tbuckley/cabot-search huggingface dataset:
Engineered microenvironments for synergistic VEGF – Integrin signalling during vascularization
Authors: Vladimíra Moulisová, Cristina Gonzalez-García, Marco Cantini, Aleixandre Rodrigo-Navarro, Jessica Weaver, Mercedes Costell, Roser Sabater i Serra, Matthew J. Dalby, Andrés J. García, Manuel Salmerón-Sánchez
Journal: Biomaterials (2017)

We have engineered polymer-based microenvironments that promote vasculogenesis both in vitro and in vivo through synergistic integrin-growth factor receptor signalling. Poly(ethyl acrylate) (PEA) triggers spontaneous organization of fibronectin (FN) into nanonetworks which provide availability of critical binding domains. Importantly, the growth factor binding (FNIII12-14) and integrin binding (FNIII9-10) regions are simultaneously available on FN fibrils assembled on PEA. This material platform promotes synergistic integrin/VEGF signalling which is highly effective for vascularization events in vitro with low concentrations of VEGF. VEGF specifically binds to FN fibrils on PEA compared to control polymers (poly(methyl acrylate), PMA) where FN remains in a globular conformation and integrin/GF binding domains are not simultaneously available. The vasculogenic response of human endothelial cells seeded on these synergistic interfaces (VEGF bound to FN assembled on PEA) was significantly improved compared to soluble administration of VEGF at higher doses. Early onset of VEGF signalling (PLCγ1 phosphorylation) and both integrin and VEGF signalling (ERK1/2 phosphorylation) were increased only when VEGF was bound to FN nanonetworks on PEA, while soluble VEGF did not influence early signalling. Experiments with mutant FN molecules with impaired integrin binding site (FN-RGE) confirmed the role of the integrin binding site of FN on the vasculogenic response via combined integrin/VEGF signalling. In vivo experiments using 3D scaffolds coated with FN and VEGF implanted in the murine fat pad demonstrated pro-vascularization signalling by enhanced formation of new tissue inside scaffold pores. PEA-driven organization of FN promotes efficient presentation of VEGF to promote vascularization in regenerative medicine applications.
Resting palliative chemotherapy in patients with gastric cancer.
Authors: Hee Yeon Lee, Young Seon Hong, Hae Myung Jeon, Cho Hyun Park, Kyo Young Song, Sang Young Roh
Journal: Journal of Clinical Oncology (2013)

122 Background: In gastric cancer, platinum and fluorouracil combination chemotherapy (CTx) is commonly used. But the optimal duration of CTx in palliative setting is not known. Thus, we reviewed the pts who rested CTx despite of persistent disease control. Methods: From Mar 2007 to Feb 2012 at Seoul St. Mary’s hospital, we retrospectively reviewed pts as follows; (1) had metastatic or recurrent gastric cancer, (2) received 9 cycles of FOLFOX as 1 st -line, (3) had no progressive disease (PD) and rested after completion of 9 th cycle. Results: Total 25 pts were reviewed. Median age was 54 (36~77) and 15 pts (60%) were male. 13 pts (52%) had recurrent disease and 12 metastatic initially. All pts were treated with oxaliplatin 100 mg/m 2 , leucovorin 400 mg/m2 on day 1 and 5-FU 1200 mg/m 2 on day 1-2 every 2 weeks. All pts had metastasis; carcinomatosis peritonei (CP, 56%), lymph node (36%), liver (20%) and bone (8%). Nine pts (48%) had non-measurable lesions and 3 no evidence of disease (NED) on CT after palliative surgery. Response evaluation was done every 3 cycles. Among 22 pts with evaluable disease, 5 (20%) showed complete response (CR), 8 (32%) partial response (PR), 2 (8%) stable disease (SD) and 7 (28%) non-CR/non-PD as best response. Median progression free survival (PFS) was 14.2 m (95% CI, 6.6-21.9). The PFS in CP vs. non-CP was 9.9 vs. 21.5 m (log rank P = .037). And PFS according to best response were as follows; 25.5 m in CR + NED group, 15.7 PR, 13.4 non-CR/non-PD and 4.3 SD (log rank P = .014). Other factors did not seem to affect PFS. Conclusions: This study suggested that resting CTx in selected pts would be reasonable in gastric cancer. Especially the presence of CP and the grade of response seemed to be important in patient selection.
Supression of tumor progression and metastasis in renal cell carcinoma by miR-192, miR-194, and miR-215.
Authors: Heba W. Z. Khella, Marize Bakhet, Ghassan Allo, Michael A. S. Jewett, Andrew Girgis, Georg A. Bjarnason, George M. Yousef
Journal: Journal of Clinical Oncology (2013)

