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Radiomics is a promising tool for the development of quantitative biomarkers to support clinical decision-making. It has been shown to improve the prediction of response to treatment and outcome in different settings, particularly in the field of radiation oncology by optimising the dose delivery solutions and reducing the rate of radiation-induced side effects, leading to a fully personalised approach. Despite the promising results offered by radiomics at each of these stages, standardised methodologies, reproducibility and interpretability of results are still lacking, limiting the potential clinical impact of these tools. In this review, we briefly describe the principles of radiomics and the most relevant applications of radiomics at each stage of cancer management in the framework of radiation oncology. Furthermore, the integration of radiomics into clinical decision support systems is analysed, defining the challenges and offering possible solutions for translating radiomics into a clinically applicable tool. [ABSTRACT FROM AUTHOR]

Personalised drug delivery enables a tailored treatment plan for each patient compared to conventional drug delivery, where a generic strategy is commonly employed. It can not only achieve precise treatment to improve effectiveness but also reduce the risk of adverse effects to improve patients' quality of life. Drug delivery involves multiple interconnected physiological and physicochemical processes, which span a wide range of time and length scales. How to consider the impact of individual differences on these processes becomes critical. Multiphysics models are an open system that allows well-controlled studies on the individual and combined effects of influencing factors on drug delivery outcomes while accommodating the patient-specific in vivo environment, which is not economically feasible through experimental means. Extensive modelling frameworks have been developed to reveal the underlying mechanisms of drug delivery and optimise effective delivery plans. This review provides an overview of currently available models, their integration with advanced medical imaging modalities, and code packages for personalised drug delivery. The potential to incorporate new technologies (i.e., machine learning) in this field is also addressed for development. [Display omitted] [ABSTRACT FROM AUTHOR]

Personalised medicine is seen as an exciting opportunity to improve the health outcomes of people with obesity. As research on phenotyping and personalised treatment for obesity rapidly advances, this study sought to understand patient preferences and perspectives on personalised medicine for obesity. A participatory world café methodology was used to garner the perspectives of people living with obesity on the potential opportunities and limitations associated with a personalised approach to obesity risk identification and treatment. Data were recorded by participants on tablemats and analysed thematically using thematic analysis. Patients expressed the hope that personalised medicine for obesity would reduce stigma, support understanding of obesity as a disease, and improve treatment outcomes and acceptance. They also expressed concern about the accuracy of personalised medicine for obesity, its implications for insurance and that further advances in individual, personalised medicine, would detract attention from social, environmental, economic and psychological drivers of obesity. This study highlights how patients are generally very optimistic about the potential for personalised obesity medicine but also raise a number of legitimate concerns that will be of interest to clinicians, industry, and policy makers. • Personalised medicine represents the future of obesity treatment and clinical practice and expectations are high for the promise of personalised medicine in preventing and treating subsets of obesity. • This study is the first known study of patient perspectives on personalised medicine for obesity. • Patients hoped personalised obesity medicine will reduce stigma, improve understanding of obesity as a disease, and lead to improved treatment acceptance, adherence and outcomes. • Patients expressed concerns about the accuracy and reliability of personalised medicine for obesity and the implications for life assurance, treatment access, mental health and other drivers of obesity. [ABSTRACT FROM AUTHOR]

• Our results confirm a significant relationship between cumulative tobramycin exposure and changes in hearing acuity. • In pediatric population, ototoxicity is not clinically perceptible. • Thus, hearing tests should be continued during adulthood to provide individualized medical guidance and to obtain a lifetime analysis of the relationship between exposure and hearing loss. Aminoglycosides (AGs), such as tobramycin, are essential antibiotics in the management of pulmonary infections in patients with cystic fibrosis (CF). They induce ototoxicity without the relationship being clearly described in the literature. Our aim is to propose a mathematical and statistical model describing the relationship between the estimated cumulative exposure (Area Under the Curve, AUC) to tobramycin and ototoxicity with audiogram interpretation in young patients with CF. Cumulative AUCs were estimated for each course of tobramycin, for the 106 individuals with CF (between 4 and 22 years of age) enrolled in this retrospective study (35 who had received IV tobramycin, 71 controls). Mean hearing loss was calculated for each audiogram and a statistical model was developed to predict hearing loss. The model confirms a significant relationship between cumulative tobramycin exposure and changes in hearing acuity: Mean hear ing loss = 2.7 + (3 × 10 − 5) × AUC _ tobr amyc in + indi vidu al _ susc epti bili ty However, the ototoxic effect is not clinically perceptible (mean hearing loss: 3.8 dB). The impact of AUC on hearing loss is minor in these subjects who received a limited number of courses of tobramycin (median: 5 courses). A significant relationship between cumulative exposure to tobramycin and ototoxicity was demonstrated. Individual treatment susceptibility should not be overlooked. As ototoxicity is not clinically perceptible in the study subjects, hearing tests should be continued during adulthood to provide individualized medical guidance and to obtain a lifetime analysis of the relationship between exposure and hearing loss. [ABSTRACT FROM AUTHOR]

In this retrospective cohort study of 276 patients with metastatic renal cell carcinoma (mRCC), we demonstrate that higher hemoglobin (Hb) levels prior to, and increases in Hb during systemic therapy predict better outcomes across three established frontline treatments. This study identifies Hb as a promising clinical marker of treatment outcomes in mRCC, of which there have been few to date. Introduction: Clinical markers of response in metastatic renal cell carcinoma (mRCC) are lacking. Low hemoglobin (Hb) is associated with poor outcomes in the IMDC risk score. This study evaluates the role of Hb as a marker of treatment outcomes in mRCC. Patients and Methods: This multicenter retrospective study evaluated 276 patients with mRCC treated with frontline immune checkpoint inhibitor (ICI) therapy, ICI and vascular endothelial growth factor (VEGF) inhibitor (VEGFI) combinations (ICI/VEGFI), or VEGFI monotherapy between 2014 and 2021. Hb levels at baseline, week 6 and 12 and at disease progression or death were recorded. Patients were categorized as responders (CR + PR) or 0.19-0.83, P = .009). Conclusion: Baseline and dynamic changes in Hb are associated with first-line treatment outcomes in patients with mRCC and represent a pragmatic early serological marker. nonresponders (SD + PD) using cross-sectional imaging at week 12. The association between baseline and dynamic changes in Hb and oncological outcomes was assessed. Results: Thirty-seven percent, 40% and 22% of patients received ICIs, ICI/VEGFI and VEGFI respectively. In patients receiving ICIs, there was a significant increase in Hb amongst responders from baseline to week 12 (P = .02). Amongst patients receiving ICI/VEGFI, there was an increase in Hb from baseline to week 12 which was greater in responders (P < .001). In patients receiving VEGFI monotherapy, responders had a higher Hb at baseline (P = .01), week 6 (P = .04), and week 12 (P = .003). An increase in Hb was a significant independent predictor of progression-free survival amongst patients receiving ICIs (HR 0.40, 95%CI. 0.19-0.83, P = .009). Conclusion: Baseline and dynamic changes in Hb are associated with first-line treatment outcomes in patients with mRCC and represent a pragmatic early serological marker. [ABSTRACT FROM AUTHOR]

