Results of shared learning of a new radiofrequency identification localization device-a UK iBRA-NET breast cancer localisation study.

INTRODUCTION: Localisation methods for surgical excision of impalpable breast lesions have advanced in recent years, with increasing utilization of new wire-free technologies. The Hologic LOCalizer™ radiofrequency identification (RFID) tag is one such device; however, as is the case when new technologies are first introduced, little is known about clinical experiences, potential complications, and learning used to overcome perioperative challenges when changing from guidewires to RFID tags. This study reports shared learning experiences of clinicians using the LOCalizer™ as part of the national iBRA-NET localisation study. METHODS: This mixed-methods study captured shared-learning themes relating to LOCalizer™ usage as part of a multicentre prospective registry study, which collected data on each LOCalizer™ placement. Prospective, anonymized clinical and demographic data were collected and managed using a Research Electronic Data Capture (REDCap) database. Shared learning was captured prospectively as part of the registry study between January 2021 and July 2022, combined with a virtual qualitative webinar-style focus group. Learning events were then coded, grouped by theme, and suggestions for practice were produced. RESULTS: Twenty-four UK breast units submitted data on 1188 patient records pertaining to RFID-guided localisation between January 2021 and July 2022, of which 59 (5.0%) included a shared-learning event. The virtual webinar was attended by 108 healthcare professionals, including oncoplastic breast surgeons and breast radiologists. Shared-learning themes were categorized into preoperative, intraoperative, and postoperative events. CONCLUSIONS: By sharing learning outcomes associated with localisation techniques in this paper, the aim is to shorten the learning curve and potential for adverse events for users new to the LOCalizer™ technique.

Breast cancer research gaps: a questionnaire-based study to determine overall priorities and compare the priorities of patients, the public, clinicians and scientists.

OBJECTIVE: This study aims to prioritise the themes identified from the three gap analyses performed by a combination of scientists, clinicians, patients and members of the public to determine areas in breast cancer care where research is lacking. We also aimed to compare the priorities of areas of agreed research need between patients, the public, clinicians and scientists. DESIGN: A cross-section of patients, public, clinicians and scientists completed a prioritisation exercise to rank the identified themes where research is lacking in breast cancer care. PARTICIPANTS: Patients, clinicians and scientists who have experienced, managed or worked in the field of breast cancer and members of the public. METHODS: The research areas identified in the Breast Cancer Campaign, Association of Breast Surgery and North West Breast Research Collaborative gap analyses were outlined as 22 themes in lay terminology. Patients, members of the public, clinicians and scientists were invited to complete the prioritisation exercise, on paper or electronically, ranking the themes from 1 to 22. Comparisons were made with arithmetic mean ranking. RESULTS: Of the 510 prioritisation exercises completed, 179 (35%) participants were patients, 162 (32%) public, 43 (8%) scientists and 122 (24%) clinicians. The theme ranked of highest priority overall was 'better prevention' (arithmetic mean rank 6.4 (SE 0.23)). 'Better prevention' was ranked top or second by patients, public and clinicians (7 (0.39), 4.7 (0.34) and 6.8 (0.5), respectively), however, scientists ranked this as their sixth most important factor (7.7 (0.92)). The public and clinicians had good agreement with patients (r=0.84 and r=0.75, respectively), whereas scientists had moderate agreement with patients (r=0.65). Certain themes were ranked significantly differently by participant groups. Compared with clinicians, patients prioritised research into 'alternative to mammograms', 'diagnostic (cancer) blood test' and 'rare cancers' (OR 2.1 (95% CI 1.3 to 3.5), p=0.002, OR 2.1 (95% CI 1.3 to 3.5), p=0.004 and OR 1.7 (95% CI 1.1 to 2.8), p=0.03). Compared with scientists, patients deprioritised 'better laboratory models' (OR 0.4 (95% CI 0.2 to 0.8), p=0.01). CONCLUSION: This study demonstrates that patients, public, clinicians and scientists have different research priorities, with scientists being a particular outlier. This highlights the need to ensure the engagement of patients and public in research funding prioritisation decisions.

