tbuckley/cabot-search huggingface dataset:
Colospheres, a new three-dimensional colon cancer model for in vitro drug screening
Authors: Louis-Bastien Weiswald, Sophie Richon, Pierre Validire, Marianne Briffod, Fabrice Cordelieres, Dominique Bellet, Virginie Dangles-Marie
Journal: Clinical Cancer Research (2007)

B41   Colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide and CRC patient death is generally attributable to metastasis growth and resistance to chemotherapy. Successful future treatments must thus rely on the development of representative model systems that have to be easily manipulated so as to evaluate the efficacy of novel therapeutics. Spheroid-like structures, referred as to colospheres, have been successfully generated in only one day from human CRC primary tumors after mechanical dissociation. We have found that the ability to form numerous colospheres was related to tumor aggressiveness in patients. Colospheres, made up exclusively of cancer cells, can also be generated from human moderately differentiated CRC tissue maintained as xenograft and display distinct features from those observed in spheroids, a more classical three-dimensional (3D) model using permanent CRC cell lines.  The present study demonstrates that 3D colospheres display phenotypic characteristics close to CRC tissues from which they derived:  i ) Classical microscopy showed that colospheres recapitulated moderately differentiated CRC morphology while spheroids mimic merely carcinoma microtumors ;  ii ) Time-lapse video microscopy revealed that colospheres derived mainly from tissue remodeling while spheroids arose from aggregation of single cells ;  iii ) Expression profiles of two colon cancer stem cells markers, CD44 and CD133, are similar in colospheres and the origin xenograft, in contrast to spheroids.  Based on these observations, colospheres represent a novel 3D model that might be useful for anticancer drug screening. To support this standpoint, we present here the results of cytotoxic assays performed with colospheres and validated with 5FU, CPT11 and L-OHP, three reference adjuvant therapies in colon cancer, taken as representative.
A phase II study of erlotinib (E) and bevacizumab (B) in chemo naive patients (pts) with locally advanced or metastatic non small cell lung cancer (NSCLC): Predictive value of molecular imaging
Authors: V. van den Boogaart, A. de Langen, H. J. Groen, J. Marcus, P. Kappert, W. Backes, B. Brans, O. Hoekstra, A. C. Dingemans, E. F. Smit
Journal: Journal of Clinical Oncology (2008)

8055 Background: In advanced NSCLC, E and B either as a single agent (E) or in combination with chemotherapy (B) have shown to improve survival. Combinations of targeted agents may prove to be effective and better tolerated than chemotherapy. Efficacy as measured by RECIST criteria may underestimate the biological activity of targeted therapy. Methods: Chemo naive pts with advanced non-squamous NSCLC were treated with B 15 mg/kg q 3 week and E 150 mg daily until progression. The phase II study was designed according to Simon’s optimal design (p0=40%, p1=60%, α=0.05, β=0.20 with early stopping rule). The primary endpoint was non- progression (NPR) at 6 weeks (wks). When 24/46 pts have NPR at 6 wks the treatment will be declared to have sufficient activity for further testing. Secondary endpoints were objective response rate (ORR), time to progression (TTP) and overall survival (OS). Dynamic 18FDG-PET, H215O-PET and DCE-MRI scanning were performed at baseline, wk 3 and wk 6. Standard uptake value (SUV) (18FDG-PET), tumor perfusion (F) (H215O-PET) and the endothelial transfer constant (Kps) (DCE-MRI) were calculated. Results: From 01–06 till 03–07 47 pts were enrolled, M/F 23/24; median age 60 (range 34–80); stage IIIB/IV 11/36; PS 0/1/2: 22/19/6. Median follow up was 15.2 months (mts). NPR after 6 wks was 75% with 26% ORR. Median TPP was 4 mts and median OS 6.9 mts. Grade ¾ adverse events (≥5%) consisted of rash (10%). Correlation of imaging results with TTP is shown in table. Conclusion: E + B was well tolerated. The 75% NPR justifies phase III testing in untreated advanced non-squamous NSCLC. A decrease in SUV and F was predictive for longer TTP, an inverse correlation was seen by Kps. 18FDG-PET, H215O-PET and DCE-MRI seem valuable biomarkers in monitoring early response to E and B in NSCLC. Correlation of imaging results with TTP CT(RECIST) FDG-PET (SUV) H2O-PET (F) DCE-MRI (Kps) Wk 3 CR/PR vs. SD/PD (4.6 vs. 2.9 mo.) (p=0.09) (n=41) 15% decrease vs. rest (5.8 vs. 2.7 mo.) (p = 0.006) (n=30) 15% decrease vs. rest (8.4 vs. 2.9 mo.) (p = 0.005) (n=19) 40% decrease vs rest (4.5 vs. 2.3 mo.) (p=0.125)(n=28) Wk 6 CR/PR vs. SD/PD (8.4 vs. 4.2 mo.) (p=0.07) (n=36) 25% decrease vs. rest (9.7 vs. 4.1 mo.) (p = 0.03) (n=22) 25% decrease vs. rest (10.5 vs. 5.8 mo.) (p = 0.3) (n=16) 40% decrease vs rest (4.0 vs. 8.3 mo) (p=0.03)(n=25) No significant financial relationships to disclose.
