Comparison of automated versus semi-automated whole blood processing systems: A systematic review.

BACKGROUND AND OBJECTIVES: Implementation of automated steps in preparing blood components for transfusion from whole blood collections has produced improvements in multiple fields. The aim of this review is to summarize data from existing literature related to automation of whole blood processing systems. MATERIALS AND METHODS: We searched MEDLINE for studies comparing semi-automated and fully automated whole blood processing systems published before 20 July 2021. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Additionally, we performed a manual search. RESULTS: We identified 500 studies, of which 459 (92%) did not meet the eligibility criteria, and finally 17 studies were included in the analysis. Manual search included six additional studies. Publication year ranged from 2004 to 2021. Automation reduced the run-time (from 92 to 76 min), improved recovery of haemoglobin in red cell concentrates (RCCs) and resulted in higher red blood cell and platelet yields. Automation also reduced discard rates due to whole blood bag ruptures (1.2%-0.1%), low volume of RCCs (<200 ml; 0.5%-0.03%) and haemolytic plasma (2.1%-0.6%). Automation could reduce the number of full-time equivalent (FTE) operators or maintain the number of FTE operators while performing additional procedures, and it reduced to 1.13 m2 the space required for the device. CONCLUSION: Automation of whole blood processing resulted in continued improvements in productivity, product quality and technical features. However, too few publications are available to reach strong conclusions. Therefore, it is necessary to expand the scientific knowledge in this field.

Novel retinoic acid 4-hydroxylase (CYP26) inhibitors based on a 3-(1H-imidazol- and triazol-1-yl)-2,2-dimethyl-3-(4-(phenylamino)phenyl)propyl scaffold.

Retinoic acid (RA), the biologically active metabolite of vitamin A, is used medicinally for the treatment of hyperproliferative diseases including dermatological conditions and cancer. The antiproliferative effects of RA have been well documented as well as the limitations owing to toxicity and the development of resistance to RA therapy. RA metabolism inhibitors (RAMBAs or CYP26 inhibitors) are attracting increasing interest as an alternative method for enhancing endogenous levels of retinoic acid in the treatment of hyperproliferative disease. Here the synthesis and inhibitory activity of novel 3-(1H-imidazol- and triazol-1-yl)-2,2-dimethyl-3-(4-(phenylamino)phenyl)propyl derivatives in a MCF-7 CYP26A1 microsomal assay are described. The most promising inhibitor methyl 2,2-dimethyl-3-(4-(phenylamino)phenyl)-3-(1H-1,2,4-triazol-1-yl)propanoate (6) exhibited an IC(50) of 13 nM (compared with standards Liarozole IC(50) 540 nM and R116010 IC(50) 10 nM) and was further evaluated for CYP selectivity using a panel of CYP with >100-fold selectivity for CYP26 compared with CYP1A2, 2C9 and 2D6 observed and 15-fold selectivity compared with CYP3A4. The results demonstrate the potential for further development of these potent inhibitors.

Synthesis and CYP26A1 inhibitory activity of novel methyl 3-[4-(arylamino)phenyl]-3-(azole)-2,2-dimethylpropanoates.

The role of all-trans-retinoic acid (ATRA) in the development and maintenance of many epithelial and neural tissues has raised great interest in the potential of ATRA and related compounds (retinoids) as pharmacological agents, particularly for the treatment of cancer, skin, neurodegenerative and autoimmune diseases. The use of ATRA or prodrugs as pharmacological agents is limited by a short half-life in vivo resulting from the activity of specific ATRA hydroxylases, CYP26 enzymes, induced by ATRA in liver and target tissues. For this reason retinoic acid metabolism blocking agents (RAMBAs) have been developed for treating cancer and a wide range of other diseases. The synthesis, CYP26A1 inhibitory activity and molecular modeling studies of novel methyl 3-[4-(arylamino)phenyl]-3-(azole)-2,2-dimethylpropanoates are presented. From this series of compounds clear SAR can be derived for 4-substitution of the phenyl ring with electron-donating groups more favourable for inhibitory activity. Both the methylenedioxyphenyl imidazole (17, IC(50) = 8 nM) and triazole (18, IC(50) = 6.7 nM) derivatives were potent inhibitors with additional binding interactions between the methylenedioxy moiety and the CYP26 active site likely to be the main factor. The 6-bromo-3-pyridine imidazole 15 (IC(50) = 5.7 nM) was the most active from this series compared with the standards liarozole (IC(50) = 540 nM) and R116010 (IC(50) = 10 nM).

Novel micelles based on amphiphilic branched PEG as carriers for fenretinide.

