Association of clinical biomarkers and response to neoadjuvant therapy in breast cancer.

INTRODUCTION: Neoadjuvant therapy is an essential component of multimodality therapy for locally advanced breast adenocarcinoma (BC). Complete pathologic response (pCR) is a useful surrogate for long-term oncologic outcome. AIM: To assess the association between clinicopathologic, molecular and immunological markers and treatment response to neoadjuvant therapy in BC. METHODS: BC patients undergoing neoadjuvant therapy were identified from a prospectively maintained institutional database. Serum haematological/biochemical values, histopathologic, immunohistochemical data and TNM stage were obtained from electronic records. Patients were categorised into complete responders vs non-complete responders and responders vs non-responders. Statistical analysis was performed via SPSS. RESULTS: Overall, 299 BC patients were included. The average age was 49.8 ± 11.5 years. A pCR was evident in 22.6% (n = 69). pCR was associated with early T stage and non-luminal subtypes (HER2 enriched [HER2 +] and triple negative [TNBC]). The neutrophil-lymphocyte ratio (NLR) pre-operatively was lower in patients with a pCR (p = 0.02). The lymphocyte-CRP ratio (LCR) was also slightly reduced in responders (p = 0.049) at diagnosis. A pre-op NLR greater than 2 was not found to be a significant predictive factor (p = 0.071) on multivariable logistic regression analysis. T stage at diagnosis (p = 0.024), N stage (p = 0.001) and breast cancer subtype (p = 0.0001) were also determined to be significant predictive factors of complete response. CONCLUSION: pCR was more likely in patients with less advanced disease in BC. The presence of HER2 + or TNBC in BC also increases the likelihood of pCR. Neoadjuvant therapy stimulates the systemic inflammatory response; however, a reduced baseline NLR may be associated with increased pCR. Confirmation with larger datasets is required.

The effect of population density on outcomes of major trauma patients in Ireland.

BACKGROUND: Time-sensitive emergencies in areas of low population density have statistically poorer outcomes. This includes incidents of major trauma. This study assesses the effect that population density at a receiving hospital of a major trauma patient has on survival. METHODS: Patients meeting Trauma Audit Research Network criteria for major trauma from 2016 to 2020 in Ireland were included in this retrospective observational study. Incident data were retrieved from the Major Trauma Audit, while data on population density were calculated from Irish state sources. The primary outcome measure of survival to discharge was compared to population density using logistic regression, adjusted for demographic and incident variables. Records were divided into population density tertiles to assess for between-group differences in potential predictor variables. RESULTS: Population density at a receiving hospital had no impact on mortality in Irish major trauma patients from our logistic regression model (OR = 1.01, 95% CI 0.98-1.05, p = 0.53). Factors that did have an impact were age, Charlson Comorbidity Index, Injury Severity Score, and the presence of an Orthopaedic Surgery service at the receiving hospital (all p < 0.001). Age and Charlson Comorbidity Index differed slightly by population density tertile; both were higher in areas of high population density (all p < 0.001). CONCLUSIONS: Survival to discharge in Irish major trauma patients does not differ substantially based on population density. This is an important finding as Ireland moves to a new trauma system, with features based on population distribution. An Orthopaedic Surgery service is an important feature of a major trauma receiving hospital and its presence improves outcomes.

Persistence and Potential Atmospheric Ramifications of Ice-Nucleating Particles Released from Thawing Permafrost.

Permafrost underlies approximately a quarter of the Northern Hemisphere and is changing amidst a warming climate. Thawed permafrost can enter water bodies through top-down thaw, thermokarst erosion, and slumping. Recent work revealed that permafrost contains ice-nucleating particles (INPs) with concentrations comparable to midlatitude topsoil. These INPs may impact the surface energy budget of the Arctic by affecting mixed-phase clouds, if emitted into the atmosphere. In two 3-4-week experiments, we placed 30,000- and 1000-year-old ice-rich silt permafrost in a tank with artificial freshwater and monitored aerosol INP emissions and water INP concentrations as the water's salinity and temperature were varied to mimic aging and transport of thawed material into seawater. We also tracked aerosol and water INP composition through thermal treatments and peroxide digestions and bacterial community composition with DNA sequencing. We found that the older permafrost produced the highest and most stable airborne INP concentrations, with levels comparable to desert dust when normalized to particle surface area. Both samples showed that the transfer of INPs to air persisted during simulated transport to the ocean, demonstrating a potential to influence the Arctic INP budget. This suggests an urgent need for quantifying permafrost INP sources and airborne emission mechanisms in climate models.

