Spatially Resolved Transcriptomics Deconvolutes Prognostic Histological Subgroups in Patients with Colorectal Cancer and Synchronous Liver Metastases.

Strong immune responses in primary colorectal cancer correspond with better patient survival following surgery compared with tumors with predominantly stromal microenvironments. However, biomarkers to identify patients with colorectal cancer liver metastases (CRLM) with good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary colorectal cancer and CRLM and to interrogate the underlying functional biology that drives disease progression. Samples from patients undergoing synchronous resection of primary colorectal cancer and CRLM were evaluated in detail through histological assessment, panel genomic and bulk transcriptomic assessment, IHC, and GeoMx spatial transcriptomics (ST) analysis. High immune infiltration of metastases was associated with improved cancer-specific survival. Bulk transcriptomic analysis was confounded by stromal content, but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for type II IFN signaling and MHC-class II antigen presentation. In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T cells and neutrophils with enrichment of Notch and TGFß signaling pathways at the metastatic tumor center. In summary, histological assessment can stratify outcomes in patients undergoing synchronous resection of CRLM, suggesting that it has potential as a prognostic biomarker. Furthermore, ST analysis has revealed significant intratumoral and interlesional heterogeneity and identified the underlying transcriptomic programs driving each phenotype. SIGNIFICANCE: Spatial transcriptomics uncovers heterogeneity between patients, between matched lesions in the same patient, and within individual lesions and identifies drivers of metastatic progression in colorectal cancer with reactive and suppressed immune microenvironments.

Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data.

PURPOSE: Precise mechanism-based gene expression signatures (GES) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signaling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumor samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumor stroma percentage can directly influence GESs, undermining the intended mechanistic signaling. EXPERIMENTAL DESIGN: Using colorectal cancer as an exemplar, we deployed numerous orthogonal profiling methodologies, including laser capture microdissection, flow cytometry, bulk and multiregional biopsy clinical samples, single-cell RNA sequencing and finally spatial transcriptomics, to perform a comprehensive assessment of the potential for the most widely used GESs to be influenced, or confounded, by stromal content in tumor tissue. To complement this work, we generated a freely-available resource, ConfoundR; https://confoundr.qub.ac.uk/, that enables users to test the extent of stromal influence on an unlimited number of the genes/signatures simultaneously across colorectal, breast, pancreatic, ovarian and prostate cancer datasets. RESULTS: Findings presented here demonstrate the clear potential for misinterpretation of the meaning of GESs, due to widespread stromal influences, which in-turn can undermine faithful alignment between clinical samples and preclinical data/models, particularly cell lines and organoids, or tumor models not fully recapitulating the stromal and immune microenvironment. CONCLUSIONS: Efforts to faithfully align preclinical models of disease using phenotypically-designed GESs must ensure that the signatures themselves remain representative of the same biology when applied to clinical samples.

Predictors of hyponatremia following elective primary unilateral knee arthroplasty at a tertiary centre: A retrospective observational cohort and predictive model.

INTRODUCTION: Hyponatremia is a common electrolyte disorder. This can be associated with nausea, disorientation and in more serious cases a decreased level of consciousness or neurological deficits. These symptoms may lead to increases in the cost of hospital care and significant morbidity. The purpose of this retrospective, observational cohort study is to investigate the impact of hyponatremia on patient and systems specific outcome measures in those undergoing elective, unilateral total knee arthroplasty (TKA) at two hospitals in Auckland, New Zealand over a twelve-month period. MATERIALS AND METHODS: Patients were stratified into two groups based on the presence or absence of post-operative hyponatremia (defined as a blood sodium of <135 mmol/L with a concurrent decrease of ≥5 mmol/L between the pre- and post-operative recordings). Outcomes collected included Quality of Recovery - 15 (QOR) scores, time to assisted mobilisation, discharge ICD-10 complication codes and hospital length of stay. RESULTS: During the study period 236 patients underwent surgery. Eighty-six (36.4%) patients met criteria for post-operative hyponatremia. This finding was associated with prolongation of the hospital length of stay (4.17 (3.26-5.18) versus 4.28 (3.31-5.45) days, p = 0.031) and a reduction in the QOR score on the second post-operative day (113.0 (99.5-126.5) versus 105.0 (94.0-118.0), p = 0.039). There was no difference in the time to assisted mobilisation. CONCLUSIONS: Hyponatremia is a common finding following TKA. This abnormality is associated with small changes in patient specific outcome measures. These implications of these findings may become more significant in settings where same day or rapid discharge from hospital is targeted.

Non-technical skills and legal awareness in UK surgical training: A potential strategy for reducing medical error and subsequent harm.

Medical error and the potential subsequent harm caused to patients, relatives and healthcare professionals have been identified as a serious public health concern. Non-technical error has been implicated as a contributing cause in a significant number of adverse events. Modern surgical training in the United Kingdom has evolved to include non-technical skills training to complement traditional technical training. The recognition of non-technical training as well as a renewed focus on legal learning outcomes during training may promote a culture of greater risk awareness and subsequent clinical risk reduction.

A prospective study of gastro-oesophageal reflux disease symptoms and quality of life 1-year post-laparoscopic sleeve gastrectomy.

