Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis.

The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.

Successful Control of Heavy Menstrual Bleeding Using High-Intensity Focused Ultrasound Ablation of Fibroid Uterus in a Woman With Eisenmenger Syndrome.

Uterine fibroid causes heavy menstrual bleeding and can be difficult to manage particularly in patients with complicated medical history. We present a woman with Eisenmenger syndrome, who presented with heavy menses due to fibroid uterus. She was advised against having hormonal therapy or major surgery under general anesthesia. We successfully controlled her heavy menses and avoided surgery using high-intensity focused ultrasound ablation of her fibroid.

Diagnostic Performance of Risk of Malignancy Algorithm (ROMA), Risk of Malignancy Index (RMI) and Expert Ultrasound Assessment in a Pelvic Mass Classified as Inconclusive by International Ovarian Tumour Analysis (IOTA) Simple Rules.

The accurate prediction of malignancy for a pelvic mass detected on ultrasound allows for appropriate referral to specialised care. IOTA simple rules are one of the best methods but are inconclusive in 25% of cases, where subjective assessment by an expert sonographer is recommended but may not always be available. In the present paper, we evaluate the methods for assessing the nature of a pelvic mass, including IOTA with subjective assessment by expert ultrasound, RMI and ROMA. In particular, we investigate whether ROMA can replace expert ultrasound when IOTA is inconclusive. This prospective study involves one cancer centre and three general units. Women scheduled for an operation for a pelvic mass underwent a pelvic ultrasound pre-operatively. The final histology was obtained from the operative sample. The sensitivity, specificity and accuracy for each method were compared with the McNemar test. Of the 690 women included in the study, 171 (25%) had an inconclusive IOTA. In this group, expert ultrasound was more sensitive in diagnosing a malignant mass compared to ROMA (81% vs. 63%, p = 0.009) with no significant difference in the specificity or accuracy. All assessment methods involving IOTA had similar accuracies and were more accurate than RMI or ROMA alone. In conclusion, when IOTA was inconclusive, assessment by expert ultrasound was more sensitive than ROMA, with similar specificity.

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.

BACKGROUND: Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear. METHODS: Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination (nivolumab and ipilimumab-cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed. RESULTS: 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9-33.4) versus not-reached (P = 2.8 × 10-6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment. CONCLUSIONS: Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.

Immunotherapy induced enterocolitis and gastritis - What to do and when?

Oncological treatment has been revolutionised by the advent of immune checkpoint inhibitors (ICPi), which block inhibitory immune pathways to enhance anti-tumour responses and improve survival. This mode of action is non-specific so can cause immune-related adverse events, of which diarrhoea and enterocolitis are amongst the most common. ICPi-enterocolitis frequently leads to cancer therapy interruption. ICPi-gastritis typically occurs at a later stage of ICPi therapy and can present more insidiously with nausea and vomiting. ICPi-enterocolitis and gastritis are treated with corticosteroids, with refractory cases typically requiring biologic therapy. This review will briefly consider the pathogenesis of ICPi-induced GI disease, before focussing on the practical management of these conditions. The anticipated global increase in ICPi use across cancer types highlights the importance of prospective research in order that we can understand the immuno-microbiology of ICPi-enterocolitis and gastritis. This will lead to predictive biomarkers and help to define optimal treatment regimens.

Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?

BACKGROUND: Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes. METHODS: A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed. RESULTS: In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab (p < 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS (p = 0.008) and Mayo (p = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab (p = 0.03). CONCLUSIONS: CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.

Rate-controlled intraventricular endoscopic irrigation via bipolar foot pedal activation: technical note.

Irrigation during intraventricular endoscopic surgery is critical for visualization, with normal intracranial pressure maintained by balancing fluid ingress and egress. Although irrigation is typically achieved through manual manipulation of inexact stopcocks, the authors have developed a rate-controlled, foot pedal-activated system for precise intraventricular irrigation by using a standard irrigating bipolar electrocautery machine.This study is a retrospective review of patients who underwent endoscopic intraventricular surgery between January 1, 2018, and September 25, 2019, in which this irrigation system was used. Important components of this system include a bipolar module irrigation regulator that is set to a desired rate, a secure connection of the bipolar irrigation tubing to the endoscope, and one or more open egress ports on the endoscope for passive fluid drainage. Nineteen consecutive patients were identified on review (average age ± SD, 4.3 ± 4.1 years). Procedures performed included third ventriculostomies (n = 10); arachnoid/choroid cyst fenestrations/resections (n = 3); biopsy/tumor resection (n = 1); and combined procedures (n = 5). Foot pedal-controlled irrigation provided visualization of all intraventricular structures. A single operator was able to control the endoscope, endoscopic instruments, and irrigation, with assistance as indicated for more complex maneuvers. There were no perioperative complications. Because this setup is easily constructed from a standard irrigating bipolar machine, delivers precise irrigation flow rates, and facilitates a single-surgeon bimanual technique, these data support the utility of foot-controlled irrigation for endoscopic intraventricular surgery.