Abnormal hair growth in patients (pts) with metastatic colorectal cancer (mCRC) treated with the anti-epidermal growth factor receptor (EGFr) monoclonal antibody (mAb) panitumumab (Pmab)
Authors: E. E. Tubb, M. Nugent, J. Spielberger, R. A. Axelrod, E. P. Mitchell
Journal: Journal of Clinical Oncology (2008)

15065 Background: Pmab is a fully human mAb against EGFr approved by the US FDA for treating pts with mCRC who have disease progression on or following regimen based on fluoropyrimidine, oxaliplatin, and irinotecan. Due to the important role of the EGFr in skin growth, cutaneous reactions are common adverse events of Pmab, mainly an acneiform follicular eruption. Other skin toxicities of Pmab include hypertrichosis and trichomegaly. The mechanism behind the EGFr-induced hair growth is poorly understood. This study attempted to find patterns distinguishing the group of pts that developed hypertrichosis from the group of pts which did not. Methods: The dermatological manifestations of 24 pts on four clinical studies were noted. When comparing skin toxicities of the pts, the worst severity grade developed while on study was used. Hypertrichosis is defined as excessive hair growth growing in places that do not normally have hair and not induced by androgens. Trichomegaly is defined as excessive growth of the eyelashes. Pts were separated into a group that developed hypertrichosis and a group that did not, with further delineation according to gender, race and therapy (tx) regimen. Results: 41.6% of pts developed hypertrichosis or trichomegaly in a median 3.46 months after the first dose of Pmab. The majority of pts developed hair growth on the cheeks, upper lip, chin; two pts had periobital and three had chest hair growth. No statistically significant differences were noted in gender, race, or median age of pts with and without hypertrichosis. There is no correlation between hypertrichosis and severity of the other skin toxicities, monotx or combination tx, or presence of anti-tumor response. Patterns of hair growth and histologic features will be presented. Conclusions: Pmab may alter the growth cycle of the hair follicle in both men and women. The characteristic trichomegaly and hypertrichosis are related to duration of tx and show no relationship to the other skin toxicities. A higher response rate was observed in pts with hypertrichosis, but this is related to the duration of anti-tumor tx. Further studies are needed to characterize the etiology and mechanism of this cutaneous toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Amgen, Genentech, Pfizer, sanofi-aventis
Treatment effect of panitumumab in subsets by epidermal growth factor receptor (EGFR) status from a phase 3 randomized controlled trial
Authors: Salvatore Siena, Yves Humblet, Eric Van Cutsem, Marc Peeters, Alain Hendlisz, Bart Neyns, Jean-Luc Canon, Jean-Luc Van Laethem, Joan Maurel, Gary Richardson
Journal: Annals of Oncology (2006)
A dose dense low toxicity salvage regimen for histologically aggressive non-Hodgkin’s lymphoma (NHL): Gemcitabine, rituximab, oxaliplatin combination (GROC) plus pegfilgrastim
Authors: F. Cabanillas, I. Liboy, E. Rodriguez-Monge, O. Pavia, N. Robles, N. Maldonado, E. Rivera, L. Suau
Journal: Journal of Clinical Oncology (2006)

17513 High dose chemo/autologous stem cell transplant (ASCT) is standard treatment for relapsed aggressive NHL. However many are unable to receive ASCT because they are refractory to salvage therapy, too old or too sick. More effective, less toxic salvage regimens are needed prior to ASCT. Gemcitabine (G) and Oxaliplatin (O) are active agents in NHL and exhibit synergism so their combination is attractive to explore together with Rituximab (R). We hereby report the results of a phase I-II trial designed to explore the GROC regimen administered every 14 days with Pegfilgrastim support. After the first 6 pts were entered, the phase I portion