor±tamoxifen). Those with low GG or not included for other reasons (estimation~1,300) will be followed as an observational parallel cohort with HT alone. Sample size is based on 4-year OS as primary endpoint (87.5 vs 80%), bilateral α=0.05, β=0.20 and HR= 0.60. Secondary endpoints include assessment of competing risks for mortality, cost-effectiveness and Q-TWiST analysis, geriatric items (e.g. Lee’s 4-year mortality score and G8 screening tool), acceptability, quality of life (QLQ-C30 and specific elderly scale ELD15), and translational research on ageing/prognostic biomarkers and pharmacogenetic. The trial has been just opened to inclusion in February 2012.
Abstract 1621: SRGAP2 expression levels may induce a biphasic metastatic phenotype in osteosarcoma cell lines
Authors: Tracy Marko, Ghaidan Shamsan, David Largaespada
Journal: Cancer Research (2016)

Abstract The purpose of this study is to characterize the role of Slit-Robo GTPase-Activating Protein 2 (SRGAP2) in osteosarcoma (OS) metastasis. OS is the most common primary bone tumor and the eighth leading pediatric cancer. Despite combined therapies, treatment failure is experienced within 5 years of diagnosis by over 40% of patients, generally due to metastatic disease. Using the conditional Sleeping Beauty transposon mutagenesis system, our laboratory recently identified candidate tumor promoting genes in transgenic mice that develop OS, including the potential tumor suppressor SRGAP2 involved in regulating actin dynamics. We hypothesized that loss of SRGAP2 would increase the metastatic potential of OS cell lines in vitro and in vivo, whereas gain would decrease metastatic potential. Gene expression was amplified with a stably integrated, tetracycline-inducible over expression vector containing SRGAP2 cDNA and gene silencing was accomplished with a clustered regularly interspaced short palindromic repeat (CRISPR) targeting the gene. Studies were conducted in the well-characterized murine osteosarcoma cell lines K12 and its more aggressive derivative K7M2 and human osteosarcoma cell lines HOS and its more aggressive derivative 143B. Compared to luciferase-controls, overexpression and knockout of SRGAP2 had no effect on cell proliferation in K12, K7M2, HOS, and 143B (n = 4). A reduction of soft agar colony formation was observed in knockout cell lines but not in cell lines with SRGAP2 overexpression for K12 and 143B (n = 3); HOS cell lines did not form colonies in soft agar. Interestingly, overexpression of SRGAP2 decreased wound-healing closure in 143B and K12 lines, but increased closure time in HOS (n = 4). Tail vein injections in NRG mice are currently being investigated. Overexpression of SRGAP2 in K12 decreased development of macrometastases in lungs, whereas knockout of SRGAP2 eliminated gross detection of lung masses (n = 3). Future studies include imaging fixed cells to determine if SRGAP2 knockout and overexpression affects cell morphology and completing studies with K7M2 lines. These results suggest that SRGAP2 has a biphasic phenotype in osteosarcoma cell lines, with an optima in expression for efficient metastasis. It's dual role of deforming cell membranes independent of its ability to activate Rac GTPases and alter actin dynamics may be responsible for the observed results. Citation Format: Tracy Marko, Ghaidan Shamsan, David Largaespada. SRGAP2 expression levels may induce a biphasic metastatic phenotype in osteosarcoma cell lines. [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 1621.
