Guy's and St Thomas' NHS Foundation Trust

Background Objective neuromuscular monitoring remains the single most reliable method to ensure optimal perioperative neuromuscular management. Nevertheless, the prediction of clinical neuromuscular endpoints by means of Pharmacokinetic (PK) and Pharmacodynamic (PD) modelling has the potential to complement monitoring and improve perioperative neuromuscular management.s Study objective The present study aims to assess the performance of published Rocuronium PK/PD models in predicting intraoperative Train-of-four (TOF) ratios when benchmarked against electromyographic TOF measurements. Design Observational trial. Setting Tertiary Belgian hospital, from August 2020 up to September 2021. Patients and interventions Seventy-four patients undergoing general anaesthesia for elective surgery requiring the administration of rocuronium and subject to continuous EMG neuromuscular monitoring were included. PK/PD-simulated TOF ratios were plotted and synchronised with their measured electromyographic counterparts and their differences analysed by means of Predictive Error derivatives (Varvel criteria). Main results Published rocuronium PK/PD models overestimated clinically registered TOF ratios. The models of Wierda, Szenohradszky, Cooper, Alvarez-Gomez and McCoy showed significant predictive consistency between themselves, displaying Median Absolute Performance Errors between 38% and 41%, and intra-individual differences (Wobble) between 14 and 15%. The Kleijn model outperformed the former with a lower Median Absolute Performance Error (16%, 95%CI [0.01; 57]) and Wobble (11%, 95%CI [0.01; 34]). All models displayed considerably wide 95% confidence intervals for all performance metrics, suggesting a significantly variable performance. Conclusions Simulated TOF ratios based on published PK/PD models do not accurately predict real intraoperative TOF ratio dynamics.

Breast cancer is a historic disease. The first written documentation describing breast cancer was in Edwin Smith Papyrus in 3000 bc [1]. Since then, there have been several theories attempting to explain possible underlying causes of breast cancer; none of them were scientifically based. It was not until much later that the nature of breast cancer began to unravel [2].

Sentinel lymph node biopsy (SLNB) is now standard of care for patients with no axillary nodal metastasis identified clinically or radiologically pre-operatively, as nodal status remains one of the most important prognostic factors in invasive breast cancer. More recently, targeted axillary dissection (TAD) with SLNB has been shown to be valuable for patients with excellent/complete response to neo-adjuvant chemotherapy. Both SLNB and TAD specimens require thorough and careful handling and examination in the pathology laboratory in order to deliver accurate clinical results. We describe here the methods used in histopathology laboratories for the assessment of these specimens and suggestions for features to be included in histology reports.

Essential thrombocythemia (ET), one of the BCR-ABL-negative myeloproliferative neoplasms (MPNs), is a hematopoietic malignancy characterized by overproduction of platelets due to clonal expansion of megakaryocytes. Enhanced constitutive JAK-STAT (janus kinase 2—signal transducer and activator of transcription) signaling is central to disease pathophysiology. ET, presenting with persistent thrombocytosis, may represent a myriad of conditions and careful establishing of an accurate diagnosis is key to subsequent optimal management. This chapter reviews in detail goals of therapy in ET and treatment strategies incorporating cytoreductive, noncytoreductive, and novel therapies. Finally, approaches to specific scenarios and their management are discussed including young patients, triple-negative for classical driver mutation ET patients, pregnancy, and splanchnic vein thrombosis.

The combination of radioactive colloid (RI, Tc99) with a blue dye (BD) for visual reference has traditionally been regarded as the gold standard for the mapping and identification of sentinel lymph nodes (SLNs), following the first landmark trials validating the outcomes of SLN biopsy (SLNB) [1–4]. The isotope is usually injected in the sub-areolar region or within the parenchyma around the tumour, a few hours before the operation. The BD is injected intra-operatively under anaesthesia, and the breast is massaged to facilitate tracer migration towards the axilla. The tracers reach the SLN via the lymphatic system. The SLN is then detected using a hand-held gamma probe or by following a blue lymphatic to a blue SLN. The procedure is conventionally considered complete when the residual gamma probe signal in the axilla is less than 10% of the maximum signal of the lymph node retrieved [4]. This technique results in detection rates as high as 99% with a false-negative rate of less than 5% and axillary recurrence rates lower than 2% [5–7]. The procedure is reasonably intuitive, is easy to standardise and has therefore gained wide acceptance. This combined technique over time has become the benchmark or the reference for SLNB procedures.