Trends in Complications Among Patients Undergoing Aortic Valve Replacement in the United States.

BACKGROUND: The treatment of severe aortic stenosis has evolved considerably since the introduction of transcatheter aortic valve replacement (TAVR), yet trends in complications for patients undergoing TAVR or surgical aortic valve replacement (SAVR) at a national level have yet to be evaluated. METHODS AND RESULTS: We performed a retrospective cohort study using Medicare data to evaluate temporal trends in complications among beneficiaries, aged ≥65 years, treated with elective isolated transfemoral TAVR or SAVR between 2012 and 2019. The study end point was the occurrence of a major complication (composite outcome) during index and up to 30 days after. Multivariable logistic regression was used to assess odds of complications for TAVR and SAVR, individually over time, and for TAVR versus SAVR, over time. The cohort included 211 212 patients (mean±SD age, 78.6±7.3 years; 45.0% women). Complication rates during index following elective isolated aortic valve replacement decreased from 49% in 2012 to 22% in 2019. These reductions were more pronounced for TAVR (41% to >19%, Δ=22%) than SAVR (51% to >47%, Δ=4%). After risk adjustment, the risk of any complication with TAVR was 47% (P<0.0001) lower compared with SAVR in 2012, and 78% (P<0.0001) lower in 2019. TAVR was independently associated with reduced odds of complications each year compared with 2012, with the magnitude of benefit increasing over time (2013 versus 2012: odds ratio [OR], 0.89 [95% CI, 0.81-0.97]; 2019 versus 2012: OR, 0.35 [95% CI, 0.33-0.38]). These findings are consistent for complications up to 30 days from index. CONCLUSIONS: Between 2012 and 2019, the risk of complications after aortic valve replacement among Medicare beneficiaries decreased significantly, with larger absolute and relative changes among patients treated with TAVR than SAVR.

Decreasing pacemaker implantation rates with Evolut supra-annular transcatheter aortic valves in a large real-world registry.

BACKGROUND: Permanent pacemaker implantation (PPI) rates following transcatheter aortic valve replacement (TAVR) remain a concern. We assessed the PPI rates over time in patients implanted with an Evolut supra-annular, self-expanding transcatheter valve from the US STS/ACC TVT Registry. METHODS: Patients who underwent TAVR with an Evolut R, Evolut PRO or Evolut PRO+ valve between July 2018 (Q3) and June 2021 (Q2) were included. PPI rates were reported by calendar quarter. In-hospital PPI rates were reported as proportions and 30-day rates as Kaplan-Meier estimates. A Cox regression model was used to determine potential predictors of a new PPI within 30 days of the TAVR procedure. RESULTS: From July 2018 to June 2021, 54,014 TAVR procedures were performed using Evolut valves. Mean age was 79.3 ± 8.8 years and 49.2 % were male. The 30-day PPI rate was 16.6 % in 2018 (Q3) and 10.8 % in 2021 (Q2, 34.9 % decrease, p < 0.001 for trend across all quarters). The in-hospital PPI rate decreased by 40.1 %; from 14.7 % in 2018 (Q3) to 8.8 % in 2021 (Q2) (p < 0.001 for trend across all quarters). Significant predictors of a new PPI within 30 days included a baseline conduction defect, history of atrial fibrillation, home oxygen, and diabetes mellitus. CONCLUSION: From 2018 to 2021, TAVR with an Evolut transcatheter heart valve in over 50,000 patients showed a significant decreasing trend in the rates of in-hospital and 30-day PPI, representing the lowest rate of PPI in any large real-world registry of Evolut. During the same evaluated period, high device success and shorter length of stay was also observed.

Deriving acceptable limits for non-mutagenic impurities in medicinal products - Durational adjustments.

