Venous thromboembolism (VTE) is common in patients with brain tumors, and underlying mechanisms are unclear. We hypothesized that podoplanin, a sialomucin-like glycoprotein, increases the risk of VTE ...in primary brain tumors via its ability to induce platelet aggregation. Immunohistochemical staining against podoplanin and intratumoral platelet aggregates was performed in brain tumor specimens of 213 patients (mostly high-grade gliomas 89%) included in the Vienna Cancer and Thrombosis Study, a prospective observational cohort study of patients with newly diagnosed cancer or progressive disease aimed at identifying patients at risk of VTE. Platelet aggregation in response to primary human glioblastoma cells was investigated in vitro. During 2-year follow-up, 29 (13.6%) patients developed VTE. One-hundred fifty-one tumor specimens stained positive for podoplanin (33 high expression, 47 medium expression, 71 low expression). Patients with podoplanin-positive tumors had lower peripheral blood platelet counts (P < .001) and higher D-dimer levels (P < .001). Podoplanin staining intensity was associated with increasing levels of intravascular platelet aggregates in tumor specimens (P < .001). High podoplanin expression was associated with an increased risk of VTE (hazard ratio for high vs no podoplanin expression: 5.71; 95% confidence interval, 1.52-21.26; P = .010), independent of age, sex, and tumor type. Podoplanin-positive primary glioblastoma cells induced aggregation of human platelets in vitro, which could be abrogated by an antipodoplanin antibody. In conclusion, high podoplanin expression in primary brain tumors induces platelet aggregation, correlates with hypercoagulability, and is associated with increased risk of VTE. Our data indicate novel insights into the pathogenesis of VTE in primary brain tumors.
•Brain tumor patients have a very high risk of VTE.•Podoplanin expression by primary brain tumors induces platelet aggregation and is associated with hypercoagulability and a high risk of VTE.
Low‐molecular‐weight‐heparins (LMWHs) have been established for the treatment of cancer‐associated venous thromboembolism (VTE). Recently published randomized controlled trials (RCTs) have compared ...direct oral anticoagulants (DOACs) with LMWHs. The aim of this systematic review and meta‐analysis was to evaluate efficacy and safety of DOACs versus LMWHs and update the evidence for treatment of VTE in cancer.
Biomedical databases were screened for RCTs evaluating DOACs for cancer‐associated VTE. Primary efficacy and safety outcomes of this meta‐analysis were recurrent VTE and major bleeding at 6 months. Secondary outcomes comprised clinically relevant nonmajor bleeding (CRNMB), major gastrointestinal (GI) and genitourinary bleeding, mortality, fatal bleeding/pulmonary embolism, and treatment discontinuation rate. We performed prespecified subgroup analyses. Pooled relative risk (RR) and 95% confidence intervals (CIs) were obtained by the Mantel‐Haenszel method within a random‐effect model.
We screened 759 articles and included 4 RCTs (n = 2894). DOACs significantly reduced recurrent VTEs compared to LMWHs (5.2% vs 8.2%; RR, 0.62 95% CI, 0.43‐0.91), but were associated with a nonsignificant increase in major bleedings (4.3% vs 3.3%; RR, 1.31 95% CI, 0.83‐2.08) and a significant increase in CRNMB (10.4% vs 6.4%; RR, 1.65 95% CI, 1.19‐2.28). Mortality risks were comparable between groups (RR, 0.99 95% CI, 0.83‐1.18). Preterm treatment discontinuation was less common with DOACs (RR, 0.88 95% CI, 0.81‐0.96). Major bleeding was more frequent in patients with GI cancer treated with DOACs (RR, 2.30 95% CI, 1.08‐4.88).
In patients with cancer‐associated VTE, DOACs are more effective in preventing recurrent VTE compared to LMWH. However, risk of bleeding is increased with DOACs, especially in patients with GI cancer.
Abstract
Background
Coronavirus disease 19 (COVID-19)-associated pulmonary aspergillosis (CAPA) emerged as important fungal complications in patients with COVID-19-associated severe acute respiratory ...failure (ARF). Whether mould active antifungal prophylaxis (MAFP) can prevent CAPA remains elusive so far.
Methods
In this observational study, we included all consecutive patients admitted to intensive care units with COVID-19-associated ARF between September 1, 2020, and May 1, 2021. We compared patients with versus without antifungal prophylaxis with respect to CAPA incidence (primary outcome) and mortality (secondary outcome). Propensity score adjustment was performed to account for any imbalances in baseline characteristics. CAPA cases were classified according to European Confederation of Medical Mycology (ECMM)/International Society of Human and Animal Mycoses (ISHAM) consensus criteria.
