Our experience in developing and operating the Airway Intervention Registry for Recurrent Respiratory Papillomatosis (AIR-RRP): national data collection [version 2; peer review: 2 approved].

Recurrent respiratory papillomatosis (RRP) is characterised by benign wart-like growths in the respiratory tract caused by the human papillomavirus (HPV). These warts vary in size and grow quickly, causing voice changes and airway obstruction. Whilst the condition is rare, RRP is more common and aggressive in children. There is currently no curative treatment for HPV, therefore RRP is managed by maintaining a safe airway and a serviceable voice by repeated surgery to remove the growths. A lack of specific diagnostic codes prevents reliable case ascertainment of RRP from routine administrative databases such as Hospital Episode Statistics. In 2017 a cross-sectional survey identified 918 RRP patients in the UK, half of whom had received surgical intervention for RRP in the previous 12 months with 16 different interventions. Randomised controlled trials for RRP interventions are difficult due to the rarity of the disease, variation in severity and progression and non-standard care across the NHS. Consequently, there is a lack of definitive efficacy and safety evidence. The only national guidance for RRP interventions is "Radiofrequency cold ablation for respiratory papillomatosis" (NICE IPG434, 2017) which recommended further data collection due to lack of evidence. However, due to the wide variation in RRP management across the NHS, clinical opinion favoured that any data collection should include a comparison of safety and efficacy of all RRP interventions in order to advise which improved patient outcomes and quality of life. To address lack of evidence, and inform the future care of RRP patients, we developed a registry and used it to collect real-world data from patients receiving treatment for RRP in NHS hospitals across the UK. The purpose of this paper is to share lessons learned from this national data collection exercise to inform future clinical registry development.

RAC1B function is essential for breast cancer stem cell maintenance and chemoresistance of breast tumor cells.

Breast cancer stem cells (BCSC) are presumed to be responsible for treatment resistance, tumor recurrence and metastasis of breast tumors. However, development of BCSC-targeting therapies has been held back by their heterogeneity and the lack of BCSC-selective molecular targets. Here, we demonstrate that RAC1B, the only known alternatively spliced variant of the small GTPase RAC1, is expressed in a subset of BCSCs in vivo and its function is required for the maintenance of BCSCs and their chemoresistance to doxorubicin. In human breast cancer cell line MCF7, RAC1B is required for BCSC plasticity and chemoresistance to doxorubicin in vitro and for tumor-initiating abilities in vivo. Unlike Rac1, Rac1b function is dispensable for normal mammary gland development and mammary epithelial stem cell (MaSC) activity. In contrast, loss of Rac1b function in a mouse model of breast cancer hampers the BCSC activity and increases their chemosensitivity to doxorubicin treatment. Collectively, our data suggest that RAC1B is a clinically relevant molecular target for the development of BCSC-targeting therapies that may improve the effectiveness of doxorubicin-mediated chemotherapy.

Variation in IL6ST cytokine family function and the potential of IL6 trans-signalling in ERα positive breast cancer cells.

High expression of the transmembrane receptor IL6ST (gp130) has been identified as a predictive biomarker of endocrine treatment response in ERα-positive breast cancers. To investigate its function further in this disease, this study evaluated the expression, function and signalling of IL6ST in ERα-positive breast cancer cell lines and investigated crosstalk between ERα and IL6ST. IL6ST was differentially expressed in ERα-positive breast cancer cell lines (low in MCF-7, high in ZR751 and T47D), while multiple soluble isoforms of IL6ST were identified. IL6ST is the common signal transducing receptor component for the IL6ST family of cytokines and the effects of seven IL6ST cytokines on these cell lines were studied. These cytokines caused differential growth and migration effects in these cell lines e.g. MCF-7 cells were growth-stimulated, while ZR751 cells were inhibited by IL6 and OSM.. Activation of the STAT and ERK pathways is associated with these responses. Evidence to support trans-signalling involved in cell growth and migration was obtained in both MCF-7 and ZR751 models. Interaction between cytokines and estrogen on ERα-positive cell lines growth were analysed. High expression of IL6ST (in ZR751) may lead to growth inhibition by interacting cytokines while lower expression (in MCF-7) appears associated with proliferation. High IL6ST expression is consistent with a more beneficial clinical outcome if cytokine action contributes to anti-estrogen action.