This study reports on the preparation and evaluation of amphiphilic macromolecules based on branched polyethylene glycol covalently linked with alkyl hydrocarbon chains. These macromolecules easily dissolved in an aqueous environment, with formation of micellar nanoaggregates endowed with hydrophobic inner cores capable of hosting fenretinide by complexation. The complexes increased fenretinide aqueous solubility, while hindering its release as a free drug in an aqueous environment. Particle size analysis indicated dimensional suitability of the complexes for intravenous administration. Neuroblastoma cell lines (SH-SY5Y and NGP) exhibited increased sensitivity to fenretinide in complex as compared to free drug, associated with higher intracellular concentrations of fenretinide observed after treatment with the complex. Transmission electronic microscopy images revealed endocytosis of the micellar complex. Moreover, fenretinide conversion to its metabolite 4-oxo-fenretinide was delayed in cells treated with the complex, further supporting the hypothesis that fenretinide may be absorbed by micellar transport and exposed to the cytoplasm for conversion to its metabolite only after micelle destabilization.

Role of UDP-glucuronosyltransferase isoforms in 13-cis retinoic acid metabolism in humans.

13-cis Retinoic acid (13cisRA, isotretinoin) is an important drug in both dermatology, and the treatment of high-risk neuroblastoma. 13cisRA is known to undergo cytochrome P450-mediated oxidation, mainly by CYP2C8, but phase II metabolic pathways have not been characterized. In the present study, the glucuronidation activities of human liver (HLM) and intestinal microsomes (HIM), as well as a panel of human UDP-glucuronosyltransferases (UGTs) toward both 13cisRA and the 4-oxo metabolite, 4-oxo 13cisRA, were compared using high-performance liquid chromatography. Both HLM and, to a greater extent, HIM catalyzed the glucuronidation of 13cisRA and 4-oxo 13cisRA. Based on the structures of 13cisRA and 4-oxo 13cisRA, the glucuronides formed are conjugated at the terminal carboxylic acid. Further analysis revealed that UGT1A1, UGT1A3, UGT1A7, UGT1A8, and UGT1A9 were the major isoforms responsible for the glucuronidation of both substrates. For 13cisRA, a pronounced substrate inhibition was observed with individual UGTs and with HIM. UGT1A3 exhibited the highest rate of activity toward both substrates, and a high rate of activity toward 13cisRA glucuronidation was also observed with UGT1A7. However, for both substrates, K(m) values were above concentrations reported in clinical studies. Therefore, UGT1A9 is likely to be the most important enzyme in the glucuronidation of both substrates as this enzyme had the lowest K(m) and is expressed in both the intestine and at high levels in the liver.

Men with prostate cancer over the first year of illness: their experiences as biographical disruption.

GOALS: This paper is one of five interrelated papers about cancer, drawn from a larger study exploring the experiences of 66 people diagnosed with cancer. Findings are reported separately because the way in which people experience cancer can vary by cancer type. Here, we determine the utility of liminality and biographical disruption as explanatory theories in relation to men's experiences of prostate cancer. We situate and explore notions of liminality and disruption in relation to self, identity and context to inform debate about the provision of supportive care and highlight the contribution this study makes to the understandings of men's health. MATERIALS AND METHODS: This is a qualitative interview study of 66 people diagnosed with cancer. The study included five cancer types: gynaecological, prostate, lung, breast and colorectal. This paper illustrates the experiences of ten men diagnosed with prostate cancer. Three serial interviews were conducted at (1) diagnosis, (2) treatment and (3) follow-up. Drawing on the constant comparative method (Glaser and Strauss 1967), a descriptive and thematic approach to data analysis was adopted. This descriptive analysis evidenced that cancer caused disruption to people's lives. In order to move beyond this level of description, begin to explain this and develop theoretical insight, we drew on concepts of biographical disruption (Bury, Sociol Health Illn 4(2):167-182, 1982; Bury, Sociol Health Illn 13(4):451-468, 1991; Bury, Sociol Health Illn 23(3):263-285, 2001) and liminality (Navon and Morag, Soc Sci Med 58(11):2337-2347, 2004). MAIN RESULTS: Notions of biography and identity weave their way through men's accounts of prostate cancer. Physical side effects and reconstructed futures each form key parts of men's narratives. CONCLUSIONS: Our findings add to existing knowledge of supportive care needs for men living with prostate cancer. We suggest that studies exploring supportive care need to remain mindful of the disruption that cancer causes both during and after treatment, the complexity of such experience and respective demands on supportive care.

Transitional experiences of women with breast cancer within the first year following diagnosis.

