Metabolic syndrome in castration-resistant prostate cancer patients treated with abiraterone.

BACKGROUND: Metabolic syndrome (MS) has not yet been studied in castration-resistant prostate cancer (CRPC) men treated with novel hormonal therapies. The study aims to assess the impact of MS on outcome from time starting abiraterone. PATIENTS AND METHODS: We retrospectively evaluated a consecutive series of metastatic CRPC patients treated with abiraterone after docetaxel failure. MS, as defined by modified Adult Treatment Panel (ATP) III criteria, was assessed at the time of initiation of abiraterone, during treatment and follow-up. RESULTS: Sixty-seven of 178 patients evaluated (37.6%) met MS criteria at baseline, before abiraterone initiation, whereas for 11 (9.9%) without MS before treatment with abiraterone this occurred during treatment. Median PFS was equal to 4.7 months for patients with MS versus 9 months for those without MS. Patients with MS had an increased risk of 71% of progression or death for all causes than patients without MS (HR = 1.7, 95% CI [1.2-2.4], P = 0.03). Median OS was 14.7 months and 22.3 months in patients with and without MS, respectively. After adjusting for covariates, MS resulted not significantly associated to OS (HR = 1.42, 95% CI [0.91-2.22], P = 0.073). CONCLUSIONS: The presence of MS is a significant risk factor for shorter PFS in CRPC patients treated with abiraterone, even if it does not show a significant impact on OS. A prospective evaluation is warranted.

Endometriosis and endometrial cancer: A propensity score-adjusted real-world data study.

Endometriosis is a benign condition characterized by the presence of ectopic endometrial tissue. Our study investigated the effect of endometriosis on the risk of endometrial cancer (EC) and the prognosis of endometriosis-associated EC. In our study, 197,196 patients with endometriosis and without a previous diagnosis of EC were compared with 6,455,556 females encountering health services for examinations, with body mass index (BMI) data, and without endometriosis or EC. A propensity score generated 197,141 matched pairs. In the endometriosis cohort, 875 cases of EC were seen, whereas 558 were in the control group: the hazard ratio (HR) was 1.56 (95% CI 1.40-1.73, p < 0.001). Women with endometriosis were more likely to develop invasive endometrioid (p = 0.005) and clear cell (p < 0.001) EC. There was no difference in overall survival between endometriosis-associated EC and EC without endometriosis. Our epidemiological findings were consistent with the evidence of an association between endometriosis and EC.

TransFAIR study: a European multicentre experimental comparison of EHR2EDC technology to the usual manual method for eCRF data collection.

PURPOSE: Regulatory authorities including the Food and Drug Administration and the European Medicines Agency are encouraging to conduct clinical trials using routinely collected data. The aim of the TransFAIR experimental comparison was to evaluate, within real-life conditions, the ability of the Electronic Health Records to Electronic Data Capture (EHR2EDC) module to accurately transfer from EHRs to EDC systems patients' data of clinical studies in various therapeutic areas. METHODS: A prospective study including six clinical trials from three different sponsors running in three hospitals across Europe has been conducted. The same data from the six studies were collected using both traditional manual data entry and the EHR2EDC module. The outcome variable was the percentage of data accurately transferred using the EHR2EDC technology. This percentage was calculated considering all collected data and the data in four domains: demographics (DM), vital signs (VS), laboratories (LB) and concomitant medications (CM). RESULTS: Overall, 6143 data points (39.6% of the data in the scope of the TransFAIR study and 16.9% when considering all data) were accurately transferred using the platform. LB data represented 65.4% of the data transferred; VS data, 30.8%; DM data, 0.7% and CM data, 3.1%. CONCLUSIONS: The objective of accurately transferring at least 15% of the manually entered trial datapoints using the EHR2EDC module was achieved. Collaboration and codesign by hospitals, industry, technology company, supported by the Institute of Innovation through Health Data was a success factor in accomplishing these results. Further work should focus on the harmonisation of data standards and improved interoperability to extend the scope of transferable EHR data.

Clinical research and burnout syndrome in Italy - only a physicians' affair?

BACKGROUND: The burnout phenomenon has been extensively investigated among health care professionals, particularly focusing on physicians and nurses. However, literature concerning burnout in clinical research is poor and often neglects the other professional categories involved. METHODS: In March 2019, all members of Italian Group of Clinical Research Coordinator were invited to participate to a web survey, consisting of three sections: general information and workload; Maslach Burnout Inventory (MBI) test; subjective perception of oneself's work stress and possible causes. RESULTS: The majority of respondents felt a form of distress. The main source was contract type (31.2%), followed by workload (20.5%) and lack of skills recognition (17.8%). Results from MBI test confirmed the interviewees' subjective perception: an intermediate level of emotional exhaustion (19.1 points) and a very high sense of reduced professional achievement (26.8 points) were observed. Both depersonalization and sense of reduced professional achievement showed weak to moderate correlations with emotional exhaustion. Emotional exhaustion was associated with contract type with high significance. CONCLUSION: It is necessary to act on those qualitative factors that are greatly increasing the level of perceived stress, jeopardizing the quality of clinical research coordinators work and significantly amplifying the phenomenon of migration towards the private sector.