ICH Q3A/B guidelines are not intended for application during the clinical research phase of development and durationally adjusted qualification thresholds are not included. A central tenet of ICH Q3A is that lifetime exposure to 1 mg/day of an unqualified non-mutagenic impurity (NMI) is not a safety concern. An analysis of in vivo toxicology data from 4878 unique chemicals with established NO(A)ELs was conducted to determine whether durationally adjusted qualification limits can be supported. Although not recommended in ICH Q3A/B, a conservative approach was taken by using allometric scaling in the analysis. Following allometric scaling of the 5th percentile of the distribution of NO(A)ELs from available chronic toxicology studies, it was reconfirmed that there is a safety basis for the 1 mg/day qualification threshold in ICH Q3A. Additionally, allometric scaling of the 5th percentile of the distribution of NO(A)ELs from sub-acute and sub-chronic toxicology studies could support acceptable limits of 20 and 5 mg/day for an unqualified NMI for dosing durations of less than or greater than one month, respectively. This analysis supports durationally adjusted NMI qualification thresholds for pharmaceuticals that protect patient safety and contribute to 3Rs efforts for qualifying impurities using new approach methods.

New limits proposed for the management of non-mutagenic impurities.

Multiple international guidelines exist that describe both quality and safety considerations for the control of the broad spectrum of impurities inherent to drug substance and product manufacturing processes. However, regarding non-mutagenic impurities (NMI) the most relevant ICH Q3A/B guidelines are not applicable during early phases of drug development leading to confusion about acceptable limits at this stage. Thus, there is need for more flexible approaches that ensure that patient safety remains paramount, while taking into consideration the limited duration of exposure. An EFPIA survey, which collected quantitative data from different types of studies applied to qualify impurities in accordance with ICH Q3A, shows that no toxicities could be attributed to any of the 467 impurities at any tested level in vivo. This data combined with earlier published toxicological datasets encompassing drug substances and intermediates, food related substances and chemicals provide convincing evidence that for NMIs, the application of a generic 5 mg/day limit for an exposure duration <6 months, and a 1 mg/day generic limit for life-long exposure, provides sufficient margins to ensure patient safety. Hence, application of these absolute limits to trigger qualification studies (instead of the relative limits described in Q3A/B), is considered warranted. This approach will prevent conduct of unnecessary dedicated impurity qualification studies and the resulting use of animals.

Temporal Trends, Outcomes, and Predictors of Next-Day Discharge and Readmission Following Uncomplicated Evolut Transcatheter Aortic Valve Replacement: A Propensity Score-Matched Analysis.

BACKGROUND: Next-day discharge (NDD) outcomes following uncomplicated self-expanding transcatheter aortic valve replacement have not been studied. Here, we compare readmission rates and clinical outcomes in NDD versus non-NDD transcatheter aortic valve replacement with Evolut. METHODS AND RESULTS: Society of Thoracic Surgeons/American College of Cardiology TVT (Transcatheter Valve Therapy) Registry patients (n=29 597) undergoing elective transcatheter aortic valve replacement with self-expanding supra-annular valves (Evolut R, PRO, and PRO+) from July 2019 to June 2021 were stratified by postprocedure length of stay: ≤1 day (NDD) versus >1 day (non-NDD). Propensity score matching was used to compare risk adjusted 30-day readmission rates and 1-year outcomes in NDD versus non-NDD, and multivariable regression to determine predictors of NDD and readmission. Between the first and last calendar quarter, the rate of NDD increased from 45.4% to 62.1% and median length of stay decreased from 2 days to 1. Propensity score matching produced relatively well-matched NDD and non-NDD cohorts (n=10 549 each). After matching, NDD was associated with lower 30-day readmission rates (6.3% versus 8.4%; P<0.001) and 1-year adverse outcomes (death, 7.0% versus 9.3%; life threatening/major bleeding, 1.6% versus 3.4%; new permanent pacemaker implantation/implantable cardioverter-defibrillator, 3.6 versus 11.0%; [all P<0.001]). Predictors of NDD included non-Hispanic ethnicity, preexisting permanent pacemaker implantation/implantable cardioverter-defibrillator, and previous surgical aortic valve replacement. CONCLUSIONS: Most patients undergoing uncomplicated self-expanding Evolut transcatheter aortic valve replacement are discharged the next day. This study found that NDD can be predicted from baseline patient characteristics and was associated with favorable 30-day and 1-year outcomes, including low rates of permanent pacemaker implantation and readmission.

