Cancer-associated fibroblasts produce matrix-bound vesicles that influence endothelial cell function.

Intercellular communication between different cell types in solid tumors contributes to tumor growth and metastatic dissemination. The secretome of cancer-associated fibroblasts (CAFs) plays major roles in these processes. Using human mammary CAFs, we showed that CAFs with a myofibroblast phenotype released extracellular vesicles that transferred proteins to endothelial cells (ECs) that affected their interaction with immune cells. Mass spectrometry-based proteomics identified proteins transferred from CAFs to ECs, which included plasma membrane receptors. Using THY1 as an example of a transferred plasma membrane-bound protein, we showed that CAF-derived proteins increased the adhesion of a monocyte cell line to ECs. CAFs produced high amounts of matrix-bound EVs, which were the primary vehicles of protein transfer. Hence, our work paves the way for future studies that investigate how CAF-derived matrix-bound EVs influence tumor pathology by regulating the function of neighboring cancer, stromal, and immune cells.

Repair of lateral temporo-sphenoidal encephalocoele via an endoscopic transorbital approach: ex vivo 3D printed simulation followed by in vivo deployment.

BACKGROUND: A temporo-sphenoidal encephalocoele occurs when temporal lobe herniates through a defect in the greater wing of the sphenoid bone into the sphenoid air sinus. The natural history is not well-understood, though presentation in adulthood with CSF rhinorrhoea and/or meningitis is typical. Lateral pneumatisation of the sphenoid sinus and elevated BMI may be contributory. AIMS: We explored the feasibility of a transorbital approach (TOA) for repair, using a combination of 3D modelling and simulation. We then successfully deployed this technique in vivo. METHODS: CT imaging for three patients who had previously undergone transcranial repair of lateral temporo-sphenoidal encephalocoele was used to generate data allowing 3D printed models of the skull base to be produced. The transorbital approach was simulated by performing a lateral orbitotomy followed by drilling of the sphenoid wing to expose the antero-basal middle fossa. 3D object scanning was used to create virtual models of the skull base post-surgery, from which surgical access was quantified in two ways: the area (mm2) of the middle fossa exposed by the TOA and the vertical attack angle. RESULTS: The mean surface area of the cranial access window achieved by simulated TOA was 325mm2. The mean vertical attack angle was 25°. One patient was subsequently treated successfully via TOA with no recurrence of their CSF leak, no orbital morbidity, excellent cosmesis, but resolving V2 numbness (follow-up 7 months). CONCLUSIONS: We have shown that the transorbital approach provides adequate surgical access. In our single case, surgical repair of a lateral temporo-sphenoidal encephalocoele via TOA was feasible, safe, and effective. This approach may offer some advantages compared with transcranial or endonasal approaches.

Exploring the influence of nasal morbidity on quality of life following endoscopic endonasal skull base surgery: a retrospective cohort study of 95 patients.

The endoscopic endonasal approach is more disruptive to normal anatomy (particularly nasal mucosa) than the transseptal submucosal microscopic approach. This may result in greater postoperative nasal morbidity, in turn reducing quality of life. We aimed to assess the severity and time course of nasal morbidity, and its impact on quality of life, following endoscopic endonasal skull base surgery in this retrospective cohort study. We identified 95 patients who underwent endoscopic endonasal skull base surgery for anterior skull base pathologies. Nasal-specific questions from the Sino-Nasal Outcome Test-22 (SNOT-22) and the Anterior Skull Base inventory (ASB-12) were combined with quality-of-life questions. Patient demographics, diagnosis, and operative data were collected from electronic records. Age of the cohort ranged from 14-83 years. Time elapsed since surgery ranged from 3-85 months. 85/95 (89%) felt that nasal morbidity associated with surgery was acceptable, given the underlying reason for, and outcome of surgery; 10/95 (11%) did not. 71/95 (75%) reported no change or improvement in olfaction 3-months following surgery. 24/95 (25%) reported a deterioration in olfaction which was mild in 7%, moderate in 7%, and severe in 11%. Nasal crusting, nasal obstruction, and headache were moderately problematic symptoms but improved significantly by 3-month follow-up. Nasal discharge, nasal pain, and nasal whistling were mildly problematic and improved significantly by 3-months. 62/95 (65%) patients reported 'no change' in day-to-day activities due to the effects on their nose after surgery. 19/95 (20%) had 'mild inconvenience', 8/95 (8%) 'moderate inconvenience' and 6/95 (6%) 'severe inconvenience'. Endoscopic anterior skull base surgery is associated with nasal morbidity. Whilst 35% of patients appreciate a consequent negative impact on day-to-day life, the overwhelming majority feel that nasal morbidity is acceptable, given the wider surgical goals.

