Infections in the Emergency Department: improving diagnosis and prognosis

Early warning scores (EWS) were designed to predict chance of deterioration in hospitalised patients. In 2016 qSOFA was introduct as part of the new sepsis criteria.1 In chapter 3 we started a prospective multicentre study to compare the performance of qSOFA, NEWS, MEWS and SIRS in the ED in patients with suspected infection. All patients 18 years and older and with suspected infection were included. We compared the scores of NEWS ≥5, MEWS ≥3 , qSOFA≥ 2 and SIRS≥2 to predict 30 days mortality and ICU admission. NEWS ≥5 showed to have the best balance between sensitvity (75.8% (95%CI 63.3-85.8), specificity (65.9% (95%CI 63.2-68.5) and NPV (98.2% (95% CI 97.3-98.9) for early identification of high risk patients with suspected infection in the ED. In chapter 4 we conducted an observational, retrospective multicenter cohort study. All patients aged 18 and over with suspicion of COVID-19 who visited the ED were enrolled. Multipele variables were collected and analysed as potential risk factors for poor outcome. Ten predictors of poor outcome were identifed, The AUC was 0.86 (95%CI 0.83-0.89), with a Brier score of 0.32 and, and R2 of 0.41. The AUC in the external validation in 500 patients was 0.70 (95%CI 0.65-0.75). The COVERED risk score showed an excellent discriminatory ability also in an external validation. In chapter 5 we aimed to prospectively validate the COVID-19 Reporting and Data System (CO-RADS) at the ED and we analyzed whether the CT- severity Score (CTSS) was associated with hospital admission, ICU and mortality. Diagnostic accuracy measures were calculated for CO-RADS using PCR as reference. The area under the curve (AUC) of 0.91 (95%CI 0.89-0.94) was found for CO-RADS using PCR as reference. The optimal CO-RADS cutoff was 4 with a sensitivity of 89.4% (CI 84.7-93.0) and specificity of 87.2% ICI 83.9-89.9). A significant association between CTSS and admission , ICU and 30 day mortality was found, adjusted ORs per point increase in CTSS were 1.19 (CI 1.09-1.28), 1.23 (1.15-132), 1.14 (1.07-1.22) respectively. This findings support the use of CO-RADS and CTSS in triage and diagnosis for patients presenting with possible COVID-19 at the ED. In chapter 6 we compared the diagnostic accuracy of lung ultrasound (LUS) with chest CT in suspected COVID-19 patients at the ED. Area under the receiver operating characteristic (AUROC) was 0.81 (95% CI 0.75-0.88) for LUS and 0.89 (95% CI 0.84-0.94) for CT. Sensitivity and specificity for LUS were 91.9% (95%CI 84.0-96.7) and 71.0% (95%CI61.1-79.6) respectively versus 88.4% (95% CI79.7-94.3) and 82.0% (95% CI 73.1-89.0) for CT. Agreement between LUS and CT was 0.65 and inter-observer agreement for LUS was good 0.89 (95% CI 0.83-0.93). LUS can safely exclude clinically relevant COVID-19 pneumonia and may aid in COVID-19 diagnosis in high prevalence situations. In chapter 7 we investigated whether the optimal use of procalcitonin (PCT) is different in patients with and without proven viral infections for the purpose of excluding bacteremia. The study was a prospective observational study where all patients 18 year and older for whom a blood culture and viral test were ordered in the ED were included. PCT had an area under the curve of 0.85% (95%CI 0.80-0.91) for prediction of bacteremia. In patients with proven viral infection PCT < 0.5ug/L had a sensitivity of 100% (95%CI 63.1-100) and specificity of 81.2% (95% CI75.1-86.3) to exclude bacteremia. This study suggest that a PCT concentration of < 0.5ug/L makes bacteremia unlikely in patients with a viral infection

Case report on the role of radiofrequency-assisted spleen-preserving surgery for splenic metastasis in the era of check-point inhibitors.

RATIONALE: An isolated splenic metastasis is a rare phenomenon noted in advanced stage melanoma. We report the role of radiofrequency (RF) -based splenic-preserving splenectomy in a patient with a solitary splenic metastasis from advanced stage melanoma that was managed with checkpoint inhibitors. PATIENT CONCERNS: We report a case of a 60-year-old man who presented with multiple lung metastases and a solitary splenic metastasis with advanced stage melanoma following excision of primary from his trunk 2.3 years back. DIAGNOSIS: Considering the diagnosis of advanced stage melanoma with multiple lung metastases and a solitary splenic metastasis, and its ongoing progressive nature. This case was discussed in the tumour board meeting. INTERVENTIONS: A decision was made to commence treatment with immunotherapy in the form of PD-1 inhibitor (programmed cell death 1 receptor) pembrolizumab. Follow-up restaging computer tomography (CT) scan of the abdomen and chest showed a significant reduction in the lung and chest wall lesions, but the splenic lesion remained unchanged. Given the lack of response to treatment in the splenic metastasis and the significant decrease in lung metastases, the multidisciplinary team decided that a partial splenectomy combined with continued immunotherapy treatment would be appropriate as the success of immunotherapy was imminent within the splenic preservation. OUTCOMES: The postoperative recovery was smooth and the patient was discharged from hospital on the sixth postoperative day with normal platelets and white blood cells. The histopathological analysis of the resected specimen showed a metastatic melanoma with negative margins.At 10-month follow-up after the splenic resection the patient had not experienced further tumour recurrences. LESSONS: Spleen-preserving resection for an isolated, solitary splenic metastasis of melanoma is a feasible approach as it not only preserves the ongoing efficacy of checkpoint inhibitors by preserving the physiological T cell milieu, but the immunomodulation properties of RF can produce potentially additional therapeutic benefit

