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Sentinel-lymph-node mapping has been advocated as an alternative staging technique for endometrial cancer. The aim of this study was to measure the sensitivity and negative predictive value of sentinel-lymph-node mapping compared with the gold standard of complete lymphadenectomy in detecting metastatic disease for endometrial cancer. In the FIRES multicentre, prospective, cohort study patients with clinical stage 1 endometrial cancer of all histologies and grades undergoing robotic staging were eligible for study inclusion. Patients received a standardised cervical injection of indocyanine green and sentinel-lymph-node mapping followed by pelvic lymphadenectomy with or without para-aortic lymphadenectomy. 18 surgeons from ten centres (tertiary academic and community non-academic) in the USA participated in the trial. Negative sentinel lymph nodes (by haematoxylin and eosin staining on sections) were ultra-staged with immunohistochemistry for cytokeratin. The primary endpoint, sensitivity of the sentinel-lymph-node-based detection of metastatic disease, was defined as the proportion of patients with node-positive disease with successful sentinel-lymph-node mapping who had metastatic disease correctly identified in the sentinel lymph node. Patients who had mapping of at least one sentinel lymph node were included in the primary analysis (per protocol). All patients who received study intervention (injection of dye), regardless of mapping result, were included as part of the assessment of mapping and in the safety analysis in an intention-to-treat manner. The trial was registered with ClinicalTrials.gov, number NCT01673022 and is completed and closed. Between Aug 1, 2012, and Oct 20, 2015, 385 patients were enrolled. Sentinel-lymph-node mapping with complete pelvic lymphadenectomy was done in 340 patients and para-aortic lymphadenectomy was done in 196 (58%) of these patients. 293 (86%) patients had successful mapping of at least one sentinel lymph node. 41 (12%) patients had positive nodes, 36 of whom had at least one mapped sentinel lymph node. Nodal metastases were identified in the sentinel lymph nodes of 35 (97%) of these 36 patients, yielding a sensitivity to detect node-positive disease of 97·2% (95% CI 85·0–100), and a negative predictive value of 99·6% (97·9–100). The most common grade 3–4 adverse events or serious adverse events were postoperative neurological disorders (4 patients) and postoperative respiratory distress or failure (4 patients). 22 patients had serious adverse events, with one related to the study intervention: a ureteral injury incurred during sentinel-lymph-node dissection. Sentinel lymph nodes identified with indocyanine green have a high degree of diagnostic accuracy in detecting endometrial cancer metastases and can safely replace lymphadenectomy in the staging of endometrial cancer. Sentinel lymph node biopsy will not identify metastases in 3% of patients with node-positive disease, but has the potential to expose fewer patients to the morbidity of a complete lymphadenectomy. Indiana University Health, Indiana University Health Simon Cancer Center, and the Indiana University Department of Obstetrics and Gynecology.

Sentinel lymph node (SLN) biopsy has been investigated as an alternative to conventional pelvic and para-aorticlymphadenectomy for the surgical staging of endometrial cancer. Clinical trials have established the accuracy of sentinel nodes in the detecting metastatic disease. Novel advancements in tracers from the historically favored blue dyes and radio labeled colloids to near infrared imaging of fluorescent dyes has improved the ability to detect sentinel nodes and increased options for surgeons. The uterine cervix has been shown to be a feasible and accurate injection site for tracer, though the potential for under-evaluation of the para-aortic nodes remains a controversy, particularly for high-risk cancers. Additionally, sentinel node evaluation provides qualitatively different information than traditional staging techniques by identifying lymph nodes outside of traditional sampling locations and through the identification of very low volume meta static disease implants, such as isolated tumor cells. It is unclear how this altered staging information should be interpreted, guide the prescription of adjuvant therapy and its impact on long term clinical outcomes such as recurrence and survival. In this review we will discuss the evidence that has supported the use of the SLN technique in the staging of endometrial cancer, the options for surgical technique and the implications of managing the results of staging pathology.

Historically lymphadenectomy was performed, but it is associated with increased morbidity without a survival benefit for early-stage disease.1 SLN mapping and biopsy have increasingly been used to identify lymph node metastasis while minimizing the risks of lymphadenectomy. The reported mapping failure rate was 14.3% in patients undergoing robotic staging for apparent early-stage disease; of these, 16.9% had lymph node metastasis on lymphadenectomy.4 Figure 1. [...]sensitive Firefly does not illuminate anatomy that does not contain ICG (Figure 1B). [...]the surgeon cannot see the relationship between channels and anatomic structures in real time.

