Preanalytical temperature and storage stability of specific IgE antibodies in serum.

Allergen-specific serum immunoglobulin E (sIgE) levels are a cornerstone in allergy diagnostics. While immunoglobulins are known to be relatively stable molecules, the influence of preanalytical factors on the stability of sIgE is not thoroughly investigated. We studied the effect of several preanalytical factors: (1) delayed centrifugation of serum samples in tubes with separating gel for 10, 24 and 48 h, (2) prolonged storage at 5 °C for 3, 7, 10 and 14 days, (3) storage tube type (primary tube with separating gel or secondary tube), (4) repeated freeze-thawing cycles, and (5) prolonged storage at -20 °C for 4 and 8 weeks. We found that sIgE is stable at room temperature for 48 h before centrifugation and for 10 days at 5 °C after centrifugation. There was no effect of the separating gel after storing serum for 1 week in the freezer. However, storage for 4-8 weeks, and introducing more than one freeze-thaw cycle resulted in a larger variation of sIgE levels. In conclusion, we found that sIgEs are stable under various preanalytical conditions, which allows for flexible handling of samples for a comprehensive portfolio of sIgE analyses.

New Insights in Coagulation and Fibrinolysis in Patients with Primary Brain Cancer: A Systematic Review.

Patients with primary brain tumors have a high incidence of thrombosis and hemorrhage. The underlying mechanism is believed to be derangement of their hemostatic system. To get nearer a clarification of this, we aimed to systematically review the existing literature regarding primary and secondary hemostasis as well as fibrinolysis in patients with primary brain tumor. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases PubMed, Embase, and Web of Science were searched on December 15, 2020, without time restrictions. Studies were included if they evaluated at least one blood coagulation and/or fibrinolysis parameter in patients with primary brain cancer. In total, 26 articles including 3,288 patients were included. Overall, increased activity of secondary hemostasis was observed as increased prothrombin fragment 1 + 2 and endogenous thrombin generation levels were found in glioma patients compared with controls. Furthermore, data showed a state of hypofibrinolysis with increased plasminogen activator inhibitor 1 and prolonged clot lysis time in glioma patients. In contrast, no consistent increase in the primary hemostasis was identified; however, data suggested that increased sP-selectin could be a biomarker of increased venous thromboembolism risk and that increased platelet count may be prognostic for survival. Lastly, data indicated that fibrinogen and D-dimer could hold prognostic value. In conclusion, this review indicates that an increased activity of secondary hemostasis and impaired fibrinolysis could be important players in the pathogeneses behind the high risk of thromboembolisms observed in brain cancer patients. Thus, long-term thromboprophylaxis may be beneficial and additional studies addressing this issue are wanted.

Inflammation-scores as prognostic markers of overall survival in lung cancer: a register-based study of 6,210 Danish lung cancer patients.

BACKGROUND: Inflammation-scores based on general inflammation markers are suggested as prognostic markers of overall survival (OS) in lung cancer. However, whether these inflammation-scores improves the prognostication performed by well-established prognostic markers is unsettled. In a large register-based lung cancer patient cohort, nine different inflammation-scores were compared, and their ability to optimize the prognostication of OS was evaluated. METHODS: Lung cancer patients diagnosed from 2009-2018 in The Central Denmark Region were identified in the Danish Lung Cancer Registry. Pre-treatment inflammation markers were extracted from the clinical laboratory information system. Prognostication of OS was evaluated by Cox proportional hazard models. Comparison of the inflammation-scores and their added value to established prognostic markers were assessed by Akaike's information criteria and Harrel's C-index. RESULTS: In total, 5,320 patients with non-small cell lung cancer (NSCLC) and 890 patients with small cell lung cancer (SCLC) were identified. In NSCLC, the Aarhus composite biomarker score (ACBS), including albumin, C-reactive protein, neutrophil count, lymphocyte count and haemoglobin, and the neutrophil-lymphocyte-ratio (NLR) were superior. Furthermore, they improved the prognostication of OS significantly (p <0.0001) (ACBS: HR: 2.24 (95%CI: 1.97-2.54); NLR: HR: 1.58 (95%CI: 1.47 - 1.69)). In SCLC, three scores were equally superior and improved the prognostication of OS p < 0.0001): neutrophil-lymphocyte-ratio (HR:1.62 (95%CI: 1.38-1.90)), modified Glasgow Prognostic Score (mGPS) (HR:1.70 (95%CI: 1.55-1.86) and the Combined NLR and GPS (CNG) (HR:2.10 (95%CI: 1.77-2.49). CONCLUSIONS: The ACBS was the optimal score in NSCLC, whereas neutrophil-lymphocyte-ratio, mGPS and CNG were equally superior in SCLC. Additionally, these inflammation-scores all optimised the prognostication of OS and added value to well-established prognostic markers.

