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The TNF family member receptor activator for NF-κB ligand (RANKL) and its receptors RANK and osteoprotegerin are key regulators of bone remodeling but also influence cellular functions of tumor and immune effector cells. In this work, we studied the involvement of RANK–RANKL interaction in NK cell–mediated immunosurveillance of acute myeloid leukemia (AML). Substantial levels of RANKL were found to be expressed on leukemia cells in 53 of 78 (68%) investigated patients. Signaling via RANKL into the leukemia cells stimulated their metabolic activity and induced the release of cytokines involved in AML pathophysiology. In addition, the immunomodulatory factors released by AML cells upon RANKL signaling impaired the anti-leukemia reactivity of NK cells and induced RANK expression, and NK cells of AML patients displayed significantly upregulated RANK expression compared with healthy controls. Treatment of AML cells with the clinically available RANKL Ab Denosumab resulted in enhanced NK cell anti-leukemia reactivity. This was due to both blockade of the release of NK-inhibitory factors by AML cells and prevention of RANK signaling into NK cells. The latter was found to directly impair NK anti-leukemia reactivity with a more pronounced effect on IFN-γ production compared with cytotoxicity. Together, our data unravel a previously unknown function of the RANK–RANKL molecule system in AML pathophysiology as well as NK cell function and suggest that neutralization of RANKL with therapeutic Abs may serve to reinforce NK cell reactivity in leukemia patients.

BackgroundThe presence of circulating tumor cells (CTCs) in patients with breast cancer correlates to a bad prognosis. Yet, CTCs are detectable in only a minority of patients with progressive breast cancer, and factors that influence the abundance of CTCs remain elusive.MethodsWe conducted CTC isolation and enumeration in a selected group of 73 consecutive patients characterized by progressive invasive breast cancer, high tumor load and treatment discontinuation at the time of CTC isolation. CTCs were quantified with the Parsortix microfluidic device. Clinicopathological variables, blood counts at the time of CTC isolation and detailed treatment history prior to blood sampling were evaluated for each patient.ResultsAmong 73 patients, we detected at least one CTC per 7.5 ml of blood in 34 (46%). Of these, 22 (65%) had single CTCs only, whereas 12 (35%) featured both single CTCs and CTC clusters. Treatment with the monoclonal antibody denosumab correlated with the absence of CTCs, both when considering all patients and when considering only those with bone metastasis. We also found that low red blood cell count was associated with the presence of CTCs, whereas high CA 15-3 tumor marker, high mean corpuscular volume, high white blood cell count and high mean platelet volume associated specifically with CTC clusters.ConclusionsIn addition to blood count correlatives to single and clustered CTCs, we found that denosumab treatment associates with most patients lacking CTCs from their peripheral circulation. Prospective studies will be needed to validate the involvement of denosumab in the prevention of CTC generation.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1067-y) contains supplementary material, which is available to authorized users.

Background: The type and number of symptoms in emergency patients differ widely.

Abdominal pain (AP) is a common reason for presentation to an emergency department (ED). With this prospective, observational all-comer study, we aimed to answer three questions: Which diagnoses are most often missed? What is the incidence of extra-abdominal causes? What is the prognosis of abdominal pain in a tertiary urban European ED? Participants were systematically interviewed for the presence of 35 predefined symptoms. For all patients with abdominal pain, the index visit diagnoses were recorded. Related representation was defined as any representation, investigation, or surgery related to the index visit (open time frame). If a diagnosis changed between index visit and representation, it was classified as missed diagnosis. Among 3960 screened presentations, 480 (12.1%) were due to AP. Among 63 (13.1%) related representations, the most prevalent causes were cholelithiasis, gastroenteritis, and urinary retention. A missed diagnosis was attributed to 27 (5.6%) presentations. Extra-abdominal causes were identified in 162 (43%) presentations. Thirty-day mortality was comparable to that of all other ED patients (2.2% vs. 2.1%). Patients with abdominal pain had a low risk of representation, and the majority of representations due to missed diagnoses were of benign origin. The high incidence of extra-abdominal causes is noteworthy, as this may induce change to differential diagnosis of abdominal pain.

Study Objective: Enhancement of a routine complete blood count (CBC) for detection of sepsis in the emergency department (ED) has pragmatic utility for early management. This study evaluated the performance of monocyte distribution width (MDW) alone and in combination with other routine CBC parameters as a screen for sepsis and septic shock in ED patients. Methods:A prospective cohort analysis of adult patients with a CBC collected at an urban ED from January 2020 through July 2021. The performance of MDW, white blood count (WBC) count, and neutrophil-to-lymphocyte-ratio (NLR) to detect sepsis and septic shock (Sepsis-3 Criteria) was evaluated using diagnostic performance measures. Results:The cohort included 7952 ED patients, with 180 meeting criteria for sepsis; 43 with septic shock and 137 without shock. MDW was highest for patients with septic shock (median 24.8 U, interquartile range [IQR] 22.0-28.1) and trended downward for patients with sepsis without shock (23.9 U, infection (20.4 U, then controls (18.6 U,). In isolation, MDW detected sepsis and septic shock with an area under the receiver operator characteristic curve (AUC) of 0.80 (95% confidence interval [CI] 0.77-0.84) and 0.85 (95% CI 0.80-0 .91), respectively. Optimal performance was achieved in combination with WBC count and NLR for detection of sepsis (AUC 0.86, 95% CI 0.83-0.89) and septic shock (0.86, 95% CI 0.80-0.92). Conclusion:A CBC differential panel that includes MDW demonstrated strong performance characteristics in a broad ED population suggesting pragmatic value as a rapid screen for sepsis and septic shock.

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