Background: Patients with urolithiasis have access to a wide range of efficacious therapeutic surgical options, including shockwave lithotripsy (SWL), retrograde ureteric or intrarenal surgery with semi-rigid and flexible ureteroscopes (URS or fURS) and percutaneous nephrolithotomy (PCNL). In recent years, there have been many peer-reviewed publications evaluating new techniques and new equipment, such as pulse-modulated Holmium:YAG and thulium fibre lasers. However, when reviewing this extensive literature, it becomes apparent that there is no consensus on what constitutes a 'successful' stone treatment outcome.Objectives: The purpose of this article is to review the existing measures of 'success' after the ureteroscopic treatment of urolithiasis and to promote a standardised and holistic approach to reporting outcomes in clinical trials.Methods: Our narrative review focussed on studies examining measures of success in urolithiasis treatment published within the last 10 years.Conclusions: Due to markedly different reported outcome measures of treatments for urolithiasis, comparing results between studies can be difficult. In addition to measuring clinical outcomes, there is an increasing acknowledgement of the importance of patient-reported outcome measures (PROMs) in determining treatment success, and the need to consider the cost-effectiveness and environmental sustainability of various treatments. We suggest that all future studies on this common urological condition should incorporate holistic and tranpsarent outcome measures.Level of evidence: Not applicable

Prostate cancer (PCa) is the second most common cancer diagnosed in men. While radical prostatectomy and radiotherapy are often successful in treating localised disease, post-treatment recurrence is common. As the androgen receptor (AR) and androgen hormones play an essential role in prostate carcinogenesis and progression, androgen deprivation therapy (ADT) is often used to deprive PCa cells of the pro-proliferative effect of androgens. ADTs act by either blocking androgen biosynthesis (e.g. abiraterone) or blocking AR function (e.g. bicalutamide, enzalutamide, apalutamide, darolutamide). ADT is often effective in initially suppressing PCa growth and progression, yet emergence of castrate-resistant PCa and progression to neuroendocrine-like PCa following ADT are major clinical challenges. For this reason, there is an urgent need to identify novel approaches to modulate androgen signalling to impede PCa progression whilst also preventing or delaying therapy resistance.The mechanistic convergence of androgen and epitranscriptomic signalling offers a potential novel approach to treat PCa. The epitranscriptome involves covalent modifications of mRNA, notably, in the context of this review, the N(6)-methyladenosine (m6A) modification. m6A is involved in the regulation of mRNA splicing, stability, and translation, and has recently been shown to play a role in PCa and androgen signalling. The m6A modification is dynamically regulated by the METTL3-containing methyltransferase complex, and the FTO and ALKBH5 RNA demethylases.Given the need for novel approaches to treat PCa, there is significant interest in new therapies that target m6A that modulate AR expression and androgen signalling. This review critically summarises the potential benefit of such epitranscriptomic therapies for PCa patients.

Prostate cancer (PCa) is a leading male malignancy worldwide, often progressing to bone metastasis, with limited curative options. Extracellular vesicles (EVs) have emerged as key players in cancer communication and metastasis, promoting the formation of supportive microenvironments in distant sites. Our previous studies have highlighted the role of PCa EVs in modulating osteoblasts and facilitating tumor progression. However, the early pre-metastatic changes induced by PCa EVs within the bone microenvironment remain poorly understood. To investigate the early effects of repeated exposure to PCa EVs in vivo, mimicking EVs being shed from the primary tumor, PCa EVs isolated from cell line PC3MLuc2a were fluorescently labelled and repeatedly administered via tail vein injection to adult CD1 NuNu male mice for a period of 4 weeks. In vivo imagining, histological analysis and gene expression profiling were performed to assess the impact of PCa EVs on the bone microenvironment. We demonstrate for the first time that PCa EVs home to both bone and lymph nodes following repeated exposures. Furthermore, the accumulation of EVs within the bone leads to distinct molecular changes indicative of disrupted bone homeostasis (e.g., changes to signaling pathways such as Paxillin p = 0.0163, Estrogen Receptor p = 0.0271, RHOA p = 0.0287, Ribonucleotide reductase p = 0.0307 and ERK/MAPK p = 0.0299). Changes in key regulators of these pathways were confirmed in vitro on human osteoblasts. In addition, our data compares the known gene signature of osteocytes and demonstrates a high proportion of overlap (52.2%), suggesting a potential role for this cell type in response to PCa EV exposure. No changes in bone histology or immunohistochemistry were detected, indicating that PCa EV mediated changes were induced at the molecular level. This study provides novel insights into the alterations induced by PCa EVs on the bone microenvironment. The observed molecular changes indicate changes in key pathways and suggest a role for osteocytes in these EV mediated early changes to bone. Further research to understand these early events may aid in the development of targeted interventions to disrupt the metastatic cascade in PCa.

