Cancer and renal insufficiency results of the BIRMA study

Background: Half of anticancer drugs are predominantly excreted in urine. Dosage adjustment in renal insufficiency (RI) is, therefore, a crucial issue. Moreover, patients with abnormal renal function are at high risk for drug-induced nephrotoxicity. The Belgian Renal Insufficiency and Anticancer Medications (BIRMA) study investigated the prevalence of RI in cancer patients, and the profile/dosing of anticancer drugs prescribed. Methods:Primary end point: to estimate the prevalence of abnormal glomerular filtration rate (GFR; estimated with the abbreviated Modification of Diet in Renal Disease formula) and RI in cancer patient. Secondary end point: to describe the profile of anticancer drugs prescribed (dose reduction/nephrotoxicity). Data were collected for patients presenting at one of the seven Belgian BIRMA centres in March 2006. Results: A total of 1218 patients were included. The prevalence of elevated SCR (1.2 mg per 100 ml) was 14.9%, but 64.0% had a GFR90 ml min 1 per 1.73 m 2. In all, 78.6% of treated patients (n1087) were receiving at least one drug needing dosage adjustment and 78.1% received at least one nephrotoxic drug. In all, 56.5% of RI patients receiving chemotherapy requiring dose reduction in case of RI did not receive dose adjustment. Conclusions: The RI is highly frequent in cancer patients. In all, 80% of the patients receive potentially nephrotoxic drugs and/or for which dosage must be adjusted in RI. Oncologists should check the appropriate dose of chemotherapeutic drugs in relation to renal function before prescribing. © 2010 Cancer Research UK.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study)

Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months

TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer.

PURPOSE: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from metastatic castration-resistant prostate cancer (mCRPC) patients starting a new line of AR signalling inhibitors (ARSi). EXPERIMENTAL DESIGN: Between March 2014 and April 2017, we recruited mCRPC patients (n=168) prior to ARSi in a cohort study encompassing 10 European centres. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA). Targeted CTC RNA-seq allowed the detection of eight AR splice variants (ARVs). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss-of-heterozygosity, mutations and structural rearrangements in ctDNA. Clinical or radiological progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox-regression models. RESULTS: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumour burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value (HR 1.88, 95%CI 1.18-3.00, p = 0.008), and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs 7.51 vs 2.62 months, p < 0.0001), which was validated in an independent mCRPC cohort (n=202) starting first-line ARSi (median, 14.3 vs 6.39 vs 2.23 months, p < 0.0001). CONCLUSIONS: In an all-comer cohort, tumour burden estimates and TP53 outperform any AR perturbation to infer prognosis

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.The Belgian Foundation Against Cancer (grant number C/2014/227); Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society (grant number 00000000116000000206); Royal College of Surgeons/Cancer Research UK (C19198/A1533); The Cancer Research Funds of Radiumhemmet, through the PCM program at KI (grant number 163012); The Erling-Persson family foundation (grant number 4-2689-2016); the Swedish Research Council (grant number K2010-70X-20430-04-3), and the Swedish Cancer Foundation (grant number 09-0677)

Customer value disclosure and cost of equity capital

Purpose – This paper seeks to examine the association between a firm's extent and precision of customer value disclosure and its implied cost of equity capital. In addition, it aims to investigate whether industry competition intensity attenuates this association. Design/methodology/approach – The content of corporate websites from four continental European countries is analysed on the presence and precision of customer value information and empirically test whether content and precision are associated with the firm's implied cost of equity capital measurement. Findings – The results show a negative association between cross‐sectional differences in the extent of customer value disclosure and cross‐sectional differences in a firm's cost of equity capital. In addition, the precision of the customer value information disclosed affects this association. It is observed that a negative relationship between quantitative (or hard) customer value disclosure and a firm's cost of equity capital, but not for qualitative (or soft) customer value disclosure. As expected, industry competition intensity attenuates the association between quantitative customer value disclosures and a firm's cost of equity capital. Research limitations/implications – The paper considers web placement of customer value disclosure although a firm might disclose such information through other information channels as well. Practical implications – A firm tends to benefit economically from more precise customer value disclosure. Originality/value – The paper extends existing evidence by considering the capital market implications of disclosing customer value information. In addition, it examines whether industry competition affects the association between customer value disclosure and the firm's cost of equity capital

A business process mining application for internal transaction fraud mitigation

Corporate fraud these days represents a huge cost to our economy. In the paper we address one specific type of corporate fraud, internal transaction fraud. Given the omnipresence of stored history logs, the field of process mining rises as an adequate answer to mitigating internal transaction fraud. Process mining diagnoses processes by mining event logs. This way we can expose opportunities to commit fraud in the followed process. In this paper we report on an application of process mining at a case company. The procurement process was selected as example for internal transaction fraud mitigation. The results confirm the contribution process mining can provide to business practice

Formal participation in the IASB's due process of standard setting:A multi-issue/multiperiod analysis

This paper sets out to enquire about the nature of constituents' participation in the IASB's due process in terms of representation (constituents' diversity and characteristics) and drivers to participate. We choose to adopt a multi-issue/multi-period approach to investigate constituents' formal participation. An analysis of comment letters sent directly to the IASB over the period 2002–2006, reveals that preparers sent most letters followed by the accounting profession and standard setters. With regard to timing, we find that preparers concentrate their participation efforts at a later stage in the process compared to the other constituents, who react earlier. Formal indirect participation in the IASB's due process by submitting comment letters to EFRAG is infrequently used by European constituents. In those cases where constituents exert influence to both IASB and EFRAG, they often use exactly the same comment letter. Concentrating on the drivers to participate, the data reveal that preparers, accountants and standard setters react significantly more when proposals have a major impact on the accounting numbers of a company. Users, stock exchanges and their supervisory authorities write significantly more comment letters when disclosure issues are at stake. Finally, participating preparers in the IASB's due process are larger and more profitable than non-participating preparers