Lessons learned from COVID-19 for clinical research operations in Italy: what have we learned and what can we apply in the future?

The coronavirus disease 2019 (COVID-19) pandemic has stressed the importance of health research as never before. In the specific domain of clinical research, the effort to rapidly find responses to health challenges and therapeutic hypotheses has highlighted the need for efficient, timely, ethically correct research. The guidelines published by the Agenzia Italiana del Farmaco have shown that some useful changes are feasible: simple and rapid methods have been implemented to conduct clinical research in the emergency conditions of the pandemic, maintaining high levels of quality. In this perspective, four Italian scientific associations operating in clinical research have worked together to evaluate which measures, among the ones implemented during the pandemic, have been particularly significant and potentially effective under normal conditions or in case of emergencies, and that therefore will be useful in the future as well.

How Many Cancer Clinical Trials Can a Clinical Research Coordinator Manage? The Clinical Research Coordinator Workload Assessment Tool.

PURPOSE: Cancer clinical trials (CTs) are now more complex than ever before and require dedicated personnel (clinical research coordinators [CRCs]) to perform regulatory and administrative activities and protocol- and patient-related procedures. We developed a simple tool to measure the workload (WL) of CRCs involved in cancer research and to estimate personnel requirements within a Clinical Trial Center. METHODS: A literature review and 2-month period in which CRCs recorded their activities in a diary provided valuable information that led to the Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Workload Assessment Tool (IWAT) being divided into three sections: Protocol, On-Treatment Patients, and Follow-Up Patients. Twelve full-time senior CRCs from three sites of the Network measured their monthly WL for 30 months to evaluate IWAT reproducibility and accuracy. RESULTS: The IWAT proved to be a user-friendly tool (3-6 minutes required for each CT), with high reproducibility (interobserver reproducibility ranged from 82% to 100% for each IWAT item). In December 2017, the Network had 185 ongoing CTs, with a median of 2.5 active centers for each CT. On the basis of 448 total IWAT measures by CRCs, the majority of trials were academic (57%) or dealt with advanced disease (77%). The median IWAT WL score for each study was 20.98 ± 22.90 (range, 2-188) and 475 ± 229 (range, 150 [junior staff] - 930 [extreme heavy WL]) for each CRC. On the basis of our experience, a monthly WL score of 500-600 was considered an appropriate value for a full-time CRC. CONCLUSION: The IWAT could prove useful in evaluating CT complexity, estimating appropriate CRC WLs, and defining personnel requirements. Independent validation by other CRCs working in different organizational contexts and in different countries is needed.

Performances of a Solution to Semi-Automatically Fill eCRF with Data from the Electronic Health Record: Protocol for a Prospective Individual Participant Data Meta-Analysis.

Clinical trial data collection still relies on a manual entry from information available in the medical record. This process introduces delay and error risk. Automating data transfer from Electronic Health Record (EHR) to Electronic Data Capture (EDC) system, under investigators' supervision, would gracefully solve these issues. The present paper describes the design of the evaluation of a technology allowing EHR to act as eSource for clinical trials. As part of the EHR2EDC project, for 6 ongoing clinical trials, running at 3 hospitals, a parallel semi-automated data collection using such technology will be conducted focusing on a limited scope of data (demographic data, local laboratory results, concomitant medication and vital signs). The evaluation protocol consists in an individual participant data prospective meta-analysis comparing regular clinical trial data collection to the semi-automated one. The main outcome is the proportion of data correctly entered. Data quality and associated workload for hospital staff will be compared as secondary outcomes. Results should be available in 2020.

[Clinical research coordinators: a crucial resource.] / Coordinatori di ricerca clinica: una risorsa indispensabile.

The increasing complexity that characterizes the world of clinical trials, both in terms of procedures and bureaucracy, has made it necessary to create dedicated infrastructures composed of experienced and qualified personnel, who constantly work to ensure high ethical and qualitative standards. A key role in these infrastructures is played by the clinical research coordinator, a key figure able to manage the workflow required, placing himself as a reference for the coordination of the various activities and professional figures involved. The literature has widely demonstrated how the presence of this professional figure is a valid contribution both from a documentary and administrative point of view as well as a crucial resource for what concerns the indicators of ethics and quality of research. Despite that, there is no yet an institutional recognition of the professional figure, neither a specific economical agreement within the National Health System. The lack of institutional recognition is causing a worrying phenomenon of migration of qualified personnel towards contract research organizations and pharmaceutical companies. That could be detrimental to the competitiveness of Italian clinical research and hinder the possibility of offering innovative experiments therapies to patients, with serious ethical consequences.