Competency in trauma surgery: a national survey of trainees and consultants.

BACKGROUND: The current sparsity of surgical trainees' exposure to training in operative trauma surgery is multifactorial. This concern has been addressed in the revised Intercollegiate Surgical Curriculum Programme (ISCP) for general and vascular surgery (2021). In the lead up to its implementation, we aimed to assess both trainee and consultant confidence levels as a surrogate reflection in the core competency operative skills in general emergency trauma surgery, identify individual experience in commonly performed trauma procedures and gauge interest in a career in trauma surgery. METHOD: An online survey was circulated to general surgery and vascular surgery trainees and consultants. Self-reported competencies were assessed using a 1-10 confidence rating scale. Most questions were based on competencies in emergency trauma surgery as set out by the ISCP. RESULTS: Out of 251 surgical trainees and consultants, 119 responded to our survey (47.4% response rate). Less than half (44.1%; n = 52) of respondents had experienced a trauma thoracotomy. Respondents scored 'somewhat' or 'not at all' competent in the majority of competencies assessed. CONCLUSION: Self-reported competencies in operative trauma skills across all subgroups were sub-standard with incremental levels of perceived competence proportional to years of surgical training. Our data supports the necessity of the new curriculum, in addition to modern training pathways with direct exposure to operative trauma surgery involving dedicated trauma centres and networks, and responsibility of training pathways in the provision of training trauma surgery.

Discovery of structural diverse reversible BTK inhibitors utilized to develop a novel in vivo CD69 and CD86 PK/PD mouse model.

For the past two decades, BTK a tyrosine kinase and member of the Tec family has been a drug target of significant interest due to its potential to selectively treat various B cell-mediated diseases such as CLL, MCL, RA, and MS. Owning to the challenges encountered in identifying drug candidates exhibiting the potency block B cell activation via BTK inhibition, the pharmaceutical industry has relied on the use of covalent/irreversible inhibitors to address this unmet medical need. Herein, we describe a medicinal chemistry campaign to identify structurally diverse reversible BTK inhibitors originating from HITS identified using a fragment base screen. The leads were optimized to improve the potency and in vivo ADME properties resulting in a structurally distinct chemical series used to develop and validate a novel in vivo CD69 and CD86 PD assay in rodents.

Multiomics in the central Arctic Ocean for benchmarking biodiversity change.

Multiomics approaches need to be applied in the central Arctic Ocean to benchmark biodiversity change and to identify novel species and their genes. As part of MOSAiC, EcoOmics will therefore be essential for conservation and sustainable bioprospecting in one of the least explored ecosystems on Earth.

Investigation of the monopole magneto-chemical potential in spin ices using capacitive torque magnetometry.

The single-ion anisotropy and magnetic interactions in spin-ice systems give rise to unusual non-collinear spin textures, such as Pauling states and magnetic monopoles. The effective spin correlation strength (Jeff) determines the relative energies of the different spin-ice states. With this work, we display the capability of capacitive torque magnetometry in characterizing the magneto-chemical potential associated with monopole formation. We build a magnetic phase diagram of Ho2Ti2O7, and show that the magneto-chemical potential depends on the spin sublattice (α or ß), i.e., the Pauling state, involved in the transition. Monte Carlo simulations using the dipolar-spin-ice Hamiltonian support our findings of a sublattice-dependent magneto-chemical potential, but the model underestimates the Jeff for the ß-sublattice. Additional simulations, including next-nearest neighbor interactions (J2), show that long-range exchange terms in the Hamiltonian are needed to describe the measurements. This demonstrates that torque magnetometry provides a sensitive test for Jeff and the spin-spin interactions that contribute to it.

Annual cycle observations of aerosols capable of ice formation in central Arctic clouds.

The Arctic is warming faster than anywhere else on Earth, prompting glacial melt, permafrost thaw, and sea ice decline. These severe consequences induce feedbacks that contribute to amplified warming, affecting weather and climate globally. Aerosols and clouds play a critical role in regulating radiation reaching the Arctic surface. However, the magnitude of their effects is not adequately quantified, especially in the central Arctic where they impact the energy balance over the sea ice. Specifically, aerosols called ice nucleating particles (INPs) remain understudied yet are necessary for cloud ice production and subsequent changes in cloud lifetime, radiative effects, and precipitation. Here, we report observations of INPs in the central Arctic over a full year, spanning the entire sea ice growth and decline cycle. Further, these observations are size-resolved, affording valuable information on INP sources. Our results reveal a strong seasonality of INPs, with lower concentrations in the winter and spring controlled by transport from lower latitudes, to enhanced concentrations of INPs during the summer melt, likely from marine biological production in local open waters. This comprehensive characterization of INPs will ultimately help inform cloud parameterizations in models of all scales.