INTRODUCTION: There are concerns that laparoscopic sleeve gastrectomy (LSG) can cause severe gastro-oesophageal reflux disease (GORD). The aim of this study was to assess GORD symptoms and quality of life following LSG. METHODS: A prospective study of patients undergoing LSG (2014-2016) was performed with follow-up by DeMeester Reflux/Regurgitation Score, Bariatric Quality of Life Index (BQLI) and Bariatric Analysis and Reporting Outcome System (BAROS) Score pre-operatively, 6 months and 1-year post-operatively. RESULTS: Twenty-two patients were studied. Mean modified DeMeester Reflux/Regurgitation Score improved from 2.25 (±0.67) pre-operatively to 0.81 (±0.25) at 12 months (P = 0.04). At 12 months, two patients had symptomatic reflux, but overall satisfaction score was unaffected. Mean BQLI Score underwent a non-significant improvement at 12 months. BAROS Score showed all patients to have excellent (n = 19) or very good (n = 3) results (12 months). CONCLUSION: GORD symptoms improve for most patients' 1-year post-operatively. A small proportion of patients will develop troublesome GORD, but overall satisfaction remains high.

Plasma Ropivacaine Concentrations Following Local Infiltration Analgesia in Total Knee Arthroplasty: A Pharmacokinetic Study to Determine Safety Following Fixed-Dose Administration.

BACKGROUND AND OBJECTIVES: The primary aim of this study was to examine the pharmacokinetics of ropivacaine in patients undergoing elective total knee arthroplasty with local infiltration analgesia as the primary analgesic method. We also sought to determine the incidence of biochemical toxicity through measurement of plasma ropivacaine concentrations over the first 24 hours postoperatively. METHODS: This was a prospective, observational study of 15 patients undergoing elective total knee arthroplasty. Local infiltration analgesia was administered by standard technique with 300 mg ropivacaine and epinephrine 5 µg/mL. Total ropivacaine concentrations were taken at specified time intervals in the 24 hours after tourniquet release and analyzed by liquid chromatography-mass spectrometry. RESULTS: Fifteen patients were enrolled into the study. The median peak ropivacaine concentration was 0.57 µg/mL, with a range of 0.32 to 0.88 µg/mL, and occurred between 6 and 24 hours. Age (P = 0.04), weight (P = 0.04), creatinine (P = 0.02), and female sex (P = 0.03) were important predictors of peak concentration. Age (P = 0.02), female sex (P = 0.01), and baseline α1 acid glycoprotein concentrations (P = 0.03) were important predictors for the area under the curve from a ropivacaine concentration versus time plot. CONCLUSIONS: The peak total ropivacaine concentration was below quoted toxic concentrations (2.2 µg/mL) in all patients. This peak occurred later than has previously been described in those undergoing neuraxial or peripheral nerve block, occurring between 6 and 24 hours. The influence of age, weight, and renal function on systemic ropivacaine concentration should be considered when planning local infiltration analgesia. Female sex is a factor that has not previously been associated with peak ropivacaine concentrations.

The role of methylene blue in serotonin syndrome: a systematic review.

BACKGROUND: A recent series of case reports has demonstrated a significant, previously unrecognized drug interaction between serotonin reuptake inhibitors (SRIs) and methylene blue (MB). OBJECTIVE: The authors review the case reports and clinical audits relevant to this interaction and consider the diagnosis of serotonin syndrome in these cases. METHOD: Articles were obtained from a systematic search of MEDLINE and PsychInfo databases, and from the bibliographies of relevant articles. Studies were considered relevant if the patient received MB and developed an acute confusional state, neuropsychiatric complications, or autonomic instability. RESULTS: The review identified nine case reports and two retrospective reviews; 26 patients developed an acute confusional state after MB infusion; 24 of these patients were taking an SRI, and 1 was taking clomipramine. Serotonin syndrome was a possible diagnosis in all 25 of these patients. CONCLUSION: SRIs can interact with MB, causing a serious adverse reaction consistent with serotonin syndrome.

[Serotonin syndrome following methylene blue infusion during parathyroidectomy: a case report and literature review].

PURPOSE: To report a case of autonomic, neurological and neuromuscular instability following methylene blue infusion for parathyroidectomy; to advance the argument for a diagnosis of serotonin syndrome; and to consider this diagnosis in previous, unexplained reports of adverse reactions amongst patients undergoing parathyroidectomy using methylene blue. CLINICAL FEATURES: Methylene blue was administered to a 58-yr-old woman undergoing a parathyroidectomy under general anesthesia. The patient had a background of obsessive compulsive disorder treated with paroxetine. Postoperatively, she demonstrated symptoms and signs of serotonin syndrome; specifically tachycardia, agitation, dystonia and abnormal eye movements. These clinical findings spontaneously resolved themselves over the subsequent 48 hr. CONCLUSION: An interaction between methylene blue and serotonergic agents may give rise to the serotonin syndrome. Consideration should be given to avoiding methylene blue in patients taking serotonergic agents. The diagnosis should be considered in patients with autonomic, neuromuscular or neurological changes and should be managed accordingly.