Evaluation of the point-of-care devices KetoSureTM and StatStrip Express® blood ketone tests using ß-hydroxybutyrate spiked samples.

Measurement of ß-hydroxybutyrate (BHB) in blood is used clinically as a measure of ketosis when diabetic ketoacidosis is expected. With the introduction of point-of-care testing (POCT) for blood-BHB, nonproductive time is reduced to a minimum in a potential critical situation; however, studies have observed inferior quality of POCT-BHB. Recently, the POCT device KetoSure (Roche) has been introduced to the clinic. In this study, we evaluated the imprecision and linearity of KetoSure and compared this to the established StatStrip Express (Nova Biomedical) based on spiked full blood samples. We found comparable imprecision for KetoSure and StatStrip Express. However, linearity was only observed in the lower part of the measuring range for both devices. In a method comparison, higher values of BHB were measured by KetoSure than by an enzymatic endpoint spectrophotometric reference method (mean bias: 21% (95% confidence interval (CI): 4%-37%)). Conversely, StatStrip Express returned lower values of BHB (mean bias: -16% (95% CI: -38%-7%), while the widely applied POCT device FreeStyle Precision Neo (Abbott) returned values equivalent with the reference method (mean bias: 5% (95% CI: -14%-24%). In samples with concentrations of BHB above the measuring range, the POCT devices could be provoked to return falsely low results. In conclusion, the quality of KetoSure is in line with other established POCT devices; however, the KetoSure measures higher concentrations than other POCT devices. As, linearity only was observed in the lower part of the measuring range and as falsely low measures could be provoked, we advise users to interpret results with precaution.

Reference intervals for platelet large cell ratio, platelet distribution width, plateletcrit and standard haematological parameters determined on the Sysmex XN-10 in a cohort of 30,917 Danish blood donors.

With the introduction of the Sysmex XN-10, new platelet indices reflecting platelet maturity can be obtained alongside with a full blood count. Therefore, the need for verified reference intervals is present. The purpose of this study was to establish reference intervals for the platelet indices: platelet large cell ratio (P-LCR), platelet distribution width (PDW) and plateletcrit (PCT) in a large Scandinavian cohort. Furthermore, we aimed to verify previously established reference intervals of haematological parameters included in a full blood count. Blood samples were obtained from healthy Danish blood donors and analysed by use of the Sysmex XN-10 analyser (Sysmex, Kobe, Japan). Non-parametric 95% reference intervals were determined as the 2.5 and 97.5 percentile and presented with 90% confidence intervals (CI). In total, 30,917 blood donors were included and the following reference intervals were established: P-LCR, ratio: 17.3 (90% CI: 17.2 - 17.5) - 46.2 (90% CI:45.9 - 46.4); P DW, fL:9.5 (90% CI: 9.5 - 9.5) - 17.2 (90% CI: 17.2 - 17.3) and PCT, fraction: 0.18 (0.18 - 0.18) - 0.38 (0.38 - 0.39). The reference intervals were stable across age and sex. Furthermore, reference intervals for the remaining haematological parameters included in a full blood count were verified and found in line with the previously established reference intervals.

Hyperfibrinolysis in Patients with Solid Malignant Neoplasms: A Systematic Review.