A randomised controlled trial of Pre-Operative Oncotype DX testing in early-stage breast cancer (PRE-DX study) - Study protocol.

BACKGROUND: The Oncotype DX® Breast Recurrence Score assay can guide recommendations made to patients with oestrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer regarding post-surgery adjuvant therapy. Standard practice is to order the test in the post-operative setting on a specimen from the excised invasive carcinoma. However, it has been shown to be technically possible to perform the test on the diagnostic core biopsy. By testing the diagnostic core biopsy in the pre-operative setting, the wait for excised invasive carcinoma Recurrence Score results could be reduced allowing patients to be more accurately counselled regarding their treatment pathway sooner with any adjuvant treatment recommendations expedited. This would allow for more efficient streaming of follow up appointments. The aim of this study is to compare the impact on the patient treatment pathway of performing the Oncotype DX® test on the diagnostic core biopsy pre-operatively (intervention) as opposed to the excised invasive carcinoma (control). METHODS AND ANALYSIS: This parallel group randomised controlled trial aims to recruit 330 newly diagnosed patients with grade 2 or grade 3, ER+, HER2-, invasive intermediate risk early-stage breast cancer. Participants will be randomised 2:1 to the preoperative testing of the diagnostic core biopsy compared to the post-operative testing of the excision specimen. The primary endpoint is number of clinical touchpoints between treating team and patient from initial approach until offer and prescription of the first adjuvant treatment. Secondary endpoints include time from diagnosis to offer and prescription of the first adjuvant treatment, patient-reported anxiety scores and health cost impact analysis collected at baseline, following the post-operative clinic and following the offer of adjuvant treatment, and number of alterations in treatment sequence from original planned surgical treatment to neoadjuvant therapy. TRIAL REGISTRATION: The study was registered on ISRCTN (ISRCTN14337451) on the 16th August 2022.

A Retrospective Audit of the Triage Process Introduced for Breast Referrals Received During the Covid-19 Pandemic.

PURPOSE: Due to restrictions on breast clinic appointments during the Covid-19 pandemic, a triage process was introduced for new patient referrals. The robustness of this process was examined by analysing the incidence of cancer diagnosis and wait times to treatment. METHODS: Patients were triaged by secondary care consultant surgeons to an urgent appointment if they had high-risk symptoms based on prespecified guidelines eg, a lump or previous cancer. Those with non-urgent symptoms were seen on a deferred basis. A retrospective audit of patients referred between March 23 and July 20, 2020 was performed, to investigate incidence of cancer, concordance of primary and secondary care diagnosis, and the wait times to first appointment. RESULTS: Most patients with breast-related symptoms received a face-to-face appointment (69%) with a Primary Care Physician (PCP) or Nurse Practitioner (NP), with 544 (31%) having a telephone PCP/NP appointment. Of 2023 patients, 1461 were triaged by the receiving breast unit to an urgent appointment, 461 to a deferred appointment and 101 to a breast pain telephone clinic. A diagnosis of breast cancer was made in 111/1461 (7.6%), 5/461 (1.1%) and 0% in these triaged groups respectively, and the median wait time to first appointment was 14 days (range 1-94), 32 days (range 6-114) and 21 days (range 10-52, P < .001). CONCLUSION: The one-stop triage process was safe, with statistically fewer cancer diagnoses in patients allocated a deferred appointment, at a rate similar to that seen in a screening population.