Management of the axilla has seen a significant evolution over the last four decades with an increasing trend towards de-escalation to reduce morbidity and enhance quality of life (QOL) without comprising long-term oncological outcomes in breast cancer patients. The introduction of newer systemic treatments has, to a great deal, driven this approach of de-escalation. Axillary lymph node dissection (ALND) remained the standard of care for several decades until the late twentieth century. In 1971, the NSABP-B04 trial laid the foundation for de-escalation of axillary surgery. It reported no benefit in overall survival (OS) with ALND when compared with total mastectomy alone or total mastectomy followed by chest wall and regional nodal irradiation (RNI) in clinically node-negative patients with early-stage breast cancer (EBC) [1]. However, despite these results, ALND continued to be the standard of care for several years. This was primarily the case as ALND did not only provide local control but also prognostic information by accurately staging the axilla which in turn guided the recommendations for optimal adjuvant therapy. Towards the end of the twentieth century, the NSABP-B32 and a trial conducted in Milan showed that SLNB could be safely used instead of ALND to provide the same information with considerably less morbidity in patients with EBC [2, 3]. The earlier part of the twenty-first century then saw the role of ALND diminish in patients with EBC having positive sentinel nodes (SN) with trials such as AMAROS and ACOSOG-Z11 [4, 5]. This chapter will mainly focus on the potential role of diminishing ALND in patients receiving neo-adjuvant chemotherapy (NACT) based on recent evidence and guidelines. This concept currently applies to patients with operable breast cancer (cT1–3, N0-cN1) as the feasibility and accuracy of SLNB post-NACT are questionable in patients with locally advanced breast cancer (LABC-T4, cN2, inflammatory breast cancer).

The lymphatic system represents a part of the immune system, and it is constituted by a network of lymphatic vessels, lymph nodes (LNs), lymphatic organs and tissues. Tumoural cells are carried in the lymphatic system and trapped in the LNs, commonly metastatic sites. In the late 1800s, Sappey was the first to describe breast lymphatic drainage, demonstrating that axillary LNs collect up to 80% of the breast lymph Nowadays, every newly diagnosed BC patient undergoes a pre-operative assessment of the axilla. Moreover, recent clinical trials have proved that, in early-stage BC with no pre-operative nodal involvement (N0), de-escalating axillary surgical treatment involves no prognostic detriment. Thus, establishing the gold standard to determine cN0 is pivotal. The diagnostic methods at our disposal usually range from physical examination and ultrasound (US) scan to fine-needle aspiration cytology (FNAC) or core needle biopsy (CNB).

Introduction Psoriatic arthritis (PsA) affects around 150 000 people in the UK of whom around 50% require treatment with biologics. The most used biologics for PsA target tumour necrosis factor (TNF) or interleukin-17A (IL-17A). About 50% of patients respond to each, but it is not currently possible to predict response for individual patients, necessitating sequential treatment steps. A recent proof of concept study in PsA suggested that using peripheral immunophenotype to choose therapy could improve time to treatment response. This study will test the hypothesis, within an open-label parallel-group biomarker-stratified multicentre randomised controlled trial, which the baseline proportion of CD4+T cells with an activated type 17 immunophenotype (Th17 levels) predicts response to IL-17A or TNF inhibitors in PsA. Additional analyses will identify if the model can be refined by combining additional clinical and immunophenotypic factors. Statistical modelling will be used to predict the likely effectiveness of these approaches compared with standard care. Methods and analysis Patients with PsA eligible to start their first biologic as part of standard care are recruited and baseline blood tests are taken for immunophenotyping. Participants are stratified equally by Th17 levels and randomised 1:1 to receive either TNF (adalimumab) or IL-17A (secukinumab) inhibitors. The primary analysis will establish the interaction between baseline immunophenotype and treatment on the primary outcome (achievement of minimal disease activity criteria at week 24). In secondary analysis, modelling will identify if this prediction model can be optimised further by incorporating clinical phenotypes and additional immunophenotyping techniques. Ethics and dissemination Ethical approval for the study was granted by the North West Preston Research Ethics Committee (ref 21/NW/0016). Dissemination will be via conference presentations and peer-reviewed publications, aiming to impact on treatment guidelines. Trial registration number ISRCTN17228602 .