A framework for fibrolamellar carcinoma research and clinical trials.

Fibrolamellar carcinoma (FLC), a rare, lethal hepatic cancer, occurs primarily in adolescents and young adults. Unlike hepatocellular carcinoma, FLC has no known association with viral, metabolic or chemical agents that cause cirrhosis. Currently, surgical resection is the only treatment demonstrated to achieve cure, and no standard of care exists for systemic therapy. Progress in FLC research illuminates a transition from an obscure cancer to one for which an interactive community seems poised to uncover fundamental mechanisms and initiate translation towards novel therapies. In this Roadmap, we review advances since the seminal discovery in 2014 that nearly all FLC tumours express a signature oncogene (DNAJB1-PRKACA) encoding a fusion protein (DNAJ-PKAc) in which the J-domain of a heat shock protein 40 (HSP40) co-chaperone replaces an amino-terminal segment of the catalytic subunit of the cyclic AMP-dependent protein kinase (PKA). Important gains include increased understanding of oncogenic pathways driven by DNAJ-PKAc; identification of potential therapeutic targets; development of research models; elucidation of immune mechanisms with potential for the development of immunotherapies; and completion of the first multicentre clinical trials of targeted therapy for FLC. In each of these key areas we propose a Roadmap for future progress.

Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer.

The tumor immune microenvironment (TIME) is commonly infiltrated by diverse collections of myeloid cells. Yet, the complexity of myeloid-cell identity and plasticity has challenged efforts to define bona fide populations and determine their connections to T-cell function and their relationship to patient outcome. Here, we have leveraged single-cell RNA-sequencing analysis of several mouse and human tumors and found that monocyte-macrophage diversity is characterized by a combination of conserved lineage states as well as transcriptional programs accessed along the differentiation trajectory. We also found in mouse models that tumor monocyte-to-macrophage progression was profoundly tied to regulatory T cell (Treg) abundance. In human kidney cancer, heterogeneity in macrophage accumulation and myeloid composition corresponded to variance in, not only Treg density, but also the quality of infiltrating CD8+ T cells. In this way, holistic analysis of monocyte-to-macrophage differentiation creates a framework for critically different immune states.

Frailty and emergency abdominal surgery: A systematic review and meta-analysis.

INTRODUCTION: Patients aged ≥65 years currently account for approximately 55% of all emergent operations. However, these patients account for 75% of post-operative mortality. Older age has long been associated with adverse outcomes from emergency surgery. However, old age is a heterogenous state. Recent studies have indicated that frailty may more accurately reflect true biological age and perioperative risk than chronological age alone in patients undergoing elective surgery. Few studies have evaluated the impact of frailty on post-operative outcomes in this setting. METHODS: A systematic, electronic search for relevant publications was performed in November 2019 using Pubmed and Embase from 2009 to 2019. The latest search for articles was performed on February 16th, 2020. Articles were excluded if frailty was not measured using a frailty tool, or if patients did not undergo emergency general surgery (EGS). RESULTS: The prevalence of frailty amongst patients undergoing emergency abdominal surgery was 30.8%. The all-cause mortality rate was 15.68%. The mortality rate amongst the frail undergoing EGS was 24.7%. Frailty was associated with an increased mortality rate compared with the non-frail (odds ratio (OR) 4.3, 95% CI 2.25-8.19%, p < 0.05, I2 = 80%). CONCLUSIONS: There is strong evidence to suggest that frailty in the older population predicts post-operative mortality, complications, prolonged length of stay and the loss of independence. Collaborative working with medicine for the elderly physicians to target modifiable aspects of the frailty syndrome in the perioperative pathway may improve outcomes. Frailty scoring should be integrated into acute surgical assessment practice to aid decision-making and development of novel postoperative strategies.

Discovering dominant tumor immune archetypes in a pan-cancer census.

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.

FLT3L Release by Natural Killer Cells Enhances Response to Radioimmunotherapy in Preclinical Models of HNSCC.