Solid malignant neoplasms have the capability of disturbing the fibrinolytic system, leading to primary hyperfibrinolysis, a paraneoplastic syndrome that potentially results in severe bleeding. Yet, the full extent of primary hyperfibrinolysis in solid malignant neoplasms is unknown. Thus, the purpose of this study was to systematically review the current literature regarding clinical manifestations, biochemical diagnosis, and treatment of primary hyperfibrinolysis in patients with solid malignant neoplasms. The review was performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases PubMed, Embase, Scopus, and Web of Science were searched on December 5, 2019, without time limits. Studies were included if they comprised at least one biochemical marker of fibrinolysis in addition to fibrinogen degradation products such as D-dimer, and furthermore included a correlation between biochemical marker and clinical outcome. In total, 12 studies were included. All studies were case reports including a total of 21 patients. Prostate cancer was the most frequently represented cancer type (76%), and the majority of cancer patients had metastatic disease (81%). Spontaneous bleeding was the clinical presentation in the majority of patients (76%), and the most frequently localization for the bleedings was subcutaneous. Antifibrinolytic agents were the most commonly used treatment and ceased bleedings in 80% of patients. Three patients died of uncontrolled bleedings. In conclusion, primary hyperfibrinolysis induced by solid malignant neoplasms is a rare but potentially life-threatening condition that should be considered, especially in patients with metastatic disease presenting with serious, spontaneous subcutaneous bleedings. A standardized diagnostic strategy is strongly needed.

Anti-transglutaminase IgA antibody measurement in coeliac disease: Method comparison IDS-iSYS vs. Thermo Fisher Phadia.

In coeliac disease, the diagnostic work-up is based on a combination of clinical, histopathological and serological evaluation. Among the serological tests, the presence of tissue transglutaminase (tTG) IgA antibodies is the cornerstone owed to a high sensitivity and specificity. Recently, Immunodiagnostic Systems Ltd (IDS) introduced the fully automated chemiluminescent autoimmune assays for use on the IDS-iSYS Multi-Discipline Automated System. In this study, we aimed to compare the performance of the IDS-iSYS assay to the Thermo Fisher Phadia assay and to establish the upper reference limit of tTG IgA in a healthy population from Denmark based on the IDS-iSYS assay. We discovered a total imprecision of CV = 12.2% (2.87 AU/mL) and CV = 10.6% (47.55 AU/mL). Moreover, we compared the performance of IDS-iSYS assay to Thermo Fisher Phadia assay in 236 samples from unselected patients submit for tTG IgA testing and found a concordance of 97% (p < .0001). Furthermore, in 150 healthy blood donors, we established the upper reference limit of 3.26 AU/mL (95% CI: 3.10 - 3.90) was identified. Our study validates the performance of the IDS-iSYS tTG IgA assay and demonstrates results in concordance with the established Thermo Fisher Phadia. Furthermore, it provides estimates for the upper reference interval limit of the tTG-IgA.

The prognostic role of inflammation-scores on overall survival in lung cancer patients.

OBJECTIVE: Inflammation has been validated as a host-related prognostic marker in cancer. The Glasgow Prognostic score (GPS) and neutrophil-to-lymphocyte ratio (NLR) are suggested measures of inflammation. However, the allocation of patients has been questioned. Hence, optimized inflammation-scores has been developed, such as the combined NLR and GPS (CNG) system, and the Aarhus composite biomarker score (ACBS). So far, these optimized inflammation-scores have not been validated in lung cancer patients. We evaluated if the optimized inflammation-scores were prognostic markers of inferior survival in lung cancer patients. Furthermore, we tested which of the optimized inflammation-scores led to better patient-allocation. MATERIAL AND METHODS: The cohort of this prospective study composed of 275 non-small cell lung cancer patients. We evaluated pre-diagnostic serum biomarkers for GPR, NLR, platelet-to-lymphocyte ratio as well as the optimized inflammation-scores CNG and ABCS as predictors of overall survival (OS), and we examined the patient-allocation derived from each inflammation-score. RESULTS: Each of the evaluated inflammation-scores could predict the overall survival even when adjustments were made for comorbidity and clinicopathological characteristics. When comparing the scores, the optimized inflammation-scores CNG and ACBS led to a better and more balanced patient-allocation. In the early clinical stages I & II, the optimized scores could reveal a subgroup of patients with poorer survival that is similar to stage III. CONCLUSION: In this cohort of lung cancer patients, we demonstrate that inflammation-scores are prognostic markers of inferior survival. Furthermore, we demonstrate that the optimized inflammation-scores CNG and ACBS lead to better patient-allocation independently of the clinicopathological characteristics and comorbidity.