Exploring the Impact of Using Patient-Specific 3D Prints during Consent for Skull Base Neurosurgery.

Objectives Informed consent is fundamental to good practice. We hypothesized that a personalized three-dimensional (3D)-printed model of skull base pathology would enhance informed consent and reduce patient anxiety. Design Digital images and communication in medicine (DICOM) files were 3D printed. After a standard pre-surgery consent clinic, patients completed part one of a two-part structured questionnaire. They then interacted with their personalized 3D printed model and completed part two. This explored their perceived involvement in decision-making, anxiety, concerns and also their understanding of lesion location and surgical risks. Descriptive statistics were used to report responses and text classification tools were used to analyze free text responses. Setting and Participants In total,14 patients undergoing elective skull base surgery (with pathologies including skull base meningioma, craniopharyngioma, pituitary adenoma, Rathke cleft cyst, and olfactory neuroblastoma) were prospectively identified at a single unit. Results After 3D model exposure, there was a net trend toward reduced patient-reported anxiety and enhanced patient-perceived involvement in treatment. Thirteen of 14 patients (93%) felt better about their operation and 13/14 patients (93%) thought all patients should have access to personalized 3D models. After exposure, there was a net trend toward improved patient-reported understanding of surgical risks, lesion location, and extent of feeling informed. Thirteen of 14 patients (93%) felt the model helped them understand the surgical anatomy better. Analysis of free text responses to the model found mixed sentiment: 47% positive, 35% neutral, and 18% negative. Conclusion In the context of skull base neurosurgery, personalized 3D-printed models of skull base pathology can inform the surgical consent process, impacting the levels of patient understanding and anxiety.

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target.

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.

Emotional visual stimuli and simulated laparoscopic surgical performance: A pilot cohort study.

BACKGROUND: Exposure to stress prior to or during surgery can negatively impact performance. Management of stress is an essential non-technical skill required for safe practice. The effects of exposure to emotional visual stressors on surgical performance are poorly understood. This study aims to develop a model to investigate effects of emotive visual stimuli on simulated laparoscopic performance. METHODS AND MATERIALS: A single-centre cohort study. Thirty novice, simulator-naïve medical students were randomly allocated to view either positive, negative, or neutral emotional images (sourced from validated image registry). Participants focused for 5 s on the image before completing a peg-threading laparoscopic task. Time, instrument distance, speed, acceleration, motion smoothness, and ambidexterity were recorded automatically with instrument tracking software. 8 task cycles were completed; 3 control practices followed by 5 with the stimuli, according to group allocation. RESULTS: The final performance metrics of students (time, distance, speed, and motion smoothness) were not significantly different when comparing positive and neutral stimuli groups to those shown negative stimuli. However, changes were seen in the rate of performance improvements (positive: p = 0.711, p = 0.837, p = 0.297, and p = 0.393) (neutral: p = 0.285, p = 0.918, p = 0.835, and p = 0.396). Participation improved performance metrics overall (p=<0.001, p=<0.001, p = 0.088, p = 0.025, p=<0.001). CONCLUSION: Model systems may be valuable for investigating the impact of stress on surgeon performance. The effect of emotive visual stimuli on surgical performance is complex. This model may aid the further exploration of these relationships and ultimately can provide an environment in which surgeons can develop strategies to mitigate the adverse effect of stressors.

Postoperative Diabetes Insipidus Mimicking Radiological Findings and Symptoms of Intracranial Hypotension: A Case Report.

