Recycling Apparent Waste Into Biologicals: The Case of Umbilical Cord Blood in Italy and Spain

Most public cord blood banking programs are currently facing financial difficulties due to a progressive decline in the number of cord blood transplants performed worldwide and to a high discard rate of the donated units caused by progressively increasing thresholds of the stem cell dose required to perform safe and effective hemopoietic cord blood transplants. Recycling a proportion of unused cord blood units to prepare novel cord blood components obtained with minimal manipulation (platelets, plasma, red blood cells) and to develop more technologically complex products regulated in the US as Cellular and Gene Therapy Products and in Europe as Advanced Therapy Medicinal Products [e.g. virus-specific T cells (VST), natural killer (NK) cells, induced pluripotent stem cells (iPSCs) is a promising strategy to increase the therapeutic value and reduce the financial deficits of public cord blood banking. Based on encouraging preliminary evidences reported in the literature, additional laboratory studies, large multicenter clinical trials and international regulatory harmonization are necessary to achieve these important goals. This article describes organizational, methodological and regulatory advancements developed in Italy and Spain to promote the clinical use of cord blood platelets, plasma and red blood cells.

Vendor-neutral sequences (VENUS) and fully transparent workflows improve inter-vendor reproducibility of quantitative MRI

Purpose: We developed a transparent end-to-end qMRI workflow that starts with a vendor-neutral acquisition and tested the hypothesis that vendor-neutral sequences (VENUS) decrease inter-vendor variability of T1, MTR and MTsat measurements. Methods: We developed and deployed a vendor-neutral 3D spoiled gradient-echo (SPGR) sequence on three clinical scanners by two MRI vendors and acquired T1 maps on the NIST phantom, as well as T1, MTR and MTsat maps in three healthy participants. We performed hierarchical shift function analysis in vivo to characterize the differences between scanners when VENUS is used instead of commercial vendor implementations. Inter-vendor deviations were compared for statistical significance to test the hypothesis. Results: In the NIST phantom, VENUS reduced inter-vendor differences from 8 - 19.4% to 0.2 - 5% with an overall accuracy improvement, reducing ground truth T1 deviation from 7 - 11% to 0.2 - 4%. In vivo we found that the variability between vendors is significantly reduced (p = 0.015) for all maps (T1, MTR and MTsat) using VENUS. Conclusion: We conclude that vendor-neutral workflows are feasible and compatible with clinical MRI scanners. The significant reduction of inter-vendor variability using VENUS has important implications for qMRI research and for the reliability of multicenter clinical trials.

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.

Streptomyces sp.—A Treasure Trove of Weapons to Combat Methicillin-Resistant Staphylococcus aureus Biofilm Associated with Biomedical Devices

Biofilms formed by methicillin-resistant S. aureus (MRSA) are among the most frequent causes of biomedical device-related infection, which are difficult to treat and are often persistent and recurrent. Thus, new and effective antibiofilm agents are urgently needed. In this article, we review the most relevant literature of the recent years reporting on promising anti-MRSA biofilm agents derived from the genus Streptomyces bacteria, and discuss the potential contribution of these newly reported antibiofilm compounds to the current strategies in preventing biofilm formation and eradicating pre-existing biofilms of the clinically important pathogen MRSA. Many efforts are evidenced to address biofilm-related infections, and some novel strategies have been developed and demonstrated encouraging results in preclinical studies. Nevertheless, more in vivo studies with appropriate biofilm models and well-designed multicenter clinical trials are needed to assess the prospects of these strategies.

Therapeutic aspects of melatonin applications

The results of multicenter clinical trials show the broad potential of melatonin since discovery of this adaptogen to the present day. Melatonin is a neuropeptide that is synthesized mainly in the small brain gland, the pineal gland, and has a unique effect in humans and animals. Using melatonin, the pineal gland participates in the organization of circadian periodism and regulation of cyclic processes, acting as an intermediary between the pacemaker mechanism of the suprachiasmatic nuclei (SCN) and peripheral organs. The pineal gland and the SCN of the hypothalamus form part of the system of the so-called biological clock of the body, which plays a key role in the mechanisms of regulation of the biological clock via circadian rhythms and ageing. Initially, melatonin was only considered a hormone involved in the synchronization of the mechanisms of the circadian rhythm, but later it was found that, in addition to this hormonal function, it takes part in the regulation of the seasonal cycle in animals and humans.At present, melatonin drugs have shown high efficacy and safety in various sleep-wake disorders regardless of their genesis, disorganization of circadian rhythms, stress adjustment disorders, rapid change of time zones, shift work and in complex therapy of patients with cerebrovascular diseases.The article considers the multimodal capabilities of melatonin, including adaptogenic, biorhythmogenic, hypnotic, immunostimu-lating, antioxidant effects. The role of melatonin in the treatment of various central nervous system disorders, including neurodegenerative diseases, has been determined.The review emphasizes the wide-ranging effects of melatonin and offers great opportunities for measuring melatonin as a biomarker for early detection and follow-up of various diseases.