AIMS AND OBJECTIVES: To explore the experiences of 12 women with breast cancer, involved in a large longitudinal qualitative study designed to explore the experiences of people with cancer within the first year following diagnosis. BACKGROUND: To understand experiences of breast cancer further as a chronic illness, this study draws on biographically informed and embodied perspectives of chronic illness. DESIGN: Qualitative, longitudinal study. METHOD: Interviews were conducted at three time-points within the first year following diagnosis with 12 women with breast cancer. Drawing on the constant comparative method, a descriptive and thematic approach to data analysis was adopted. To move beyond the descriptive level, we drew on the concepts of biographical disruption and embodiment to further explore and explain the disruption that was evident in these women's lives as a result of their diagnosis. RESULTS: Two key concepts emerged from the data: 'Identity Transition: moving between health and illness' and 'Making the Transition to the Future? Living with breast cancer and moving on'. Identity transition emerged as a result of the changes and adaptations participants were required to make as a result of their diagnosis. Making the transition to the future emerged as a result of the challenges these women faced living with cancer. CONCLUSIONS: This study showed that the longitudinal exploration of the experiences of cancer within the first year following diagnosis provides a vital understanding of the impact cancer can have on one's identity from the moment of diagnosis onwards. RELEVANCE TO CLINICAL PRACTICE: This study has implications for cancer services because it highlights the need for interventions that support people to both successfully manage the experience of cancer diagnosis and treatment and equip themselves with the necessary techniques to negotiate transitions towards the future and living with cancer.

Treatment decision-making in cancer care: the role of the carer.

AIMS AND OBJECTIVES: This study explores the role of the carer in treatment decision-making in cancer care. BACKGROUND: Literature about involvement in treatment decision-making tends to focus on patients and clinicians, with the carer rarely included. The absence of carers is problematic because the management of illness is often carried out in the context of complex networks of relationships. Although current policy encourages health care practitioners to work in partnership with family members, implementation is troubled by a lack of understanding of the significance of interpersonal relationships and interactions and the role of the relationship throughout the course of the illness experience. Despite awareness, there is little systematic, coherent analysis of the complexity of these interactional dynamics and, in particular, consideration of the implications for involvement and treatment decision-making. DESIGN: Qualitative, longitudinal. METHODS: Three serial semi-structured interviews with 66 patients and 43 carers within the first year following a diagnosis of cancer. A descriptive and thematic approach to data analysis was adopted. RESULTS: Carers are involved in treatment decision-making in cancer care and contribute to the involvement of patients through their actions during, before and after consultations with clinicians. Carers can act as conduits for information from patient to clinician and from clinician to patient. They can also act as facilitators during deliberations, helping patients to consider whether to have treatment or not and which treatment. CONCLUSIONS: Our study has highlighted the deficiency of models that fail to acknowledge the role of the carer in the treatment decision-making process. We propose the adoption of a relational approach by the inclusion of the carer in conceptual frameworks and recommend triadic (patient, carer and professional) models of involvement. RELEVANCE TO CLINICAL PRACTICE: Cancer care clinicians should recognise and actively involve the carer as well as the patient in treatment decision-making.

The use of technology in cancer care: applying Foucault's ideas to explore the changing dynamics of power in health care.

AIM: This study is a report to identify the utility of a hand-held side-effect monitoring system for people receiving chemotherapy in the home care setting. BACKGROUND: Increasingly, health care is being provided in people's own homes and communities rather than in hospitals. This has driven the development of technologies which support patients in the home environment. The meaning of such technologies can be explored from a Foucauldian perspective to shed light on how they enable new forms of medical surveillance. METHOD: An intervention study was performed in 2006 using new technologies for people receiving chemotherapy. Questionnaires were completed by 56 people affected by cancer who used the new technology; 12 of these people were then interviewed. Secondary analysis of the interview data is presented in this paper, drawing on Foucault's writing about surveillance and power in medical settings. FINDINGS: The interview transcripts contain numerous examples of people affected by cancer reflecting on issues such as power and surveillance in cancer care. While these terms are ordinarily considered to reflect negative elements of care, they were used by participants in an empowering manner. CONCLUSION: Theoretical insights can help nurses to think critically about the advances of technology. In particular, there are implications for how nurses consider the relationship of technology to patients and for power dynamics in healthcare relationships. We suggest that there is a need to problematize and celebrate the growth of technologically-driven health surveillance.

Effect of Processing Delay and Storage Conditions on Urine Albumin-to-Creatinine Ratio.