385 Background: miRNAs play a crucial rule in tumor progression and metastasis. We previously identified miR-192, miR-194 and miR-215 to be down-regulated in metastatic compared to primary clear cell renal cell carcinoma (ccRCC). In this work, we examine the role of miR-192, miR-194, and miR-215 in RCC progression and aggressiveness. Methods: We examined the role of these three miRNAs on tumor cell migration and invasion abilities using RCC cell line models. We performed target prediction analysis and experimentally validated the targets using independent approaches. In addition, we examined the clinical utility of miR-215 as a potential prognostic marker in RCC by measuring miR-215 expression using qRT-PCR in 61 formalin-fixed paraffin-embedded tissues from primary ccRCC and correlated the expression levels with clinical outcome. Results: Restoration of miR-192, miR-194, and miR-215 expression decreased cell migration and invasion in RCC cell lines. Target prediction analysis identified three potential targets of these miRNAs; MDM2, TYMS, and SIP1/ZEB2. We validated the miRNA-target interaction experimentally using three approaches. First by measuring the effect of miRNA overexpression on mRNA and protein levels of the predicted target, then by measuring the effect of miRNA overexpression on a luciferase signal of a vector containing the 3’UTR of the predicted target, and finally, by validating these interactions in vivoby examining the presence of an inverse correlation between miRNA changes and the expression levels of their targets on clinical specimens. In 61 patients with resected ccRCC tumors, we found that low miR-215 expression in the primary was associated with a significantly reduced recurrence-free survival. (26.4 vs. 49.2 months, respectively, p = 0.0320). Conclusions: Our analysis showed that miR-192, miR-194, and miR-215 are involved in RCC metastasis and that miR-215 predicts for recurrence in patients with resected RCC. Our findings pave the way to the clinical use of miRNAs as prognostic markers and potential therapeutic targets.
Phase II study 2000mg of intravesical gemcitabine in marker lesions
Authors: F. M. Calais Da Silva, F. E. Calais
Journal: Journal of Clinical Oncology (2005)

4593 Background: The purpose of the trial designed for multiple superficial tumors of the bladder is to study the ablative or reductive activity of intravesical Gemcitabine on a papillary marker lesion Leaving a marker may be an interesting strategy: the effectiveness of the intravesical treatment can be assessed in a short period of time and furthermore the response the marker may turn out to be an important prognostic factor when correlated with the further recurrence rate. Gemcitabine can be considerate an ideal endovesical chemotherapy agent due to is high molecular weight, with no systemic absorption. Gemcitabine has been studied as a single agent in advanced or metastatic bladder cancer whit 24–28% of responses Methods: All patients with multiple primary and recurrent resectable histologically Ta T1 papillary TCC of the bladder will be considered for the trial all the visible lesions must be resected, except for one marker lesion The patient will then receive weekly instillations of Gemcitabine 2000mg in 50ml of sterile water during 8 weeks staring within 7–15 days after TUR. Control cystoscopy will be performed 12 weeks after TUR. If the marker lesion is still present or other growths are seen, they will be resected and biopsies of normal bladder mucosa performed. If no lesion is seen, a biopsy at the site of the marker will be taken. Results: We have 42 patients, 28 complete responses (66,6%) 14 non responders (33,3%). From 42 multiple patients, 24 are recurrent and 9 primary; 21 - Ta G1, 8 - TaG2, 4 - TaG3, 1 - T1G1, 28- T1 G2. In the non responders group there were no augmentation on TNM classification. Side effects in 6 patients, 2 had one case of hematuria and 4 had mild to strong dysuria Conclusions: We conclude that gencitabine is an active drug in bladder cancer and it wil be needed a randomized phase III protocol to have more data No significant financial relationships to disclose.
High-dose interleukin-2 registry, PROCLAIM: Modern data on toxicities and outcomes.
Authors: James N Lowder, Sandra Aung, Michael K.K. Wong, Gregory A. Daniels, Howard Kaufman, David F. McDermott, Michael Morse
Journal: Journal of Clinical Oncology (2014)