Cancer screening programmes aim to save lives and reduce cancer burden through prevention or early detection of specific cancers. Risk stratification, where one or more elements of a screening programme are systematically tailored based on multiple individual-level risk factors, could improve the balance of screening benefits and harms and programme efficiency. In this article, we explore the resulting ethical issues and how they impact risk-stratified screening policymaking using Beauchamp and Childress's principles of medical ethics. First, in line with universal screening programme principles, we acknowledge that risk-stratified screening should be introduced only when the expected total benefits outweigh the harms, and where it has a favourable overall impact compared to alternative options. We then discuss how these are difficult to both value and quantify, and that risk models typically perform differently in sub-populations. Second, we consider whether screening is an individual right and whether it is fair to offer more or less intensive screening to some and not others based on personal characteristics. Third, we discuss the need to maintain respect for autonomy, including ensuring informed consent and considering the screening implications for those who cannot or choose not to participate in the risk assessment. In summary, from an ethical perspective, focusing on population-level effectiveness alone is insufficient when planning risk-stratified screening programmes and the range of ethical principles must be considered. • Risk stratification raises ethical issues that must be considered in policymaking. • Beneficence and non-maleficence are hard to quantify and compare across subgroups. • Including certain characteristics in risk assessment can be justified, with caution. • Autonomy necessitates clear communication and informed consent/dissent. [ABSTRACT FROM AUTHOR]

Sequencing of tumour tissue with comprehensive gene panels is increasingly used to guide treatment in precision oncology. Analysis of tumour–normal pairs allows in contrast to tumour-only assessment direct discrimination between somatic and germline alterations, which might have important implications not only for the patients but also their families. We performed tumour normal sequencing with a large gene panel in 1048 patients with advanced cancer to support treatment decision. Sequencing results were correlated with clinical and family data. We identified 156 likely pathogenic or pathogenic (LP/P) germline variants in cancer predisposition genes (CPGs) in 144 cases (13.7%). Of all patients, 8.8% had a LP/P variant in autosomal-dominant cancer predisposition genes (AD-CPGs), most of them being genes with high or moderate penetrance (ATM , BRCA2, CHEK2 and BRCA1). In 48 cases, the P/LP variant matched the expected tumour spectrum. A second variant in tumour tissue was found in 31 patients with AD-CPG variants. Low frequency mutations in either TP53 , ATM or DNMT3A in the normal sample indicated clonal haematopoiesis in five cases. Tumour–normal testing for personalised treatment identifies germline LP/P variants in a relevant proportion of patients with cancer. The majority of them would not have been referred to genetic counselling based on family history. Indirect functional readouts of tumour–normal sequencing can provide novel links between CPGs and unexpected cancers. The interpretation of increasingly complex datasets in precision oncology is challenging and concepts of interdisciplinary personalised cancer prevention are needed to support patients and their families. • Significant amount of relevant germline variants is detected by blood-tumour testing. • Carriers do not always fulfil clinical criteria for cancer predisposition. • Blood–Tumour testing identifies novel links between cancer predisposition genes and cancer types. • Family-specific screening strategies are required when cancer predisposition genes are found in atypical tumours. [ABSTRACT FROM AUTHOR]

Adolescent and young adult (AYA) patients with cancer are poorly recruited to molecularly targeted trials and have not witnessed the advances in cancer treatment and survival seen in other age groups. We report here a pan-European proof-of-concept study to identify actionable alterations in some of the worst prognosis AYA cancers: bone and soft tissue sarcomas. Patients aged 12–29 years with newly diagnosed or recurrent, intermediate or high-grade bone and soft tissue sarcomas were recruited from six European countries. Pathological diagnoses were centrally reviewed. Formalin-fixed tissues were analysed by whole exome sequencing, methylation profiling and RNA sequencing and were discussed in a multidisciplinary, international molecular tumour board. Of 71 patients recruited, 48 (median 20 years, range 12–28) met eligibility criteria. Central pathological review confirmed, modified and re-classified the diagnosis in 41, 3, and 4 cases, respectively. Median turnaround time to discussion at molecular tumour board was 8.4 weeks. whole exome sequencing (n = 48), methylation profiling (n = 44, 85%) and RNA sequencing (n = 24, 50%) led to therapeutic recommendations for 81% patients, including 4 with germ line alterations. The most common were for agents targeted towards tyrosine kinases (n = 20 recommendations), DNA repair (n = 18) and the PI3K/mTOR/AKT pathway (n = 15). Recommendations were generally based on weak evidence such as activity in a different tumour type (n = 68, 61%), reflecting the dearth of relevant molecular clinical trial data in the same tumour type. We demonstrate here that comprehensive molecular profiling of AYA patients' samples is feasible and deliverable in a European programme. • AYA cancers have been neglected by molecular profiling initiatives. • Most AYA sarcomas of adequate sample quality have identifiable actionable mutations. • Clinical evidence to support personalised treatment for AYAs is weak or absent. • International molecular profiling is feasible and necessary to fill research gaps. • More effort is needed to enable AYA patients' access to molecularly focused trials. [ABSTRACT FROM AUTHOR]

3D printing in the pharmaceutical and healthcare settings is expanding rapidly, such as the rapid prototyping of orthotics, dental retainers, drug-loaded implants, and pharmaceutical solid oral dosage forms. Through 3D printing, we have the capability to precisely control dose, release kinetics, and several aesthetic features of dosage forms such as colour, shape, and texture. Additionally, polypills can be created with combinations of medications in one solid dosage form at completely customisable strengths that would be extremely difficult to obtain commercially. As the technology and formulations developed through 3D printing are expanding, the development of new hybrid materials to obtain superior formulations are also gaining momentum. In this review we collate data on the importance of developing hybrid formulations of polymers, drugs and excipients necessary to produce reliable and high-quality 3D printed dosage forms with a special emphasis on fused deposition modelling (FDM). FDM technology is one of the most widely used forms of 3D printing and has demonstrated compatibility with unique polymer-based hybrids to allow for enhanced drug delivery, protection of thermolabile drugs, modifiable release kinetics, and more. The data collated covers different categories of hybrids as well as the methods used to fabricate them, and their respective effects on the properties of 3D printed solid oral dosage forms. Therefore, this review will provide an overview of upcoming and emerging trends in pharmaceutical 3D printing formulation compositions. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: To tailor cardiovascular interventions, the use of three-dimensional (3D), patient-specific phantoms (3DPSP) encompasses patient education, training, simulation, procedure planning, and outcome-prediction.Aim: This systematic review and meta-analysis aims to investigate the current and future perspective of 3D printing for cardiovascular interventions.Methods: We systematically screened articles on Medline and EMBASE reporting the prospective use of 3DPSP in cardiovascular interventions by using combined search terms. Studies that compared intervention time depending on 3DPSP utilisation were included into a meta-analysis.Results: We identified 107 studies that prospectively investigated a total of 814 3DPSP in cardiovascular interventions. Most common settings were congenital heart disease (CHD) (38 articles, 6 comparative studies), left atrial appendage (LAA) occlusion (11 articles, 5 comparative, 1 randomised controlled trial [RCT]), and aortic disease (10 articles). All authors described 3DPSP as helpful in assessing complex anatomic conditions, whereas poor tissue mimicry and the non-consideration of physiological properties were cited as limitations. Compared to controls, meta-analysis of six studies showed a significant reduction of intervention time in LAA occlusion (n=3 studies), and surgery due to CHD (n=3) if 3DPSPs were used (Cohen's d=0.54; 95% confidence interval 0.13 to 0.95; p=0.001), however heterogeneity across studies should be taken into account.Conclusions: 3DPSP are helpful to plan, train, and guide interventions in patients with complex cardiovascular anatomy. Benefits for patients include reduced intervention time with the potential for lower radiation exposure and shorter mechanical ventilation times. More evidence and RCTs including clinical endpoints are needed to warrant adoption of 3DPSP into routine clinical practice. [ABSTRACT FROM AUTHOR]

Quantitative measurement of plasma Epstein–Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients. Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA. The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS. NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing. • PCR-based analysis of plasma EBV DNA has limited sensitivity in predicting recurrences of NPC. • Sequencing analysis of post-treatment plasma EBV DNA improves the sensitivity for both local and distant relapses of NPC. • Sequencing analysis of post-treatment plasma EBV DNA could better stratify the mortality risk of NPC patients than PCR. [ABSTRACT FROM AUTHOR]