Infection after ureteroscopy for ureteric stones: analysis of 71 305 cases in the Hospital Episode Statistics database.

OBJECTIVES: To investigate the burden of infectious complications following ureteroscopy (URS) for ureteric stones on a national level in England using data from the Hospital Episodes Statistics (HES) data warehouse. MATERIALS AND METHODS: A retrospective cohort was identified and followed up in HES during the period April 2013 to March 2020 for all procedure codes relating to ureteroscopic stone treatment (M27.1, M27.2, M27.3). Treatment episodes relating to the first URS ('index ureteroscopy') for each patient were further analysed. All subsequent admissions within 30 days were also captured. The primary outcome was diagnosis of urinary tract infection (UTI; including all codes relating to a UTI/sepsis within the first 30 days of index URS). Secondary outcomes were critical care attendance, attendance at the accident and emergency department (A&E) within 30 days, and mortality. RESULTS: A total of 71 305 index ureteroscopies were eligible for analysis. The median age was 55 years, and 81% of procedures were elective and 45% were undertaken as day-cases. At the time of index URS, 16% of patients had diabetes, 0.5% had coexisting neurological disease and 40% had an existing stent/nephrostomy. Overall, 6.8% of the cohort (n = 4822) had a diagnosis of UTI within 30 days of index URS (3.9% immediately after surgery). A total of 339 patients (0.5%) required an unplanned stay in critical care during their index URS admission; 8833 patients (12%) attended A&E within 30 days. Overall mortality was 0.18% (60 in-hospital, 65 within 30 days); 40 deaths (0.056%) included infection as a contributing cause of death. CONCLUSION: We present the largest series evaluating infectious complications after ureteroscopic stone treatment. The procedure is safe, with low inpatient infective complication and critical care admission rates.

Toll-like receptor 2 orchestrates a tumor suppressor response in non-small cell lung cancer.

Targeting early-stage lung cancer is vital to improve survival. However, the mechanisms and components of the early tumor suppressor response in lung cancer are not well understood. In this report, we study the role of Toll-like receptor 2 (TLR2), a regulator of oncogene-induced senescence, which is a key tumor suppressor response in premalignancy. Using human lung cancer samples and genetically engineered mouse models, we show that TLR2 is active early in lung tumorigenesis, where it correlates with improved survival and clinical regression. Mechanistically, TLR2 impairs early lung cancer progression via activation of cell intrinsic cell cycle arrest pathways and the proinflammatory senescence-associated secretory phenotype (SASP). The SASP regulates non-cell autonomous anti-tumor responses, such as immune surveillance of premalignant cells, and we observe impaired myeloid cell recruitment to lung tumors after Tlr2 loss. Last, we show that administration of a TLR2 agonist reduces lung tumor growth, highlighting TLR2 as a possible therapeutic target.

FAK promotes stromal PD-L2 expression associated with poor survival in pancreatic cancer.

BACKGROUND: Pancreatic Cancer is one of the most lethal cancers, with less than 8% of patients surviving 5 years following diagnosis. The last 40 years have seen only small incremental improvements in treatment options, highlighting the continued need to better define the cellular and molecular pathways contributing to therapy response and patient prognosis. METHODS: We combined CRISPR, shRNA and flow cytometry with mechanistic experiments using a KrasG12Dp53R172H mouse model of pancreatic cancer and analysis of publicly available human PDAC transcriptomic datasets. RESULTS: Here, we identify that expression of the immune checkpoint, Programmed Death Ligand 2 (PD-L2), is associated with poor prognosis, tumour grade, clinical stage and molecular subtype in patients with Pancreatic Ductal Adenocarcinoma (PDAC). We further show that PD-L2 is predominantly expressed in the stroma and, using an orthotopic murine model of PDAC, identify cancer cell-intrinsic Focal Adhesion Kinase (FAK) signalling as a regulator of PD-L2 stromal expression. Mechanistically, we find that FAK regulates interleukin-6, which can act in concert with interleukin-4 secreted by CD4 T-cells to drive elevated expression of PD-L2 on tumour-associated macrophages, dendritic cells and endothelial cells. CONCLUSIONS: These findings identify further complex heterocellular signalling networks contributing to FAK-mediated immune suppression in pancreatic cancer.