was completed; recommended dose: R = 375 mg/m 2 on day 1, G = 1,250 mg/M2 on day 2, O = 100 mg/m 2 on day 2 and Neulasta 6 mg day 3. So far we have entered 21 pts of which 19 are currently evaluable. Median age = 58 (range = 27–88); 9 were refractory to 1st line therapy, 5 were on 1st relapse, 3 on 2nd and 2 &gt;2 relapses, 12 had high LDH, 10 high Beta-2-M. Using IWG/PET criteria ORR = 79%, CR = 42%, PR = 37%. There was a correlation between response to preceding chemo regimen and response to GROC ( table ). In 6 the response to GROC was better than to preceding regimen while only in 2 was the response worse. At 1 year the projected OS is 49% and PFS 34%. So far, only 5 of 15 responders have relapsed. An intriguing finding is that in 6 of 15 responders, PFS has been longer with GROC than with preceding regimen and shorter in only 1. Grade 4 hematologic toxicity occurred only once. No neutropenic fevers seen. Most common toxicity was reversible transaminitis in 13 (grade 1–2 in 10, grade 3 in 3), neuropathy in 9 (grade 1–2 in 8, grade 3 in 1), diarrhea in 3 (grade 4 in 1). We could deliver courses at a median interval of 14 days. Conclusions: 1- GROC is an effective dose dense salvage regimen. 2- It appears effective even in pts with poor prognostic features including primary refractory disease. 3-Hematologic toxicity is very low and non-hematologic toxicity acceptable. [Table: see text] [Table: see text]
Combined administration of hydrophilic antimitotic desoxyepothilone B and vinorelbine induce PUMA, suppression of microtubule dynamics, development of hypodiploidy and multinucleation, cell cycle perturbation at G2/M and apoptosis in advanced breast carcinoma (ABC) characterised by MDR-1 (Pgp),bcl-2 and mutant b-tubulin
Authors: G. N. John, J. Giannios, E. Michailakis, S. Konstandinidou, G. Xepapadakis, N. Alexandropoulos, T. Kononas
Journal: Journal of Clinical Oncology (2004)

2087 Introduction: Low aqueous solubility of VRL is a high substrate for ATP dependent drug efflux proteins such as MDR-1(Pgp) and MRP2(ABCC2) inserted in plasma membrane of tumor cells.Furthermore,b-tubulin mutations are cross-resistant to VRL. Methods: We treat with MTC such as VRL and dEpoB advanced mammary carcinoma characterised by overexpression of bcl-2,MDR-1(Pgp),MRP2(ABCC2) and mutant b-tubulin according to PCR,WB and IHC analysis. MT polymerising agent dEpoB is more soluble in aqueous solvents than VRL reducing affinity for Pgp by being a poor substrate. Results: Post-treatment,although VRL and dEpoB are structurally unrelated,they bind to mutually exclusive sites on the tubulin unit.After binding of MTCs to MT,there was synergistic phosphorylation of bcl-2,overexpression of bax,circumvention of expression of altered b-tubulin polypeptides, MDR-1 and MRP-2 due to high hydrophilicity of dEpoB and PUMA. Flow cytometry showed blockage of cell proliferation at the metaphase-anaphase (G2/M) interface of the cell cycle.There was an enhancement in hypodiploid population of tumor cells,multinucleation,aberrant spindle formation,nuclear convolution,suppression of MT-dynamics and formation of MT bundling.Both drugs induced release of cyt-c from isolated mitochondria after interaction of mitochondrial tubulin with the voltage-dept anion channel of the permeability transition pore.There was potent immunosuppression by inhibiting T-cell proliferation.Methylene blue, BrdU and MTT exhibited inhibition of tumor cell proliferation. We observed nuclear factor kB-induced apoptosis displayed by features such as nuclear condensation and fragmentation,Annexin V staining,cleavage of poly(ADP-ribose)polymerase and activation of caspases. Conclusion: We observed synergy between dEpoB and vinorelbine in potentiation of apoptosis in advanced breast carcinoma circumventing chemoresistance. No significant financial relationships to disclose.
Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC Trial.