The 21-gene assay provides prognostication for estrogen receptor positive, human epidermal growth factor receptor-2 negative (ER+/HER2-) early female breast cancer patients. This signature has not been validated in male breast cancer (MBC). A systematic review and meta-analysis was performed in accordance to the PRISMA guidelines. Retrospective cohort studies comparing 21-gene assay scores in female and MBC were included. Dichotomous variables were pooled as odds ratios (OR) and associated 95% confidence intervals (CI) using the Mantel–Haenszel method. Six studies including 176,338 patients were included (mean age of 63.4 years, range: 33–88). Of these, 1.0% had MBC (1826/176,338) and 99.0% were female patients (174,512/176,338). MBC patients were more likely to have increased tumour stage, nodal involvement, and grade 3 disease (all P < 0.001) In MBC patients, the mean score was 18.8 (range: 11–26) vs. 13.4 (range 0–33) in female patients (P < 0.001). In MBC patients, 22.4% had scores >30 (408/1822) versus 18.3% in female patients (31,852/174,500). In female patients, 52.0% had scores <18 (90,787/174,500) versus 47.8% in MBC (471/1822). Overall, patients with female patients were as likely to have scores <18 (OR: 1.04, 95% CI: 0.94–1.16), scores 18–30 (OR: 1.12, 95% CI: 1.00–1.26) and scores >30 (OR: 0.69, 95% CI: 0.45–1.07) as MBC patients. There are similar anticipated scores for female and MBC undergoing 21-gene expression assay testing for early stage, ER+/HER2-breast cancer. In the absence of stage matching, cautious interpretation of these results is required. Validation of the 21-gene assay in MBC is still required. • Overall, Recurrence Scores (RS) were similar in male and female patients. • RS testing in male breast cancer (MBC) favoured RS > 30 (P < 0.001). • Female patients were more likely to have RS < 18 (P < 0.001). • At meta-analysis, there was no difference in RS among female and MBC patients. • In the absence of matching, cautious interpretation of RS in MBC is required. [ABSTRACT FROM AUTHOR]

• Trifluridine metabolism by the faecal microbiota shows inter-donor variability. • The microbiota biotransforms trifluridine via a multi-route pathway. • Abundance of Clostridium perfringens correlates with the rate of trifluridine metabolism. • Microbiome trifluridine metabolism can be prevented with a molecular decoy. The gut microbiome can metabolise hundreds of drugs, potentially affecting their bioavailability and pharmacological effect. As most gut bacteria reside in the colon, drugs that reach the colon in significant proportions may be most impacted by microbiome metabolism. In this study the anti-colorectal cancer drug trifluridine was used as a model drug for characterising metabolism by the colonic microbiota, identifying correlations between bacterial species and individuals' rates of microbiome drug inactivation, and developing strategies to prevent drug inactivation following targeted colonic delivery. High performance liquid chromatography and ultra-high performance liquid chromatography coupled with high resolution tandem mass spectrometry demonstrated trifluridine's variable and multi-route metabolism by the faecal microbiota sourced from six healthy humans. Here, four drug metabolites were linked to the microbiome for the first time. Metagenomic sequencing of the human microbiota samples revealed their composition, which facilitated prediction of individual donors' microbial trifluridine inactivation. Notably, the abundance of Clostridium perfringens strongly correlated with the extent of trifluridine inactivation by microbiota samples after 2 hours (R2 = 0.8966). Finally, several strategies were trialled for the prevention of microbial trifluridine metabolism. It was shown that uridine, a safe and well-tolerated molecule, significantly reduced the microbiota's metabolism of trifluridine by acting as a competitive enzyme inhibitor. Further, uridine was found to provide prebiotic effects. The findings in this study greatly expand knowledge on trifluridine's interactions with the gut microbiome and provide valuable insights for investigating the microbiome metabolism of other drugs. The results demonstrate how protection strategies could enhance the colonic stability of microbiome-sensitive drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

• Pharmacogenomics is essential for personalized breast cancer treatment, utilizing genetic insights to customize therapy and improve outcomes by understanding genetic variations that influence drug metabolism, response, and toxicity. • Genetic polymorphisms in drug-metabolizing enzymes and transporters significantly affect chemotherapy and targeted therapy pharmacokinetics, impacting treatment efficacy and safety. Biomarkers related to hormone receptor status and mutations are crucial for guiding therapy selection. • Despite advancements in breast cancer pharmacogenomics, further efforts are needed to discover new genetic markers and refine treatment strategies. Future goals should include integrating pharmacogenomic data into clinical practice, enhancing real-time treatment monitoring, and ensuring equitable access to genetic testing through collaborative efforts. Pharmacogenomics has become integral to personalised medicine in breast cancer, utilising genetic insights to customize treatment strategies and enhance patient outcomes. Understanding how genetic variations influence drug metabolism, response, and toxicity is crucial for guiding treatment selection and dosing regimens. Genetic polymorphisms in drug-metabolizing enzymes and transporters significantly impact pharmacokinetic variability, influencing the efficacy and safety of chemotherapy agents and targeted therapies. Biomarkers associated with the hormone receptor status of breast cancer and mutations serve as key determinants of treatment response, aiding in the selection of therapies. Despite substantial progress in understanding the pharmacogenomic landscape of breast cancer, efforts to identify novel genetic markers and refine treatment optimisation strategies are required. Genome-wide association studies and advanced sequencing technologies hold promise for uncovering genetic determinants of drug response variability and elucidating complex pharmacogenomic interactions. The future of pharmacogenomics in breast cancer lies in real-time treatment monitoring, the discovery of additional predictive markers, and the seamless integration of pharmacogenomic data into clinical decision-making processes. However, translating pharmacogenomic discoveries into routine clinical practice requires collaborative efforts among stakeholders to address implementation challenges and ensure equitable access to genetic testing. By embracing pharmacogenomics, clinicians can tailor treatment approaches to individual patients, maximizing therapeutic benefits while minimizing adverse effects. This review discusses the integration of pharmacogenomics in breast cancer treatment, highlighting the significance of understanding genetic influences on treatment response and toxicity, and the potential of advanced technologies in refining treatment strategies. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia is now standard of care for neonates with hypoxic-ischemic encephalopathy (HIE) in high income countries (HIC). Conversely, compelling trial evidence suggests that hypothermia is ineffective, and may be deleterious, in low- and middle-income countries (LMIC), likely reflecting the lower proportion of infants who had sentinel events at birth, suggesting that injury had advanced to a stage when hypothermia is no longer effective. Although hypothermia significantly reduced the risk of death and disability in HICs, many infants survived with disability and in principle may benefit from targeted add-on neuroprotective or neurorestorative therapies. The present review will assess biomarkers that could be used to personalize treatment for babies with HIE – to determine first whether an individual infant is likely to respond to hypothermia, and second, whether additional treatments may be beneficial. [ABSTRACT FROM AUTHOR]

• The treatment response could be affected by multiple factors including epigenetic factors. • PCR Array shows difference in lncRNAs expression between Responder and non-Responder patients. • We confirm a decrease of MEG3 expression levels in non-Responder patients compared to Responders. • The variant allele of rs941576 SNV has a potential dose-dependent effect on Disease Activity Index. • MEG3 lncRNA could be a useful genomic biomarker predictor of treatment efficacy in PsA patients. We aimed to identify an expression profile of lncRNAs potentially related to treatment response in Psoriatic arthritis (PsA) patients, to be used as potential genomic biomarkers predictors of drug treatment effectiveness. In addition, we evaluated a possible association between lncRNAs genetic variants and the response to therapy using the clinical parameter of Disease Activity Index. For the expression study, we collected 48 treated PsA patients, monitoring the treatment response for 12 months. We initially used PCR Array and, then, we validated the results with qRT-PCR. We also retrospectively genotyped 163 treated PsA patients. Firstly, we observed a significant difference in the expression level between Responder and non-Responder patients, of 4 lncRNAs in the group of PsA patients treated with TNFi and of 3 lncRNAs in the group of patients treated with IL17i. Then, we confirmed a significant decrease of MEG3 expression in non-Responder patients compared to Responders, also considering separately the single groups of patients treated with TNFi and IL17i. In addition, our results seem to highlight a potential dose-dependent effect of rs941576 (MEG3) variant allele on Disease Activity Index. Our study suggests a possible role of the lncRNA MEG3 in the treatment response to biological drugs. [ABSTRACT FROM AUTHOR]