Endocrine disturbances such as diabetes insipidus (DI) and syndrome of inappropriate antidiuretic hormone secretion (SIADH) are recognized complications of craniopharyngioma surgery, which occur due to damage to structures that produce or store antidiuretic hormone (ADH). Intracranial hypotension is a clinical syndrome that presents with headache and typical radiological features and can occur due to a leak of cerebral spinal fluid (CSF) in operations that involve the opening of the arachnoid (e.g., craniopharyngioma surgery). We describe a patient presenting with headache, radiological evidence of intracranial hypotension, and chronic DI after craniopharyngioma surgery. This occurred in the absence of evidence of a CSF leak. The headache and radiological findings resolved after the identification and treatment of DI. Intracranial hypotension may have occurred secondary to dehydration in chronic DI. A 48-year-old woman presented with progressive visual field loss due to cystic recurrence of a craniopharyngioma. She underwent redo (second) extended endoscopic transsphenoidal surgery, having previously undergone an uncomplicated debulking procedure two years prior. Her redo operation was uneventful, and her vision improved postoperatively. A lumbar drain was placed preoperatively to protect the skull base repair and was removed after 48 hours. In the initial postoperative period, she developed a clinical (polyuria) and biochemical picture consistent with DI, subsequently reverting to a SIADH, after which fluid and sodium homeostasis appeared to normalize, and she was discharged. Two months after discharge, she re-presented with new headaches eased by lying flat. Magnetic resonance imaging (MRI) brain showed bilateral convexity subdural effusions and diffuse pachymeningeal enhancement, suggesting intracranial hypotension and raising concern for postoperative CSF leak. MRI spine did not show a CSF fistula at the site of the previous lumbar drain. Transsphenoidal examination under anesthesia showed a well-healed skull base repair and no evidence of CSF leak. She concurrently reported polyuria and polydipsia. A formal water deprivation test confirmed central DI. Treatment with desmopressin improved her headache, and a follow-up MRI brain showed resolution of the previous stigmata of intracranial hypotension. This case report reminds physicians and neurosurgeons that systemic disorders (such as dehydration) can cause intracranial hypotension.

The Impact of Novel Nontechnical Stressors (Visual and Auditory) on Simulated Laparoscopic Task Performance Among Surgeons and Students.

Background: Surgical training emphasizes technical competence. Growing evidence indicates that nontechnical skills are also significant in determining performance. Critically, surgeons should be aware how performance is affected by pressure or distraction. We assessed the impact of novel auditory and visual stressors on performance during a simulated laparoscopic task. We hypothesized that the stressors would worsen performance, and that stress-induced diminution in performance would be inversely related to surgical experience. Methods: Twenty participants (10 surgeons and 10 medical students) completed a peg-threading task using a laparoscopic simulator: three times under control conditions, next with a visual distraction overlay (progressive red saturation of the surgical field, timing personalized to the user's index performance), and then with an auditory distraction overlay (operating theater environment noise). Task completion time and instrument tracking metrics (instrument tip distance traveled and instrument smoothness) were measured. Results: Under control conditions, surgeons completed the task significantly faster, with greater economy of movement, and improved instrument smoothness-compared with students. When exposed to distracting stimuli, the groups behaved differently. Surgeons completed the task more slowly, instrument movements became less smooth (significantly so under audio distraction conditions), but total distance traveled by instruments was unchanged. By contrast, student performance was not impaired and, in some ways, improved. Conclusion: The impact of visual and auditory distraction on surgical performance can be modeled in a laparoscopic simulation environment. The effect of distraction varies according to expertise. This environment may be an effective setting within which to learn to mitigate stress-induced diminution in performance.

The digital Cullen chart: a red colour perimetry aid for visual field examination.