Drug sensitivity of NSCLC specimens to HDAC inhibitors and combination with standards of care.

HGF expression in CAFS and MSCs.

Growth of NSCLC specimens in the 3D-TGA.

A schematic of the patient derived 3D-TGA method.

Achievable peak serum concentration of chemotherapies in humans and associated references.

Drug sensitivity of NSCLC specimens to standard of care reagents.

The purity of human epithelial tumour cells entered into the 3D-TGA.

Growth of cells from different solid tumors in the 3D-TGA.

Legends for the supplementary figures

Renal colic is the pain experienced by a patient when a renal calculus (kidney stone) causes partial or complete obstruction of part of the renal outflow tract. The standard analgesic regimes for renal colic are often ineffective; in some studies, less than half of patients achieve complete pain relief, and a large proportion of patients require rescue analgesia within 4 h. Current analgesic regimes are also associated with significant side effects including nausea, vomiting, drowsiness and respiratory depression. It has been hypothesised that beta adrenoreceptor agonists, such as salbutamol, may reduce the pain of renal colic. They have been shown to impact a number of factors that target the physiological causes of pain in renal colic (ureteric spasm and increased peristalsis, increased pressure at the renal pelvis and prostaglandin release with inflammation). There is biological plausibility and a body of evidence sufficient to suggest that this novel treatment for the pain of renal colic should be taken to a phase II clinical trial. The aim of this trial is to test whether salbutamol is an efficacious analgesic adjunct when added to the standard analgesic regime for patients presenting to the ED with subsequently confirmed renal colic. A phase II, randomised, placebo-controlled trial will be performed in an acute NHS Trust in the East Midlands. Patients presenting to the emergency department with pain requiring IV analgesia and working diagnosis of renal colic will be randomised to receive standard analgesia ± a single intravenous injection of Salbutamol. Secondary study objectives will explore the feasibility of conducting a larger, phase III trial. The trial will provide important information about the efficacy of salbutamol as an analgesic adjunct in renal colic. It will also guide the development of a definitive phase III trial to test the cost and clinical effectiveness of salbutamol as an analgesic adjunct in renal colic. Salbutamol benefits from widespread use across the health service for multiple indications, extensive staff familiarity and a good side effect profile; therefore, its potential use for pain relief may have significant benefits for patient care. ISRCTN Registry ISRCTN14552440 . Registered on 22 July 2019

Abstract Introduction COVID-19 may negatively affect peri-operative outcomes, requiring strategies to allow operating whilst minimising risk. We present our endourology service provision throughout the “lockdown” period. Method Endourological operations 23rd March to 11th May 2020 were designated to the base hospital or independent “green” site by urgency and comorbidity status. Base hospital emergencies underwent surgery in main theatres, whilst elective patients had dedicated “COVID-free” theatres and wards. A portable Holmium laser enabled lasertripsy at the independent site. After 27th April, elective cases required a negative swab and 2-week self-isolation pre-operatively. Results 70 operations were performed: 42 ureteroscopies, 20 stent procedures, 8 PCNLs. Mean age was 57 and 58 at base and independent sites respectively, mean ASA 2.1 and 1.9. 37 operations (53%) occurred at the base hospital, including 14 emergencies (38%). 19 patients received post-operative COVID-19 swabs: 3 positives (8%), all emergencies. 2 patients (5%) died of COVID-19 pneumonia within 35 days; both had negative pre-operative swabs. Of 33 patients at the independent site, 3 (9%) received post-operative swabs, all negative. None had COVID-19 symptoms post-operatively. Conclusions “COVID-free” hospitals, wards and theatres enable elective operating whilst minimising peri-operative virus risk. Further utilisation of independent hospitals would more safely allow operating throughout the pandemic.