A phase I/II trial of RAD 001 with gefitinib in patients with castrate metastatic prostate cancer and glioblastoma multiforme
Authors: D. R. Shaffer, L. E. Abrey, K. Beekman, C. Eicher, M. Morris, S. Slovin, J. Feldstein, S. Larson, N. Rosen, H. I. Scher
Journal: Journal of Clinical Oncology (2006)

14520 Background: Inactivation of the Pten tumor suppressor gene, leading to constitutive activation of the PI3K/AKT/mTOR pathway, is correlated with resistance to EGFR-targeted therapies. This trial tested the concept that inhibition of mTOR by RAD 001 (NOVARTIS) will restore sensitivity to EGFR inhibition by gefitinib (ASTRA ZENECA), in patients with progressive PC and GBM. Methods: Phase I was designed to determine a safe and tolerable dose and the pharmacokinetics (PK) of RAD (30/ 50/ 70 mg po weekly) with a fixed dose of gefitinib (250 mg po qd) in patients with PC and GBM. Phase II evaluated the proportion of PC patients with no change or a decline in PSA at 12 weeks, without clinical or radiographic progression. FDG PET imaging and immunohistochemistry were included as correlative studies. Results: 12 patients (2 GBM, 10 PC) were treated in Phase I, and 22 of 27 PC patients have been treated in Phase II. (The GBM Phase II results are reported separately). 20/32 (63%) of PC patients had received prior chemotherapy. No dose limiting toxicities were observed in Phase I, and 70 mg of RAD 001 weekly with gefitinib 250 mg qd was studied as the Phase II dose. PK parameters estimated during a 3 week single agent lead-in phase and during subsequent combined therapy suggested no clinically relevant PK interactions between RAD and gefitinib. The most common drug-related grade 3/4 toxicities were lymphopenia (28%) and elevated ALT (7%). Serial FDG PET scans showed &gt; 25% decline in SUV uptake in 9/23 evaluable patients during the first week of treatment; of these, 3 patients showed no progression at 12 weeks. Overall, 5/29 PC patients showed no progression at 12 weeks, 3 (60%) of whom had received prior chemotherapy. Conclusions: Combination therapy with RAD 70 mg weekly and gefitinib 250 mg daily appears to be safe and is associated with modest activity in metastatic prostate cancer. Support: Novartis Pharmaceuticals, Astra Zeneca Pharmaceuticals. [Table: see text]
Results of a clinical pharmacokinetic (PK) bioequivalence (BE) study of liposomal paclitaxel (LEP-ETU) versus paclitaxel (T) in patients with advanced cancer
Authors: A. R. Tan, A. R. Hanauske, H. Gelderblom, M. E. Scheulen, L. J. Van Warmerdam, H. Rosing, G. J. Fetterly, V. S. Shu, J. W. Sherman, E. H. Rubin
Journal: Journal of Clinical Oncology (2006)

2017 Background: LEP-ETU is an easy-to-use liposomal formulation of paclitaxel developed to reduce toxicities associated with the excipient polyoxyethylated castor oil that is used in paclitaxel (Taxol [T]), while maintaining or enhancing efficacy. A phase I study of LEP-ETU demonstrated an MTD of 325 mg/m 2 and a similar PK profile at a dose of 175 mg/m 2 compared to published T data (Damjanov et al, J Clin Oncol 2005;23 Suppl:147s). Methods: This randomized, two-period crossover, clinical BE study was designed to directly compare the PK of paclitaxel following intravenous administration of LEP-ETU and T delivered over 180 minutes at a dose of 175 mg/m 2 in patients with a variety of advanced solid tumors. Patients were randomized to receive either one treatment cycle of LEP-ETU followed by one cycle of T, or one cycle of T followed by one cycle of LEP-ETU. Eligible patients were permitted to continue LEP-ETU treatment in an extension study. Results: Fifty-eight patients were treated, and 32 evaluable patients were analyzed for BE. The latter group of patients met pre-specified evaluability criteria of having received 100% of each dose during the specified administration interval and having had the necessary blood samples drawn to determine Cmax and AUC. Mean total paclitaxel Cmax values for LEP-ETU and T were 4955.0 ng/mL and 5108.8 ng/mL, respectively. Mean total paclitaxel AUC0–8 values for LEP-ETU and T were 15853.8 ng·h/mL and 18550.8 ng·h/mL, respectively. Ratios of the geometric means of LEP-ETU divided by T for Cmax were 97% (90% CI, 91%-103%) and for AUC0–8 were 84% (90% CI, 80%-90%). These results meet the established 80–125% BE criteria. The most frequently reported adverse events were fatigue, alopecia, and myalgia. Of the 37 patients deemed suitable to continue LEP-ETU treatment in the extension study, 57% have received = 4 cycles of LEP-ETU with at least stable disease. Conclusion: LEP-ETU has met BE criteria compared to T. A comparative efficacy and safety study of LEP-ETU and T at a dose of 175 mg/m 2 has been planned to confirm the potential of LEP-ETU to have comparable or improved treatment effect with a better safety profile than T. [Table: see text]
Expression and genetic variants in stress-related signaling pathways in lethal and nonlethal prostate cancer.