430 Background: High dose interleukin-2 is an FDA-approved treatment for metastatic melanoma (mM) and renal cell carcinoma (mRCC) that consistently delivers durable CRs in up to 10% of patients. Concerns of treatment related toxicities are a major barrier to IL-2 administration. Nonsystematic reviews show that HD IL-2 therapy is safe, however treatment protocols have evolved to a series of best practices within over 60 HD IL-2 centers in the US. Methods: In order to capture current practices and generate modern data on toxicities and outcomes, PROCLAIM, a HD IL-2 observational database, was initiated in 2011. One goal of the registry is to survey real world HD IL-2 clinical experience used in the treatment of patients with mM, mRCC or other metastatic malignancies. A retrospective cohort was initiated for hypothesis generation and to inform the prospective cohort which has currently &gt; 470 patients enrolled. We report here on the retrospective data comprising 267 patients (mRCC,97) treated between 2007-2012. Results: Analysis of the retrospective data show that no deaths were reported, compared to the historic mortality rate of 4% (n=255 mRCC)(Fyfe,1995). Toxicites are acute and abate rapidly after cessation of IL-2. Center-specific reasons for stopping dosing to end a cycle, as well as tolerance of elevated creatinine levels varied significantly. There were striking differences between the median number of doses administered per cycle per center, clustering around 4-6 vs. 8-14. There appears to be a trend towards higher and more durable responses with higher dose density per cycle. Conclusions: HD IL-2 can be a safe and effective immunotherapy that can be given over a short duration and delivers consistent durable therapeutic responses. The rapid resolution of its toxicities allows for its use with other therapies either in sequence or in combination; trials are currently in progress.
Dynamic molecular changes with VEGF targeted therapy in metastatic clear cell renal cancer.
Authors: Thomas Powles, Kevin Sharpe, Dan Berney, Irfan Kayani, Rukma Doshi, Grant Duncan Stewart, Andrew Reynolds, Axel Bex, Naveed Sarwar, Simon Chowdhury
Journal: Journal of Clinical Oncology (2013)

437 Background: The purpose of this study was to investigate for specific molecular changes associated with VEGF targeted in metastatic clear cell renal cancer (mRCC). This was achieved by taking tissue before and after VEGF TKI therapy. Methods: The study combined the data from 3 similar phase II prospective studies, investigating the role of VEGF therapy (pazopanib or sunitinib) prior to planned nephrectomy in untreated mRCC. A structured treatment break occurred during the planned nephrectomy (4 weeks). Paired tumour samples before and after 12-16 weeks of pazopanib or sunitinib were collected from these studies. Histopathology assessment (Furman grade, Ki-67, vascular density [CD31]), growth factor expression [FGF-2, c-MET, S-6-protein kinase] and immune parameters (CD3, 4, 8, PDL-1, FOXP3) before and after therapy were compared. Sequential functional imaging [FDG-PET] was performed to address the relationship between the primary tumour and metastatic sites. Results: Overall 62 patients had sequential tissue taken from these 3 prospective trials. Adequate quantities of sequential tissue were available from 48 patients. Pathological examination of the matched pairs before and after VEGF TKI showed a significant increase in tumour grade, Ki-67, lymphocyte infiltrate, and necrosis (p&gt;0.05), there was also a significant decrease in CD31 (p&lt;0.05). Significant changes to FGF-2, c-MET and FOXP3 expression was seen in the treated samples (p&lt;0.05). FDG-PET results from 23 patients showed a significant correlation in the response seen in the primary renal tumour and metastatic sites with sunitinib (r=0.46 p&lt;0.001). During the structured treatment break for nephrectomy (4 weeks) 37% of patients had disease progression (RECIST v1.1) underlining the aggressive nature of the disease after VEGF TKI therapy. This was associated with an increased risk of death on multivariate analysis (HR: 3.17; 95% CI, 1.46-6.86, p&lt;0.03). Conclusions: These results suggest VEGF targeted therapy is associated with a more aggressive tumor phenotype. Changes to immune parameters and up regulation of growth factors potentially implicated in resistance to VEGF targeted therapy occurred.
Irinotecan, mitomycin, and raltitrexed (CMT) combination chemotherapy in heavily pretreated colorectal cancer (CRC) patients.
Authors: J. Rebollo, M. S. Gonzalez, E. Calvo, P. Bretcha, J. Farre, C. Dussan, M. Duarte, A. Brugarolas
Journal: Journal of Clinical Oncology (2011)

