Improving eSource Site Start-Up Practices.

Background: eSource software that copies patient electronic health record data into a clinical trial electronic case report form holds promise for increasing data quality while reducing data collection, monitoring and source document verification costs. Integrating eSource into multicenter clinical trial start-up procedures could facilitate the use of eSource technologies in clinical trials. Methods: We conducted a qualitative integrative analysis to identify eSource site start-up key steps, challenges that might occur in executing those steps, and potential solutions to those challenges. We then conducted a value analysis to determine the challenges and solutions with the greatest impacts for eSource implementation teams. Results: There were 16 workshop participants: 10 pharmaceutical sponsor, 3 academic site, and 1 eSource vendor representatives. Participants identified 36 Site Start-Up Key Steps, 11 Site Start-Up Challenges, and 14 Site Start-Up Solutions for eSource-enabled studies. Participants also identified 77 potential impacts of the Challenges upon the Site Start-Up Key Steps and 70 ways in which the Solutions might impact Site Start-Up Challenges. The most important Challenges were: (1) not being able to identify a site eSource champion and (2) not agreeing on an eSource approach. The most important Solutions were: (1) vendors accepting electronic data in the FHIR standard, (2) creating standard content for eSource-related legal documents, and (3) creating a common eSource site readiness checklist. Conclusions: Site start-up for eSource-enabled multi-center clinical trials is a complex socio-technical problem. This study's Start-Up Solutions provide a basic infrastructure for scalable eSource implementation.

Digitalizing the Clinical Research Informed Consent Process: Assessing the Participant Experience in Comparison With Traditional Paper-Based Methods.

PURPOSE: Consent processes are critical for clinical care and research and may benefit from incorporating digital strategies. We compared an electronic informed consent (eIC) option to paper consent across four outcomes: (1) technology burden, (2) protocol comprehension, (3) participant agency (ability to self-advocate), and (4) completion of required document fields. METHODS: We assessed participant experience with eIC processes compared with traditional paper-based consenting using surveys and compared completeness of required fields, over 3 years (2019-2021). Participants who consented to a clinical trial at a large academic cancer center via paper or eIC were invited to either pre-COVID-19 pandemic survey 1 (technology burden) or intrapandemic survey 2 (comprehension and agency). Consent document completeness was assessed via electronic health records. RESULTS: On survey 1, 83% of participants (n = 777) indicated eIC was easy or very easy to use; discomfort with technology overall was not correlated with discomfort using eIC. For survey 2, eIC (n = 262) and paper consenters (n = 193) had similar comprehension scores. All participants responded favorably to at least five of six agency statements; however, eIC generated a higher proportion of positive free-text comments (P < .05), with themes such as thoroughness of the discussion and consenter professionalism. eIC use yielded no completeness errors across 235 consents versus 6.4% for paper (P < .001). CONCLUSION: Our findings suggest that eIC when compared with paper (1) did not increase technology burden, (2) supported comparable comprehension, (3) upheld key elements of participant agency, and (4) increased completion of mandatory consent fields. The results support a broader call for organizations to offer eIC for clinical research discussions to enhance the overall participant experience and increase the completeness of the consent process.

Assessing the clinical utility of measuring Insulin-like Growth Factor Binding Proteins in tissues and sera of melanoma patients.

BACKGROUND: Different Insulin-like Growth Factor Binding Proteins (IGFBPs) have been investigated as potential biomarkers in several types of tumors. In this study, we examined both IGFBP-3 and -4 levels in tissues and sera of melanoma patients representing different stages of melanoma progression. METHODS: The study cohort consisted of 132 melanoma patients (primary, n = 72; metastatic, n = 60; 64 Male, 68 Female; Median Age = 56) prospectively enrolled in the New York University School of Medicine Interdisciplinary Melanoma Cooperative Group (NYU IMCG) between August 2002 and December 2006. We assessed tumor-expression and circulating sera levels of IGFBP-3 and -4 using immunohistochemistry and ELISA assays. Correlations with clinicopathologic parameters were examined using Wilcoxon rank-sum tests and Spearman-rank correlation coefficients. RESULTS: Median IGFBP-4 tumor expression was significantly greater in primary versus metastatic patients (70% versus 10%, p = 0.01) A trend for greater median IGFBP-3 sera concentration was observed in metastatic versus primary patients (4.9 microg/ml vs. 3.4 microg/ml, respectively, p = 0.09). However, sera levels fell within a normal range for IGFBP-3. Neither IGFBP-3 nor -4 correlated with survival in this subset of patients. CONCLUSION: Decreased IGFBP-4 tumor expression might be a step in the progression from primary to metastatic melanoma. Our data lend support to a recently-described novel tumor suppressor role of secreting IGFBPs in melanoma. However, data do not support the clinical utility of measuring levels of IGFBP-3 and -4 in sera of melanoma patients.