Reproductive history differs by molecular subtypes of breast cancer among women aged ≤ 50 years in Scotland diagnosed 2009-2016: a cross-sectional study.

BACKGROUND: The aetiology of breast cancers diagnosed ≤ 50 years of age remains unclear. We aimed to compare reproductive risk factors between molecular subtypes of breast cancer, thereby suggesting possible aetiologic clues, using routinely collected cancer registry and maternity data in Scotland. METHODS: We conducted a cross-sectional study of 4108 women aged ≤ 50 years with primary breast cancer diagnosed between 2009 and 2016 linked to maternity data. Molecular subtypes of breast cancer were defined using immunohistochemistry (IHC) tumour markers, oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), and tumour grade. Age-adjusted polytomous logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of number of births, age at first birth and time since last birth with IHC-defined breast cancer subtypes. Luminal A-like was the reference compared to luminal B-like (HER2-), luminal B-like (HER2+), HER2-overexpressed and triple-negative breast cancer (TNBC). RESULTS: Mean (SD) for number of births, age at first birth and time since last birth was 1.4 (1.2) births, 27.2 (6.1) years and 11.0 (6.8) years, respectively. Luminal A-like was the most common subtype (40%), while HER2-overexpressed and TNBC represented 5% and 15% of cases, respectively. Larger numbers of births were recorded among women with HER2-overexpressed and TNBC compared with luminal A-like tumours (> 3 vs 0 births, OR 1.87, 95%CI 1.18-2.96; OR 1.44, 95%CI 1.07-1.94, respectively). Women with their most recent birth > 10 years compared to < 2 years were less likely to have TNBC tumours compared to luminal A-like (OR 0.63, 95%CI 0.41-0.97). We found limited evidence for differences by subtype with age at first birth. CONCLUSION: Number of births and time since last birth differed by molecular subtypes of breast cancer among women aged ≤ 50 years. Analyses using linked routine electronic medical records by molecularly defined tumour pathology data can be used to investigate the aetiology and prognosis of cancer.

MYC sensitises cells to apoptosis by driving energetic demand.

The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.

Validation of a Standardised Duplex Ultrasound Classification System for the Reporting and Grading of Peripheral Arterial Disease.

OBJECTIVE: Duplex ultrasound (DUS), a non-invasive means of arterial mapping, allows for the reliable diagnosis of peripheral arterial disease (PAD). One of the authors (C.P.O.), developed a standardised DUS based scoring system, devised for rapid detection and reporting of PAD. The purpose of this study was to validate this system, and to determine the diagnostic performance both overall and per disease severity. METHODS: In total, 250 participants were recruited, based on diagnosis of (n = 125) or absence of PAD (n = 125) from general practice registers. Right and left legs per subject were handled as independent readings, determining actual PAD status via ankle brachial pressure index (ABPI) < 0.9, and then further grading disease severity using suggested ABPI ranges. Data were excluded if no corresponding ABPI value was obtained per DUS determination or if the ABPI reading was > 1.4, owing to the risk of false negatives due to incompressible vessels. Diagnostic sensitivity and specificity were obtained overall, and per severity classification. Furthermore, inter-rater agreement between ABPI and DUS determined PAD severity was determined by linear weighted Cohen's kappa. RESULTS: The sensitivity and specificity in the detection of disease overall was 81.0% (95% confidence interval [CI] 73.4 - 87.2) and 86.3% (95% CI 82.3 - 89.8), respectively. From mild to severe PAD, sensitivity increased from 71.1% (95% CI 55.7 - 83.6) to 89.3% (95% CI 71.8 - 97.7). Furthermore, a Cohen's kappa value of 0.63 (95% CI 0.57 - 0.69) was obtained, indicating moderate agreement between the two diagnostic methods. CONCLUSION: The findings of this study validate the diagnostic performance of the standardised DUS scoring system, as well as its capacity to grade severity of disease, offering a potential tool for the identification of PAD in community/research settings following initial screening methods. Confirmatory work could include a comparison of DUS determined disease with gold standard methods of non-invasive angiography, and novel tools such as toe flex near infrared spectroscopy and multisite photoplethysmography.