BACKGROUND: 30 years ago, a paper chart was developed in Edinburgh by Cullen et al. and validated as a swift, supplementary method for perimetric evaluation of visual fields. We have re-developed this concept in digital form (on smartphone screen) and assessed its sensitivity and specificity in detecting visual field loss, by comparison with formal machine-based perimetry. METHODS: Patients with sellar and parasellar tumours, being managed in a single neurosurgical centre, underwent formal visual field perimetry as part of standard care. They also underwent assessment using the smartphone-based Cullen chart. 37 eye testing episodes were assessed, incorporating pre- and post-treatment assessments for a range of potentially compressive pathologies (non-secretory and secretory pituitary adenoma, craniopharyngioma, and parasellar meningioma). The smartphone-based Cullen chart was compared with formal machine-based perimetry for concordance in detecting visual field loss. RESULTS: The digital Cullen chart had a sensitivity of 75% and specificity of 98% compared with machine-based perimeters. The positive predictive value was 93% and the negative predictive value was 92%. CONCLUSIONS: For the visual field assessment of patients with sellar/parasellar tumours, this simple and swift smartphone-based chart shows good concordance with machine-based perimeters. With amendments to the user interface, there may be potential for telemetric patient-led visual field monitoring.

Development and validation of a hedgehog heparin-binding assay for high-throughput screening.

Sonic hedgehog (Shh) is a morphogenic protein with critical roles in embryogenesis and the development of some cancers. Hence, identifying inhibitors of the Shh pathway is of great therapeutic value. Heparin and HSPGs act as crucial modulators of Shh activity. To identify molecules that antagonize Shh binding to heparin we have developed a solid-phase plate-based assay. The N-terminal domain of Shh (ShhN) protein is first coated in 384-well plates and the direct binding of fluorescein-labeled heparin (flu-heparin) assessed by measuring the fluorescence signal after incubation and wash steps. Binding of ShhN protein to the 384-well plates was confirmed and optimized by a standard ELISA using a monoclonal antibody recognizing folded ShhN. The assay was validated using whole plate minimum and maximum signal wells with a Z' of 0.68-0.75 determined. Herein, we describe the development and validation of a high throughput screen to identify small molecule antagonists of Shh heparin binding. Overall, this method•Results in an optimized and validated assay for hedgehog heparin binding.•Delivers a cost effective high-throughput screen format for hedgehog heparin antagonist screening.

Oncogenic BRAF, unrestrained by TGFß-receptor signalling, drives right-sided colonic tumorigenesis.

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFß signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFß-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFß-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.

Glutathione transferase Omega 1 confers protection against azoxymethane-induced colorectal tumour formation.

Inflammatory bowel disease (IBD) is characterized by multiple alterations in cytokine expression and is a risk factor for colon cancer. The Omega class glutathione transferase GSTO1-1 regulates the release of the pro-inflammatory cytokines interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) by deglutathionylating NEK7 in the NLRP3 inflammasome. When treated with azoxymethane and dextran sodium sulphate (AOM/DSS) as a model of IBD, Gsto1-/- mice were highly sensitive to colitis and showed a significant increase in the size and number of colon tumours compared with wild-type (WT) mice. Gsto1-/- mice treated with AOM/DSS had significantly lower serum IL-1ß and IL-18 levels as well as significantly decreased interferon (IFN)-γ, decreased pSTAT1 and increased pSTAT3 levels in the distal colon compared with similarly treated WT mice. Histologically, AOM/DSS treated Gsto1-/- mice showed increased active chronic inflammation with macrophage infiltration, epithelial dysplasia and invasive adenocarcinoma compared with AOM/DSS treated WT mice. Thus, this study shows that GSTO1-1 regulates IL-1ß and IL-18 activation and protects against colorectal cancer formation in the AOM/DSS model of IBD. The data suggest that while GSTO1-1 is a new target for the regulation of the NLRP3 inflammasome-associated cytokines IL-1ß and IL-18 by small molecule inhibitors, there is a possibility that anti-inflammatory drugs targeting these cytokines may potentiate colon cancer in some situations.

Is a Single-Dose, Single-Agent Perioperative Antibiotic Protocol Adequate for Endoscopic Endonasal Skull Base Surgery? A 10-Year Review of 422 Cases.