Ultra-micro samples can be used for mRNA quantification of lung cancer biomarkers.

BACKGROUND: Isolating sufficient material for molecular testing remains challenging in non-small cell lung cancer (NSCLC). The use of new ultra-microsamples (uMS) is proven sufficient for DNA and mRNA detection, but whether uMS are useful for quantifying mRNA expression is unknown. We investigated if uMS from lung cancer patients can be used to generate quantitative data on mRNA expression. METHODS: uMS were collected from primary tumors and lymph nodes from patients suspected of having lung cancer. mRNA was isolated, reverse-transcribed into cDNA and quantified with quantitative PCR assays for hepatocyte growth factor receptor (MET), hepatocyte growth factor (HGF), epidermal growth factor receptor (EGFR) and amphiregulin (AREG) mRNA. The fraction of tumor cells to normal cells was estimated in each sample. RESULTS: MET, HGF, EGFR, and AREG expression were evaluated in 90 samples (30 containing cancer cells and 60 without cancer cells). MET and EGFR expression were negligible in samples without cancer cells. In samples containing cancer cells, MET and EGFR could be quantified in 13 samples each. Adjustment for tumor-cell fraction made it possible to obtain a quantitative result for the tumor-cell mRNA expression of MET and EGFR. In contrast, AREG and HGF were expressed in samples without tumor cells. These samples were used to establish the AREG and HGF mRNA expression in normal cells. Seven out of 14 AR-positive and two out of eight HGF-positive samples with tumor cells were above a cut-off of the mean + 2SD established in samples without tumor cells. CONCLUSION: We demonstrate that uMS contain high-quality mRNA, and quantitative studies can be performed when the tumor-cell fraction is considered.

Pretreatment Platelet Count is a Prognostic Marker in Lung Cancer: A Danish Registry-based Cohort Study.

BACKGROUND: Thrombocytosis has been associated with a poor prognosis in a wide range of malignancies. However, the results have been conflicting for lung cancer. Therefore, we evaluated the prognostic value of platelet count in a large cohort of lung cancer patients. PATIENTS AND METHODS: All lung cancer patients diagnosed in The Central Denmark Region from 2009 to 2018 were included in the study. Data from the Danish Lung Cancer Registry were combined with data from the clinical laboratory information system on pretreatment platelet count. Platelet count was defined as low, normal, or high based on being below, within, or above the reference intervals. The prognostic value of platelet count was assessed by the Cox proportional hazard model. C-statistics were conducted to investigate if the platelet count added additional prognostic value to existing prognostic markers. RESULTS: Totally, 6,758 patients with non-small-cell lung cancer (NSCLC) and 1150 patients with small-cell lung cancer (SCLC) were included. Low and high platelet count were significantly associated with decreased overall survival (OS) in NSCLC patients (low: adjusted hazard ratio (HR)=1.75 (95% confidence interval [CI]: 1.49-2.06); high: adjusted HR=1.24 (95% CI: 1.16-1.33)). In SCLC patients, only low platelet count was significantly associated with decreased OS (adjusted HR = 2.71 [95% CI: 2.02-3.65]). C-statistics showed that the prognostic models were significantly improved by the addition of platelet count for both NSCLC and SCLC patients (P < .0001). CONCLUSION: Low and high platelet count were adverse prognostic factors in NSCLC patients, while only low platelet count was a prognostic marker in SCLC patients.