N-Nitrosodimethylamine investigations in Muta™Mouse define point-of-departure values and demonstrate less-than-additive somatic mutant frequency accumulations.

The N-nitrosamine, N-nitrosodimethylamine (NDMA), is an environmental mutagen and rodent carcinogen. Small levels of NDMA have been identified as an impurity in some commonly used drugs, resulting in several product recalls. In this study, NDMA was evaluated in an OECD TG-488 compliant Muta™Mouse gene mutation assay (28-day oral dosing across seven daily doses of 0.02-4 mg/kg/day) using an integrated design that assessed mutation at the transgenic lacZ locus in various tissues and at the endogenous Pig-a gene-locus, along with micronucleus frequencies in peripheral blood. Liver pathology was determined together with NDMA exposure in blood and liver. The additivity of mutation induction was assessed by including two acute single-dose treatment groups (i.e. 5 and 10 mg/kg dose on Day 1), which represented the same total dose as two of the repeat dose treatment groups. NDMA did not induce statistically significant increases in mean lacZ mutant frequency (MF) in bone marrow, spleen, bladder, or stomach, nor in peripheral blood (Pig-a mutation or micronucleus induction) when tested up to 4 mg/kg/day. There were dose-dependent increases in mean lacZ MF in the liver, lung, and kidney following 28-day repeat dosing or in the liver and kidney after a single dose (10 mg/kg). No observed genotoxic effect levels (NOGEL) were determined for the positive repeat dose-response relationships. Mutagenicity did not exhibit simple additivity in the liver since there was a reduction in MF following NDMA repeat dosing compared with acute dosing for the same total dose. Benchmark dose modelling was used to estimate point of departure doses for NDMA mutagenicity in Muta™Mouse and rank order target organ tissue sensitivity (liver > kidney or lung). The BMD50 value for liver was 0.32 mg/kg/day following repeat dosing (confidence interval 0.21-0.46 mg/kg/day). In addition, liver toxicity was observed at doses of ≥ 1.1 mg/kg/day NDMA and correlated with systemic and target organ exposure. The integration of these results and their implications for risk assessment are discussed.

Concomitant Left Atrial Appendage Occlusion and Transcatheter Aortic Valve Replacement Among Patients With Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is common in patients undergoing transcatheter aortic valve replacement (TAVR) and is associated with increased risk of bleeding and stroke. While left atrial appendage occlusion (LAAO) is approved as an alternative to anticoagulants for stroke prevention in patients with AF, placement of these devices in patients with severe aortic stenosis, or when performed at the same time as TAVR, has not been extensively studied. METHODS: WATCH-TAVR (WATCHMAN for Patients with AF Undergoing TAVR) was a multicenter, randomized trial evaluating the safety and effectiveness of concomitant TAVR and LAAO with WATCHMAN in AF patients. Patients were randomized 1:1 to TAVR + LAAO or TAVR + medical therapy. WATCHMAN patients received anticoagulation for 45 days followed by dual antiplatelet therapy until 6 months. Anticoagulation was per treating physician preference for patients randomized to TAVR + medical therapy. The primary noninferiority end point was all-cause mortality, stroke, and major bleeding at 2 years between the 2 strategies. RESULTS: The study enrolled 349 patients (177 TAVR + LAAO and 172 TAVR + medical therapy) between December 2017 and November 2020 at 34 US centers. The mean age of patients was 81 years, and the mean scores for CHA2DS2-VASc and HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly) were 4.9 and 3.0, respectively. At baseline, 85.4% of patients were taking anticoagulants and 71.3% patients were on antiplatelet therapy. The cohorts were well-balanced for baseline characteristics. The incremental LAAO procedure time was 38 minutes, and the median contrast volume used for combined procedures was 119 mL versus 70 mL with TAVR alone. At the 24-month follow-up, 82.5% compared with 50.8% of patients were on any antiplatelet therapy, and 13.9% compared with 66.7% of patients were on any anticoagulation therapy in TAVR + LAAO compared with TAVR + medical therapy group, respectively. For the composite primary end point, TAVR + LAAO was noninferior to TAVR + medical therapy (22.7 versus 27.3 events per 100 patient-years for TAVR + LAAO and TAVR + medical therapy, respectively; hazard ratio, 0.86 [95% CI, 0.60-1.22]; Pnoninferiority<0.001). CONCLUSIONS: Concomitant WATCHMAN LAAO and TAVR is noninferior to TAVR with medical therapy in severe aortic stenosis patients with AF. The increased complexity and risks of the combined procedure should be considered when concomitant LAAO is viewed as an alternative to medical therapy for patients with AF undergoing TAVR. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03173534.