With the onset of COVID-19, the development of ex vivo laboratory models became an urgent priority to study host-pathogen interactions in response to the pandemic. In this study, we aimed to establish an ex vivo mucosal tissue explant challenge model for studying SARS-CoV-2 infection and replication. Nasal or oral tissue samples were collected from eligible participants and explants generated from the tissue were infected with various SARS-CoV-2 strains, including IC19 (lineage B.1.13), Beta (lineage B.1.351) and Delta (lineage B.1.617.2). A qRT-PCR assay used to measure viral replication in the tissue explants over a 15-day period, demonstrated no replication for any viral strains tested. Based on this, the ex vivo challenge protocol was modified by reducing the viral infection time and duration of sampling. Despite these changes, viral infectivity of the nasal and oral mucosa was not improved. Since 67% of the enrolled participants were already vaccinated against SARS-CoV-2, it is possible that neutralizing antibodies in explant tissue may have prevented the establishment of infection. However, we were unable to optimize plaque assays aimed at titrating the virus in supernatants from both infected and uninfected tissue, due to limited volume of culture supernatant available at the various collection time points. Currently, the reasons for the inability of these mucosal tissue samples to support replication of SARS-CoV-2 ex vivo remains unclear and requires further investigation.

Importance Although several clinician- and patient-reported outcome measures have been developed for trials in hidradenitis suppurativa (HS), there is currently no consensus on which measures are best suited for use in clinical practice. Identifying validated and feasible measures applicable to the practice setting has the potential to optimize treatment strategies and generate generalizable evidence that may inform treatment guidelines. Objective To establish consensus on a core set of clinician- and patient-reported outcome measures recommended for use in clinical practice and to establish the appropriate interval within which these measures should be applied. Evidence Review Clinician- and patient-reported HS measures and studies describing their psychometric properties were identified through literature reviews. Identified measures comprised an item reduction survey and subsequent electronic Delphi (e-Delphi) consensus rounds. In each consensus round, a summary of outcome measure components and scoring methods was provided to participants. Experts were provided with feasibility characteristics of clinician measures to aid selection. Consensus was achieved if at least 67% of respondents agreed with use of a measure in clinical practice. Findings Among HS experts, response rates for item reduction, e-Delphi round 1, and e-Delphi round 2 surveys were 76.4% (42 of 55), 90.5% (38 of 42), and 92.9% (39 of 42), respectively; among patient research partners (PRPs), response rates were 70.8% (17 of 24), 100% (17 of 17), and 82.4% (14 of 17), respectively. The majority of experts across rounds were practicing dermatologists with 18 to 19 years of clinical experience. In the final e-Delphi round, most PRPs were female (12 [85.7%] vs 2 males [11.8%]) and aged 30 to 49 years. In the final e-Delphi round, HS experts and PRPs agreed with the use of the HS Investigator Global Assessment (28 [71.8%]) and HS Quality of Life score (13 [92.9%]), respectively. The most expert-preferred assessment interval in which to apply these measures was 3 months (27 [69.2%]). Conclusions and Relevance An international group of HS experts and PRPs achieved consensus on a core set of HS measures suitable for use in clinical practice. Consistent use of these measures may lead to more accurate assessments of HS disease activity and life outcomes, facilitating shared treatment decision-making in the practice setting.

Introduction/Background High grade endometrioid endometrial cancer (HGEEC) is a heterogeneous group of tumors with unclear prognostic features. The aim of the present study is to evaluate the independent risk factors for recurrence and mortality and to describe the recurrence patterns of HGEEC. Methodology Ninety-six consecutive cases of HGEEC treated with primary surgery in a single Tertiary Center were retrospectively reviewed. Clinicopathological and treatment details were recorded, and all patients were closely followed up. Results Disease-free, overall and cancer-specific survival rates were 83.8%, 77.8% and 83.6%, respectively. Cervical stromal involvement was independently related to recurrence (HR = 25.67; 95%CI 2.95–223.30; p = 0.003) and cancer-related death (HR = 15.39; 95%CI 1.29–183.43; p = 0.031) after adjusting for other pathological and treatment variables. Recurrence rate was 16%, with 60% of these cases having lung metastases and only one case with single vaginal vault recurrence. 81.81% of the recurrences presented with symptoms and not a single recurrence was diagnosed in routine follow-up clinical examination. Conclusion In conclusion, the recurrence pattern may suggest that patient-initiated follow-up (PIFU) could be considered a potential alternative to clinical-based follow-up for HGEEC survivors, especially for patients without cervical involvement and after two years from treatment. Additional caution is needed in patients with cervical stromal involvement. Disclosures Authors have nothing to disclose