[Clinical research: enough players to get out there?] / Ricerca clinica: abbastanza giocatori per vincere la partita?

Despite the presence of experienced and multidisciplinary staff is now essential due to the increasing complexity of clinical research, many national collective health contracts do not yet contemplate the new professional figures. This instability risks causing an alarming professional gap, especially for non-profit clinical research. For this reason, we would try to evaluate the extent to which the problem is widespread among Italian clinical research coordinators, verifying how much the Italian institutes have permanently integrated this professional figure into organic plant, through stable and specific employment contracts. In November 2016, when the Italian Government has declared for the first time its intention to prevent further renewal of contracts with atypical employment, we conducted a survey with the intent of mapping the extent of the contractual issues related to the figure of the clinical research coordinator. Two years later, we repeated the survey to see if something was changed and if it was any improvement in the employment situation. In November 2016, only a small fraction of the respondents (13.8%) was hired with a permanent contract, while the majority (73.2%) were employed with an atypical one. Regarding the impossibility to renew the atypical contracts due to the new Government provisions starting from January 2017: the 67.5% of the respondents stated that the issue would directly affect him. Two years later, the situation looks even worse: only the 11.5% of the respondents are hired on a permanent contract, while there is a very high percentage (74.8%) of atypical contracts, with even some coordinators who say they have been working for several months as unpaid volunteers. It is interesting to note that over 30% of staff with atypical contracts work in research institutes and research-related scientific societies, with a strong interest in non-profit clinical research. Adopt Clinical Trials Units officially and contractually recognized would be essential to bring back our nation on the top of the world health systems ranking, but yet the Italian research-dedicated infrastructures continue to be a ghost reality, deeply characterized by a continuous professional turnover and by the lack of long-term prospects. In the absence of a permanent solution, Italy is unlikely to reach the required standards, denying patients of possible therapeutic available options. Our non-profit research will pay the most for it.

Inflammatory Biomarkers as Predictors of Response to Immunotherapy in Urological Tumors.

Immunotherapy represents the new era of cancer treatment because of its promising results in various cancer types. In urological tumors, the use of the immune-checkpoint inhibitors (ICIs) is increasingly spreading. Although not all patients and not all diseases respond equally well to immunotherapy, there is an increasing need to find predictive markers of response to ICIs. Patient- and tumor-related factors may be involved in primary and secondary resistance to immunotherapy: tumor-derived protein and cytokines, tumor mutational burden, and patient performance status and comorbidities can condition tumor response to ICIs. Recently, some of these factors have been evaluated as potential biomarkers of response, with conflicting results. To date, the expression of programmed death-ligand 1 (PD-L1) and the presence of deficient mismatch repair (dMMR) in tumor tissue are the only biomarkers capable of guiding the clinician's decision in urothelial cancer and prostate cancer, respectively. In this review, we performed a comprehensive search of the main publications on biomarkers that are predictive of response to ICIs in urological cancers. Our aim was to understand whether existing data have the potential to drive clinical decision-making in the near future.

AR Copy Number and AR Signaling-directed Therapies in Castrationresistant Prostate Cancer.

BACKGROUND: Adaptive upregulation of Androgen Receptor (AR) is the most common event involved in the progression from hormone sensitive to Castration-Resistant Prostate Cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. OBJECTIVE: In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR Copy Number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. CONCLUSION: Outcomes of CRPC patients are reported to be highly variable as the consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design.

Circulating AR copy number and outcome to enzalutamide in docetaxel-treated metastatic castration-resistant prostate cancer.

In the present study, we aimed to evaluate the association of circulating AR copy number (CN) and outcome in a cohort of patients with advanced castration-resistant prostate cancer (CRPC) treated with enzalutamide after docetaxel. Fifty-nine CRPC patients were evaluated. AR CN was analyzed with real-time and digital PCR in the serum collected at starting of treatment. Progressive disease was defined on the basis of Prostate Cancer Working Group 2 criteria. AR CN gain was found in 21 of 59 (36%) patients. Median baseline PSA, alkaline phosphatase and lactate dehydrogenase levels were higher in the AR CN gained group (p = 0.007, p = 0.003, p = 0.0009, respectively). Median PFS of patients with AR CN gain was 2.4 (95%CI: 1.9-3.2) vs. 4.0 months (95%CI: 3.0-6.5) of those with no gain (p = 0.0004). Median OS of patients with AR CN gain was 6.1 (95%CI: 3.4-8.6) vs. 14.1 months (95%CI: 8.2-20.5) of those with no gain (p = 0.0003). At multivariate analysis, PSA decline ≥ 50% and AR CN showed a significant association with PFS (p = 0.008 and p = 0.002, respectively) and OS (p = 0.009 and p = 0.001, respectively). These findings indicate that the detection of circulating AR CN gain is a promising non-invasive biomarker for outcome prediction to enzalutamide treatment in CRPC patients.