Targeted Treatment of Soft-Tissue Sarcoma.

Background: Soft-tissue sarcoma (STS) is a heterogeneous group of sarcomas with a low incidence. The treatment of advanced disease is poor, and mortality is high. We aimed to generate an overview of the clinical experiences with targeted treatments based on a pre-specified target in patients with STS. Methods: A systematic literature search was conducted in PubMed and Embase databases. The programs ENDNOTE and COVIDENCE were used for data management. The literature was screened to assess the article's eligibility for inclusion. Results: Twenty-eight targeted agents were used to treat 80 patients with advanced STS and a known pre-specified genetic alteration. MDM2 inhibitors were the most-studied drug (n = 19), followed by crizotinib (n = 9), ceritinib (n = 8), and 90Y-OTSA (n = 8). All patients treated with the MDM2 inhibitor achieved a treatment response of stable disease (SD) or better with a treatment duration of 4 to 83 months. For the remaining drugs, a more mixed response was observed. The evidence is low because most studies were case reports or cohort studies, where only a few STS patients were included. Conclusions: Many targeted agents can precisely target specific genetic alterations in advanced STS. The MDM2 inhibitor has shown promising results.

Role of high­sensitivity C­reactive protein in patients with sarcoma.

Immunotherapy has shown promising results in lung cancer and melanomas; however, the responses have been poor in patients with sarcoma. Understanding the relationship between the immune system and sarcoma is essential to develop improved immunotherapy approaches. High-sensitivity C-reactive protein (hs-CRP) has been proposed as a prognostic marker in other cancer types; however, to the best of our knowledge, the association between hs-CRP levels and mortality in patients with sarcoma has not been investigated. The present prospective, non-randomised, non-interventional explorative study investigated the prognostic value of hs-CRP in patients with sarcoma. Patients referred to the sarcoma centre of Aarhus University Hospital (Aarhus, Denmark) were included between April 2014 and December 2020. Clinical data were obtained from the national quality sarcoma database and biomarkers other than hs-CRP were obtained from the clinical laboratory information system. The study cohort consisted primarily of patients with localised sarcoma. hs-CRP was significantly higher in patients with bone sarcoma (P=0.022) and soft tissue sarcoma (STS; P<0.001) compared with control patients. For STS, grade III tumours but not metastatic disease were associated with a higher hs-CRP level (P=0.0001). Elevated hs-CRP levels were associated with increased overall mortality [hazard ratio (HR), 1.91; 95% CI, 1.33-2.75; P=0.001]. Furthermore, elevated hs-CRP levels were also associated with decreased progression-free survival (HR, 1.64; 95% CI, 1.17-2.29; P=0.004). Furthermore, for patients with hs-CRP <8 mg/l, higher hs-CRP was associated with an increased risk of recurrent disease and reduced overall survival compared with those of patients with low hs-CRP. In conclusion, the present study demonstrated that hs-CRP was a prognostic factor for overall mortality and progression-free survival in patients with localised sarcoma at the time of diagnosis. Further studies are required to investigate the mechanism behind the association between hs-CRP and sarcoma prognosis and its potential use in clinical practice.

Macrophage Biomarkers sCD163 and sSIRPα in Serum Predict Mortality in Sarcoma Patients.

Most soft tissue sarcoma (STS) patients do not respond to traditional checkpoint inhibitor treatment, which may be due to infiltrating immunosuppressive tumour-associated macrophages. This study investigated the prognostic value of four serum macrophage biomarkers. Methods: Blood samples were taken from 152 patients with STS at the time of diagnosis; clinical data were prospectively collected. The concentrations of four macrophage biomarkers (sCD163, sCD206, sSIRPα, sLILRB1) were measured in serum, dichotomised based on median concentration, and evaluated either individually or when combined with established prognostic markers. Results: All macrophage biomarkers were prognostic of overall survival (OS). However, only sCD163 and sSIRPα were prognostic for recurrent disease (sCD163: hazard ratio (HR): 1.97 (95% CI: 1.10-3.51) and sSIRPα: HR: 2.09 (95% CI: 1.16-3.77)). A prognostic profile was made based on sCD163 and sSIRPα; it also included c-reactive protein and tumour grade. Patients with intermediate- or high-risk prognostic profiles (adjusted for age and tumour size) had a higher risk of recurrent disease compared to low-risk patients (HR: 2.64 (95% CI: 0.97-7.19)) and (HR 4.3 (95% CI: 1.62-11.47)), respectively. Conclusion: This study demonstrated that serum biomarkers of immunosuppressive macrophages were prognostic for OS; when combined with well-established markers of recurrence they allowed for a clinically relevant categorising of patients.