Results
We included 132 patients, of whom 75 (57%) received antifungal prophylaxis (98% posaconazole). Ten CAPA cases were diagnosed, after a median of 6 days following ICU admission. Of those, 9 CAPA cases were recorded in the non-prophylaxis group and one in the prophylaxis group, respectively. However, no difference in 30-day ICU mortality could be observed. Thirty-day CAPA incidence estimates were 1.4% (95% CI 0.2–9.7) in the MAFP group and 17.5% (95% CI 9.6–31.4) in the group without MAFP (
p
= 0.002). The respective subdistributional hazard ratio (sHR) for CAPA incidence comparing the MAFP versus no MAFP group was of 0.08 (95% CI 0.01–0.63;
p
= 0.017).
Conclusion
In ICU patients with COVID-19 ARF, antifungal prophylaxis was associated with significantly reduced CAPA incidence, but this did not translate into improved survival. Randomized controlled trials are warranted to evaluate the efficacy and safety of MAFP with respect to CAPA incidence and clinical outcomes.
In contrast to venous thromboembolism, little is known about arterial thromboembolism in patients with cancer. The aim of this study was to quantify the risk and explore clinical risk factors of ...arterial thromboembolism in patients with cancer, and investigate its potential impact on mortality. Patients with newly-diagnosed cancer or progression of disease after remission were included in a prospective observational cohort study and followed for two years. Between October 2003 and October 2013, 1880 patients (54.3% male; median age 61 years) were included. During a median follow up of 723 days, 48 (2.6%) patients developed arterial thromboembolism 20 (41.7%) myocardial infarction, 16 (33.3%) stroke and 12 (25.0%) peripheral arterial events, 157 (8.4%) developed venous thromboembolism, and 754 (40.1%) patients died. The cumulative 3-, 6-, 12-, and 24-month risks of arterial thromboembolism were 0.9%, 1.1%, 1.7%, and 2.6%, respectively. Male sex (subdistribution hazard ratio=2.9, 95%CI: 1.5-5.6;
=0.002), age (subdistribution hazard ratio per 10 year increase=1.5, 1.2-1.7;
<0.001), hypertension (3.1, 1.7-5.5;
<0.001), smoking (2.0, 1.1-3.7;
=0.022), lung cancer (2.3, 1.2-4.2;
=0.009), and kidney cancer (3.8, 1.4-10.5;
=0.012) were associated with a higher arterial thromboembolism risk. Furthermore, the occurrence of arterial thromboembolism was associated with a 3.2-fold increased risk of all-cause mortality (hazard ratio=3.2, 95%CI: 2.2-4.8;
<0.001). Arterial thromboembolism is a less common complication in patients with cancer than venous thromboembolism. The risk of arterial thromboembolism is high in patients with lung and kidney cancer. Patients with cancer who develop arterial thromboembolism are at a 3-fold increased risk of mortality.
Tertiary lymphoid structures (TLS) are associated with favorable outcome in non-metastatic colorectal carcinoma (nmCRC), but the dynamics of TLS maturation and its association with effective ...anti-tumor immune surveillance in nmCRC are unclear. Here, we hypothesized that not only the number of TLS but also their composition harbors information on recurrence risk in nmCRC. In a comprehensive molecular, tissue, laboratory, and clinical analysis of 109 patients with stage II/III nmCRC, we assessed TLS numbers and degree of maturation in surgical specimens by multi-parameter immunofluorescence of follicular dendritic cell (FDC) and germinal center (GC) markers. TLS formed in most tumors and were significantly more prevalent in highly-microsatellite-instable (MSI-H) and/or BRAF-mutant nmCRC. We could distinguish three sequential TLS maturation stages which were characterized by increasing prevalence of FDCs and mature B-cells: 1 Early TLS, composed of dense lymphocytic aggregates without FDCs, 2 Primary follicle-like TLS, having FDCs but no GC reaction, and 3 Secondary follicle-like TLS, having an active GC reaction. A simple integrated TLS immunoscore reflecting these parameters identified a large subgroup of nmCRC patients with a very low risk of recurrence independently of clinical co-variables such as ECOG performance status, age, stage, and adjuvant chemotherapy. We conclude that (1) mismatch repair and BRAF mutation status are associated with the formation of TLS in nmCRC, (2) TLS formation in nmCRC follows sequential maturation steps, culminating in germinal center formation, and (3) this maturation process harbors important prognostic information on the risk of disease recurrence.