Immunotherapy-related hepatitis: real-world experience from a tertiary centre.

OBJECTIVE: Immune checkpoint inhibitors like anti-programmed cell death protein 1 (PD-1) drugs Nivolumab and Pembrolizumab and anti-cytotoxic T-lymphocyte associated (CTLA-4) drug Ipilimumab have become standard of care in many metastatic cancers. Immunotherapy-related hepatitis and cholangitis present a diagnostic and management challenge, being rare and incompletely characterised. We aim to report the incidence, features and treatments used for this in a real-world setting and to identify useful biomarkers, which can be used to predict effective use of steroids. DESIGN: Retrospective review of 453 patients started on immunotherapy over 7 years. SETTING: Tertiary hepatology and oncology centre. PATIENTS: 21 patients identified with immunotherapy-related hepatotoxicity. RESULTS: Hepatitis was most common in those receiving dual therapy (incidence 20%), with 75% of Grade 4 hepatitis cases occurring with ipilimumab-containing regimens. Corticosteroid monotherapy is first line treatment, but doses above 60 mg OD prednisolone do not demonstrate any additional benefit in time to hepatitis resolution. The alanine transaminase (ALT) reduction in steroid-responsive hepatitis is typically rapid (with a halving of ALT within 11 days). The commencement of additional immunosuppression (typically mycophenolate) appears safe and prompts a more rapid fall in ALT than corticosteroid use alone. Infliximab was safely used twice as hepatitis treatment. We also describe one patient with rare immunotherapy-induced biliary disease. CONCLUSIONS: Vigilance is required for detection of immunotherapy-associated liver disease as, other than dual immunotherapy, we can identify no predictive factors for its development. Our data suggest that corticosteroid response is not dependent on the higher dosing regimens. Early escalation of immunosuppression may be of benefit in the absence of a rapid response to corticosteroids.

Efficacy and safety of ultrasound-guided high-intensity focused ultrasound for uterine fibroids: a preliminary experience.

The objective of this prospective cohort study was to evaluate the therapeutic efficacy and safety of ultrasound-guided high-intensity focussed ultrasound (HIFU) in the treatment of uterine fibroids. Twenty premenopausal women with symptomatic fibroids underwent ultrasound-guided HIFU therapy. Twenty-two fibroids with a median baseline volume of 127.0 cm3 (range 18.5-481.2 cm3) were treated. The percentages fibroid volume reduction were 46.9 (range -8.8-73.1) at 1-month, 57.4 (-51.5-95.2) at 3-month, 60.1 (-18.9-97.8) at 6-month and 75.9 (-33.7-99.3) at 12-month, after treatment. The modified Uterine Fibroid Symptom and Quality of Life (UFS-QOL) scores were reduced by 40.7% (0-59.3%) at 3-month, 45.5% (0-70.4%) at 6-month and 44.9% (0-71.4%) at 12-month after treatment. Three patients required subsequent surgical interventions. No significant complications were encountered. Ultrasound-guided HIFU appears to be effective and safe for the treatment of symptomatic uterine fibroids in selected patients. Impact statement What is already known on this subject? Ultrasound-guided high-intensity focussed ultrasound (HIFU) is a relatively new uterine-sparing treatment for fibroids. Most clinical reports are from China, which suggest that this treatment is a safe and effective modality. However, in many other countries, HIFU treatment for fibroids, especially using ultrasound as image guidance, is still considered novel with limited clinical experience. What do the results of this study add? This preliminary report adds to our limited local experience on HIFU and provides reassurance on our continual utilisation of this treatment modality for fibroids. With the increasing demand of uterine-sparing alternatives, experiences shared among different countries are important to make this treatment modality generalisable and universally acceptable. What are the implications of these findings for clinical practice and/or further research?Ultrasound-guided HIFU (USgHIFU) can potential be offered as an alternative treatment modality for women with fibroids.

Cost-effectiveness of Intraoperative MRI for Treatment of High-Grade Gliomas.