Angina contributes to significant morbidity worldwide. The evaluation of angina is variable and complicated by multiple factors. The diagnosis is often focussed on epicardial disease despite the knowledge that chest pain can be due to cardiac, non-cardiac, macro, and microvascular causes. Standardised diagnostic pathways and novel approaches to angina assessment may offer the opportunity to improve our understanding of angina and apply a personalised approach to treatment. [ABSTRACT FROM AUTHOR]

We employed a Sendai virus-based reprogramming method to transform human lymphoblastoid cell lines (LCL) derived from two individuals diagnosed with phenylketonuria (PKU) into induced pluripotent stem cells (iPSC). This reprogramming process involved the expression of the four Yamanaka factors: KLF4, OCT4, SOX2, and C-MYC. The resulting patient-specific iPSCs exhibited a normal karyotype and expressed endogenous pluripotent markers NANOG and OCT-4. Notably, these iPSCs demonstrated strong differentiation capabilities, giving rise to cell populations representing the ectoderm, endoderm, and mesoderm germ layers. [ABSTRACT FROM AUTHOR]

Phenylketonuria is a rare autosomal recessive metabolic disorder mainly due to a significant reduction in the enzyme phenylalanine hydroxylase, resulting in elevation of phenylalanine in the blood. Here, we have established two fibroblast-derived induced pluripotent stem cell lines using Sendai virus-based reprogramming. The established induced pluripotent stem cell lines exhibited a normal karyotype and expressed markers of pluripotency assessed through quantitative PCR, flow cytometry and immunocytochemistry. These cell lines also demonstrated the ability to differentiate into the three primary germ layers of the human body, including ectoderm, endoderm, and mesoderm. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and has poor prognosis. There are few biomarkers to inform treatment decisions, and collecting tumour samples for testing is challenging. Circulating tumour cells (CTCs) from patients with PDAC liquid biopsies were expanded ex vivo to form CTC-derived organoid cultures, using a laboratory-developed biomimetic cell culture system. CTC-derived organoids were tested for sensitivity to a PDAC panel of nine drugs, with tests conducted in triplicate, and a weighted cytotoxicity score (CTS) was calculated from the results. Clinical response to treatment in patients was evaluated using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 criteria at the time of blood sampling and 3 months later. The correlation between CTS and clinical response was then assessed. A total of 41 liquid biopsies (87.8% from patients with Stage 4 disease) were collected from 31 patients. The CTC-derived organoid expansion was achieved in 3 weeks, with 87.8% culture efficiency. CTC-derived organoid cultures were positive for EpCAM staining and negative for CD45 staining in the surface marker analysis. All patients had received a median of two lines of treatment prior to enrolment and prospective utility analysis indicated significant correlation of CTS with clinical treatment response. Two representative case studies are also presented to illustrate the relevant clinical contexts. CTCs were expanded from patients with PDAC liquid biopsies with a high success rate. Drug sensitivity profiles from CTC-derived organoid cultures correlated meaningfully with treatment response. Further studies are warranted to validate the predictive potential for this approach. • Circulating tumour cells (CTCs) from patients with pancreatic ductal adenocarcinoma were collected and expanded ex vivo to form organoids. • CTC-derived organoids were tested for sensitivity to a panel of pancreatic ductal adenocarcinoma treatments. • Drug sensitivity results correlated with clinical outcomes in patients. • First study to correlate drug sensitivity results from CTCs with clinical outcomes. • This system can potentially facilitate treatment selection and monitor resistance. [ABSTRACT FROM AUTHOR]

Insights regarding individual patient prognosis may improve exercise therapy by informing patient expectations, promoting exercise adherence, and facilitating tailored care. Therefore, the aim was to develop and evaluate personalised outcomes forecasts for functional claudication distance over six months of supervised exercise therapy for patients with intermittent claudication. Data of 5 940 patients were eligible for analysis. Neighbours based predictions were generated via an adaptation of predictive mean matching. Data from the nearest 223 matches (a.k.a. neighbours) for an index patient were modelled via Generalised Additive Model for Location Scale and Shape (GAMLSS). The realised outcome measures were then evaluated against the GAMLSS model, and the average bias, coverage, and precision were calculated. Model calibration was analysed via within sample and of sample analyses. Neighbours based predictions demonstrated small average bias (– 0.04 standard deviations; ideal = 0) and accurate average coverage (48.7% of realised data within 50% prediction interval; ideal = 50%). Moreover, neighbours based predictions improved prediction precision by 24%, compared with estimates derived from the whole sample. Both within sample and of sample testing showed predictions to be well calibrated. Neighbours based prediction is a method for generating accurate personalised outcomes forecasts for patients with intermittent claudication undertaking supervised exercise therapy. Future work should examine the influence of personalised outcomes forecasts on clinical decisions and patient outcomes. [ABSTRACT FROM AUTHOR]

Clinical diagnostic sequencing of circulating tumour DNA (ctDNA) is well advanced for adult patients, but application to paediatric cancer patients lags behind. To address this, we have developed a clinically relevant (67 gene) NGS capture panel and accompanying workflow that enables sensitive and reliable detection of low-frequency genetic variants in cell-free DNA (cfDNA) from children with solid tumours. We combined gene panel sequencing with low pass whole-genome sequencing of the same library to inform on genome-wide copy number changes in the blood. Analytical validity was evaluated using control materials, and the method was found to be highly sensitive (0.96 for SNVs and 0.97 for INDEL), specific (0.82 for SNVs and 0.978 for INDEL), repeatable (>0.93 [95% CI: 0.89–0.95]) and reproducible (>0.87 [95% CI: 0.87–0.95]). Potential for clinical application was demonstrated in 39 childhood cancer patients with a spectrum of solid tumours in which the single nucleotide variants expected from tumour sequencing were detected in cfDNA in 94.4% (17/18) of cases with active extracranial disease. In 13 patients, where serial samples were available, we show a close correlation between events detected in cfDNA and treatment response, demonstrate that cfDNA analysis could be a useful tool to monitor disease progression, and show cfDNA sequencing has the potential to identify targetable variants that were not detected in tumour samples. This is the first pan-cancer DNA sequencing panel that we know to be optimised for cfDNA in children for blood-based molecular diagnostics in paediatric solid tumours. [Display omitted] • Developed a pan-paediatric solid tumour NGS capture panel for cfDNA profiling. • Method validated to clinical reporting standards. • Simultaneous Copy Number Variation detection by low-pass WGS. • Correlation between ctDNA detection and treatment response. • ctDNA sequencing may identify additional targetable variants. [ABSTRACT FROM AUTHOR]

We study physicians' incentives to use personalised medicine techniques, replicating the physician's trade-offs under the option of personalised medicine information. In a laboratory experiment conducted in two French Universities, prospective physicians played a real-effort game. We vary both the information structure (free access versus paid access to personalised medicine information) and the payment scheme (pay-for-performance (P4P), capitation (CAP) and fee-for-service (FFS)), implementing a within-subject design. Our results are threefold: (i) Compared to FFS and CAP, the P4P scheme strongly and positively impacts the decision to adopt personalised medicine. (ii) Although expected to dominate the other schemes, P4P is not always efficient in transforming free access to personalised medicine into higher quality of care. (iii) When it has to be paid for and after controlling for self-selection, personalised medicine is positively associated with quality, suggesting that subjects tend to make better use of information that comes at a cost. We find this effect to be stronger for males than for females prospective physicians. Quantification of our results however suggests that this positive impact is not strong enough to justify generalising the payment for personalised medicine access. Finally, we develop a theoretical model that includes in its set-up a commitment device component, which is the mechanism that we inferred from the data of the experiment. Our model replicates the principal results of the experiment, reinforcing the interpretation that the higher quality provided by subjects who bought personalised medicine can be interpreted as a commitment device effect. [ABSTRACT FROM AUTHOR]