Epigenome-wide DNA methylation profiling of conditioned pain modulation in individuals with non-specific chronic low back pain.

BACKGROUND: The pathoanatomic cause of chronic low back pain (cLBP) cannot be identified for up to 90% of individuals. However, dysfunctional processing of endogenous nociceptive input, measured as conditioned pain modulation (CPM), has been associated with cLBP and may involve changes in neuronal gene expression. Epigenetic-induced changes such as DNA methylation (DNAm) have been associated with cLBP. METHODS: In the present study, the relationship between CPM and DNAm changes in a sample of community-dwelling adults with nonspecific cLBP (n = 48) and pain-free controls (PFC; n = 50) was examined using reduced representation bisulfite sequencing. Gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify key pathways involved in efficient versus deficient CPM. RESULTS: Based on CPM efficiency, we identified 6006 and 18,305 differentially methylated CpG sites (DMCs) with q values < 0.01 among individuals with cLBP and PFCs, respectively. Most of the DMCs were hypomethylated and annotated to genes of relevance to pain, including OPRM1, ADRB2, CACNA2D3, GNA12, LPL, NAXD, and ASPHD1. In both cLBP and PFC groups, the DMCs annotated genes enriched many GO terms relevant to pain processing, including transcription regulation by RNA polymerase II, nervous system development, generation of neurons, neuron differentiation, and neurogenesis. Both groups also enriched the pathways involved in Rap1-signaling, cancer, and dopaminergic neurogenesis. However, MAPK-Ras signaling pathways were enriched in the cLBP, not the PFC group. CONCLUSIONS: This is the first study to investigate the genome-scale DNA methylation profiles of CPM phenotype in adults with cLBP and PFCs. Based on CPM efficiency, fewer DMC enrichment pathways were unique to the cLBP than the PFCs group. Our results suggest that epigenetically induced modification of neuronal development/differentiation pathways may affect CPM efficiency, suggesting novel potential therapeutic targets for central sensitization. However, CPM efficiency and the experience of nonspecific cLBP may be independent. Further mechanistic studies are required to confirm the relationship between CPM, central sensitization, and nonspecific cLBP.

Coblation intracapsular tonsillectomy: A cohort study of NHS practice in England using Hospital Episode Statistics.

OBJECTIVES: To identify paediatric intracapsular Coblation tonsillectomy procedures from routine administrative data in England, and determine their safety. DESIGN: Retrospective observational cohort study of four ENT centres using routine data from Hospital Episode Statistics (HES). SETTING: Acute NHS trusts in England conducting exclusively intracapsular Coblation tonsillectomy. PARTICIPANTS: Children (≤16 years old) undergoing bilateral intracapsular Coblation tonsillectomy. MAIN OUTCOME MEASURES: Number of procedures, readmissions for pain, readmissions for bleeding and requirement for additional surgery for regrowth. RESULTS: A total of 5525 procedures were identified. The median patient age was 4 (IQR 2-5). In-hospital complications occurred in 1%, with 0.1% returning to theatre for arrest of primary tonsil bleeding. Almost half of the procedures were conducted as a day-case (44%), with only a small proportion staying in hospital more than one night (7%). Within 28 days, 1.2% of patients were readmitted with bleeding, 0.7% with infection and 0.3% with pain; 0.2% of patients required return to theatre for control of secondary haemorrhage. Longitudinal follow-up has found that revision tonsil surgery is 0.3% at 1 year (n = 4498), 1.1% at 2 years (n = 2938), 1.7% at 3 years (n = 1781), 1.9% at 4 years (n = 905) and 2.2% at 5 years (n = 305). CONCLUSIONS: Intracapsular coblation tonsillectomy safety outcomes in this study show primary and secondary bleeding rates and emergency return to theatre rates are lower than all tonsillectomy techniques reported in the National Prospective Tonsillectomy Audit and also lower than previously published Hospital Episode Statistics analysis of tonsillectomy procedures.