Objective Postoperative meningitis is a rare but potentially fatal complication of endoscopic endonasal skull base surgery. Prophylactic antibiotic use varies considerably worldwide. We sought to analyze the safety of a single-agent, single-dose protocol. Design, Setting, and Participants A retrospective review of 422 procedures performed during 404 admission episodes from 2009 to 2019, encompassing sella, parasella, and other anterior skull base pathologies. Main Outcome Measures Primary outcome measure was development of meningitis within 30 days of surgery. Additional information collected: underlying pathological diagnosis, intraoperative cerebrospinal fluid (CSF) leak, postoperative CSF leak, and primary or revision surgery. Results Of 404 admission episodes for endoscopic anterior skull base surgery, 12 cases developed meningitis. Seven had positive CSF cultures and all 12 recovered. For pathology centered on the sella (including pituitary adenoma), the rate of meningitis was 1.1% (3/283). For pathologies demanding an extended approach (including meningioma and craniopharyngioma), the rate of meningitis was 14.5% (9/62). Postoperative CSF leak requiring surgical repair increased the relative risk by 37-fold. There were no cases of meningitis following repair of long-standing CSF fistula or encephalocoele (0/26) and no cases following surgery for sinonasal tumors with skull base involvement (0/33). Conclusion For sella-centered pathologies, a single dose of intravenous co-amoxiclav (or teicoplanin) is associated with rates of meningitis comparable to those reported in the literature. Postoperative meningitis was significantly higher for extended, intradural transphenoidal approaches, especially when postoperative CSF leak occurred. Fastidious efforts to prevent postoperative CSF leak are crucial to minimizing risk of meningitis.

Using Automated Continuous Instrument Tracking to Benchmark Simulated Laparoscopic Performance and Personalize Training.

OBJECTIVE: Laparoscopic simulation is widely used in surgical training. However, the impact of training on performance is difficult to assess. Observation is time-intensive and subjective. SurgTrac laparoscopic box-trainer instrument tracking software provides continuous, automated, real-time, objective performance feedback. We used this data to assess the relationship between task attempts and performance. We assessed whether improvement in performance with repetition could be modeled in learning curves that might be used for benchmarking. DESIGN: Anonymized SurgTrac data for performances undertaken between 10/2016 and 05/2019 were retrospectively extracted. The thread transfer task, a basic instrument handling task, was assessed. Task duration and instrument-based metrics were analyzed; total distance travelled by instrument tips, average speed, average acceleration, and the ratio of movements between the left and right hands. Curve estimation regression was used to assess the relationship between attempt number and metrics for pooled data across the entire cohort of users and amongst individual users with ≥50 attempts. Threshold for significance p = 0.05. SETTING: SurgTrac has generated the largest available database of performances in box trainer simulated tasks with 64,000 activities performed by over 1450 users in 77 countries to date. PARTICIPANTS: Data was derived from the unselected world-wide cohort of SurgTrac users. No participants were excluded. RESULTS: Five hundred seventy-eight users performed 13,027 attempts in the thread transfer task. Across the entire cohort, SurgTrac performance metrics were significantly associated with attempt number. Task duration and total distance decreased with attempt number. This benefit persisted across 100 attempts. Ambidexterity increased with attempt number. Individual candidate performance improved in line with predicted learning curves for better performing candidates. CONCLUSIONS: We analyzed the largest database of simulated laparoscopic task performances. Performance improves with practice. Using learning curves derived from peer-group performances as benchmarks, users may be regularly and objectively assessed to support personalization of training.

CSF rhinorrhoea after endonasal intervention to the anterior skull base (CRANIAL): proposal for a prospective multicentre observational cohort study.