Inclusion of Metabolic Tumor Volume in Prognostic Models of Bone and Soft Tissue Sarcoma Increases the Prognostic Value.

Sarcomas are rare and have a high mortality rate. Further prognostic classification, with readily available parameters, is warranted, and several studies have examined circulating biomarkers and PET parameters separately. This single-site, retrospective study aimed to examine the prognostic values of several scoring systems in combination with PET parameters. We included 148 patients with sarcoma, who were treated and scanned at Aarhus University Hospital from 1 January 2016 to 31 December 2019. The Akaike information criterion and Harrell's concordance index were used to evaluate whether the PET parameters added prognostic information to existing prognostic models using circulating biomarkers. Of the PET parameters, metabolic tumor volume (MTV) performed best, and when combined with the existing prognostic models, the prognostic value improved in all models. Backward stepwise selection was used to create a new model, SBSpib, which included albumin, lymphocytes, and one PET parameter, MTV. It has scores ranging from zero to three and increasing hazard ratios; HR = 4.83 (1.02-22.75) for group one, HR = 7.40 (1.6-33.42) for group two, and HR = 17.32 (3.45-86.93) for group three. Consequently, implementing PET parameters in prognostic models improved the prognostic value. SBSpib is a new prognostic model that includes both circulating biomarkers and PET parameters; however, validation in another sarcoma cohort is warranted.

Neurofilament Light Chain and Glial Fibrillary Acidic Protein as early prognostic biomarkers after out-of-hospital cardiac arrest.

AIMS: Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP) are proteins released into the bloodstream upon hypoxic brain injury. We evaluated the biokinetics and examined the prognostic performance of serum NfL and GFAP in comatose out-of-hospital cardiac arrest (OHCA) patients. Furthermore, we compared the prognostic performance to that of serum Neuron Specific Enolase (NSE). METHODS: This is a sub-study of the "Targeted temperature management for 48 vs 24 hours" (NCT01689077) trial. NfL and GFAP serum values from 82 patients were examined in blood samples collected at 24, 48 and 72 hours (h) after reaching target temperature of 33 ± 1 °C. This temperature was reached within a median of 281-320 minutes after intensive care unit admission. GFAP was analysed at 48 and 72 h. The neuroprognostic performance of NfL and GFAP was evaluated after 6 months follow-up. RESULTS: NfL and GFAP values were significantly higher in patients with a poor outcome (Cerebral Performance Category (CPC) score 3-5) vs. good outcome (CPC 1-2). NfL 24 h: 1371.5 (462.0; 2125.1) vs. 24.8 (14.0; 61.6). GFAP 48 h: 1285.3 (843.9; 2236.7) vs. 361.2 (200.4; 665.6) (both p < 0.001). Both biomarkers were promising markers of poor functional outcome at 24 and 48 h respectively: NfL 24 h: AUROC 0.95 (95% CI: 0.91-1.00). GFAP 48 h: AUROC 0.88 (95% CI: 0.81-0.96). NfL and GFAP both predicted outcome better than NSE at 48 h (both p < 0.01). At 72 h NfL but not GFAP outperformed NSE (p = 0.01). CONCLUSION: Serum NfL and GFAP may be strong biomarkers of poor functional outcome after OHCA from an early timepoint.

A Cohort Study of Free Light Chain Ratio in Combination with Serum Protein Electrophoresis as a First-Line Test in General Practice.