Authors: J. Randolph Hecht, Yung-Jue Bang, Shukui Qin, Hyun-Chul Chung, Jian-Ming Xu, Joon Oh Park, Krzysztof Jeziorski, Yaroslav Shparyk, Paulo M. Hoff, Alberto F. Sobrero, Pamela Salman, Jin Li, Svetlana Protsenko, Marc E. Buyse, Karen Afenjar, Tomomi Kaneko, Allison Kemner, Sergio Santillana, Michael F. Press, Dennis J. Slamon
Journal: Journal of Clinical Oncology (2013)

LBA4001 Background: HER2 amplification is common in upper GI tract (UGIT) adenocarcinomas and inhibition improves clinical outcomes. Lapatinib ditosylate (L), a dual anti EGFR and anti HER2 tyrosine kinase inhibitor with preclinical activity against these cancers, was investigated in a phase III, randomized, double blind trial evaluating efficacy and safety in combination with CapeOx as first-line treatment of advanced or metastatic HER2+ UGIT ACs. Methods: Subjects had measurable and/or non-measurable disease with overexpression or amplification of HER2 (IHC2+ and FISH amplified, or IHC 3+, or FISH, CISH, or SISH amplified). HER2 status was reviewed by the central lab. Subjects were randomized 1:1 to CapeOx q3w (oxaliplatin 130mg/m 2 day 1; capecitabine 850mg/m 2 /BID days 1 – 14), and daily L (1250mg) (CapeOx+L) or placebo (CapeOx+P). The primary efficacy population (PEP) comprised all subjects whose tumors were centrally confirmed to be FISH amplified. The primary endpoint was overall survival (OS) of the PEP. Secondary endpoints included progression free survival (PFS), overall response rate (ORR) and safety. Results: 545 pts were randomized and 487 had HER2+ centrally confirmed. The primary endpoint was not reached with a hazard ratio (HR) for OS of CapeOx+L compared to CapeOx+P of 0.91 (95% CI 0.73, 1.12, p=0.35); median 12.2 vs. 10.5 months, respectively. HR for uncensored PFS was 0.86 (95% CI 0.71 - 1.04, p=0.10); median 6.0 vs. 5.4 months. The analysis of PFS censored by the time of subsequent anticancer therapy as per protocol showed a HR of 0.82 (95% CI 0.68, 1.00, p=0.04). ORR was 53% in the CapeOx+L arm and 40% in the CapeOx+P arm. Pre-specified subgroup analyses showed significant improvements in OS in Asian pts (HR= 0.68) and those under 60 years (HR=0.69). There was no association between IHC and OS. Toxicity profiles were similar except for increased overall diarrhea, and skin toxicity and grade 3+ diarrhea (12 vs 3%) with CapeOx+L. Conclusions: The addition of L to CapeOx did not reach its primary endpoint, though certain subgroups showed improvement. Further clinical and molecular analyses will be presented. Clinical trial information: NCT00680901.
Anaemia in patients with transitional cell carcinoma (TCC) of the bladder treated with radiotherapy
Authors: C. Joynson, P. Symonds, S. Sundar
Journal: Journal of Clinical Oncology (2006)

14569 Background: Treatment of muscle invasive TCC of the bladder with radiotherapy allows organ preservation and is frequently used in the UK especially in patients not medically fit for cystectomy. Anaemia is known to be an indicator of poor response to radiotherapy in head and neck and cervical carcinomas. This study describes the prevalence and type of anaemia in patients with TCC of the bladder and looks at the impact anaemia has on treatment outcome. Methods: Retrospective review of notes was performed on patients treated radically between 1992 and1997. Potential patient, tumour and treatment prognostic indicators were reported. Patients were labelled as being anaemic if their pre treatment haemoglobin level was below the normal range (below 13.5g/dl for men and below 11.5g/dl for women). Time to local recurrence, metastases and overall survival was recorded. Recurrence free survival and overall survival actuarial estimations were done using the Kaplan Meier method and compared by log rank testing. Multivariate analysis was carried out using Cox Regression method, correcting for potential confounding factors. Results: Data on 100 patients were available for analysis. 52 patients were anaemic with 75% of these having a normochromic, normocytic anaemia. Univariate analysis showed no significant difference in time to local recurrence, a trend to shorter time to metastases, and a significant reduction in overall survival in anaemic patients (p = 0.04). Two year survival was 43% and 22% for non anaemic and anaemic patients respectively. Multivariate analysis using covariates tumour stage, grade, and serum creatinine found anaemia to be poor prognostic indicator for overall survival (p = 0.005) and time to metastases (p = 0.003). Conclusions: Anaemia is highly prevalent in patients with bladder cancer. This retrospective study shows anaemic patients to have a worse outcome with radiotherapy treatment than patients with a normal haemoglobin level. This is not accounted for by a difference in local control which may be expected from hypoxic radiobiological principles. Anaemia may be indicative of more aggressive malignancy or sub clinical metastases. No significant financial relationships to disclose.