PURPOSE: Natural killer (NK) cells are type I innate lymphoid cells that are known for their role in killing virally infected cells or cancer cells through direct cytotoxicity. In addition to direct tumor cell killing, NK cells are known to play fundamental roles in the tumor microenvironment through secretion of key cytokines, such as FMS-like tyrosine kinase 3 ligand (FLT3L). Although radiotherapy is the mainstay treatment in most cancers, the role of radiotherapy on NK cells is not well characterized. EXPERIMENTAL DESIGN: This study combines radiation, immunotherapies, genetic mouse models, and antibody depletion experiments to identify the role of NK cells in overcoming resistance to radiotherapy in orthotopic models of head and neck squamous cell carcinoma. RESULTS: We have found that NK cells are a crucial component in the development of an antitumor response, as depleting them removes efficacy of the previously successful combination treatment of radiotherapy, anti-CD25, and anti-CD137. However, in the absence of NK cells, the effect can be rescued through treatment with FLT3L. But neither radiotherapy with FLT3L therapy alone nor radiotherapy with anti-NKG2A yields any meaningful tumor growth delay. We also identify a role for IL2 in activating NK cells to secrete FLT3L. This activity, we show, is mediated through CD122, the intermediate affinity IL2 receptor, and can be targeted with anti-CD25 therapy. CONCLUSIONS: These findings highlight the complexity of using radio-immunotherapies to activate NK cells within the tumor microenvironment, and the importance of NK cells in activating dendritic cells for increased tumor surveillance.

geneshot: gene-level metagenomics identifies genome islands associated with immunotherapy response.

Researchers must be able to generate experimentally testable hypotheses from sequencing-based observational microbiome experiments to discover the mechanisms underlying the influence of gut microbes on human health. We describe geneshot, a novel bioinformatics tool for identifying testable hypotheses based on gene-level metagenomic analysis of WGS microbiome data. By applying geneshot to two independent previously published cohorts, we identify microbial genomic islands consistently associated with response to immune checkpoint inhibitor (ICI)-based cancer treatment in culturable type strains. The identified genomic islands are within operons involved in type II secretion, TonB-dependent transport, and bacteriophage growth.

The Use of Clinical Parameters as Adjuncts to Endoscopic Evaluation of Mural Thickening on Conventional Computed Tomography in Diagnosing Malignancy.

BACKGROUND: Mural thickening (MT) on computed tomography (CT) poses a diagnostic dilemma in the absence of clear reporting guidelines. The aim of this study was to analyse CT reports, identifying patients in whom gastrointestinal wall MT was observed, and to correlate these reports with subsequent endoscopic evaluation. METHODS: Patients with MT who had follow-up endoscopy were included in the study (n = 308). The cohort was subdivided into upper gastrointestinal mural thickening (UGIMT) & lower gastrointestinal mural thickening (LGIMT). RESULTS: In total, 55.71% (n = 122) of colonoscopies and 61.8% (n = 55) of gastroscopies were found to be normal. Haemoglobin (HB) level in combination with MT was a predictor of neoplasia in both arms (p = 0.04 UGIMT cohort, p < 0.001 LGIMT cohort). In addition to this, age was a significant correlative parameter in both UGIMT and LGIMT cohorts (p = 0.003, p < 0.001 respectively). Dysphagia and weight loss were associated with UGI malignancies (38 and 63% respectively) and rectal bleeding was correlative in 20% of patients with LGI malignancies. CONCLUSION: HB, advancing age, and red flag symptoms are potentially useful adjuncts to MT in predicting upper and lower gastrointestinal malignancies. We propose the adoption of a streamlined pathway to delineate patients who should undergo endoscopic investigation following CT identification of MT.

Neoadjuvant chemotherapy for luminal a breast cancer: Factors predictive of histopathologic response and oncologic outcome.

BACKGROUND: The benefit of chemotherapy (NAC) for patients with ER/PR positive, HER2 negative breast cancer is unclear. Our aim was to determine factors associated with histopathologic response and oncologic outcome following NAC in this group. METHODS: Consecutive female patients undergoing neoadjuvant therapy and surgery for locally advanced Luminal A breast cancer between 2010 and 2015 were studied. Multivariable linear, logistic, and Cox regression analysis was undertaken. RESULTS: 114 patients were studied. Pathological complete response (pCR) was achieved in 7.9% of patients, ypN0 in 25.5%, and downstaging in 33.6%. However, 43.9% exhibited a Sataloff C-D response. Tumor grade independently predicted pCR (P = 0.039), while PR score predicted ypN0 (P = 0.017) and downstaging (P=0.029). 5-year invasive disease-free (iDFS) and overall survival (OS) were 68.5 ± 4.7% and 77.7 ± 4.3%, respectively. CONCLUSION: After NAC for Luminal A breast cancer, pCR rates are low. Patients with high grade tumors with weak PR expression exhibit the most promising response rates.

Impact of targeted trainer feedback via video review on trainee performance of laparoscopic cholecystectomy.