TRAIL Delivered by Mesenchymal Stromal/Stem Cells Counteracts Tumor Development in Orthotopic Ewing Sarcoma Models.

Ewing sarcoma (EWS) is the second most frequent pediatric malignant bone tumor. EWS patients have not seen any major therapeutic progress in the last thirty years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro-apoptotic cytokine TNF-Related Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, certain EWS cell lines appear resistant to recombinant human (rh) TRAIL-induced apoptosis. We therefore hypothesized that a TRAIL presentation at the surface of the carrier cells might overcome this resistance and trigger apoptosis. For this purpose, human adipose mesenchymal stromal/stem cells (MSC) transfected in a stable manner to express full-length human TRAIL were co-cultured with several human EWS cell lines, inducing apoptosis by cell-to-cell contact even in cell lines initially resistant to rhTRAIL or AMG655, an antibody agonist to the death receptor, DR5. In vivo, TRAIL delivered by MSCs was able to counteract tumor progression in two orthotopic models of Ewing sarcoma, associated with caspase activation, indicating that a cell-based delivery of a potent apoptosis-inducing factor could be relevant in EWS. This article is protected by copyright. All rights reserved

The Potential Role of Lysosomal Sequestration in Sunitinib Resistance of Renal Cell Cancer

Renal cell carcinoma (RCC) is a highly vascularized tumor type, which is often associated with inactivated mutations in the von Hippel-Lindau gene that drives proangiogenic signaling pathways. As such, new therapies for the treatment of RCC have largely been focused on blocking angiogenesis. Sunitinib, an antiangiogenic tyrosine kinase inhibitor, is the most frequently used first-line drug for the treatment of RCC. Although treatment with sunitinib improves patient outcome considerably, acquired resistance will emerge in all cases. The molecular mechanisms of resistance to sunitinib are poorly understood, but in the past decade, several of these have been proposed. Lysosomal sequestration of sunitinib was reported as a potential resistance mechanism to sunitinib. In this review, the underlying molecular mechanisms of lysosomal sunitinib sequestration and the potential strategies to overcome this resistance are discussed to be able to further improve the treatment of RCC

RIP4 inhibits STAT3 signaling to sustain lung adenocarcinoma differentiation.

Loss of epithelial differentiation and extracellular matrix (ECM) remodeling are known to facilitate cancer progression and are associated with poor prognosis in patients with lung cancer. We have identified Receptor-interacting serine/threonine protein kinase 4 (RIP4) as a regulator of tumor differentiation in lung adenocarcinoma (AC). Bioinformatics analyses of human lung AC samples showed that poorly differentiated tumors express low levels of RIP4, whereas high levels are associated with better overall survival. In vitro, lung tumor cells expressing reduced RIP4 levels showed enhanced activation of STAT3 signaling and had a greater ability to invade through collagen. In contrast, overexpression of RIP4 inhibited STAT3 activation, which abrogated interleukin-6-dependent induction of lysyl oxidase, a collagen cross-linking enzyme. In an autochthonous mouse model of lung AC initiated by Kras(G12D) expression with loss of p53, Rip4 knockdown tumors progressed to a poorly differentiated state marked by an increase in Hmga2, reduced Ttf1, and enrichment of genes regulating extracellular remodeling and Jak-Stat signaling. Tail vein injections of cells overexpressing Rip4 showed a reduced potential to invade and form tumors, which was restored by co-expression of Stat3. Altogether, our work has identified that loss of RIP4 enhances STAT3 signaling in lung cancer cells, promoting the expression of ECM remodeling genes and cancer dedifferentiation

TRAIL-receptor preferences in pancreatic cancer cells revisited: Both TRAIL-R1 and TRAIL-R2 have a licence to kill