Deleted In Cancer 1 (DICE1): Search for a function in prostate carcinoma (PCa)
Authors: S. Filleur, I. Wieland, T. Nelius, R. Kennedy, W. De Riese, P. Wieacker
Journal: Journal of Clinical Oncology (2007)

15634 Background: Recently, DICE1 gene (MIM 604331 ) was identified to colocalize with the microsatellite marker D13S284 in 13q14.3, a region frequently affected by allelic deletion in PCa. We previously showed that DICE1 mRNA expression is down-regulated in PCa cell lines compared to normal prostate tissue, due to DICE1 promoter hypermethylation; suggesting that DICE1 is a tumor suppressor gene. Methods: Human PCa cell lines PC3 and DU145 were lipo-transfected with mammalian expression plasmids encoding for the full length DICE1 gene or for its N- (APAI construct) and C-terminal (DEAD construct) fragments. The constructs expression was determined by semi-quantitative PCR and quantified by Real-time PCR. Clonogenic formation and apoptotic assays were performed. Results: The PCR analysis showed that the expression of DICE1, APAI and DEAD domains in transfected PC3 and DU145 cell lines was increased 30.6, 75.2 and 27.9 fold in PC3 cells and 4.3, 5 and 2.5 fold in DU145 cells, respectively, compared to non-transfected cells. The function analysis showed that the ectopic expression of DICE1 suppressed clonogenic growth of PC3 and DU145 cell lines. Surprisingly, we showed that like DICE1, DEAD and APAI inhibit the PC3 and DU145 clonogenic growth suggesting that both regions are involved in prostate tumor growth inhibition. The apoptosis assay could not show any DNA fragmentation activity for DICE1. Conclusions: We demonstrated that DICE1 is a tumor suppressor in PCa. DICE1 mRNA expression is down-regulated in PCa cell lines compared to normal prostate tissue and its ectopic expression in PCa cell lines inhibits their capacity to form clonogenic colonies in vitro. The functional analysis could not reveal any role of DICE1 in PCa apoptosis, suggesting that other molecular mechanisms are involved. No significant financial relationships to disclose.
OP0082-HPR Fear-Avoidance Beliefs of Physical Activity in Adults with Rheumatoid Arthritis
Authors: H. Lööf, I. Demmelmaier, E. Welin Henriksson, S. Lindblad, B. Nordgren, C.H. Opava, U.-B. Johansson
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> A minority of people with RA perform maintained health enhancing physical activity (HEPA). Psychosocial factors seem to be the most salient and consistent factors to explain HEPA variation [1]. Furthermore, avoidance of physical activity could result in negative physical consequences and in psychological changes [2]. The Fear-Avoidance Belief Questionnaire (FABQ) seems to be the best available instrument to measure the concept of fear and avoidance behaviors of physical activity [3]. <h3>Objectives</h3> The objective of this study was to describe fear-avoidance beliefs of physical activity and explore how they correlate to socio-demographic, disease-specific and psychosocial factors in adults with RA. <h3>Methods</h3> This cross-sectional study is a part of a study focusing physical activity (the PARA 2010 study). The present study included 2351 patients from six rheumatology clinics. The participants answered the modified version of the FABQ and questionnaires on socio-demographic, disease-related, and psychosocial factors. The statistical analysis, performed in two steps, was aimed to evaluate factors associated with fear-avoidance beliefs. The model fit was estimated using Nagelkerkés R<sup>2</sup>. <h3>Results</h3> High level of pain (OR 1.99 95%, CI 1.40 - 2.84) and poor health (OR 1.59, 95% CI 1.10 - 2.29) were the two disease-specific factors most indicative of high mFABQ. Being male (OR 1.55, 95% CI 1.26–1.91) and having a below average income (OR 1.35, 95% CI 1.12–1.63) were associated with an increased risk of high fear-avoidance beliefs. Regarding psychosocial factors, low health related quality of life, HRQoL (OR 0.44, 95% CI 0.35–0.55) and low exercise self-efficacy, ESES (OR 0.66, 95% CI 0.52–0.82) were significantly associated with high fear-avoidance beliefs (Nagelkerkés R<sup>2</sup> 0.27). <h3>Conclusions</h3> High fear-avoidance beliefs in patients with RA were associated with being male, below average income, high level of pain, poor health, low health related quality of life and low exercise self-efficacy. The present findings indicate that such beliefs about physical activity are complex and multidimensional. <h3>References</h3> Demmelmaier I, Bergman P, Nordgren B, Jensen I, Opava CH. Current and maintained health-enhancing physical activity in rheumatoid arthritis: a cross-sectional study. Arthritis Care Res (Hoboken). 2013;65:1166-76. Turk DC, Monarch ES. Biopsychosocial perspective on chronic pain. In: Turk DC, Gatchel RJ, editors. Psychological approaches to pain management: a practitioner9s handbook. New York: Guilford; 2002. Lundberg M, Grimby-Ekman, A, Verbunt, J, Simmonds MJ. Pain-related fear: a critical review of the related measures. Pain Research and Treatment 2011; 494196. doi: 10.1155/2011/494196. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1244