Sentinel lymph node (SLN) mapping with indocyanine green (ICG) detected by robotic near infrared (NIR) imaging is a feasible technique. The optimal site of injection (cervical or endometrial) for endometrial cancer has yet to be determined. We prospectively evaluated SLN mapping after cervical and endometrial injections of ICG to compare the detection rates and patterns of nodal distribution. Twenty-nine subjects with endometrial cancer undergoing robotic hysterectomy with lymphadenectomy by a single surgeon received SLN mapping with robotic fluorescence imaging. Seventeen patients received cervical injections of 1 mg of ICG and 12 patients received hysteroscopic endometrial injections of 0.5-mg ICG. Detection rates between the 2 groups were compared using Fisher exact tests. Continuous variables such as operating room times and body mass index were compared using t tests. The SLN detection rate was 82% (14/17) for cervical and 33% (4/12) for hysteroscopic injection (P= 0.027). Sentinel lymph nodes were seen bilaterally in 57% (8/14) of the cervical injection group and 50% (2/4) of the hysteroscopic group. Para-aortic SLNs were seen in 71% (10/14) of patients who mapped after cervical injection and 75% (3/4) patients who mapped after hysteroscopic injection. There was 1 false-negative SLN in the cervical injection group. Cervical ICG injection achieves a higher SLN detection rate and a similar anatomic nodal distribution as hysteroscopic endometrial injection for SLN mapping in patients with endometrial cancer.

Ultimately, to determine whether the limitations of sentinel lymph node biopsy to characterise the extent of nodal metastases negatively affects outcomes for patients needs be determined in prospective studies: either a long term observational trial, or a trial in which women with high grade endometrial cancers are randomised to sentinel lymph node biopsy or lymphadenectomy. References 1 EC Rossi, LD Kowalski, J Scalici, A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer...

Opinion statement Lymph node status is one of the most important factors in determining prognosis and the need for adjuvant treatment in endometrial cancer (EMCA). Unfortunately, full lymphadenectomy bears significant surgical and postoperative risks. The majority of patients with clinical stage I disease will not have metastatic disease; thus, a full lymphadenectomy only increases morbidity in this population of patients. The use of the sentinel lymph node (SLN) biopsy has emerged as an alternative to complete lymphadenectomy in EMCA. By removing the highest yield lymph nodes, the SLN biopsy has the same diagnostic ability as lymphadenectomy while minimizing morbidity. The sensitivity of sentinel lymph node identification with robotic fluorescence imaging for detecting metastatic endometrial and cervical cancer (FIRES) trial published this year is the largest prospective, multi-institution trial investigating the accuracy of the SLN biopsy for endometrial and cervical cancer. Results of this trial found an excellent sensitivity (97.2%) and false negative rate (3%) with the technique. The conclusions from the FIRES trial and those of a recent meta-analysis are that SLN biopsy has an acceptable diagnostic accuracy in detecting lymphatic metastases, and can replace lymphadenectomy for this diagnostic purpose. There remains controversy surrounding the SLN biopsy in high-risk disease and the use of adjuvant therapy in the setting of low volume disease detected with ultrastaging. Current data suggests that the technique is accurate in high-risk disease and that the increased detection of metastasis helps guide adjuvant therapy such that oncologic outcomes are likely not affected by forgoing a full lymphadenectomy. Further prospective study is needed to investigate the impact of low volume metastatic disease on oncologic outcomes and the need for adjuvant therapy in these patients.

Cryptococcus neoformans is a facultative intracellular pathogen and its interaction with macrophages is a key event determining the outcome of infection. Urease is a major virulence factor in C. neoformans but its role during macrophage interaction has not been characterized. Consequently, we analyzed the effect of urease on fungal-macrophage interaction using wild-type, urease-deficient and urease-complemented strains of C. neoformans. The frequency of non-lytic exocytosis events was reduced in the absence of urease. Urease-positive C. neoformans manifested reduced and delayed intracellular replication with fewer macrophages displaying phagolysosomal membrane permeabilization. The production of urease was associated with increased phagolysosomal pH, which in turn reduced growth of urease-positive C. neoformans inside macrophages. Interestingly, the ure1 mutant strain grew slower in fungal growth medium which was buffered to neutral pH (pH 7.4). Mice inoculated with macrophages carrying urease-deficient C. neoformans had lower fungal burden in the brain than mice infected with macrophages carrying wild-type strain. In contrast, the absence of urease did not affect survival of yeast when interacting with amoebae. Because of the inability of the urease deletion mutant to grow on urea as a sole nitrogen source, we hypothesize urease plays a nutritional role involved in nitrogen acquisition in the environment. Taken together, our data demonstrate that urease affects fitness within the mammalian phagosome, promoting non-lytic exocytosis while delaying intracellular replication and thus reducing phagolysosomal membrane damage, events that could facilitate cryptococcal dissemination when transported inside macrophages. This system provides an example where an enzyme involved in nutrient acquisition modulates virulence during mammalian infection.