Introduction/Background Ovarian cancer is the 6th most common malignancy with a 35% survival rate across all stages at 10 years. Ultrasound is a widely used tool for ovarian tumour diagnosis and accurate pre-operative diagnosis is essential for appropriate patient management. Artificial intelligence is an emerging field within gynaecology and has been shown to aid in the ultrasound diagnosis of ovarian cancers. Methodology EMBASE and MEDLINE databases were searched. All type of clinical studies that used artificial intelligence in ultrasound for the diagnosis of ovarian malignancies were screened. Studies with the histopathological findings as standard were used. The diagnostic performance of each study was analysed, and the pooled diagnostic performance was assessed. Results The initial search identified 3726 papers of which 166 were suitable for abstract screening. In the final analysis, 16 papers were included with different sample sizes and different methods used. There was a combined total of 18451 ultrasound images examined through the final included studies. The overall sensitivity was 85% (95% CI 0.84–0.85) and specificity was 93% (95% CI 0.93–0.94). • Download figure • Open in new tab • Download powerpoint Abstract #392 Figure 1 Conclusion Artificial intelligence plays an important role in aiding the ultrasound diagnosis of ovarian cancer. Further prospective work is required to further validate AI for use in clinical practice. Disclosures nothing to declare

Introduction/Background Near infrared imaging, also known as Thermography is an imaging that uses infrared to detect the temperature of the tissues. This works on the basis that the tumour cells generate a higher metabolic rate, which results in a higher blood flow. Numerous studies have proven the benefits of thermography in detection of breast cancer, mainly being non invasive and cost effective. The aim of this study is to explore if thermal imaging can be used for the mapping the abdominal wall tumours in advanced stage gynaecological cancer. • Download figure • Open in new tab • Download powerpoint Abstract #55 Figure 1 Methodology This is a pilot novel prospective cohort study that was conducted in a tertiary cancer centre in London between September 2022 and March 2023. It was registered as a quality improvement project and has been approved by the audit lead. The patients were consented for the anonymized use of thermal images while in surgery. Consent forms were obtained and imaging done as per the Trust policy. No data was transferred or stored outside the trust. Inclusion criteria included patients with a malignant tumour on imaging or biopsy. Patients with class III obesity were excluded from the study. Images of the abdominal wall were taken prior to skin incision, using FLIR ONE thermal camera (FLIR Systems ®). The temperature and colour difference in the diseased areas were recorded. The results were corelated to intraoperative and histological findings. Results Seventeen patients were included in this pilot study. Twelve patients had an advanced stage disease (Stage two or higher) at the time of the surgery, of which nine had a positive detection on thermography. Detection rate was 100% for abdominal wall and hernial sac tumours. Conclusion Thermal cameras can be used for the surface mapping of various gynaecological tumours, prior to surgical interventions. However, randomized controlled studies are needed to validate our findings. Disclosures Larger randomized controlled studies are needed to validate the findings of our pilot study. We would recommend the use of a high resolution camera.