Background Intraoperative MRI has been shown to improve gross-total resection of high-grade glioma. However, to the knowledge of the authors, the cost-effectiveness of intraoperative MRI has not been established. Purpose To construct a clinical decision analysis model for assessing intraoperative MRI in the treatment of high-grade glioma. Materials and Methods An integrated five-state microsimulation model was constructed to follow patients with high-grade glioma. One-hundred-thousand patients treated with intraoperative MRI were compared with 100 000 patients who were treated without intraoperative MRI from initial resection and debulking until death (median age at initial resection, 55 years). After the operation and treatment of complications, patients existed in one of three health states: progression-free survival (PFS), progressive disease, or dead. Patients with recurrence were offered up to two repeated resections. PFS, valuation of health states (utility values), probabilities, and costs were obtained from randomized controlled trials whenever possible. Otherwise, national databases, registries, and nonrandomized trials were used. Uncertainty in model inputs was assessed by using deterministic and probabilistic sensitivity analyses. A health care perspective was used for this analysis. A willingness-to-pay threshold of $100 000 per quality-adjusted life year (QALY) gained was used to determine cost efficacy. Results Intraoperative MRI yielded an incremental benefit of 0.18 QALYs (1.34 QALYs with intraoperative MRI vs 1.16 QALYs without) at an incremental cost of $13 447 ($176 460 with intraoperative MRI vs $163 013 without) in microsimulation modeling, resulting in an incremental cost-effectiveness ratio of $76 442 per QALY. Because of parameter distributions, probabilistic sensitivity analysis demonstrated that intraoperative MRI had a 99.5% chance of cost-effectiveness at a willingness-to-pay threshold of $100 000 per QALY. Conclusion Intraoperative MRI is likely to be a cost-effective modality in the treatment of high-grade glioma. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Bettmann in this issue.

Gastrointestinal disease burden and mortality: A public hospital-based study from 2005 to 2014.

BACKGROUND AND AIM: Gastrointestinal (GI) diseases account for substantial morbidity, mortality, and health care utilization. This public hospital-based study assessed the incidence and time trend of hospitalization and mortality of major GI diseases over one decade. METHODS: We conducted an observational study using population-wide database managed by the Hong Kong Hospital Authority with a principal diagnosis of GI diseases defined by International Classification of Disease, 9th Revision, Clinical Modification coding. We measured age-standardized incidence of hospitalization, emergency admissions, multiple admissions, and in-hospital mortality from 2005 to 2014 using Poisson regression. RESULTS: The annual incidence of hospitalization for GI diseases increased from 4713 to 5241 per 100 000 discharges (incidence rate ratio [IRR] = 1.004; 95% confidence interval [CI]: 1.003-1.005). GI infections and cancers showed the highest rates of hospitalization in 2014. Hospitalization for GI cancers (IRR = 1.014; 95% CI: 1.013-1.016) and non-infectious enterocolitis (IRR = 1.058; 95% CI: 1.055-1.061) increased, whereas peptic ulcer disease has decreased. Hospitalization for Crohn's disease showed the most significant rise (126%). Annual incidence of hospitalization for Clostridium difficile infections increased by fivefold (IRR = 1.221; 95% CI: 1.178-1.266), while a 66% reduction was observed for peptic ulcer bleeding (IRR = 0.894; 95% CI: 0.889-0.899). GI cancers had the highest in-hospital mortality rate in 2014, especially colorectal cancer and gastric cancer. CONCLUSIONS: This study showed an increased hospitalization burden of GI cancers and Crohn's disease, and a reduction in overall mortality for GI diseases. These data provide insight into epidemiological changes of GI diseases in the 21st century and implications for hospital burden and need of resource re-allocation.

Extracellular Vesicles as a Platform for Glioma Therapeutic Development.

Normal and pathologic cells secrete extracellular vesicles (EV), which are defined as 30-2,000 nm spherical organelles. It has been found that EV mediate various biological functions including cellular remodeling and export of biomolecules, extracellular communication, immune stimulation and suppression, and modulation of the cellular microenvironment. EV secreted by human glioma cells contain a wealth of tumor-specific proteins and nucleic acids that can be isolated from patients with these neoplasms. Thus, EV contribute to the development of biomarkers, and additionally have certain therapeutic potential for possible use in neuro-oncology and neurosurgery.

Patients on Long-Term Warfarin Undergo Gynecological Surgeries: A 10-Year Review of Perioperative Anticoagulation.

OBJECTIVE: The aim of this study was to review our experience with patients having gynaecological surgeries while on long-term anticoagulation and to postulate a better guide for their perioperative management. MATERIAL AND METHODS: A retrospective review of all women on long-term warfarin who underwent gynaecological surgeries from January 2003 to December 2012. Data from medical records including operation reports and inpatient and outpatient charts were reviewed and analyzed. RESULTS: Sixty-seven cases from 58 patients were identified. Twenty and 38 patients underwent major and minor gynaecological surgeries, respectively. The incidence of postoperative bleeding was higher after major surgery (4 cases, 20%) than after minor surgery (1 case, 2.1%; P = 0.025). All bleeding complications occurred between postoperative day 3 and day 10. Three patients, who had resumption of warfarin at a lower dose and slowly stepped up, had no bleeding complications. None of our patients developed venous thromboembolic complications. There was one mortality due to septic shock. CONCLUSION: Patients on long-term anticoagulation have a trend of increased bleeding complications after major gynaecological surgeries than in minor gynaecological surgeries. We suggest that delaying resumption of warfarin at a lower dose may have a role in reducing the risk of postoperative bleeding without increasing the risk of venous thromboembolism.