DMSOP-cleaving enzymes are diverse and widely distributed in marine microorganisms.

Dimethylsulfoxonium propionate (DMSOP) is a recently identified and abundant marine organosulfur compound with roles in oxidative stress protection, global carbon and sulfur cycling and, as shown here, potentially in osmotolerance. Microbial DMSOP cleavage yields dimethyl sulfoxide, a ubiquitous marine metabolite, and acrylate, but the enzymes responsible, and their environmental importance, were unknown. Here we report DMSOP cleavage mechanisms in diverse heterotrophic bacteria, fungi and phototrophic algae not previously known to have this activity, and highlight the unappreciated importance of this process in marine sediment environments. These diverse organisms, including Roseobacter, SAR11 bacteria and Emiliania huxleyi, utilized their dimethylsulfoniopropionate lyase 'Ddd' or 'Alma' enzymes to cleave DMSOP via similar catalytic mechanisms to those for dimethylsulfoniopropionate. Given the annual teragram predictions for DMSOP production and its prevalence in marine sediments, our results highlight that DMSOP cleavage is likely a globally significant process influencing carbon and sulfur fluxes and ecological interactions.

Clinical Impact of Standardized TAVR Technique and Care Pathway: Insights From the Optimize PRO Study.

BACKGROUND: Procedural success and clinical outcomes after transcatheter aortic valve replacement (TAVR) have improved, but residual aortic regurgitation (AR) and new permanent pacemaker implantation (PPI) rates remain variable because of a lack of uniform periprocedural management and implantation. OBJECTIVES: The Optimize PRO study evaluates valve performance and procedural outcomes using an "optimized" TAVR care pathway and the cusp overlap technique (COT) in patients receiving the Evolut PRO/PRO+ (Medtronic) self-expanding valves. METHODS: Optimize PRO, a nonrandomized, prospective, postmarket study conducted in the United States, Canada, Europe, Middle East, and Australia, is enrolling patients with severe symptomatic aortic stenosis and no pre-existing pacemaker. Sites follow a standardized TAVR care pathway, including early discharge and a conduction disturbance management algorithm, and transfemoral deployment using the COT. RESULTS: A total of 400 attempted implants from the United States and Canada comprised the main cohort of this second interim analysis. The mean age was 78.7 ± 6.6 years, and the mean Society of Thoracic Surgeons predictive risk of mortality was 3.0 ± 2.4. The median length of stay was 1 day. There were no instances of moderate or severe AR at discharge. At 30 days, all-cause mortality or stroke was 3.8%, all-cause mortality was 0.8%, disabling stroke was 0.7%, hospital readmission was 10.1%, and cardiovascular rehospitalization was 6.1%. The new PPI rate was 9.8%, 5.8% with 4-step COT compliance. In the multivariable model, right bundle branch block and the depth of the implant increased the risk of PPI, whereas using the 4-step COT lowered 30-day PPI. CONCLUSIONS: The use of the TAVR care pathway and COT resulted in favorable clinical outcomes with no moderate or severe AR and low PPI rates at 30 days while facilitating early discharge and reproducible outcomes across various sites and operators. (Optimize PRO; NCT04091048).