The neurobiological mechanisms that regulate the appetite-stimulatory properties of cannabis sativa are unresolved. This work examined the hypothesis that cannabinoid-1 receptor (CB1R) expressing neurons in the mediobasal hypothalamus (MBH) regulate increased appetite following cannabis vapor inhalation. Here we utilized a paradigm where vaporized cannabis plant matter was administered passively to rodents. Initial studies in rats characterized meal patterns and operant responding for palatable food following exposure to air or vapor cannabis. Studies conducted in mice used a combination of in vivo optical imaging, electrophysiology and chemogenetic manipulations to determine the importance of MBH neurons for cannabis-induced feeding behavior. Our data indicate that cannabis vapor increased meal frequency and food seeking behavior without altering locomotor activity. Importantly, we observed augmented MBH activity within distinct neuronal populations when mice anticipated or consumed food. Mechanistic experiments demonstrated that pharmacological activation of CB1R attenuated inhibitory synaptic tone onto hunger promoting Agouti Related Peptide (AgRP) neurons within the MBH. Lastly, chemogenetic inhibition of AgRP neurons attenuated the appetite promoting effects of cannabis vapor. Based on these results, we conclude that MBH neurons contribute to the appetite stimulatory properties of inhaled cannabis.

BackgroundAcute respiratory distress syndrome (ARDS) is an often fatal neutrophil-dominant lung disease. Although influenced by multiple proinflammatory mediators, identification of suitable therapeutic candidates remains elusive. We aimed to delineate the presence of mitochondrial formylated peptides in ARDS and characterise the functional importance of formyl peptide receptor 1 (FPR1) signalling in sterile lung inflammation.MethodsMitochondrial formylated peptides were identified in bronchoalveolar lavage fluid (BALF) and serum of patients with ARDS by liquid chromatography–tandem mass spectrometry. In vitro, human neutrophils were stimulated with mitochondrial formylated peptides and their effects assessed by flow cytometry and chemotaxis assay. Mouse lung injury was induced by mitochondrial formylated peptides or hydrochloric acid. Bone marrow chimeras determined the contribution of myeloid and parenchymal FPR1 to sterile lung inflammation.ResultsMitochondrial formylated peptides were elevated in BALF and serum from patients with ARDS. These peptides drove neutrophil activation and chemotaxis through FPR1-dependent mechanisms in vitro and in vivo. In mouse lung injury, inflammation was attenuated in Fpr1−/− mice, effects recapitulated by a pharmacological FPR1 antagonist even when administered after the onset of injury. FPR1 expression was present in alveolar epithelium and chimeric mice demonstrated that both myeloid and parenchymal FPR1 contributed to lung inflammation.ConclusionsWe provide the first definitive evidence of mitochondrial formylated peptides in human disease and demonstrate them to be elevated in ARDS and important in a mouse model of lung injury. This work reveals mitochondrial formylated peptide FPR1 signalling as a key driver of sterile acute lung injury and a potential therapeutic target in ARDS.

Background Atopic dermatitis is a chronic inflammatory condition with substantial burden and limited treatment options for adolescents with moderate-to-severe disease. Significantly more patients treated with dupilumab vs. placebo achieved Investigator’s Global Assessment 0/1 at week 16. Objective The objective of this study was to assess the impact of dupilumab treatment vs. placebo on the achievement of clinically meaningful improvements in atopic dermatitis signs, symptoms and quality of life. Methods R668-AD-1526 LIBERTY AD ADOL was a randomized, double-blinded, parallel-group, phase III clinical trial. Two hundred and fifty-one adolescents with moderate-to-severe atopic dermatitis received dupilumab 300 mg every 4 weeks (q4w; n  = 84), dupilumab 200 or 300 mg every 2 weeks (q2w; n  = 82), or placebo ( n  = 85). A post-hoc subgroup analysis was performed on 214 patients with Investigator’s Global Assessment > 1 at week 16. Measures of atopic dermatitis signs, symptoms, and quality of life were assessed. Clinically meaningful improvement in one or more of three domains of signs, symptoms, and quality of life was defined as an improvement of ≥ 50% in Eczema Area and Severity Index, ≥ 3 points in Peak Pruritus Numerical Rating Scale, or ≥ 6 points in the Children’s Dermatology Life Quality Index from baseline. Results Of patients receiving dupilumab q2w, 80.5% [66/82] experienced clinically meaningful improvements in atopic dermatitis signs, symptoms, or quality of life at week 16 (vs. placebo, 20/85 [23.5%], difference 57.0% [95% confidence interval 44.5–69.4]; q4w vs. placebo, 53/84 [63.1%], difference 39.6% [95% confidence interval 25.9–53.3]; both p  < 0.0001). Results were similar in adolescents with Investigator’s Global Assessment > 1 at week 16 (q2w, 46/62 [74.2%] vs. placebo, 18/83 [21.7%], difference 52.5% [95% confidence interval 38.5–66.6]; q4w, 38/69 [55.1%] vs. placebo, difference 33.4% [95% confidence interval 18.7–48.1]; both p  < 0.0001). Conclusions Dupilumab provided clinically meaningful improvements in signs, symptoms, and quality of life in adolescents with moderate-to-severe atopic dermatitis among patients with Investigator’s Global Assessment > 1 at week 16. Treatment responses should be interpreted in the context of such clinically relevant patient-reported outcome measures. Trial Registration ClinicalTrials.gov; NCT03054428. Video abstract 1xjYruyFf8S4AJRGhPEPuT Adolescents with atopic dermatitis: does dupilumab improve their signs, symptoms, and quality of life? (MP4  212916 kb)