Introduction/Background Ovarian cancer has the worst prognosis among all gynaecological cancers. The pre-operative and intraoperative diagnosis of ovarian tumours is imperative to ensure the right operation is performed and to improve patients’ outcomes. Methodology This was a retrospective study from January 2017 to December 2021. Cases submitted for intraoperative frozen section diagnosis for the ovary and subsequent histopathological diagnosis were analysed. Frozen section cases were categorized as benign, borderline and malignant.In cases where a pre-operative US and MRI subjective impression of the examiner was given, the diagnosis on imaging was compared to the final histological diagnosis. Statistical analysis was performed using Stata MP v17.0 software (USA, 2023) and the diagnostic performance of US, MRI and frozen section compared to the final histological diagnosis was recorded. Results A total of 156 ovarian masses were examined by frozen section. In the histopathological examination, 123/156 of these tumours were epithelial tumours. Pre-operative US subjective impression was made in 63/156 cases and preoperative MRI subjective impression was made in 129/156 cases.For benign, borderline and malignant tumours, frozen section demonstrated a sensitivity of 90.8% (95%CI 81.9–96.2), 86.8% (95%CI 71.9–95.6) and 97.6% (95%CI 87.4–99.9) respectively, US demonstrated a sensitivity 95.2% (95%CI 76.2–99.9), 20% (95% 4.33–48.1), 57.1% (95%CI 28.9–82.3) respectively and MRI demonstrated a sensitivity of 100% (95%CI 80.5–100), 31.5% (95%CI 19.5–45.6) and 63.2% (95%CI 46–78.2) respectively. Conclusion Frozen section remains an accurate intraoperative tool for diagnosing the malignant potential of ovarian masses. However, across both imaging modalities and FS, the diagnosis of borderline ovarian tumours remains challenging. Disclosures nothing to declare

Introduction/Background Mixed endometrial carcinoma refers to rare endometrial tumours that are comprised of two or more distinct histotypes, at least one of which is serous or clear cell. Limited data is available on the recurrence rates for mixed epithelial endometrial carcinoma, as it comrises a relatively understudied subtype of endometrial cancer. The aim of this study is to evaluate the epidemiology, treatment outcomes and survival rates of patients with mixed endometrial carcinoma. Methodology Medical records of the patients diagnosed with mixed endometrial carcinoma between March 2010 and January 2020 reviewed retrospectively. Clinicopathological variables and treatment strategies were assessed, and overall survival (OS) and disease-free survival (DFS) rates were evaluated. Results A total of 34 patients were included in the study. Histology of endometrioid and serous component was found in 26 (76.5%) patients, followed by serous and clear cell components (5/354 14.5%) and a mixture of endometrioid, serous and clear cell components (3/34, 8.8%). The median age was 70 years (range 52–84), and median follow-up time was 55 months. Most patients (70%) were treated with laparoscopy. Overall, the 5-year disease-free survival rate (DFS) and the 5-year overall survival (OS) rate was 50.4% and 52.4%, respectively. Advanced disease stage was found to be independently correlated with worse 5-year disease-free survival (DFS) and overall survival (OS) rates (p<0.001). Conclusion The management of mixed epithelial endometrial carcinoma presents several challenges for clinicians and researchers that need to be addressed to improve oncologic outcomes. Accurate and early diagnosis plays a fundamental role to determine the appropriate treatment plan. Improved diagnostic techniques, such as molecular profiling and imaging technologies, as well as identification of specific biomarkers associated with the distinct features of the tumour, can help clinicians effectively stratify the patients and tailor treatment accordingly. Undoubtedly, the implementation of molecular analysis will offer further diagnostic and management insights. Disclosures no

Feticide is the practice of inducing fetal demise before the termination of pregnancy. In England and Wales, it is recommended for terminations of pregnancy beyond 21+6 weeks of gestation. This project analyses the trends in feticide in singleton pregnancy in England and Wales between 2012 and 2020. This project was a retrospective study that analysed data extracted from the Health and Social Act 4 (HSA4) forms submitted to the Department of Health and Social Care (DHSC). The data extracted by the DHSC included the prevalence of feticide, methods of feticide and termination, statutory grounds, gestation, service provider, maternal age, ethnicity and obstetric history. In addition, data analysis was carried out to identify trends. Between 2012 and 2020, there were 9310 feticides in England and Wales, undertaken in 0.5% of all abortions. The prevalence of feticide fluctuated; however, there was an overall decrease from 1084 cases in 2012 to 1000 cases in 2020. Intracardiac injection of potassium chloride was the most frequent method of achieving feticide (67.2%). Just over half (55.8%) of feticides took place under Ground E of the Abortion Act 1967, with the main indication being congenital malformations of the nervous system. Two-fifths (40.2%) of feticides took place at 23 weeks, 22.8% at 22 weeks and 13.5% between 20 and 21 weeks. The remainder occurred at later gestations: 17.5% at 24-29 weeks and 5.9% beyond 29 weeks. During our study period, it was more common for feticides to be carried out as part of a medical termination than a surgical termination and 60.3% occurred in NHS hospitals. Women undergoing feticide were mostly aged 30-34 years (38.3%) and of White ethnicity (78.6%). Feticide is an essential component of comprehensive abortion care for women undergoing late second and third-trimester abortions. This study provides insight into how feticide is carried out in England and Wales and demonstrates the effect of the COVID-19 pandemic on reducing feticide prevalence. Future research should analyse in more detail the use of the different methods of feticide.