Authors: Donghao Lu, Jessica Carlsson, Sabina Davidsson, Ove Andrén, Kathryn Penney, Lorelei A. Mucci, Unnur Anna Valdimarsdottir, Fang Fang, Katja Fall
Journal: Journal of Clinical Oncology (2016)

5032 Background: Recent data suggest that dysregulated stress-related signaling pathways may play a role in prostate cancer progression. We aim to compare expression of selected genes in the adrenergic, glucocorticoid, dopaminergic, and serotoninergic signaling pathways in tumor tissue from men with lethal and nonlethal prostate cancer, and to explore whether genetic variants may explain potential variation. Methods: We included 504 Swedish men diagnosed with incidental prostate cancer through TURP during 1977-1998 with up to 28 years of follow up. For those with tumor tissue available (N = 396), we measured mRNA expression of 223 selected genes included in predetermined stress-related signaling pathways. Using DNA from normal prostate tissue (N = 262), we genotyped 14 stress-related genes (29 SNPs). Associations of pathway gene expression and genetic variants with lethal prostate cancer were assessed as primary outcomes, and with tumor biomarkers as secondary outcomes. Results: Differential mRNA expression of genes in the serotoninergic pathway was associated with risk of lethal prostate cancer (p = 0.007); similar but somewhat weaker associations were noted for the adrenergic (p = 0.014) and glucocorticoid (p = 0.020) pathways. None of the studied genetic variants were associated with risk of lethal cancer after correcting for multiple testing, but a link was suggested for variants of HTR2A (rs2296972; OR 0.5, 95% CI 0.3-0.8, p = 0.002) and NR3CI (rs33388; OR 1.6, 95% CI 1.0-2.4, p = 0.035) genes (within the serotoninergic and glucocorticoid signaling pathways) in over-dominant models. No significant association between genotypes and mRNA expression of any individual gene in the corresponding pathways were observed. Genetic variants of HTR2A and NR3CI were associated with increased prostatic intraepithelial neoplasia and cell proliferation (all p < 0.05), respectively. Conclusions: Our findings lend some support to the hypothesis that dysregulated signaling in stress-related molecular pathways, particularly the serotoninergic, is involved in prostate cancer progression. If confirmed, this finding could open up new paths for research targeted towards reducing prostate cancer progression.
Clinical outcomes and response of patients applying topical therapy for pyoderma gangrenosum: A prospective cohort study
Authors: Kim S. Thomas, Anthony D. Ormerod, Fiona E. Craig, Nicola Greenlaw, John Norrie, Eleanor Mitchell, James M. Mason, Graham A. Johnston, Shyamal Wahie, Hywel C. Williams, Julie Barnes, Brian Barnes, Fiona Craig, Katharine Foster, Nicola Greenlaw, Ellie Harrison, Sally Kucyj, Alan Maplethorpe, James Mason, Eleanor Mitchell, John Norrie, Anthony Ormerod, Aisha Shafayat, Daniel Simpkins, Kim Thomas, Diane Whitham, Hywel Williams, Anthony Ormerod, Fiona Craig, Linda Lawson, Alex Anstey, Catherine Watkins, Sarah Mitchell, Richard Goodwin, Cilla Benge, Gosia Skibinska, N. Ariffin, Janice Armitt, Nhlanhla Mguni, Maxwell Masuku, Kerry Goodsell, Linda Johnson, John Ingram, Girish Patel, Mabs Chowdhury, Richard Motley, Anne Thomas, Colin Long, Anew Morris, Vincent Piguet, Manju Kalavala, Ru Katugampla, Catherine Blasdale, Stephanie Lateo, Neil Rajan, Anne Thomson, Sivakumar Natarajan, Shyamal Wahie, Therese Sripathy, Maneesha Vatve, Vrinda Bajaj, Anne Thomson, Keith Freeman, Mary Carr, Adam Ferguson, Katherine Riches, Susannah Baron, Claire Fuller, Anthea Potter, Laura Brockway, Ashley Cooper, Susan Thompson, Emilia Duarte-Williamson, Catherine Smith, Gemma Minifie, Naomi Hare, Kate Thornberry, Shika Gupta, Sinead Langan, Alison Layton, Angela Wray, Benjamin Walker, Gayle Law, Elizabeth Marshall, Shernaz Walton, Katherine Ashton, Angela Oswald, Deborah Graham, Peter Jones, Vanessa Smith, Debbie