Multiple Myeloma (MM) often present with unspecific symptoms, which can lead to diagnostic delay. Serum-free light chain (sFLC) ratio is suggested to replace urine protein electrophoresis (UPE) in the diagnostic work-up of myeloma. We aimed to investigate the performance of the sFLC-ratio in general practice (GP) compared to UPE, just as we explored different sFLC-ratio cut-offs' influence on diagnostic values. In a cohort of 13,210 patients from GP measures of sFLC-ratio, serum protein electrophoresis (SPE), or UPE were compared to diagnoses of incident M-component related diseases acquired from Danish health registers. UPE and sFLC-ratio equally improved diagnostic values when combined with SPE (sensitivity: SPE and UPE: 95.6 (90.6-98.4); SPE and sFLC-ratio: 95.1 (90.2-98.0)). The addition of the sFLC-ratio to SPE resulted in the identification of 13 patients with MGUS, light chain disease and amyloidosis, which was in line with the addition of UPE to SPE. The number of false-positive tests was UPE and SPE: 364 (11%) and sFLC-ratio and SPE: 677(19%). Expanding sFLC-ratio reference range to 0.26-4.32 resulted in a significant reduction in false positives n = 226 (6%) without loss of patients with clinical plasma cell dyscrasias. sFLC-ratio improves the diagnostic value of SPE in GP. However, due to low specificity and a large number of false positives, expanded cut-off values should be considered.

The Prognostic Value of Plasma Programmed Death Protein-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) in Patients with Gastrointestinal Stromal Tumor.

BACKGROUND: This study investigates the prognostic value of plasma Programmed Death Protein-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) concentrations in patients with Gastrointestinal Stromal Tumor (GIST). METHODS: Patients with GIST were included (n = 157) from the two Danish sarcoma centers, independent of disease- and treatment status. The patients were divided into three subgroups; 1: patients with localized disease who underwent radical surgery; 2: patients with local, locally advanced, or metastatic disease; and 3: patients without measurable disease who had undergone radical surgery. Sensitive electrochemiluminescence immune-assays were used to determine PD-1 and PD-L1 concentration in plasma samples. The primary endpoint was the PFS. RESULTS: No patients progressed in group 1 (n = 15), 34 progressed in group 2 (n = 122), and three progressed in group 3 (n = 20). Significantly higher plasma concentrations of PD-1 (p = 0.0023) and PD-L1 (0.012) were found in patients in group 2 compared to PD-1/PD-L1 levels in postoperative plasma samples from patient group 1. Patients with active GIST having a plasma concentration of PD-L1 above the cutoff (225 pg/mL) had a significantly poorer prognosis compared to patients with plasma PD-L1 concentration below the cutoff. CONCLUSIONS: Plasma PD-L1 shows potential as a prognostic biomarker in patients with GIST and should be further evaluated.

Inflammation scores as prognostic biomarkers in small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Inflammation scores based on general inflammation markers as leucocyte count or C-reactive protein have been evaluated as prognostic markers of inferior survival in several cancers. In small cell lung cancer (SCLC), however, inflammation scores are less studied. In the present study, we set out to perform a systematic review and meta-analysis investigating reported associations between inflammation scores and overall survival (OS) in SCLC. METHODS: A literature search was performed in PubMed, Embase, Scopus, and Web of Science following the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) guidelines. Of the identified publications, only studies in English containing original data evaluating inflammation scores as a prognostic factor in SCLC patients were included. Hazard ratios (HRs) for OS were pooled in a random-effects model. RESULTS: In total, 33 articles were included evaluating eight different inflammation scores in 7762 SCLC patients. Seven of the identified scores were based on leucocyte count. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte (PLR) ratio were the most frequently evaluated scores (NLR: n = 23; PLR: n = 22). For NLR, a meta-analysis including 16 studies demonstrated that patients with a high NLR had a significantly shorter OS compared to patients with a low NLR (pooled HR = 1.39 (95% CI, 1.23-1.56)). For PLR, an association with survival could not be confirmed in a meta-analysis performed based on eight studies (pooled HR = 1.20 (95% CI, 0.96-1.51)). CONCLUSIONS: This review identifies that inflammation scores based on general inflammation markers have some potential as prognostic biomarkers in SCLC. The meta-analyses indicated that NLR is associated with inferior OS, whereas an association between PLR and OS could not be confirmed. Thus, NLR could be a useful biomarker of OS in SCLC patients. SYSTEMATIC REVIEW REGISTRATION: The protocol for the study was submitted to the PROSPERO database (registration number CRD42020188553 ).