INTRODUCTION: Tools for improving operative performance for surgical trainees are increasingly desirable, particularly in the context of EWTD and 'run-through' training programmes. In addition, positive direct trainer feedback to trainees can improve skill acquisition and motivation, whilst negative feedback may have the opposite effect.1 We aimed to examine the impact of targeted trainer feedback based on video analysis on trainee confidence and objective operative performance in laparoscopic cholecystectomy. METHODS: Selected procedures designated as training cases were recorded. These were assessed by the trainers using the Independence-Scaled Procedural Assessment Score for laparoscopic cholecystectomy. Targeted feedback based on video review of selected procedures was then delivered by the trainers to the trainees. Trainees completed a self-reported questionnaire based on their response to this feedback. Subsequent to the feedback intervention, further training procedures were recorded and assessed. RESULTS: A total of 6 trainees and 4 trainers participated in the study. For the pre-intervention assessment 15 cases were recorded, with a further 13 for the post-intervention assessment (total n = 28). The overall scores for the procedures performed post video feedback were improved, with a trend towards statistical significance (p = 0.08). However, there was a statistically significant improvement in the scores for performance of the triangle of Calot dissection after the feedback intervention (p = 0.009). The response rate to the questionnaire was 100%, with all trainees agreeing that they felt more confident and competent after the feedback intervention. CONCLUSION: Targeted feedback to trainees based on post-procedure video review improves trainee confidence and may also improve performance. ACGME Core Competencies; Patient Care and Procedural Skills; Practice Based Learning and Improvement.

Negative appendicectomy rates as a quality measure in a regional surgical unit: a retrospective review.

INTRODUCTION: Historically, high negative appendicectomy rates (NAR) were acceptable to offset the risks of perforation, previously exceeding 20%. With improved imaging and clinical scoring algorithms, there is growing demand for lower negative appendicectomy rates. The objectives were to (1) establish the NAR in our institution and (2) correlate clinical parameters and imaging modalities with histological findings. METHODS: Patients undergoing an appendicectomy between January 2012 and June 2018 were identified using a prospectively maintained pathology database. Histology findings were cross referenced against our radiology system, and anonymised data was collected for gender, age, WCC, Neutrophil and CRP level. RESULTS: One thousand one hundred fifty-three patients met the inclusion criteria. Fifty-three percent were males (n = 610), with 81% (n = 933) of histology reports classified as appendicitis. Sixty patients had a histologically normal appendix equating to a 5.2% NAR. If lymphoid hyperplasia, fibrosis and atrophy are included, it equates to a NAR of 14.57%. (p < 0.0001). Sixty-six percent of patients had no pre-operative imaging. CT imaging demonstrated a higher sensitivity (93.33%) and positive predictive value (99.60%) compared to ultrasonography. WCC and CRP are statistically significant in predicting appendicitis (p < 0.0001). CONCLUSION: There is no consensus on defining a negative appendicectomy or for imaging modality utilisation. CT imaging is the most sensitive and should be used in cases of diagnostic uncertainty. A standardised algorithm regarding the workup of patients with RIF pain along with a consensus on the use of imaging will further reduce negative appendicectomy rates.

Current opinions and practices for the management of acute appendicitis: an international survey.

BACKGROUND: In recent decades the management of acute appendicitis has evolved significantly. Improved access to early imaging and better clinical scoring algorithms have resulted in less negative appendicectomy rates. In addition, non-operative management has become increasingly utilized. The aim of this study was to assess the variability of management of acute appendicitis globally. METHODS: This was a multi-national targeted survey of general surgeons across 39 countries. A structured set of questions was utilized to delineate nuances between management styles of consultants and trainees. Opinions on the pathological diagnosis of appendicitis, acceptable negative appendicectomy rates, and the role of non-operative treatment of appendicitis (NOTA) were surveyed. RESULTS: A total of 304 general surgeons responded to this survey, 42% of which were consultants/attendings. Sixty-nine percent advocated that a histologically normal appendix was the most appropriate definition of a negative appendicectomy, while 29% felt that anything other than inflammation, necrosis, gangrene, or perforation was more appropriate. Forty-three percent felt that negative appendicectomy rates should be less than 10%, with 41% reporting that their own negative appendicectomy rate was < 5%. Interestingly, only 17% reported routinely using NOTA for uncomplicated appendicitis, with one-fifth stating that they would undergo NOTA if they themselves had uncomplicated appendicitis. CONCLUSION: This study represents the largest sampling of management strategies for acute appendicitis. It shows substantial global heterogeneity between clinicians regarding what constitutes a negative appendicectomy as well as the appropriateness of non-operative management.