Breast Reconstruction Outcomes with and without Strattice: Long-Term Outcomes of a Multicenter Study Comparing Strattice Immediate Implant Breast Reconstruction with Submuscular Implant Reconstruction.

BACKGROUND: Over half of immediate implant-based breast reconstructions (IBBR) are performed with an acellular dermal matrix, despite limited long-term outcome data. METHODS: The Breast Reconstruction Outcomes with and without Strattice, or BROWSE, study was a retrospective multicenter cohort study comparing consecutive patients who had undergone immediate Strattice IBBR with those who had undergone immediate IBBR with a submuscular technique between January of 2009 and December of 2015. RESULTS: This study compared 553 Strattice reconstructions with 242 submuscular reconstructions, with a median follow-up of 4.3 years (range, 2 to 9.3 years) and 5.7 years (range, 2 to 8.1 years), respectively, demonstrating an equivalent total complication rate [Strattice, n = 204 (36.9%); submuscular, n = 77 (31.8%); P = 0.17] and implant loss rate (8.5% versus 5.4%, respectively; P = 0.12). Infection rates and wound dehiscence rates were higher in the Strattice cohort [ n = 114 (20.6%) versus n = 31 (12.8%), P = 0.009; and n = 90 (16.3%) versus n = 25 (10.4%), P = 0.03, respectively]. Overall revision rates were comparable [ n = 226 (46.7%) versus n = 79 (41.1%); P = 0.2], but significantly fewer Strattice reconstructions required revision surgery for capsular contracture (5.3% versus 15.6%; P < 0.001). CONCLUSION: Although the risk of complications associated with Strattice reconstruction is numerically higher than that for submuscular coverage, the difference is small and not statistically significant, and likely outweighed by the clear reduced rate of revision surgery because of capsular contracture when Strattice is used. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Localization Techniques for Non-Palpable Breast Lesions: Current Status, Knowledge Gaps, and Rationale for the MELODY Study (EUBREAST-4/iBRA-NET, NCT 05559411).

BACKGROUND: Surgical excision of a non-palpable breast lesion requires a localization step. Among available techniques, wire-guided localization (WGL) is most commonly used. Other techniques (radioactive, magnetic, radar or radiofrequency-based, and intraoperative ultrasound) have been developed in the last two decades with the aim of improving outcomes and logistics. METHODS: We performed a systematic review on localization techniques for non-palpable breast cancer. RESULTS: For most techniques, oncological outcomes such as lesion identification and clear margin rate seem either comparable with or better than for WGL, but evidence is limited to small cohort studies for some of the devices. Intraoperative ultrasound is associated with significantly higher negative margin rates in meta-analyses of randomized clinical trials (RCTs). Radioactive techniques were studied in several RCTs and are non-inferior to WGL. Smaller studies show higher patient preference towards wire-free localization, but little is known about surgeons' and radiologists' attitudes towards these techniques. CONCLUSIONS: Large studies with an additional focus on patient, surgeon, and radiologist preference are necessary. This review aims to present the rationale for the MELODY (NCT05559411) study and to enable standardization of outcome measures for future studies.

Management of acute testicular pain in children: changing trends with improvements in scrotal ultrasonography over 18 years.