High-intensity focused ultrasound therapy.

High-intensity focused ultrasound therapy has received increasing interest in the management of benign uterine tumors. Either magnetic resonance or ultrasound imaging has been used to target and monitor the ablation process. This article provides an overview of the background, clinical use, treatment outcomes, and safety of high-intensity focused ultrasound in the treatment of uterine fibroids and adenomyosis, including a summary of clinical trials comparing magnetic resonance- or ultrasound-guided high-intensity focused ultrasound with other minimally invasive or surgical interventions. The potential of this treatment modality as an alternative uterus-sparing option for women with fibroids and adenomyosis is discussed.

A Randomized Controlled Trial Comparing Trainee-Directed Virtual Reality Simulation Training and Box Trainer on the Acquisition of Laparoscopic Suturing Skills.

OBJECTIVE: To compare the proficiency of novices in acquiring laparoscopic suturing skills following training in a virtual reality simulator or box trainer compared to no training. METHODS: This was a RCT in a university-affiliated teaching hospital recruiting participants who had no laparoscopic suturing experience to have suturing skill training in the virtual reality simulator, box trainer, or no training as control. Trainees were allowed to terminate training when they perceived competence in the procedure. Suturing skills were tested in the box trainer and scored using a modified Global Operative Assessment of Laparoscopic Skills questionnaire by their own self-evaluation and two experienced gynaecological laparoscopists. RESULTS: Of the 36 participants recruited, 27 (75%) had no laparoscopic experience. Participants with no laparoscopic experience took longer to complete training than those with experience (median 90 minutes [interquartile range (IQR) 80-115] vs. 55 min [IQR 40-65], respectively; P = 0.044). There were no differences in successful completion of the task (7/12 [58.3%], 10/12 [83.3%], 7/12 [58.3%]; P = 0.325), median suturing time in seconds (628 [IQR 460-835], 611 [IQR 434-691], 609 [IQR 540-837]; P = 0.702), mean subjective (mean ± SD 9.8 ± 1.8, 10.4 ± 2.8, 9.3 ± 2.4; P = 0.710), and objective (7.2 ± 1.8, 8.2 ± 2.1, 7.6 ± 1.7; P = 0.426) modified Global Operative Assessment of Laparoscopic Skills score in the simulator, pelvic trainer, and control groups, respectively. The intraclass correlation coefficient of the two reviewers was 0.422 (95% CI 0.159-0.717). CONCLUSION: Trainees were unable to accurately assess themselves as to skill level in laparoscopic suturing. A longer training time is required for novices to master laparoscopic suturing using a simulator or box trainer.

The circle of Willis predicts the antihypertensive effects of carotid artery stenting.

OBJECTIVE Carotid artery stenting (CAS) has antihypertensive effects, but the durability and degree of this response remain variable. The authors propose that this clinical variability is a function of the presence or absence of a complete circle of Willis (COW). Incomplete COWs perfuse through a higher-resistance pial collateral pathway, and therefore patients may require a higher mean arterial pressure (MAP). Carotid artery revascularization in these patients would reduce the end-organ collateral demand that has been hypothesized to drive the MAP response. METHODS Using a retrospective, nonrandomized within-subject case-control design, the authors compared the postoperative effects of CAS in patients with and without a complete COW by using changes in MAP and antihypertensive medication as end points. They recorded MAP and antihypertensive medications 3 months prior to surgery, preoperatively, immediately postoperatively, and at the 3-month follow-up. RESULTS Data were collected from 64 consecutive patients undergoing CAS. Patients without a complete COW (25%) were more likely to demonstrate a decrease in BP response to stenting (i.e., a drop in MAP of 10 mm Hg and/or a reduction or cessation of BP medications at 3 months postoperatively). Of the patients in the incomplete COW cohort, 75% had this outcome, whereas of those in the complete COW cohort, only 41% had it (p < 0.041). These findings remained statistically significant in a logistic regression analysis for possible confounders (p < 0.024). A receiver operating curve analysis of preoperative data indicated that a MAP > 96.3 mm Hg was 55.5% sensitive and 57.4% specific for predicting a complete COW and that patients with a MAP > 96.3 mm Hg were more likely to demonstrate a good MAP decrease following CAS (p < 0.0092). CONCLUSIONS CAS is associated with a significant decrease in MAP and/or a reduction/cessation in BP medications in patients in whom a complete COW is absent.