Androgen receptor overexpression in prostate cancer linked to Pur alpha loss from a novel repressor complex.

Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5'-untranslated region contains Pur alpha and hnRNP-K. Pur alpha expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AI-LNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored Pur alpha expression reduced AR at the transcription and protein levels. Pur alpha knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored Pur alpha protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. Pur alpha is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring Pur alpha and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC.

The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo.

BACKGROUND: Treatment options for patients with recurrent superficial bladder cancer are limited, necessitating aggressive exploration of new treatment strategies that effectively prevent recurrence and progression to invasive disease. We assessed the effects of belinostat (previously PXD101), a novel histone deacetylase inhibitor, on a panel of human bladder cancer cell lines representing superficial and invasive disease, and on a transgenic mouse model of superficial bladder cancer. METHODS: Growth inhibition and cell cycle distribution effect of belinostat on 5637, T24, J82, and RT4 urothelial lines were assessed. Ha-ras transgenic mice with established superficial bladder cancer were randomized to receive either belinostat or vehicle alone, and assessed for bladder weight, hematuria, gene expression profiling, and immunohistochemistry (IHC). RESULTS: Belinostat had a significant linear dose-dependent growth inhibition on all cell lines (IC50 range of 1.0-10.0 microM). The 5637 cell line, which was derived from a superficial papillary tumor, was the most sensitive to treatment. Belinostat (100 mg/kg, intraperitoneal, 5 days each week for 3 weeks) treated mice had less bladder weight (p < 0.05), and no hematuria compared with 6/10 control mice that developed at least one episode. IHC of bladder tumors showed less cell proliferation and a higher expression of p21WAF1 in the belinostat-treated mice. Gene expression profile analysis revealed 56 genes significantly different in the treated group; these included the upregulation of p21WAF1, induction of core histone deacetylase (HDAC), and cell communication genes. CONCLUSION: Our data demonstrate that belinostat inhibits bladder cancer and supports the clinical evaluation of belinostat for the treatment of patients with superficial bladder cancer.

The vitamin-like dietary supplement para-aminobenzoic acid enhances the antitumor activity of ionizing radiation.

PURPOSE: To determine whether para-aminobenzoic acid (PABA) alters the sensitivity of tumor cells to ionizing radiation in vitro and in vivo. METHODS AND MATERIALS: Cellular proliferation was assessed by WST-1 assays. The effects of PABA and radiation on tumor growth were examined with chick embryo and murine models. Real-time reverse transcriptase-polymerase chain reaction and Western blotting were used to quantify p21CIP1 and CDC25A levels. RESULTS: Para-aminobenzoic acid enhanced (by 50%) the growth inhibitory activity of radiation on B16F10 cells, whereas it had no effect on melanocytes. Para-aminobenzoic acid enhanced (50-80%) the antitumor activity of radiation on B16F10 and 4T1 tumors in vivo. The combination of PABA and radiation therapy increased tumor apoptosis. Treatment of tumor cells with PABA increased expression of CDC25A and decreased levels of p21CIP1. CONCLUSIONS: Our findings suggest that PABA might represent a compound capable of enhancing the antitumor activity of ionizing radiation by a mechanism involving altered expression of proteins known to regulate cell cycle arrest.

Oxalic acid alters intracellular calcium in endothelial cells.

Patients with chronic renal failure (CRF) who undergo hemodialysis experience accelerated atherosclerosis and premature death. While the cause of uremic atherogenesis is unknown, we reported that uremic levels of oxalate, an excretory metabolite, severely inhibit proliferation and migration of human endothelial cells (EC) without affecting other cell types. Since the physical, cellular and molecular events of endothelial injury are clearly established as key factors in the development of plaque, and since inhibition of proliferation and migration would enhance endothelial injury, we have proposed that oxalate is an atherogenic toxin of uremia. In the current study, we used in situ cell counting and total DNA measurement to show that the inhibitory effect of oxalate on proliferation is exclusive to endothelial cells among human cell lines tested (endothelial cells, fibroblasts, aortic smooth muscle cells (SMC), glioblastoma and embryonic kidney cells). Using the fluorescent calcium indicators fura-2 and fluo-3, we correlated the inhibition of proliferation with a prolonged elevation in intracellular free calcium levels. We also demonstrated that all cells tested internalize 14C-oxalic acid. We conclude that plasma oxalate exerts its atherogenic effects by elevating intracellular calcium exclusively in endothelial cells and preventing re-endothelialization.