Despite the success of COVID-19 vaccines in preventing infection and/or severe disease, there has been an increase in SARS-CoV-2 infections in vaccinated individuals owing to the waning vaccine-derived immunity, and the emergence of new variants which encode escape mutations in Spike. Following breakthrough infection in vaccinated individuals, an increase in neutralization breadth has been observed in sera/plasma. However, how exposure to a heterologous Spike broadens the neutralizing response at the monoclonal antibody (mAb) level is not fully understood. Through isolation of 119 mAbs from three individuals receiving two doses of BNT162b2 vaccine before becoming Delta or Omicron/BA.1 infected, we show that serum breadth occurs due to the presence of somatically mutated mAbs with broad neutralization activity indicative of re-activation and maturation of B cells generated through previous COVID-19 vaccination. Isolated mAbs frequently show reduced neutralization of current circulating variants including BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 confirming continuous selective pressure on Spike to evolve and evade neutralization. However, isolation of mAbs that display effective cross-neutralization against all variants indicates the presence of conserved epitopes on the receptor binding domain and a lesser extent the N-terminal domain. These findings have implications for the selection of Spike antigens for next-generation COVID-19 vaccines. IMPORTANCE With the emergence of SARS-CoV-2 viral variants, there has been an increase in infections in vaccinated individuals. Here, we isolated monoclonal antibodies (mAbs) from individuals experiencing a breakthrough infection (Delta or BA.1) to determine how exposure to a heterologous Spike broadens the neutralizing antibody response at the monoclonal level. All mAbs isolated had reactivity to the Spike of the vaccine and infection variant. While many mAbs showed reduced neutralization of current circulating variants, we identified mAbs with broad and potent neutralization of BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 indicating the presence of conserved epitopes on Spike. These results indicate that variant-based vaccine boosters have the potential to broaden the vaccine response.

The aim of this study was to characterize differences in directives to limit treatments and discontinue invasive mechanical ventilation (IMV) in elderly (65–80 years) and very elderly (> 80 years) intensive care unit (ICU) patients. We prospectively described new written orders to limit treatments, IMV discontinuation strategies [direct extubation, direct tracheostomy, spontaneous breathing trial (SBT), noninvasive ventilation (NIV) use], and associations between initial failed SBT and outcomes in 142 ICUs from 6 regions (Canada, India, United Kingdom, Europe, Australia/New Zealand, United States). We evaluated 788 (586 elderly; 202 very elderly) patients. Very elderly (vs. elderly) patients had similar withdrawal orders but significantly more withholding orders, especially cardiopulmonary resuscitation and dialysis, after ICU admission [67 (33.2%) vs. 128 (21.9%); p = 0.002]. Orders to withhold reintubation were written sooner in very elderly (vs. elderly) patients [4 (2–8) vs. 7 (4–13) days, p = 0.02]. Very elderly and elderly patients had similar rates of direct extubation [39 (19.3%) vs. 113 (19.3%)], direct tracheostomy [10 (5%) vs. 40 (6.8%)], initial SBT [105 (52%) vs. 302 (51.5%)] and initial successful SBT [84 (80%) vs. 245 (81.1%)]. Very elderly patients experienced similar ICU outcomes (mortality, length of stay, duration of ventilation) but higher hospital mortality [26 (12.9%) vs. 38 (6.5%)]. Direct tracheostomy and initial failed SBT were associated with worse outcomes. Regional differences existed in withholding orders at ICU admission and in withholding and withdrawal orders after ICU admission. Very elderly (vs. elderly) patients had more orders to withhold treatments after ICU admission and higher hospital mortality, but similar ICU outcomes and IMV discontinuation. Significant regional differences existed in withholding and withdrawal practices.