Characterisation of the Stromal Microenvironment in Lobular Breast Cancer.

Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer, and it exhibits a number of clinico-pathological characteristics distinct from the more common invasive ductal carcinoma (IDC). We set out to identify alterations in the tumor microenvironment (TME) of ILC. We used laser-capture microdissection to separate tumor epithelium from stroma in 23 ER+ ILC primary tumors. Gene expression analysis identified 45 genes involved in regulation of the extracellular matrix (ECM) that were enriched in the non-immune stroma of ILC, but not in non-immune stroma from ER+ IDC or normal breast. Of these, 10 were expressed in cancer-associated fibroblasts (CAFs) and were increased in ILC compared to IDC in bulk gene expression datasets, with PAPPA and TIMP2 being associated with better survival in ILC but not IDC. PAPPA, a gene involved in IGF-1 signaling, was the most enriched in the stroma compared to the tumor epithelial compartment in ILC. Analysis of PAPPA- and IGF1-associated genes identified a paracrine signaling pathway, and active PAPP-A was shown to be secreted from primary CAFs. This is the first study to demonstrate molecular differences in the TME between ILC and IDC identifying differences in matrix organization and growth factor signaling pathways.

Elevated EDAR signalling promotes mammary gland tumourigenesis with squamous metaplasia.

Ectodysplasin A receptor (EDAR) is a death receptor in the Tumour Necrosis Factor Receptor (TNFR) superfamily with roles in the development of hair follicles, teeth and cutaneous glands. Here we report that human Oestrogen Receptor (ER) negative breast carcinomas which display squamous differentiation express EDAR strongly. Using a mouse model with a high Edar copy number, we show that elevated EDAR signalling results in a high incidence of mammary tumours in breeding female mice. These tumours resemble the EDAR-high human tumours in that they are characterised by a lack of oestrogen receptor expression, contain extensive squamous metaplasia, and display strong ß-catenin transcriptional activity. In the mouse model, all of the tumours carry somatic deletions of the third exon of the CTNNB1 gene that encodes ß-catenin. Deletion of this exon yields unconstrained ß-catenin signalling activity. We also demonstrate that ß-catenin activity is required for transformed cell growth, showing that increased EDAR signalling creates an environment in which ß-catenin activity can readily promote tumourigenesis. Together, this work identifies a novel death receptor oncogene in breast cancer, whose mechanism of transformation is based on the interaction between the WNT and Ectodysplasin A (EDA) pathways.

Loss of Integrin-Linked Kinase Sensitizes Breast Cancer to SRC Inhibitors.

SRC is a nonreceptor tyrosine kinase with key roles in breast cancer development and progression. Despite this, SRC tyrosine kinase inhibitors have so far failed to live up to their promise in clinical trials, with poor overall response rates. We aimed to identify possible synergistic gene-drug interactions to discover new rational combination therapies for SRC inhibitors. An unbiased genome-wide CRISPR-Cas9 knockout screen in a model of triple-negative breast cancer revealed that loss of integrin-linked kinase (ILK) and its binding partners α-Parvin and PINCH-1 sensitizes cells to bosutinib, a clinically approved SRC/ABL kinase inhibitor. Sensitivity to bosutinib did not correlate with ABL dependency; instead, bosutinib likely induces these effects by acting as a SRC tyrosine kinase inhibitor. Furthermore, in vitro and in vivo models showed that loss of ILK enhanced sensitivity to eCF506, a novel and highly selective inhibitor of SRC with a unique mode of action. Whole-genome RNA sequencing following bosutinib treatment in ILK knockout cells identified broad changes in the expression of genes regulating cell adhesion and cell-extracellular matrix. Increased sensitivity to SRC inhibition in ILK knockout cells was associated with defective adhesion, resulting in reduced cell number as well as increased G1 arrest and apoptosis. These findings support the potential of ILK loss as an exploitable therapeutic vulnerability in breast cancer, enhancing the effectiveness of clinical SRC inhibitors. SIGNIFICANCE: A CRISPR-Cas9 screen reveals that loss of integrin-linked kinase synergizes with SRC inhibition, providing a new opportunity for enhancing the clinical effectiveness of SRC inhibitors in breast cancer.

Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells.

The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis.

Steroid Ligands, the Forgotten Triggers of Nuclear Receptor Action; Implications for Acquired Resistance to Endocrine Therapy.

PURPOSE: There is strong epidemiologic evidence indicating that estrogens may not be the sole steroid drivers of breast cancer. We hypothesize that abundant adrenal androgenic steroid precursors, acting via the androgen receptor (AR), promote an endocrine-resistant breast cancer phenotype. EXPERIMENTAL DESIGN: AR was evaluated in a primary breast cancer tissue microarray (n = 844). Androstenedione (4AD) levels were evaluated in serum samples (n = 42) from hormone receptor-positive, postmenopausal breast cancer. Levels of androgens, progesterone, and estradiol were quantified using LC/MS-MS in serum from age- and grade-matched recurrent and nonrecurrent patients (n = 6) before and after aromatase inhibitor (AI) therapy (>12 months). AR and estrogen receptor (ER) signaling pathway activities were analyzed in two independent AI-treated cohorts. RESULTS: AR protein expression was associated with favorable progression-free survival in the total population (Wilcoxon, P < 0.001). Pretherapy serum samples from breast cancer patients showed decreasing levels of 4AD with age only in the nonrecurrent group (P < 0.05). LC/MS-MS analysis of an AI-sensitive and AI-resistant cohort demonstrated the ability to detect altered levels of steroids in serum of patients before and after AI therapy. Transcriptional analysis showed an increased ratio of AR:ER signaling pathway activities in patients failing AI therapy (t test P < 0.05); furthermore, 4AD mediated gene changes associated with acquired AI resistance. CONCLUSIONS: This study highlights the importance of examining the therapeutic consequences of the steroid microenvironment and demonstrable receptor activation using indicative gene expression signatures.

Safety, effectiveness and costs of percutaneous mitral valve repair: A real-world prospective study.

AIMS: Percutaneous mitral valve leaflet repair is a treatment option for some people with severe mitral valve regurgitation for whom conventional mitral valve surgery is clinically inappropriate. This study aimed to determine the safety, efficacy, and costs of percutaneous mitral valve leaflet repair, using the MitraClip device in a UK setting. METHODS AND RESULTS: This was a prospective, single-armed registry with a follow-up of 2 years that reported a range of procedural, clinical and patient-orientated outcomes. Registry data were linked to routine data sources to allow for more comprehensive follow up concerning mortality and healthcare resource use. The registry received data for 199 mainly elective patients with mixed mitral regurgitation aetiology. A MitraClip device was implanted in 187 patients (94%), with a procedural success rate of 86%, with 8% of patients having a serious in-hospital adverse event (including 5% mortality). Percutaneous mitral valve leaflet repair reduced mitral regurgitation from 100% MR grade ≥ 3+ to 7% at discharge. There were corresponding improvements in New York Heart Association functional class, reducing from 92% (class ≥ 3) at baseline to 18% at 6 weeks. There were significant improvements in generic and disease specific quality of life indicators up to 2 years. The all-cause mortality rate was estimated to be 12.7% (95% CI 7.5 to 17.7%) at 1 year. Percutaneous mitral valve leaflet repair was associated with reduced hospital readmissions and potential cost-savings in post-procedural care. CONCLUSION: This study shows that percutaneous mitral valve leaflet repair using MitraClip is a relatively safe and effective treatment in patients unable to tolerate surgery and has the potential to reduce ongoing healthcare costs in the UK.

Prostatic urethral lift (UroLift): a real-world analysis of outcomes using hospital episodes statistics.