BACKGROUND: The endonasal transsphenoidal approach (TSA) has emerged as the preferred approach in order to treat pituitary adenoma and related sellar pathologies. The recently adopted expanded endonasal approach (EEA) has improved access to the ventral skull base whilst retaining the principles of minimally invasive surgery. Despite the advantages these approaches offer, cerebrospinal fluid (CSF) rhinorrhoea remains a common complication. There is currently a lack of comparative evidence to guide the best choice of skull base reconstruction, resulting in considerable heterogeneity of current practice. This study aims to determine: (1) the scope of the methods of skull base repair; and (2) the corresponding rates of postoperative CSF rhinorrhoea in contemporary neurosurgical practice in the UK and Ireland. METHODS: We will adopt a multicentre, prospective, observational cohort design. All neurosurgical units in the UK and Ireland performing the relevant surgeries (TSA and EEA) will be eligible to participate. Eligible cases will be prospectively recruited over 6 months with 6 months of postoperative follow-up. Data points collected will include: demographics, tumour characteristics, operative data), and postoperative outcomes. Primary outcomes include skull base repair technique and CSF rhinorrhoea (biochemically confirmed and/or requiring intervention) rates. Pooled data will be analysed using descriptive statistics. All skull base repair methods used and CSF leak rates for TSA and EEA will be compared against rates listed in the literature. ETHICS AND DISSEMINATION: Formal institutional ethical board review was not required owing to the nature of the study - this was confirmed with the Health Research Authority, UK. CONCLUSIONS: The need for this multicentre, prospective, observational study is highlighted by the relative paucity of literature and the resultant lack of consensus on the topic. It is hoped that the results will give insight into contemporary practice in the UK and Ireland and will inform future studies.

A Palliative Care Intervention for Patients on Phase 1 Studies.

Background: Phase 1 clinical trials remain vital for oncology care. Patients on these trials require supportive care for quality-of-life (QOL) concerns. Objective: To test a Palliative Care Intervention (PCI) for patients with solid tumors enrolled in Phase I therapeutic trials with a priori hypothesis that psychological distress, QOL, satisfaction, symptoms, and resource utilization would be improved in the PCI group. Design: This unblinded randomized trial compared the PCI with usual care in patients accrued to Phase I Clinical Trials. Subjects (n = 479) were followed for 24 weeks, with 12 weeks as the primary outcome. Setting: Two Comprehensive Cancer Centers in the United States. Subjects: A consecutive sample, 21 years or older, English fluency, with solid tumors initiating a Phase 1 trial. Measurements: Psychological Distress (Distress Thermometer), QOL total and subscales (FACT-G), satisfaction (FAM-CARE), survival, and resource utilization (chart audit). Results: PCI subjects showed improved Psychological Distress (-0.47, p = 0.015) and Emotional Well-Being (0.81, p = 0.045), with differences on variables of QOL and distress between sites. High rates of symptom-management admissions (41.3%) and low rates of Advance Directive completion (39.0%), and hospice enrollment (30.7%), despite a median survival in both groups of 10.1 months from initiating a Phase 1 study. Conclusions: A nurse-delivered PCI can improve some QOL outcomes and distress for patients participating in Phase 1 trials. Greater integration of PC is needed to provide quality care to these patients and to support transitions from treatment to supportive care, especially at the end of life. ClinicalTrials.gov Identifier: NCT01612598.

Sellar Remodeling after Surgery for Nonfunctioning Pituitary Adenoma: Intercarotid Distance as a Predictor of Recurrence.

Introduction As they grow, pituitary adenoma can remodel the sella turcica and alter anatomical relationships with adjacent structures. The intercarotid distance (ICD) at the level of the sella is a measure of sella width. The purpose of this study was to (1) assess how ICD changes after transsphenoidal surgery and (2) explore whether the extent of ICD change is associated with tumor recurrence. Methods A retrospective analysis of preoperative and postoperative coronal magnetic resonance imaging (MRI) scans was carried out by two independent assessors on patients who underwent transsphenoidal surgery for nonfunctioning pituitary macroadenomas. Preoperative tumor volume and any change in ICD following surgery were recorded and compared between groups. Logistic regression models of recurrence were generated. Results In 36 of 42 patients, ICD fell after surgery (mean = 1.8 mm) and six cases were static. At time of follow-up (mean = 77 months), 25 had not required further intervention and 17 had undergone second surgery or radiosurgery. In patients in whom no further intervention has yet been necessary, the postoperative reduction in ICD was significantly smaller than in those who required repeat intervention (1.1 vs. 2.7 mm respectively, p < 0.01). ICD decrease was weakly correlated with tumor volume ( r = 0.35). ICD decrease was a significant predictor of recurrence (odds ratio [OR] = 3.15; 95% confidence interval [CI]: 1.44-6.87), largely independent of tumor volume. Conclusion For most patients, ICD falls following surgical excision of a nonfunctioning pituitary macroadenoma. A greater reduction in ICD postsurgery appears to predict recurrence. Change in ICD shows promise as a radiographic tool for prognosticating clinical course after surgery.