• Immunosuppression is key for sustained graft survival after renal transplantation. • Optimally balanced immunosuppressive therapy is challenged by PK variability. • MIPD may aid to achieve personalised, effective and safe immunosuppressive therapy. • Various MIPD models are available but their clinical application remains limited. • Harmonised models and informative biomarkers are key to advance personalized dosing. Immunosuppressive therapy is pivotal for sustained allograft and patient survival after renal transplantation. However, optimally balanced immunosuppressive therapy is challenged by between-patient and within-patient pharmacokinetic (PK) variability. This could warrant the application of personalised dosing strategies to optimise individual patient outcomes. Pharmacometrics, the science that investigates the xenobiotic–biotic interplay using computer-aided mathematical modelling, provides options to describe and quantify this PK variability and enables identification of patient characteristics affecting immunosuppressant PK and treatment outcomes. Here, we review and critically appraise the available pharmacometric model-informed dosing solutions for the typical immunosuppressants in modern renal transplantation, to guide their initial and subsequent dosing. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor-2 (HER2) is overexpressed in 20–25% of breast cancers. Complete eradication of disease following neoadjuvant therapies and chemotherapy has been referred to as pathological complete response (pCR). To determine clinicopathological predictors of pCR to neoadjuvant therapies and to evaluate pCR as a surrogate to enhanced survival. Consecutive female patients with HER2 positive (HER+) breast cancer managed surgically in a single institution between 2005 and 2015 were included. Descriptive statistics and binary logistic regression were used to determine predictors of pCR. Appraisal of pCR as a predictor of survival was performed using Kaplan-Meier curves and Cox regression analysis. 451 patients were included with a mean age of 56.6 ± 13.4 years (range 23–95). Disease-free (DFS) and overall survival (OS) was 82.3% (371/451) and 82.6% (376/451) respectively with a median follow-up of 108.0 months (range 3–184.0). 118 were treated in the neoadjuvant setting (26.2%): tumour size <50 mm (Odds Ratio (OR): 12.156, P = 0.023) and progesterone receptor negativity (OR: 2.762, P = 0.008) independently predicted breast pCR, while ductal carcinoma (OR: 3.203, P = 0.030) and grade 3 disease (OR: 2.788, P = 0.018) predicted axillary pCR. Both breast and axillary pCR predicted enhanced DFS (Hazard Ratio (HR): 0.470 & HR: 0.449) and OS (HR: 0.383 & HR: 0.307). Axillary pCR independently predicted improved OS (HR: 0.326). pCR is sensitive biomarker and surrogate to survival outcomes in HER2+ breast cancer. Patients likely to achieve pCR may be predicted from traditional clinicopathological characteristics and molecular parameters. • Clinicopathological data predict patients who achieve pCR in HER2+ breast cancer. • pCR is a sensitive biomarker of survival in HER2 positive breast cancer. • Patients achieving pCR have reduced risk of breast cancer recurrence and mortality. • pCR can aid patient prognostication in the era of personalised medicine. [ABSTRACT FROM AUTHOR]

PEGylated liposomal doxorubicin (PLD, Caelyx®, Doxil®) has been suggested to show significant sex-based differences in plasma clearance, as well as high inter-individual variability that may be driven by monocyte counts in cancer patients. This study aimed to establish if these differences are similarly observed in rats, which exhibit similar liposome clearance mechanisms to humans, and to use this model to identify sources of inter-individual and sex-based pharmacokinetic variability. The plasma and lymphatic pharmacokinetics of PLD were evaluated in male and female rats by quantifying doxorubicin as well as the 3H-labelled liposome. In general, the pharmacokinetics of doxorubicin and the 3H-liposome did not differ significantly between male and female rats when corrected for body surface area. Female rats did, however, show significantly higher doxorubicin concentrations in lymph compared to male rats. With the exception of serum testosterone concentrations in males, none of the physiological parameters evaluated correlated with plasma clearance. Further, reanalysis of published human data that formerly reported sex-differences in PLD plasma clearance similarly revealed no significant differences in PLD plasma clearance between males and females with solid tumours, but increased plasma clearance in patients with Kaposi's sarcoma (generally HIV+/immunocompromised). These data suggest that with the exception of lymphatic exposure, there are unlikely to be significant sex effects in the pharmacokinetics of liposomes, but immune function may contribute to inter individual variability. [Display omitted] • Absence of sex differences in PLD plasma clearance in healthy animals. • No sex differences in human PLD plasma clearance when HIV+ subjects are removed. • Higher lymphatic concentrations of PLD in females compared to males. • Liposome and total doxorubicin pharmacokinetics are similar after intravenous PLD. • Immune function in humans may predict PLD plasma clearanceβ. [ABSTRACT FROM AUTHOR]

There are limited data comparing the OncotypeDX© Recurrence Score (RS) among BRCA mutation carriers and patients with sporadic breast cancer. To compare RS results among BRCA mutation carriers and patients with sporadic breast cancer in oestrogen receptor positive (ER+), human epidermal growth factor receptor-2 negative (HER2−) breast cancer. A systematic review was performed in accordance with PRISMA and MOOSE guidelines. Retrospective cohort studies comparing RS in BRCA mutation carriers and cases of sporadic cancer were included. Dichotomous variables were pooled as odds ratios (ORs) and associated 95% confidence intervals (CIs) using the Mantel–Haenszel method. Five studies involving 4286 patients were included with a mean age of 60 years (range 22–85). Overall, 7.8% were BRCA mutation carriers (333/4286). The mean RS was 18.0 (range 0–71), and the mean RS in BRCA carriers was 25 (range 10–71) versus 18.4 in cases of sporadic disease (range 0–62). Patients with sporadic cancers were more likely to have RS < 18 (OR 0.27, 95% CI 0.14–0.51, P = 0.010). BRCA mutation carriers were more likely to have RS 18–30 (OR 1.74, 95% CI 1.28–2.37, P < 0.001) and RS > 30 (OR 3.71, 95% CI 2.55–5.40, P < 0.001). There is an increased likelihood of high-risk RS among patients with known germline BRCA mutations when compared to patients developing sporadic ER+/HER2-early breast cancer. This study offers insight into genomic testing results within BRCA mutation carriers which may be useful in counselling patients with BRCA mutations in future practice. • BRCA carriers have an increased propensity for high-risk Recurrence Scores (RS). • Mean RS in cases of sporadic disease was RS 18 versus RS 25 in BRCA carriers. • Non-BRCA cancers were more likely to have RS < 18 (odds ratio (OR):0.27). • BRCA carriers were more likely to be RS 18–30 (OR: 1.74) and RS > 30 (OR: 3.71). [ABSTRACT FROM AUTHOR]