Hyponatremia in lung cancer: Incidence and prognostic value in a Danish population-based cohort study.

OBJECTIVES: Hyponatremia is a common electrolyte disorder in lung cancer patients, especially in patients with small-cell lung cancer (SCLC). It has been proposed as a prognostic indicator of higher mortality; however, data have been conflicting. Here, we determine the incidence and prognostic impact of pretreatment hyponatremia in a large Danish registry-based cohort of lung cancer patients. MATERIAL AND METHODS: Data on lung cancer patients diagnosed from January 2009 to June 2018 in The Central Denmark Region were extracted from the Danish Lung Cancer Registry and combined with data on the pretreatment sodium level extracted from the clinical laboratory information system. Hyponatremia was defined as a sodium level <135 mmol/l. Cox proportional hazard models assessed the prognostic value of hyponatremia on overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and patients with SCLC. RESULTS: A total of 6995 patients with NSCLC and 1171 with SCLC were included. The hyponatremia incidence was 16 % among patients with NSCLC and 26 % among patients with SCLC. Hyponatremia was associated with an inferior OS in patients with NSCLC (<135 mmol/l: median 0.46 years (95 % CI: 0.41-0.51) vs. ≥ 135 mmol/l: median 1.05 years (95 % CI: 1.00-1.11)), p < 0.001; adjusted hazard ratio (HR) = 1.45 (95 % CI: 1.34-1.56)) as well as in patients with SCLC in (<135 mmol/l: median 0.67 year (95 % CI: 0.58-0.73) vs. ≥ 135 mmol/l: median 0.73 years (95 % CI: 0.67-0.78); p = 0.0035; adjusted HR = 1.21 (95 % CI: 1.04-1.41)). CONCLUSION: The incidence of pretreatment hyponatremia is high in patients with SCLC as well as with NSCLC. Hyponatremia seems to be an independent predictor of inferior survival in lung cancer patients, especially in patients with NSCLC.

Pretreatment Albumin-to-Alkaline Phosphatase Ratio Is a Prognostic Marker in Lung Cancer Patients: A Registry-Based Study of 7077 Lung Cancer Patients.

The albumin-to-alkaline phosphatase ratio (AAPR) is a novel promising prognostic marker in cancer patients. However, the evidence for its significance in lung cancer is scarce. Therefore, we assessed the prognostic value of the AAPR in a large cohort of lung cancer patients. Data on lung cancer patients diagnosed from January 2009 to June 2018 were extracted from the Danish Lung Cancer Registry and combined with data on the pretreatment serum AAPR level extracted from the clinical laboratory information system (LABKA). AAPR tertiles were applied as cutoffs. Cox proportional hazard models assessed the prognostic value of the AAPR. In total, 5978 non-small cell lung cancer (NSCLC) patients and 1099 small cell lung cancer (SCLC) patients were included. Decreasing AAPR level was significantly associated with declining median overall survival (OS) in NSCLC patients (medium vs. low AAPR, adjusted HR = 0.73 (95% confidence interval (CI) 0.68-0.79); high vs. low AAPR, adjusted HR = 0.68 (95% CI 0.62-0.73)) and in SCLC patients (medium vs. low AAPR, adjusted HR = 0.62 (95% CI 0.52-0.74); high vs. low, adjusted HR = 0.59 (95% CI 0.50-0.70)). In conclusion, the AAPR was an independent prognostic factor in NSCLC and SCLC patients. The correlation seems to be level dependent, with reducing survival found to be associated with decreasing AAPR level.