Following the outbreak of the novel SARS-CoV-2 (COVID-19), the World Health Organization made a number of recommendations regarding the utilisation of healthcare services. In general, there has been a reduction in elective healthcare services including outpatient clinics, diagnostic services and elective surgery. Inevitably these reductions for all but the most urgent clinical work will have a detrimental impact on patients, and alternative ways of working including the use of telemedicine may help to mitigate this. Similarly, electronic solutions may enable clinicians to maintain inter and intra-professional working in both clinical and academic settings. Implementation of electronic solutions to minimise direct patient contact will be new to many clinicians, and the sheer number of software solutions available and varying functionality may be overwhelming to anyone unfamiliar with ‘virtual communication’. In this article, we will aim to summarise the variety of electronic communication platforms and tools available for clinicians and patients, detailing their utility, pros and cons, and some 'tips and tricks' from our experience through our work as an international research collaborative.

Objectives: Ultra-mini percutaneous nephrolithotomy (UMP) is a novel technique recently introduced allowing percutaneous renal access to stones using a specially modified 11 or 13 Fr sheath, a 6 Fr nephroscope, and permits laser fragmentation and stone evacuation. This study aimed to review the early practice of UMP in the UK. Methods: All centres in the UK which had performed UMP were contacted to submit data. Data were submitted to a central database from nine centres around the UK who performed UMP between July 2013 and December 2014. Data were collected on patient, stone, operative factors and outcomes. Results: A total of 32 UMP cases were performed in the contributing centres. Stone size ranged from 7 mm×5 mm to 24 mm×24 mm across the 32 cases, with a mean of 13 mm×10 mm. Stone-free rates were excellent with 31/32 cases stone-free post procedure; 26/32 patients were left without a nephrostomy tube. Complications were uncommon; there were two Clavien 1 complications in this series (6%). Conclusion: This study has shown the efficacy of UMP during its introduction into UK practice. It is likely that UMP will become a useful addition to the armamentarium to treat renal stones, especially smaller stones in the lower pole calyx, and in specialised cases such as paediatric stone disease and in patients with stones in calyceal diverticulae.

Objective: Patients at our institution with asymptomatic calyceal stones (<11 mm) are discharged to their GPs with a request for 12- and 24-month X-ray KUBs with specific re-referral criteria. We aimed to assess the effectiveness of this shared care protocol as well as to investigate long-term outcomes. Patients and methods: All patients satisfying the above criteria discharged during October 2009–June 2011 were reviewed for protocol compliance, symptomatic events and/or surgical intervention up to July 2015. Results: A total of 134 patients were identified. Out of 115 patients eligible for their first X-ray, and 100 patients eligible for their second X-ray, 43% and 26% respectively were performed. Of these, 75% demonstrated no progression. No patients were treated surgically solely on the basis of radiographic progression. Over a mean five-year follow-up, patients had a 39% chance of experiencing a symptomatic event and a 24% chance of requiring surgical intervention (ESWL, ureteroscopy and/or PCNL). Risk factors included a previous stone history and having a total stone size >10 mm. Conclusion: There was poor adherence to this protocol. Despite this, only symptomatic patients were treated surgically, challenging the value of indefinite surveillance of asymptomatic patients. Longitudinal studies are needed to determine a cost-effective manner in which these patients can be safely followed up.