OncotypeDX© Recurrence Score (RS) is a multigene panel used to aid therapeutic decision making in early-stage, estrogen receptor positive (ER+)/human epidermal growth factor receptor-2 negative (HER2-) breast cancer. To compare responses to neoadjuvant endocrine therapy (NET) in patients with ER+/HER2-breast cancer following substratification by RS testing. This systematic review was performed in accordance to the PRISMA guidelines. Studies evaluating pathological complete response (pCR), partial response (PR), and successful conversion to breast conservation surgery (BCS) rates following NET guided by RS were retrieved. Dichotomous outcomes were reported as odds ratios (ORs) with 95% confidence intervals (CIs) following estimation by Mantel-Haenszel method. Eight prospective studies involving 691 patients were included. The mean age was 62.6 years (range 25–85) and the mean RS was 14.5 (range 0–68). Patients with RS < 25 (OR: 4.60, 95% CI: 2.53–8.37, P < 0.001) and RS < 30 (OR: 3.40, 95% CI: 1.96–5.91, P < 0.001) were more likely to achieve PR than their counterparts. NET prescription failed to increase BCS conversion rates for patients with RS < 18 (OR: 0.23, 95% CI: 0.04–1.47, P = 0.120) and RS > 30 (OR: 1.27, 95% CI: 0.64–2.49, P = 0.490) respectively. Only 22 patients achieved pCR (2.8%) and RS group failed to predict pCR following NET (P = 0.850). Estimations from this analysis indicate that those with low-intermediate RS on core biopsy are four times more likely to respond to NET than those with high-risk RS. Performing RS testing on diagnostic biopsy may be useful in guiding NET prescription. • Using the 21-gene assay (RS) on core biopsy is useful to guide neoadjuvant therapies. • Low-intermediate RS are four times as likely to respond to endocrine therapies. • Neoadjuvant endocrine therapy (NET) failed to increase breast conservation rates. • Following RS, NET is useful for treating early estrogen receptor positive cancers. [ABSTRACT FROM AUTHOR]

[Display omitted] • Reducing the amount of TPO as low as 0.05% w/w leads to better printability outcomes with the further advantage of reduced costs and lower dose-related toxicity concerns. • The inclusion of high amounts of liquid fillers in photopolymer formulations for SLA 3D printing of medicines should take into account a likely decrease in printing quality of the final dosage form. • Glycerol cannot be used as a liquid filler for PEGDA-based photopolymer resins for SLA 3D printing due to its immiscibility with the photopolymer. Pharmaceutical three-dimensional printing (3DP) is now in its golden age. Recent years have seen a dramatic increase in the research in 3D printed pharmaceuticals due to their potential to deliver highly personalised medicines, thus revolutionising the way medicines are designed, manufactured, and dispensed. A particularly attractive 3DP technology used to manufacture medicines is stereolithography (SLA), which features key advantages in terms of printing resolution and compatibility with thermolabile drugs. Nevertheless, the enthusiasm for pharmaceutical SLA has not been followed by the introduction of novel excipients specifically designed for the fabrication of medicines; hence, the choice of biocompatible polymers and photoinitiators available is limited. This work provides an insight on how to maximise the usefulness of the limited materials available by evaluating how different formulation factors affect printability outcomes of SLA 3D printed medicines. 156 photopolymer formulations were systematically screened to evaluate the influence of factors including photoinitiator amount, photopolymer molecular size, and type and amount of liquid filler on the printability outcomes. Collectively, these factors were found highly influential in modulating the print quality of the final dosage forms. Findings provide enhanced understanding of formulation parameters informing the future of SLA 3D printed medicines and the personalised medicines revolution. [ABSTRACT FROM AUTHOR]

Effective disease surveillance, including that for COVID-19, is compromised without a standardised method for categorising the immunosuppressed as a clinical risk group. We conducted a systematic review and meta-analysis to evaluate whether excess COVID-associated mortality compared to the immunocompetent could meaningfully subdivide the immunosuppressed. Our study adhered to UK Immunisation against infectious disease (Green Book) criteria for defining and categorising immunosuppression. Using OVID (EMBASE, MEDLINE, Transplant Library, and Global Health), PubMed, and Google Scholar, we examined relevant literature between the entirety of 2020 and 2022. We selected for cohort studies that provided mortality data for immunosuppressed subgroups and immunocompetent comparators. Meta-analyses, grey literature and any original works that failed to provide comparator data or reported all-cause or paediatric outcomes were excluded. Odds Ratios (OR) and 95% confidence intervals (CI) of COVID-19 mortality were meta-analysed by immunosuppressed category and subcategory. Subgroup analyses differentiated estimates by effect measure, country income, study setting, level of adjustment, use of matching and publication year. Study screening, extraction and bias assessment were performed blinded and independently by two researchers; conflicts were resolved with the oversight of a third researcher. PROSPERO registration number is CRD42022360755. We identified 99 unique studies, incorporating data from 1,542,097 and 56,248,181 unique immunosuppressed and immunocompetent patients with COVID-19 infection, respectively. Compared to immunocompetent people (pooled OR, 95%CI), solid organ transplants (2.12, 1.50-2.99) and malignancy (2.02, 1.69-2.42) patients had a very high risk of COVID-19 mortality. Patients with rheumatological conditions (1.28, 1.13-1.45) and HIV (1.20, 1.05-1.36) had just slightly higher risks than the immunocompetent baseline. Case type, setting income and mortality data matching and adjustment were significant modifiers of excess immunosuppressed mortality for some immunosuppressed subgroups. Excess COVID-associated mortality among the immunosuppressed compared to the immunocompetent was seen to vary significantly across subgroups. This novel means of subdivision has prospective benefit for targeting patient triage, shielding and vaccination policies during periods of high disease transmission. • There is no universally accepted means of defining or subdividing the immunosuppressed. • We investigated if excess COVID mortality could risk-stratify immunosuppression. • 99 unique studies were reviewed and meta-analysed. • Mortality was highest in transplants/cancers, lowest in HIV/inflammatory conditions. • Case type, study setting & data matching and adjustment influenced risk gradients. [ABSTRACT FROM AUTHOR]

Pancreatobiliary cancer is a highly aggressive tumour with a dismal prognosis. Personalised medicine represents a promising and effective therapeutic approach for this intractable disease. In this study, we aimed to establish a system for identifying and testing genotype-oriented targeted drugs for pancreatobiliary cancers by combining exome sequencing and organoid culture of primary tumours. Tumour cells isolated from resected tumours were subjected to organoid cultures based on published protocols with modifications. Exome sequencing was performed on the primary tumours. Histopathological and molecular features of the primary tumours were validated in the corresponding organoids. Genotype-oriented candidate targeted drugs were identified from exome sequencing, and their efficacies were tested in the organoids. Organoid cultures succeeded in 30 of 54 (55.6%) cases. Six primary cancers of the biliary tract and gall bladder were subjected to exome sequencing, which revealed a variety of somatic mutations of genes involved in signalling pathways, epigenetic modifiers, genome maintenance and metabolic enzymes. Most of the organoids of these 6 cases showed identical histopathological features and genomic aberrations as those of the primary tumours. Some of the aberrations were candidates for targeted therapies. Integrin-linked kinase (ILK) was one such candidate target, and an ILK inhibitor was confirmed to suppress proliferation of patient-derived organoids. By combining exome sequencing and organoid culture, our model enabled to identify genotype-oriented targets for personalised medicine and to test efficacies of candidate targeted drugs in the organoids. The current proof-of-concept approach could increase therapeutic opportunities for patients with pancreatobiliary cancers. [Display omitted] • Organoids were obtained from 29 of 54 (53.7%) pancreatobiliary cancers. • Most of the organoids retained genotypes and histological phenotypes of primary tumours. • Exome sequencing unveiled diverse mutations in primary biliary tumours. • Organoids served for testing genotype-oriented targeted drug candidates. [ABSTRACT FROM AUTHOR]