Background TRAIL is a potent and specific inducer of apoptosis in tumour cells and therefore is a possible new cancer treatment. It triggers apoptosis by binding to its cognate, death-inducing receptors, TRAIL-R1 and TRAIL-R2. In order to increase its activity, receptor-specific ligands and agonistic antibodies have been developed and some cancer types, including pancreatic cancer, have been reported to respond preferentially to TRAIL-R1 triggering. The aim of the present study was to examine an array of TRAIL-receptor specific variants on a number of pancreatic cancer cells and test the generality of the concept of TRAIL-R1 preference in these cells. Methods TRAIL-R1 and TRAIL-R2 specific sTRAIL variants were designed and tested on a number of pancreatic cancer cells for their TRAIL-receptor preference. These sTRAIL variants were produced in HEK293 cells and were secreted into the medium. After having measured and normalised the different sTRAIL variant concentrations, they were applied to pancreatic and control cancer cells. Twenty-four hours later apoptosis was measured by DNA hypodiploidy assays. Furthermore, the specificities of the sTRAIL variants were validated in HCT116 cells that were silenced either for TRAIL-R1 or TRAIL-R2. Results Our results show that some pancreatic cancer cells use TRAIL-R1 to induce cell death, whereas other pancreatic carcinoma cells such as AsPC-1 and BxPC-3 cells trigger apoptosis via TRAIL-R2. This observation extended to cells that were naturally TRAIL-resistant and had to be sensitised by silencing of XIAP (Panc1 cells). The measurement of TRAIL-receptor expression by FACS revealed no correlation between receptor preferences and the relative levels of TRAIL-R1 and TRAIL-R2 on the cellular surface. Conclusions These results demonstrate that TRAIL-receptor preferences in pancreatic cancer cells are variable and that predictions according to cancer type are difficult and that determining factors to inform the optimal TRAIL-based treatments still have to be identified

Optimization of trauma care: A two-tiered inhospital trauma team response system

Background: To improve utilization of resources and reduce overtriage, two-tiered trauma team activation (TTA) system was implemented. The system activates a complete or selective trauma team (CTT, STT). Activation is based on the mechanism of injury (MOI), prehospital vital signs and injuries. Objectives: The objective was to evaluate the feasibility, effectiveness and safety of the implementation of a two-tiered system and whether the triage is done according to the TTA criteria. Methods: A prospective observational study was performed at the emergency department (ED) of a Level I trauma center. Data were collected on TTA criteria, patient demographics, MOI, prehospital vital signs, imaging modalities and blood gas analysis in the ED and inhospital data. Results: In 3 months, 186 patients were presented to the trauma resuscitation room. Thirty-four patients were excluded, 152 patients were included for analysis. Median age was 48 years (range 193), 64 were males. In 73, the CTT was activated, in 27 the STT, the STT was upgraded three times. Seventy-nine patients had to be admitted, the median length of stay was 5 days (range 162). Thirty-eight patients needed Intensive Care Unit (ICU) admission; the median ICU stay was 3 days (range 133). Three patients died in the resuscitation room, in total, nine patients died. Overtriage was 29 and undertriage 7. No significant difference was found for mortality, duration of hospital admission or ICU admission across the four groups (correct activation STT, undertriage, overtriage, and correct activation CTT). Conclusions: This TTA system identifies those patients in need of a CTT adequately with an undertriage percentage of 7, indicative of improved care for the severely injured and a more appropriate use of resources. With this model, the overtriage is set to an acceptable percentage of 29

Prehospital accuracy of (H)EMS pelvic ring injury assessment and the application of non-invasive pelvic binder devices

Background: Pre-hospital application of a non-invasive pelvic binder device (NIPBD) is essential to increase chances of survival by limiting blood loss in patients with an unstable pelvic ring injury. However, unstable pelvic ring injuries are often not recognized during prehospital assessment. We investigated the prehospital (helicopter) emergency medical services ((H)EMS)’ accuracy of the assessment of unstable pelvic ring injuries and NIPBD application rate. Methods: We performed a retrospective cohort study on all patients with a pelvic injury transported by (H)EMS to our level one trauma centre between 2012 and 2020. Pelvic ring injuries were included and radiographically categorized using the Young & Burgess classification system. Lateral Compression (LC) type II/III -, Anterior-Posterior (AP) type II/III - and Vertical Shear (VS) injuries were considered as unstable pelvic ring injuries. (H)EMS charts and in-hospital patient records were evaluated to determine the sensitivity, specificity and diagnostic accuracy of the prehospital assessment of unstable pelvic ring injuries and prehospital NIPBD application. Results: A total of 634 patients with pelvic injuries were identified, of whom 392 (61.8%) had pelvic ring injuries and 143 (22.6%) had unstable pelvic ring injuries. (H)EMS personnel suspected a pelvic injury in 30.6% of the pelvic ring injuries and in 46.9% of the unstable pelvic ring injuries. An NIPBD was applied in 108 (27.6%) of the patients with a pelvic ring injury and in 63 (44.1%) of the patients with an unstable pelvic ring injury. (H)EMS prehospital diagnostic accuracy measured in pelvic ring injuries alone was 67.1% for identifying unstable pelvic ring injuries from stable pelvic ring injuries and 68.1% for NIPBD application. Conclusion: The (H)EMS prehospital sensitivity of unstable pelvic ring injury assessment and NIPBD application rate is low. (H)EMS did not suspect an unstable pelvic injury nor applied an NIPBD in roughly half of all unstable pelvic ring injuries. We advise future research on decision tools to aid the routine use of an NIPBD in any patient with a relevant mechanism of injury