The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation.

The Krebs cycle-derived metabolite itaconate is highly upregulated in inflammatory macrophages and exerts immunomodulatory effects through cysteine modifications on target proteins. The NLRP3 inflammasome, which cleaves IL-1ß, IL-18, and gasdermin D, must be tightly regulated to avoid excessive inflammation. Here we provide evidence that itaconate modifies NLRP3 and inhibits inflammasome activation. Itaconate and its derivative, 4-octyl itaconate (4-OI), inhibited NLRP3 inflammasome activation, but not AIM2 or NLRC4. Conversely, NLRP3 activation was increased in itaconate-depleted Irg1-/- macrophages. 4-OI inhibited the interaction between NLRP3 and NEK7, a key step in the activation process, and "dicarboxypropylated" C548 on NLRP3. Furthermore, 4-OI inhibited NLRP3-dependent IL-1ß release from PBMCs isolated from cryopyrin-associated periodic syndrome (CAPS) patients, and reduced inflammation in an in vivo model of urate-induced peritonitis. Our results identify itaconate as an endogenous metabolic regulator of the NLRP3 inflammasome and describe a process that may be exploited therapeutically to alleviate inflammation in NLRP3-driven disorders.

Enhanced recovery and accelerated discharge after endoscopic transsphenoidal pituitary surgery: safety, patient feedback, and cost implications.

BACKGROUND: Enhanced recovery after surgery (ERAS) is a constant motivation. There is growing evidence that an endoscopic (rather than microscopic) transsphenoidal approach to pituitary tumours can play a role, facilitating faster recovery and a commensurate reduction in length of stay (LOS). Reducing LOS is beneficial to both patients and healthcare systems. We sought to assess the safety, patient feedback, and resource implications of adopting an enhanced recovery and accelerated discharge policy for elective pituitary surgery. METHODS: We retrospectively assessed two consecutive cohorts of patients undergoing elective surgery for pituitary adenoma in a single UK centre between July 2016 and November 2019. The pre-ERAS cohort included 52 sequential patients operated prior to protocol change. The ERAS cohort included 55 sequential patients operated after a protocol change. Patient demographic data, tumour characteristics, intra- and post-operative CSF leak, the rate and cause of readmission (within 30 days), and the mean and median LOS were recorded. Patient feedback was collected from a subset of patients (n = 23) in the ERAS group. RESULTS: The two cohorts were well-matched with respect to their demographic, pathological, and operative characteristics. The rates of readmission within 30 days of discharge were similar between the two groups (8% pre-ERAS cohort, 9% ERAS cohort, p = 0.75). In the pre-ERAS cohort, the mean LOS was 4.5 days and median LOS was 3 days. This compares with significant reduction in LOS for the ERAS group: mean of 1.7 days and median of 1 day (p < 0.05). Thirty-nine of 55 patients in the ERAS group were discharged on post-operative day 1. Patient feedback was very positive in the ERAS group (mean patient satisfaction score of 9.7/10 using a Likert scale). CONCLUSIONS: An enhanced recovery protocol after elective endoscopic pituitary surgery is safe, reduces length of stay, and is associated with high patient satisfaction.

Caspase-11 promotes allergic airway inflammation.

Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E2 (PGE2) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE2 suppreses caspase-11 expression in murine and human macrophages and in the airways of mice with allergic inflammation. Remarkably, caspase-11-deficient mice are strongly resistant to developing experimental allergic airway inflammation, where PGE2 is known to be protective. Expression of caspase-11 is elevated in the lung of wild type mice with allergic airway inflammation. Blocking PGE2 production with indomethacin enhances, whereas the prostaglandin E1 analog misoprostol inhibits lung caspase-11 expression. Finally, alveolar macrophages from asthma patients exhibit increased expression of caspase-4, a human homologue of caspase-11. Our findings identify PGE2 as a negative regulator of caspase-11-driven pyroptosis and implicate caspase-4/11 as a critical contributor to allergic airway inflammation, with implications for pathophysiology of asthma.