This study investigated whether the inclusion of a matrix metalloproteinase-9 (MMP-9) responsive sequence in self-assembled peptide-based brain-targeting nanoparticles (NPs) would enhance the blood-brain barrier (BBB) penetration when MMP-9 levels are elevated both in the brain and blood circulation. Brain-targeting peptides were conjugated at the N-terminus to MMP-9-responsive peptides, and these were conjugated at the N-terminus to lipid moiety (cholesteryl chloroformate or palmitic acid). Two constructs did not have MMP-9-responsive peptides. NPs were characterised for size, charge, critical micelle concentration, toxicity, blood compatibility, neural cell uptake, release profiles, and in vitro BBB permeability simulating normal or elevated MMP-9 levels. The inclusion of MMP-9-sensitive sequences did not improve the release of a model drug in the presence of active MMP-9 from NPs compared to distilled water. 19F NMR studies suggested the burial of MMP-9-sensitive sequences inside the NPs making them inaccessible to MMP-9. Only cholesterol-GGGCKAPETALC (responsive to MMP-9) NPs showed <5% haemolysis, <1 pg/mL release of IL-1β at 500 μg/mL from THP1 cells, with 70.75 ± 5.78% of NPs crossing the BBB at 24 h in presence of active MMP-9. In conclusion, brain-targeting NPs showed higher transport across the BBB model when MMP-9 levels were elevated and the brain-targeting ligand was responsive to MMP-9. [ABSTRACT FROM AUTHOR]

Background: Opioid-induced immunomodulation may be of particular importance in triple-negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and oncological outcomes and explored patterns of opioid receptor expression in TNBC.Methods: Consecutive patients with stage I-III primary TNBC were identified from a prospectively maintained database. Opioid receptor expression patterns in the tumour microenvironment were analysed using publicly available bulk and single-cell RNA-seq data.Results: A total of 1143 TNBC cases were retrospectively analysed. In multivariable analysis, higher intraoperative opioid dose was associated with favourable recurrence-free survival, hazard ratio 0.93 (95% confidence interval 0.88-0.99) per 10 oral morphine milligram equivalents increase (P=0.028), but was not significantly associated with overall survival, hazard ratio 0.96 (95% confidence interval 0.89-1.02) per 10 morphine milligram equivalents increase (P=0.2). Bulk RNA-seq analysis of opioid receptors showed that OPRM1 was nearly non-expressed. Compared with normal breast tissue OGFR, OPRK1, and OPRD1 were upregulated, while TLR4 was downregulated. At a single-cell level, OPRM1 and OPRD1 were not detectable; OPRK1 was expressed mainly on tumour cells, whereas OGFR and TLR4 were more highly expressed on immune cells.Conclusions: We found a protective effect of intraoperative opioids on recurrence-free survival in TNBC. Opioid receptor expression was consistent with a net protective effect of opioid agonism, with protumour receptors either not expressed or downregulated, and antitumour receptors upregulated. In this era of personalised medicine, efforts to differentiate the effects of opioids across breast cancer subtypes (and ultimately individual patients) should continue. [ABSTRACT FROM AUTHOR]

• Rare Class 2 CFTR mutations rescued by strategic modulator combinations. • Modulator responses vary across cell types. • A dual acting (corrector-potentiator) compound contributes to functional rescue of N1303K. F508del is prototypical of Class 2 CFTR mutations associated with protein misprocessing and reduced function. Corrector compounds like lumacaftor partially rescue the processing defect of F508del-CFTR whereas potentiators like ivacaftor, enhance its channel activity once trafficked to the cell surface. We asked if emerging modulators developed for F508del-CFTR can rescue Class 2 mutations previously shown to be poorly responsive to lumacaftor and ivacaftor. Rescue of mutant CFTRs by the correctors: AC1, AC2–1 or AC2–2 and the potentiator, AP2, was studied in HEK-293 cells and in primary human nasal epithelial (HNE) cultures, using a membrane potential assay and Ussing chamber, respectively. In HEK-293 cells, we found that a particular combination of corrector molecules (AC1 plus AC2–1) and a potentiator (AP2) was effective in rescuing both the misprocessing and reduced function of M1101K and G85E respectively. These findings were recapitulated in patient-derived nasal cultures, although another corrector combination, AC1 plus AC2–2 also improved misprocessing in these primary tissues. Interestingly, while this corrector combination only led to a modest increase in the abundance of mature N1303K-CFTR it did enable its functional expression in the presence of the potentiator, AP2, in part, because the nominal corrector, AC2–2 also exhibits potentiator activity. Strategic combinations of novel modulators can potentially rescue Class 2 mutants thought to be relatively unresponsive to lumacaftor and ivacaftor. [ABSTRACT FROM AUTHOR]

The concept of personalised medicine is likely to revolutionise the treatment of adult obstructive sleep apnoea as a result of recent advances in the understanding of disease heterogeneity by identifying clinical phenotypes, pathophysiological endotypes, biomarkers and treatable traits. Children with the condition show a similar level of heterogeneity and paediatric obstructive sleep apnoea would also benefit from a more targeted approach to diagnosis and management. This review aims to summarise the adult literature on the phenotypes and endotypes of obstructive sleep apnoea and assess whether a similar approach may also be suitable to guide the development of new diagnostic and management approaches for paediatric obstructive sleep apnoea. [ABSTRACT FROM AUTHOR]

Computed tomographic (CT) imaging at third lumbar vertebra (L3), routinely used by oncologists, represents a reliable tool to quantify muscle mass. A systematic review and meta-analysis was performed to assess the efficacy of CT scan to define muscle mass as a prognostic marker in gastric cancer (GC) patients undergoing gastrectomy and/or chemotherapy. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS) and the secondary outcomes included postoperative length of hospital stay (P-LOS), total and severe complications in GC patients undergoing gastrectomy. Three electronic bibliographic databases — MEDLINE, Web of Science and Cochrane Central Register of Controlled Trials - were used to conduct a systematic literature search based on fixed inclusion and exclusion criteria, until April 2019. The adjusted and unadjusted hazard ratio (HR), odds ratio (OR) and mean difference (MD) with 95% confidence interval (CI) were used to analyse the dichotomous variables (OS, RFS, total and severe complications) and continuous variables (P-LOS). Random- and fixed effects models were used according to the heterogeneity. A total of 5610 GC patients from 20 studies were identified. Low muscle mass at diagnosis was found in 32.7% of GC patients and was significantly associated with poorer OS (HR 2.02, 95% CI 1.71–2.38, p < 0.00001, I2 = 47%) and worse RFS (HR 1.97, 95% CI 1.71–2.26, p < 0.00001, I2 = 0%). Meta-analysis of adjusted HR from multivariable analyses confirmed the association between OS and low muscle mass (HR 1.89, 95% CI 1.68–2.12, p < 0.00001, I2 = 36%). Furthermore, low muscle mass and poorer OS were significantly associated in metastatic GC patients exclusively undergoing chemotherapy (HR 1.61, 95% CI 1.23–2.11, p < 0.0006, I2 = 18%). Moreover, preoperative low muscle mass was significantly associated with longer P-LOS (MD 1.19, 95% CI 0.68–1.71, p < 0.00001, I2 = 0%), higher risk of postoperative complications (OR 1.76, 95% CI 1.17–2.66, p = 0.007, I2 = 77%) and severe complications (OR 1.54, 95% CI 1.03–2.29, p = 0.04, I2 = 49%) in GC patients undergoing gastrectomy. Low muscle mass, assessed by L3 CT-scan, affects almost 1/3 of GC patients at diagnosis and acts as a negative prognostic marker on many clinical outcomes. Therefore, identifying GC patients with low muscle mass at diagnosis or at follow-up visit should be recommendable. Clinical nutritionists should be part of tumor boards meetings to screen low muscle mass in order to prompt personalized nutritional support. [ABSTRACT FROM AUTHOR]