Introduction: Doppler scrotal ultrasonography (US) is the modality of choice in diagnosing testicular torsion. We aimed to evaluate the performance of scrotal US in diagnosing testicular torsion over the past 18 years in our institution and determine the factors contributing to the length of wait times for it. Methods: A retrospective review was conducted of boys who presented with acute scrotal pain from 2014 to 2015. US reports, operative findings, final diagnosis and key time points of the patients' journey (time to emergency department consultation, time to admission, time to US and time to operating theatre [OT]) were collected. US performance results were compared with those observed in a historical cohort from 1998 to 2004. Wait times were compared between operated and non-operated patients. Results: Data from 519 boys with a mean age of 9.15 years was collected. Of these, 438 (84.4%) boys had undergone initial scrotal US; of these scrotal US cases, 28 were surgically explored, with 23 confirmed to have torsion. Another five cases were explored without prior US, and all were confirmed to have torsion. Performance analysis of US showed a sensitivity of 100% and a specificity of 98.8%. There was no significant difference between wait times of operated and non-operated patients. Time to US (P < 0.0001, r = 0.96) and time to OT (P < 0.0001, r = 0.64) correlated significantly with the total time from presentation to surgery. Conclusion: There has been an improvement in the diagnostic performance of scrotal US for testicular torsion over the past 18 years. Quality improvement programmes targeted at reducing wait times for patients presenting with acute scrotum should target time to US and time to OT.

Axillary sentinel lymph node identification using superparamagnetic iron oxide versus radioisotope in early stage breast cancer: The UK SentiMag trial (SMART study).

BACKGROUND & OBJECTIVES: Sentinel lymph node biopsy (SLNB) is an accurate and reliable method for staging the axilla in early breast cancer. The gold standard technique for localizing the sentinel lymph node (SLN) is the use of radioisotope with or without blue dye. However, this technique has its limitations. Various alternatives have been explored to overcome the disadvantages of the standard SLNB technique and superparamagnetic iron oxide mapping agents have garnered significant attention. The SMART study aims to compare the magnetic technique using the superparamagnetic iron oxide particles (SPIO, Sienna+®) to the radioisotope technique (Tc99) +/- blue dye, for SLN identification in patients with early breast cancer. METHODS: A prospective, multicenter study was done that recruited 109 clinically node-negative early-stage breast cancer patients from five centres in the United Kingdom (UK). The patients received radioisotope ± blue dye injections, followed by intraoperative injection of magnetic tracer prior to SLNB. The sentinel node identification rate was compared between the magnetic and standard techniques to evaluate detection rate (per patient and per node), non-inferiority and concordance. RESULTS: Data was analysed for 107 patients. The per patient detection rate was 98.13% (105/107) when using the magnetic tracer and 92.26% (103/107) when using the standard technique. The nodal detection rate was 93.07% (188/202 nodes) when using the magnetic tracer and 96.53% (195/202) when using the standard technique. Of the 31 patients with positive sentinel lymph nodes (SLNs), all 31 (100%) were detected by both techniques. CONCLUSION: Our study demonstrates that the magnetic technique is a feasible method for SLNB, with an identification rate that is not inferior to the standard technique. The magnetic technique offers a suitable alternative to the standard technique thereby avoiding the need for the complexities of nuclear medicine, the hazards of radiation and the anaphylaxis risk of blue dye.

Prediction of inotropic effect based on calcium transients in human iPSC-derived cardiomyocytes and machine learning.

Functional changes to cardiomyocytes are undesirable during drug discovery and identifying the inotropic effects of compounds is hence necessary to decrease the risk of cardiovascular adverse effects in the clinic. Recently, approaches leveraging calcium transients in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been developed to detect contractility changes, induced by a variety of mechanisms early during drug discovery projects. Although these approaches have been able to provide some predictive ability, we hypothesised that using additional waveform parameters could offer improved insights, as well as predictivity. In this study, we derived 25 parameters from each calcium transient waveform and developed a modified Random Forest method to predict the inotropic effects of the compounds. In total annotated data for 48 compounds were available for modelling, out of which 31 were inotropes. The results show that the Random Forest model with a modified purity criterion performed slightly better than an unmodified algorithm in terms of the Area Under the Curve, giving values of 0.84 vs 0.81 in a cross-validation, and outperformed the ToxCast Pipeline model, for which the highest value was 0.76 when using the best-performing parameter, PW10. Our study hence demonstrates that more advanced parameters derived from waveforms, in combination with additional machine learning methods, provide improved predictivity of cardiovascular risk associated with inotropic effects.