BACKGROUND AND OBJECTIVES: Because there is substantial biologic intraindividual variation in albumin excretion, randomized trials of albuminuria-reducing therapies may need multiple urine samples to estimate daily urinary albumin excretion. Mailing spot urine samples could offer a convenient and cost-effective method to collect multiple samples, but urine albumin-to-creatinine ratio stability in samples stored at ambient temperatures for several days is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with kidney disease provided fresh urine samples in two tubes (with and without boric acid preservative). Reference aliquots from each participant were analyzed immediately, whereas remaining aliquots were subject to different handling/storage conditions before analysis, including delayed processing for up to 7 days at three different storage temperatures (4°C, 18°C, and 30°C), multiple freeze-thaw cycles, and long-term frozen storage at -80°C, -40°C, and -20°C. We calculated the mean percentage change in urine albumin-to-creatinine ratio for each condition, and we considered samples stable if the 95% confidence interval was within a ±5% threshold. RESULTS: Ninety-three patients provided samples with detectable albuminuria in the reference aliquot. Median (interquartile range) urine albumin-to-creatinine ratio was 87 (20-499) mg/g. The inclusion of preservative had minimal effect on fresh urine albumin-to-creatinine ratio measurements but reduced the changes in albumin and creatinine in samples subject to processing delay and storage conditions. The urine albumin-to-creatinine ratio was stable for 7 days in samples containing preservative at 4°C and 18°C and 2 days when stored at 30°C. It was also stable in samples with preservative after three freeze-thaw cycles and in frozen storage for 6 months at -80°C or -40°C but not at -20°C. CONCLUSIONS: Mailed urine samples collected with preservative and received within 7 days if ambient temperature is ≤18°C, or within 2 days if the temperature is higher but does not exceed 30°C, are suitable for the measurement of urine albumin-to-creatinine ratio in randomized trials. Preserved samples frozen to -40°C or -80°C for 6 months before analysis also seem suitable.

Adaptive dosing approaches to the individualization of 13-cis-retinoic acid (isotretinoin) treatment for children with high-risk neuroblastoma.

PURPOSE: To investigate the feasibility of adaptive dosing and the impact of pharmacogenetic variation on 13-cis-retinoic acid (13-cisRA) disposition in high-risk patients with neuroblastoma. EXPERIMENTAL DESIGN: 13-cisRA (160 mg/m(2) or 5.33 mg/kg/d) was administered to 103 patients ages 21 years or less and plasma concentrations of 13-cisRA and 4-oxo-13-cisRA quantitated on day 14 of treatment. Seventy-one patients were recruited to a dose adjustment group, targeting a 13-cisRA C(max) of 2 µmol/L, with dose increases of 25% to 50% implemented for patients with C(max) values less than 2 µmol/L. A population pharmacokinetic model was applied and polymorphisms in relevant cytochrome P450 genes analyzed. RESULTS: 13-cisRA C(max) values ranged from 0.42 to 11.2 µmol/L, with 34 of 103 (33%) patients failing to achieve a C(max) more than 2 µmol/L. Dose increases carried out in 20 patients in the dose adjustment study group led to concentrations more than 2 µmol/L in 18 patients (90%). Eight of 11 (73%) patients less than 12 kg, receiving a dose of 5.33 mg/kg, failed to achieve a C(max) of 2 µmol/L or more. Significantly, lower C(max) values were observed for patients treated with 5.33 mg/kg versus 160 mg/m(2) (1.9 ± 1.2 vs. 3.1 ± 2.0 µmol/L; mean ± SD; P = 0.023). C(max) was higher in patients who swallowed 13-cisRA capsules as compared with receiving the drug extracted from capsules (4.0 ± 2.2 vs. 2.6 ± 1.8 µmol/L; P = 0.0012). The target C(max) was achieved by 93% (25/27) versus 55% (42/76) of patients in these 2 groups, respectively. No clear relationships were found between genetic variants and 13-cisRA pharmacokinetic parameters. CONCLUSIONS: Dosing regimen and method of administration have a marked influence on 13-cisRA plasma concentrations. Body weight-based dosing should not be implemented for children less than 12 kg and pharmacologic data support higher doses for children unable to swallow 13-cisRA capsules.

Antitumor activity of a duocarmycin analogue rationalized to be metabolically activated by cytochrome P450 1A1 in human transitional cell carcinoma of the bladder.