Objectives: To identify, by a systematic literature review, predictors of clinical response to methotrexate treatment in rheumatoid arthritis patients, which would facilitate personalised treatment.Methods: PubMed and Embase databases were searched for original articles. Additionally, congress abstracts of European League Against Rheumatism and American College of Rheumatology annual meetings of the past 2 years were screened. Articles describing predictors of clinical response to methotrexate after 3 to 6 months were included, since this reflects the time span used to determine treatment effectiveness and decide on treatment changes in treat-to-target recommendations.Results: Thirty articles were included, containing 100 different predictors and 11 predictive models. Nineteen predictors and 2 predictive models were studied in multiple cohorts. Female gender was found to be a predictor of non-response in two studies (odds ratios 0.55 and 0.54), but these findings could not be replicated in two other studies. In two studies, smoking predicted non-response (adjusted odds ratios 0.35 and 0.60), although this was inconsistent over all response criteria assessed. Rheumatoid factor positivity predicted non-response in two studies (adjusted hazard ratio 0.61, adjusted odds ratio 0.4), but this was not found in three other studies. Heterogeneity in studies prohibited further comparison of predictive values between studies. Additionally, a validated epigenetic model was found (area under the curve 0.90 and 0.91).Conclusions: No predictors were identified reliably predicting clinical response to methotrexate after 3 to 6 months in the individual patient: clinical predictors were weak. However, a promising epigenetic model was found that needs further validation. [ABSTRACT FROM AUTHOR]

Stress is an important predictor of long-term conditions. We examine whether hair cortisol (a biomarker of stress) is associated with incidence and accumulation of multiple long-term conditions (MLTC). We included data from 4295 individuals aged ≥50 years within the English Longitudinal Study of Ageing dataset with data on hair cortisol, sociodemographic and health behaviour variables. Cox proportional hazards models were used to quantify the association between hair cortisol at baseline and accumulation of MLTC between 2012/2013 and 2018/2019, both for individuals with and without MLTC at baseline. Our cohort included 1458 (34.0%) individuals who accumulated MLTC between 2012/2013 and 2018/2019. The proportion of individuals with zero, 1, and ≥ 2 conditions at baseline who accumulated MLTC were 12.0% (n = 127), 40.4% (n = 520), and 41.7% (n = 811), respectively. Higher cortisol levels were associated with higher risk of accumulation of MLTC in both unadjusted [HR:1.15(1.05–1.25)] and models adjusted for sociodemographic and health behaviours [HR:1.12(1.02–1.22)]. For individuals without MLTC at baseline, higher cortisol levels were significantly associated with higher risk of developing MLTC in unadjusted [HR: 1.20(1.05–1.36)] and adjusted models [HR: 1.16(1.02–1.32)]. The study provides the first evidence of the role of stress in the development and accumulation of MLTC. This modifiable risk factor could be targeted to reduce the risk of MLTC. However, further work is needed to better understand the mechanisms and pathways that link stress and accumulation of MLTC. • This is the first study to assess a link between stress biomarker and multimorbidity. • Higher levels of cortisol were associated with higher risk of multimorbidity. • This association was not mediated by sociodemographic characteristics. • The association was not mediated by health behaviours. • The findings suggest stress may be targeted to reduce risk of multimorbidity. [ABSTRACT FROM AUTHOR]

For children with cancer, the clinical integration of precision medicine to enable predictive biomarker–based therapeutic stratification is urgently needed. We have developed a hybrid-capture next-generation sequencing (NGS) panel, specifically designed to detect genetic alterations in paediatric solid tumours, which gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. In this study, we offered an NGS panel, with clinical reporting via a molecular tumour board for children with solid tumours. Furthermore, for a cohort of 12 patients, we used a circulating tumour DNA (ctDNA)–specific panel to sequence ctDNA from matched plasma samples and compared plasma and tumour findings. A total of 255 samples were submitted from 223 patients for the NGS panel. Using FFPE tissue, 82% of all submitted samples passed quality control for clinical reporting. At least one genetic alteration was detected in 70% of sequenced samples. The overall detection rate of clinically actionable alterations, defined by modified OncoKB criteria, for all sequenced samples was 51%. A total of 8 patients were sequenced at different stages of treatment. In 6 of these, there were differences in the genetic alterations detected between time points. Sequencing of matched ctDNA in a cohort of extracranial paediatric solid tumours also identified a high detection rate of somatic alterations in plasma. We demonstrate that tailored clinical molecular profiling of both tumour DNA and plasma-derived ctDNA is feasible for children with solid tumours. Furthermore, we show that a targeted NGS panel–based approach can identify actionable genetic alterations in a high proportion of patients. • The hybrid-capture panel gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded tissue. • A tailored sequencing approach identifies ≥1 genetic alteration in 70% of samples and potentially actionable genetic alterations in 51% of patients. • In paired samples, from different treatment time points, there were differences in the genetic alterations detected. [ABSTRACT FROM AUTHOR]

Despite the abundant use of polyethylene oxides (PEOs) and their integration as an excipient in numerous pharmaceutical products, there have been no previous reports of applying this important thermoplastic polymer species alone to fused deposition modelling (FDM) 3D printing. In this work, we have investigated the manufacture of oral doses via FDM 3D printing by employing PEOs as a backbone polymer in combination with polyethylene glycol (PEG). Blends of PEO (molecular weight 100 K, 200 K, 300 K, 600 K or 900 K) with PEG 6 K (plasticiser) and a model drug (theophylline) were hot-melt extruded. The resultant filaments were used as a feed for FDM 3D printer to fabricate oral dosage forms (ODFs) with innovative designs. ODFs were designed in a radiator-like geometry with connected paralleled plates and inter-plate spacing of either 0.5, 1, 1.5 or 2 mm. X-ray diffraction patterns of the filaments revealed the presence of two distinctive peaks at 2θ = 7° and 12°, which can be correlated to the diffraction pattern of theophylline crystals. Blends of PEO and PEG yielded filaments of variable mechanically resistance (maximum load at break of 357, 608, 649, 882, 781 N for filament produced with PEO 100 K, 200 K, 300 K, 600 K or 900 K, respectively). Filaments of PEO at a molecular weight of 200–600 K were compatible with FDM 3D printing process. Further increase in PEO molecular weight resulted in elevated shear viscosity (>104 Pa.S) at the printing temperature and hindered material flow during FDM 3D printing process. A minimal spacing (1 mm) between parallel plates of the radiator-like design deemed essential to boost drug release from the structure. This is the first report of utilising this widely used biodegradable polymer species (PEOs and PEG) in FDM 3D printing. [ABSTRACT FROM AUTHOR]

Abstract Changes in the nature and structure of healthcare pathways have implications for healthcare professionals' jurisdictional boundaries. The introduction of treatment focused BRCA1 and 2 genetic testing (TFGT) for newly diagnosed patients with breast cancer offers a contemporary example of pathway change brought about by technological advancements in gene testing and clinical evidence, and reflects the cultural shift towards genomics. Forming part of an ethnographically informed study of patient and practitioner experiences of TFGT at a UK teaching hospital, this paper focuses on the impact of a proposal to pilot a mainstreamed TFGT pathway on healthcare professionals' negotiations of professional jurisdiction. Based upon semi-structured interviews (n = 19) with breast surgeons, medical oncologists and members of the genetics team, alongside observations of breast multidisciplinary team meetings, during the time leading up to the implementation of the pilot, we describe how clinicians responded to the anticipated changes associated with mainstreaming. Interviews suggest that mainstreaming the breast cancer pathway, and the associated jurisdictional reconfigurations, had advocates as well as detractors. Medical oncologists championed the plans, viewing this adaptation in care provision and their professional role as a logical next step. Breast surgeons, however, regarded mainstreaming as an unfeasible expansion of their workload and questioned the relevance of TFGT to their clinical practice. The genetics team, who introduced the pilot, appeared cautiously optimistic about the potential changes. Drawing on sociological understandings of the negotiation of professional jurisdictions our work contributes a timely, micro-level examination of the responses among clinicians as they worked to renegotiate professional boundaries in response to the innovative application of treatment-focused BRCA testing in cancer care – a local and dynamic process which we refer to as an 'oncogenetic taskscape in the making'. Highlights • A micro-level examination of clinicians' work assembling an 'oncogenetic taskscape'. • Mainstreaming genomic testing requires changes to professional jurisdictions. • Technology's clinical relevance informs clinicians' acceptance of mainstreaming. • Clinical implementation of new technology requires inter-professional collaboration. [ABSTRACT FROM AUTHOR]