Pathophysiology and Biomarkers for Breast Cancer: Management using Herbal Medicines

Aim: The objective of the current manuscript is to discuss various types of cancers of breast, pathophysiology, and biomarkers used for breast cancer and potential applications of herbal remedies as a treatment tool. Methods: Literature survey was carried out using various online search engines like google scholar, ScienceDirect, Springer, Scopus, PubMed, etc. Offline libraries were also used for the compilation of data. Result and discussion: The second ground for disease casualties in females is breast cancer. The complexity of this disorder resembles a complicated environment containing varying layers of internal and external influences that are cleverly engineered for interaction to create a pliable background for the clonal progress of breast cancer cells. Biomarkers that can identify the most successful treatments or assess the reaction to therapy early in the process of treatment are useful. The possible benefits of imaging biomarkers are evident, and initial clinical results have been positive. Herbal medicines establish to be successful against the disease. Conclusion: It can be accomplished in the complete study that breast cancer is mainly universal and lethal cancer of females. Herbal medicines are widely distributed, biocompatible, biodegradable, and have the potential to treat breast cancer. Furthermore, Multicenter clinical trials are still needed for evidence of the clinical usefulness of herbal medicines.

A nationwide evaluation of the prevalence of human papillomavirus in Brazil (POP-Brazil study): protocol of data quality assurance and control (Preprint)

BACKGROUND The credibility of a study and its internal and external validity depend crucially on the quality of the data produced. Quality control aims to monitor sampling errors and measurements during the execution of a study and is based mainly on two pillars: planning and standardization of procedures. OBJECTIVE The present article aimed to describe the stages of quality control in the POP-Brazil study and to present an analysis of the quality indicators. METHODS Quality assurance and control included several phases and processes that were initiated with the planning of the study and continued through the development of the project; thus, all centers were trained in loco. RESULTS The data were through a structured questionnaire and collection of biological samples, both performed by more than 250 trained and certified health professionals. Furthermore, to correct possible inadequacies, all 119 centers (public health units) received at least one monitoring visit, which evaluated the professionals' performance and the process of completing the online data platform. The data were monitored daily and were audited through the double entry of data, performed by the central team. The reliability of data was analyzed through the test-retest method, comparing data from the online platform and a second application of the interview, and conducted through telephone, also by the central team. The agreement between the test and retest was considered good (kappa between 0.59 and 0.74). Large multicenter clinical trials are the basis of medical evidence-based and health-based prevention, so their design, logistics, and quality processes should always be carefully considered. CONCLUSIONS This article presents the processes and quality indicators in the POP-Brazil study that allow other studies to generate reliable data.

APERITIF – Automatic Patient Recruiting for Clinical Trials Based on HL7 FHIR

Clinical trials are carried out to prove the safety and effectiveness of new interventions and therapies. As diseases and their causes continue to become more specific, so do inclusion and exclusion criteria for trials. Patient recruitment has always been a challenge, but with medical progress, it becomes increasingly difficult to achieve the necessary number of cases. In Germany, the Medical Informatics Initiative is planning to use the central application and registration office to conduct feasibility analyses at an early stage and thus to identify suitable project partners. This approach aims to technically adapt/integrate the envisioned infrastructure in such a way that it can be used for trial case number estimation for the planning of multicenter clinical trials. We have developed a fully automated solution called APERITIF that can identify the number of eligible patients based on free-text eligibility criteria, taking into account the MII core data set and based on the FHIR standard. The evaluation showed a precision of 62.64 % for inclusion criteria and a precision of 66.45 % for exclusion criteria.