We identify cytochrome P450 1A1 (CYP1A1) as a target for tumor-selective drug development in bladder cancer and describe the characterization of ICT2700, designed to be metabolized from a prodrug to a potent cytotoxin selectively by CYP1A1. Elevated CYP1A1 expression was shown in human bladder cancer relative to normal human tissues. RT112 bladder cancer cells, endogenously expressing CYP1A1, were selectively chemosensitive to ICT2700, whereas EJ138 bladder cells that do not express CYP1A1 were significantly less responsive. Introduction of CYP1A1 into EJ138 cells resulted in 75-fold increased chemosensitivity to ICT2700 relative to wild-type EJ138. Negligible chemosensitivity was observed in ICT2700 in EJ138 cells expressing CYP1A2 or with exposure of EJ138 cells to CYP1B1- or CYP3A4-generated metabolites of ICT2700. Chemosensitivity to ICT2700 was also negated in EJ138-CYP1A1 cells by the CYP1 inhibitor α-naphthoflavone. Furthermore, ICT2700 did not induce expression of the AhR-regulated CYP1 family, indicating that constitutive CYP1A1 expression is sufficient for activation of ICT2700. Consistent with the selective activity by CYP1A1 was a time and concentration-dependent increase in γ-H2AX protein expression, indicative of DNA damage, associated with the activation of ICT2700 in RT112 but not EJ138 cells. In mice-bearing CYP1A1-positive and negative isogenic tumors, ICT2700 administration resulted in an antitumor response only in the CYP1A1-expressing tumor model. This antitumor response was associated with detection of the CYP1A1-activated metabolite in tumors but not in the liver. Our findings support the further development of ICT2700 as a tumor-selective treatment for human bladder cancers.

Re-engineering of the duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity.

A library of duocarmycin bioprecursors based on the CPI and CBI scaffolds was synthesized and used to probe selective activation by cells expressing CYP1A1 and 2W1, CYPs known to be expressed in high frequency in some tumors. Several CPI-based compounds were pM-nM potent in CYP1A1 expressing cells. CYP2W1 was also shown to sensitize proliferating cells to several compounds, demonstrating its potential as a target for tumor selective activation of duocarmycin bioprecursors.

The impact of retinoic acid treatment on the sensitivity of neuroblastoma cells to fenretinide.

Despite the successful introduction of 13-cis retinoic acid (13cisRA) therapy for the treatment of neuroblastoma, approximately 50% patients do not respond or experience relapse. A retinoid analogue, fenretinide [N-(4-hydroxyphenyl) retinamide; 4-HPR] can induce apoptosis in neuroblastoma cell lines and could have clinical use after therapy with 13cisRA. However, there are important questions concerning potential retinoid drug interactions which need to be addressed. The aim of this study was to investigate the influence of retinoic acid pre-treatment on fenretinide-induced apoptosis and fenretinide metabolism in neuroblastoma cell lines. Apoptosis was measured by flow cytometry of propidium iodide-stained neuroblastoma cells and a live-cell imaging assay. Intracellular fenretinide metabolism was determined by HPLC analysis. Pre-treatment of neuroblastoma cell lines with retinoic acid (RA) resulted in a significant decrease in the apoptotic response to fenretinide in three of the four lines tested. Comparison between responsive and non-responsive cell lines suggested that RA sensitivity was required to promote fenretinide resistance, and that this was mediated by up-regulation of Bcl-2 and the inhibition of pro-apoptotic fenretinide signalling pathways. Induction of the oxidative metabolism of fenretinide after RA pre-treatment did not significantly impact on intracellular parent drug levels and is unlikely to explain the decreased apoptotic response observed. The interaction between RA and fenretinide could have important implications for the scheduling of fenretinide in therapeutic protocols for neuroblastoma.

The importance of relationships in the experience of cancer: a re-working of the policy ideal of the whole-systems approach.

PURPOSE OF THE RESEARCH: This paper outlines the importance of interpersonal familial relationships in how people experience cancer. METHODS AND SAMPLE: This paper draws on data from a longitudinal, qualitative study which aimed to explore the experiences of people with cancer within the first year following diagnosis. The sample included fifteen men with colorectal cancer, 3 women with colorectal cancer, twelve women with breast cancer, nine women with gynaecological cancer, six women with lung cancer, eleven men with lung cancer and ten men with prostate cancer. Four people died during the course of the study and ten people chose to withdraw. KEY RESULTS: Close interpersonal relationships were clearly core mediating features in how the illness was experienced; for example, presenting for symptom investigation was often the result of ongoing interaction and debate between partners. We use the idea of the 'joint ownership of cancer' to elucidate the role of relationships in experiencing and understanding the disease. We propose a re-working of the notion of a whole-systems approach to include not just partnership working within health and social care agencies, but centralising the patient's interpersonal relationships as critical in each aspect of their experience of cancer. CONCLUSIONS: The findings are discussed in terms of the need for service delivery and research to be mindful of the relational aspects and implications of illness. Nurses can play a key role in how this is operationalised in supporting people affected by cancer in the context of their relationships.