e14104 Background: Therapeutic options for patients (pts) with advanced colorectal cancer (CRC) that have progressed to irinotecan- and oxaliplatin-based combination chemotherapy are few. Raltitrexed is a known active drug in advanced CRC and mitomycin and irinotecan could have synergistic effect as mitomycin upregulates the level of topoisomerase I, the target of irinotecan. Methods: Pts with advanced colorectal cancer that had been previously treated with irinotecan and oxaliplatin have been included. ECOG 0-3 pts enrolled. Chemotherapy regimen consisted of raltitrexed 3mg/m2, irinotecan 150 mg/m2 and mitomycin 5 mg/m2, repeated every two weeks until progression. Primary endpoint has been progression-free survival (PFS). Secondary endpoints been response rate, safety, and overall survival (OS). Survivals are considered from initiation of CMT regimen. Results: From 2003 to 2006 a total of 19 pts, 10 males and 9 females, median age 56 years (range 33-69) have been treated. Most pts were ECOG 0-1. One hundred and fifteen cycles (Median 6, range <2-14) have been administered. Grades 3-4 toxicity included mucositis 3 pts, myelotoxicity 3 pts (one pt died because of neutropenic sepsis) and diarrhea 1 pt. One pt had non-measurable disease. Three out of 18 pts have shown objective response and 6 stabilizations (9/1, 50% clinical benefit rate). Median PFS and OS have been 5 months (95%CI: 4.08-5.92) and 8 months (95%CI: 3.73-12.27), respectively. Eleven pts (five out of the 9 pts with clinical benefit) underwent additional salvage procedures. Conclusions: CMT combination chemotherapy has an acceptable toxicity profile with moderate activity. It can be considered as a therapeutic option in patients with advanced CRC that have progressed to conventional therapy.
Use of a Pan-Canadian indicator to measure treatment rates relative to evidence-based guidelines for rectal cancer.
Authors: Tonia Forte, Julie Klein-Geltink, Rami Rahal, Gina Lockwood, Heather E. Bryant
Journal: Journal of Clinical Oncology (2012)

177 Background: As part of the Canadian Partnership Against Cancer’s (CPAC) System Performance initiative, indicators measuring treatment practice patterns across the country are now available, offering the ability to compare against evidence-based guidelines. We report on the percentage of patients with stage II and III rectal cancer receiving pre-operative radiation treatment (RT) based on an analysis of Canadian administrative data. A retrospective chart review was conducted to examine reasons for non-treatment with RT, set performance targets, and inform quality improvements. Methods: Data on the percentage of stage II and III rectal cancer cases receiving preoperative RT were obtained from five provincial cancer registries using a standardized methodology for 2,854 cases diagnosed between 2007 and 2008, with 2009 data soon to be available. A retrospective chart review was conducted in five provinces on a random sample of 383 patients diagnosed in 2008 to examine reasons for non-referral and non-treatment. Results: Based on administrative data, an average of 45% of cases received RT preceding surgical resection for stage II or III rectal cancer, ranging from 36% to 48% across provinces. Preoperative RT rates were similar for men and women, but were lower in older patients. From 2007 to 2008, the percentage of patients receiving pre-operative RT increased in all provinces. Results from the chart review showed that, of those who did not receive preoperative RT, 33% were not referred by a surgeon to an oncologist. The most common documented reasons for non-referral were co-morbidities (26%) and patient choice (7%). Among patients referred to an oncologist, 42% were treated with preoperative RT, 30% were treated with post-operative RT and 28% received no treatment. Among those receiving no treatment, 29% were seen only by a medical oncologist, and 18% were not treated due to patient choice. Conclusions: Findings are being used to develop national targets for treatment rates and, working with national oncologist associations, to develop quality improvement strategies, including patient education efforts to promote informed decisions on treatment options.
Transient increase in serum CEA while on adjuvant chemotherapy for colon cancer: Is this of prognostic importance?
Authors: Nicola Jane Mitchell, Victoria Hinder, Melissa Murray, Jerome Macapagal, Paul Ivan Thompson, Katrina Sharples, Michael P. N. Findlay
Journal: Journal of Clinical Oncology (2014)