BACKGROUND: To determine real-world outcomes of prostatic urethral lift (UroLift) procedures conducted in hospitals across England. METHODS: A retrospective observational cohort was identified from Hospital Episode Statistics data including men undergoing UroLift in hospitals in England between 2017 and 2020. Procedure uptake, patient demographics, inpatient complications, 30-day accident and emergency re-attendance rate, requirement for further treatment and catheterization were captured. Kaplan-Meier and hazard analysis were used to analyse time to re-treatment. RESULTS: 2942 index UroLift procedures from 80 hospital trusts were analysed; 85.3% conducted as day-case surgery (admitted to hospital for a planned surgical procedure and returning home on the same day). In-hospital complication rate was 3.4%. 93% of men were catheter-free at 30 days. The acute accident and emergency attendance rate within 30 days was 12.0%. Results of Kaplan Meier analysis for subsequent re-treatment (including additional UroLift and endoscopic intervention) at 1 and 2 years were 5.2% [95% CI 4.2 to 6.1] and 11.9% [10.1 to 13.6] respectively. CONCLUSIONS: This real-world analysis of UroLift shows that it can be delivered safely in a day-case setting with minimal morbidity. However, hospital resource usage for catheterization and emergency hospital attendance in the first 30 days was substantial, and 12% required re-treatment at 2 years.

Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function.

High levels of the anti-apoptotic BCL-2 family member MCL-1 are frequently found in breast cancer and, appropriately, BH3-mimetic drugs that specifically target MCL-1's function in apoptosis are in development as anti-cancer therapy. MCL-1 also has reported non-canonical roles that may be relevant in its tumour-promoting effect. Here we investigate the role of MCL-1 in clinically relevant breast cancer models and address whether the canonical role of MCL-1 in apoptosis, which can be targeted using BH3-mimetic drugs, is the major function for MCL-1 in breast cancer. We show that MCL-1 is essential in established tumours with genetic deletion inducing tumour regression and inhibition with the MCL-1-specific BH3-mimetic drug S63845 significantly impeding tumour growth. Importantly, we found that the anti-tumour functions achieved by MCL-1 deletion or inhibition were completely dependent on pro-apoptotic BAX/BAK. Interestingly, we find that MCL-1 is also critical for stem cell activity in human breast cancer cells and high MCL1 expression correlates with stemness markers in tumours. This strongly supports the idea that the key function of MCL-1 in breast cancer is through its anti-apoptotic function. This has important implications for the future use of MCL-1-specific BH3-mimetic drugs in breast cancer treatment.

Activation of the S100A7/RAGE Pathway by IGF-1 Contributes to Angiogenesis in Breast Cancer.

BACKGROUND: Breast cancer (BC) mortality is increased among obese and diabetic patients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin S100A7, signaling through the receptor RAGE, prompts angiogenesis, inflammation, and BC progression. METHODS: We performed bioinformatic analysis of BC gene expression datasets from published studies. We then used Estrogen Receptor (ER)-positive BC cells, CRISPR-mediated IGF-1R KO BC cells, and isogenic S100A7-transduced BC cells to investigate the role of IGF-1/IGF-1R in the regulation of S100A7 expression and tumor angiogenesis. To this aim, we also used gene silencing and pharmacological inhibitors, and we performed gene expression and promoter studies, western blotting analysis, ChIP and ELISA assays, endothelial cell proliferation and tube formation assay. RESULTS: S100A7 expression correlates with worse prognostic outcomes in human BCs. In BC cells, the IGF-1/IGF-1R signaling engages STAT3 activation and its recruitment to the S100A7 promoter toward S100A7 increase. In human vascular endothelial cells, S100A7 activates RAGE signaling and prompts angiogenic effects. CONCLUSIONS: In ER-positive BCs the IGF-1 dependent activation of the S100A7/RAGE signaling in adjacent endothelial cells may serve as a previously unidentified angiocrine effector. Targeting S100A7 may pave the way for a better control of BC, particularly in conditions of unopposed activation of the IGF-1/IGF-1R axis.