Shipley, Claire Duggan, Sarah Jones, Carol Thomas, Sally-Ann Rolls, Emma Veysey, Simon Meggitt, Nick Levell, Kevin Lee, Pariyawan Rakvit, George Millington, Karen Banks-Dunnell, Natasha Chetty, Clive Grattan, Syed Shah, Donna Butcher, Marinela Nik, Kathleen Gilbanks, Neil Cox, John English, Ruth Murphy, William Perkins, Hywel Williams, Sheelagh Littlewood, Jan Bong, Moona Malik, Jonathan Batchelor, Catriona Wootton, Sue Davies-Jones, Joanne Llewellyn, Suzanne Cheng, Maulina Sharma, Janet Angus, Sandeep Varma, Stuart Cohen, John English, Ruth Murphy, William Perkins, Hywel Williams, Sheelagh Littlewood, Jan Bong, Moona Malik, Jonathan Batchelor, Catriona Wootton, Sue Davies-Jones, Joanne Llewellyn, Suzanne Cheng, Maulina Sharma, Janet Angus, Sandeep Varma, Stuart Cohen, Graham Ogg, Susan Burge, Vanessa Venning, Susan Cooper, Tess McPherson, Lisa Matter, Christopher Bower, Robert James, Shireen Velangi, Weronika Szczecinska, Tinomuda Shumba, Jane Ravenscroft, John English, Jan Bong, Azaharry Yaakub, Hong Trinh, Anna Chapman, Natalie Miller, Yana Estfan, Gwendoline Reeves, Rachel Wachsmuth, Victoria Lewis, Hazel Bell, Richard Azurdia, Maeve Walsh, Caroline Angit, Kok Ngan, Anea Young, Julie Murgaza, Paula Taylor, Hamish Hunter, Agustin Martin-Clavijo, Renuga Raghavenan, Lucy Evriviades, Helen Lewis, Giles Dunnill, Adam Bray, David De Berker, Graham Johnston, John McKenna, Catherine Shelley, Mohammad Ghazavi, Alison Hill, Maggie Kirkup, Glenn Saunders, Hugh Lloyd-Jones, Dawn Simmons, Donna Cotterill
Journal: Journal of the American Academy of Dermatology (2016)
Abstract 1275: Suppression of platelet aggregation and tumor metastasis by anti-podoplanin mAbs recognizing a novel CLEC-2 binding domain
Authors: Takaya Sekiguchi, Ai Takemoto, Naoya Fujita
Journal: Cancer Research (2016)

Abstract Tumor-induced platelet aggregation promotes tumor growth and hematogenous metastasis by secreting growth factors from platelets, by avoiding immune system and shear stress, and by stimulating the formation of tumor emboli in microvasculature. Thus, tumor-platelet interaction could be a promising target for cancer therapy. We previously identified a sialoglycoprotein podoplanin, also known as Aggrus, as a key factor in tumor-induced platelet aggregation enhancing tumor metastasis. Podoplanin is expressed in various cancers and reported to be a candidate for cancer stem cell marker. Podoplanin-induced platelet aggregation depends on binding to its platelet receptor CLEC-2. Here, we report the discovery of a novel platelet aggregation-stimulating domain PLAG4 in human podoplanin critical for the binding to CLEC-2. Mutant analyses indicated that PLAG4 exhibits a predominant CLEC-2 binding ability and platelet-aggregating function when compared to the previously reported PLAG3. Moreover, mutation of both PLAG3 and PLAG4 domains could almost completely attenuate its CLEC-2 binding ability and its platelet-aggregation activity. To validate the inhibitory effect against PLAG4 domain, we established anti-PLAG4-neutralizing monoclonal antibodies (mAbs), PG4D1 and PG4D2. Both mAbs recognized PLAG4 domain and exhibited a high affinity to podoplanin. We confirmed those neutralizing ability against PLAG4-CLEC-2 interaction and platelet aggregation. Remarkably, the administration of each mAbs significantly suppressed pulmonary metastasis of podoplanin expressing tumor. Taken together, we suggest that PLAG4 is the novel CLEC-2 binding and platelet aggregation-stimulating domain on podoplanin and has a role in podoplanin-mediated metastasis formation. Blocking the podoplanin-CLEC-2 interaction targeting PLAG3 or PLAG4 would be a promising strategy for suppressing hematogenous metastasis. Citation Format: Takaya Sekiguchi, Ai Takemoto, Naoya Fujita. Suppression of platelet aggregation and tumor metastasis by anti-podoplanin mAbs recognizing a novel CLEC-2 binding domain. [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 1275.