654 Background: Serum Carcinoembryonic Antigen (CEA) is used to monitor response to treatment in metastatic colon cancer. Transient surges in CEA can occur after initiation of chemotherapy and are not associated with worse outcome. There is little data on transient CEA surge in the adjuvant setting. We aimed to review patterns of change in CEA levels with adjuvant chemotherapy and investigate associations between transient rises and patient survival. Methods: A retrospective review of patients in Auckland with a new diagnosis of colon cancer in 2001 or 2005 was reported previously [Murray, NZMJ, 2011]. CEA results immediately pre-chemotherapy, during and up to 9 months post chemotherapy were collected and death data was updated. Increase in CEA during chemotherapy was measured as the maximum change from baseline; values more than 2 (within-person) standard deviations above baseline [Erden, Scand, J Clin Lab Inv, 2008] were classified as increased. An increase was transient if the last recorded CEA post chemotherapy was within 2 sd of baseline. Three patient groups were defined: NI (no increase in CEA); TI (transient increase in CEA); and CI (continuous increase in CEA). Kaplan-Meier methods were used to estimate 5-year survival; Cox regression and log-rank p-values were used to compare survival. Results: Of the 77 patients identified with stage II or III disease who had received adjuvant chemotherapy, 61 had sufficient CEA data to be included. The TI group were younger (median [quartiles]: TI 59 [54, 64]; NI 65 [53, 74]; CI 68 [62, 74]) but a greater proportion were stage II (TI 32%; NI 23%; CI 17%). Patients were followed up for a minimum of 7.3 years (or death). Number of deaths per group were: TI 3/19; NI 9/30; CI 7/12. The 5 year overall survival was: TI 95%; NI 83%; CI 42%. There was no significant difference between TI and NI (p = 0.1), but the confidence interval was wide (HR 0.3; 95% CI (0.07 to 1.5). For CI compared to NI, the HR was 2.8 (95% CI (1.0 to 7.6), p = 0.04). Conclusions: The observation that CEA surge does not signal poorer prognosis will be further examined as part of a separate population-based New Zealand-wide study of colorectal cancer diagnosis, treatment and outcome. Part funded by a Genesis Oncology Trust grant.
Impact of prophylactic treatments of cetuximab-based skin reactions in patients with metastatic colorectal carcinoma (mCRC): Interim analysis of the German noninterventional study ERBITAG.
Authors: Stephan Sahm, Thomas Goehler, Christiane Hering-Schubert, Jan Janssen, Michael Schwittay, Mark-Oliver Zahn, Karsten Guenter Stenzel, Alma Katharina Steinbach-Buechert, Friedrich Overkamp
Journal: Journal of Clinical Oncology (2016)

675 Background: Prophylactic treatments are widely used to ameliorate skin reactions induced by EGFR inhibition. Randomised studies have shown a positive impact of prophylactic antibiotics. Methods: Patients (Pts) with KRAS-wt and later RAS-wt mCRC treated with a first-line chemotherapy regimen plus cetuximab with written informed consent were eligible for this prospective, non-interventional study. Physicians were requested to complete a questionnaire and document any applied prophylactic and reactive skin toxicity treatment for every pt. Different prophylactic treatment regimens were categorized in 5 groups: systemic antibiotics (SA), skin care without antibiotics or corticosteroids (SC), other topical treatments (OT) (e.g. antibiotics or corticosteroids), any prophylaxis (P), and no prophylaxis (NP). Results: Data from 497 pts at 178 centers were finally collected and evaluable at data cut off. For all reported skin reactions the maximum NCI-CTCAE grade per patient and prophylactic treatment group was evaluated (table). Although none of the prophylactic regimens were significant different from NP, SA showed a numerically lower rate of all skin reactions by 8.1% (p=0.06) and of rash acneiforme by 5.3% (p=0.134) versus NP. 96.2% of reactive treatments of skin toxicities were done without consultation of a dermatologist and the medication was topical or systemic in 60.9% and 32.3%, respectively. Response to reactive treatment was complete remission or significant improvement of the skin reactions in 68.6% (topical) and 66.0% (systemic). Conclusions: Pts given prophylactic SA showed numerically fewer grade 3-4 skin reactions in comparison to NP (7.6% vs. 15.7%), but without significance. An important reason for failing significance may be the low number of pts receiving prophylactic SA (only in 18.5% of pts). Reactive treatment (systemic or topical) of skin toxicities led to an improvement in the majority of pts. Clinical trial information: http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_455. [Table: see text]