Pulmonary embolism (PE) is a frequent complication in patients with cancer 1. In contrast to PE in non-cancer patients, a considerable proportion of those in the oncological setting is detected ...incidentally on routine computed tomography (CT) staging/restaging examinations in asymptomatic (or, in hindsight, often oligosymptomatic) patients 2. Different terminologies for this phenomenon exist in the literature, including unsuspected, incidental, and asymptomatic PE, with asymptomatic PE being clearly not preferable as many patients do report symptoms in retrospect 3. Managing these so-called unsuspected pulmonary embolisms (UPEs) is a major challenge, because the clinical implications of this ill-defined condition are not fully understood and optimal therapeutic strategies are unclear 4, 5. In this issue of the European Respiratory Journal, Font et al. 6 report observational evidence from the Spanish ambispective EPIPHANY registry, which has some relevance to the emerging topic of UPE. This is one of the few studies specifically dedicated to cancer-associated PE 2, and the analysis included subject-level data on anticoagulation, recurrent thrombosis and death from more than 1000 patients with this condition, rendering it one of the largest studies to date in the field. The investigators identified distinct patterns of 30-day mortality depending on whether patients had PE that was clinically suspected or not, and did or did not present with symptoms and/or signs suggestive of PE at the time of routine CT imaging performed for reasons other than PE diagnosis. These patterns prompted the investigators to derive a new three-level empiric classification of cancer-associated PE, which distinguishes the three scenarios 1) suspected pulmonary embolism (SPE), 2) truly asymptomatic UPE (TA-UPE) and 3) UPE with symptoms (UPE-S). Two risk classification schemes for cancer-associated PE have already been developed 7, 8. What is the added value of this one? Is this new classification relevant for clinical decision making? And should it be adopted in the management of patients with cancer-associated PE?
We investigated a prospective cohort of 23 patients who had Puumala virus infection in Austria to determine predictors of infection outcomes. We reviewed routinely available clinical and laboratory ...parameters collected when patients initially sought care. Low absolute lymphocyte count and dyspnea were parameters associated with a severe course of infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Unplanned excisions (UE) of soft tissue sarcomas (STS) carry a high risk for local recurrence (LR) due to marginal/intralesional resections. However, there are reports about improved ...prognosis for UE patients who have re-resection compared with patients who undergo planned surgery. The present multicentre study was designed to define characteristics of UE patients and to investigate the impact of UE on subsequent therapy and patient outcomes.
Methods
A total of 728 STS patients (376 males, 352 females; mean age: 58 years) who underwent definite surgery at one of three tumour centres were retrospectively included. Time-to-event analyses were calculated with log-rank and Gray’s tests, excluding patients with primary metastasis (
n
= 59). A propensity-score (PS) of being in the UE group was estimated, based on differences at baseline between the UE group and non-UE group. An inverse-probability-of-UE weight (IPUEW) was generated and time-to-event analyses calculated after IPUEW weighting.
Results
Before referral, 38.6% of patients (
n
= 281) had undergone UE. Unplanned excision patients were younger (
p
= 0.036), rather male (
p
= 0.05), and had smaller (
p
< 0.005), superficially located tumours (
p
< 0.005). Plastic reconstructions (
p
< 0.005) and adjuvant radiotherapy (
p
= 0.041) more often were needed at re-resection. In univariable analysis, re-resected patients had improved overall survival (OS;
p
= 0.027) and lower risk of distant metastasis (DM;
p
= 0.002) than primarily resected patients, whereas risk of LR was similar (
p
= 0.359). After weighting for the IPUEW, however, differences in terms of OS (
p
= 0.459) and risk of DM (
p
= 0.405) disappeared.
Conclusions
The present study does not support prior findings of improved outcome for UE patients. Unplanned excisions have a major impact on subsequent therapy, yet they do not seem to affect negatively the long-term oncology outcome.
Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX are standard first-line treatment options for advanced pancreatic ductal adenocarcinoma (aPDAC), but currently no prospective randomised head-to-head ...comparison between these treatments has yet been performed.
We conducted a comparative propensity score (PS) analysis of overall (OS) and progression-free survival (PFS) in a tri-centre cohort of patients with aPDAC undergoing palliative first-line treatment with either GN or FOLFIRINOX.
In unadjusted analysis, OS and PFS were highly similar between patients treated with GN (n = 297) and FOLFIRINOX (n = 158). In detail, median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 11.2 months, 45% and 12% in the FOLFIRINOX group, respectively (log-rank p = 0.783). Accordingly, median (4.6 versus 4.8 months), 6-month (40% versus 43%) and 1-year (9% versus 9%) PFS estimates did not significantly differ (log-rank p = 0.717). However, patients treated with FOLFIRINOX were significantly younger, had fewer comorbidities, and a better Eastern Cooperative Oncology Group performance status. These imbalances were accounted for by weighting the data with the PS. In PS analysis of survival outcomes, OS and PFS remained comparable between the two treatment groups. In detail, PS-weighted median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 10.1 months, 40% and 13% in the FOLFIRINOX group (PS-weighted log-rank p = 0.449). PS-weighted PFS estimates again did not differ (PS-weighted log-rank p = 0.329).
This real-world comparative effectiveness study indicates that FOLFIRINOX and GN have similar effectiveness in the palliative first-line treatment of aPDAC.
•Propensity score–adjusted comparative effectiveness analysis.•Real-world palliative first-line treatment in advanced pancreatic cancer.•FOLFIRINOX and gemcitabine/nab-paclitaxel have similar effectiveness.•Findings are consistent across all relevant patient's subgroups.
Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker and risk factor for kidney diseases, with a potential prognostic value in critically ill patients. In this ...monocentric prospective study, we measured plasma suPAR levels immediately after ICU admission in unselected 237 consecutive patients using a turbidimetric assay. Primary objective was the prognostic value for ICU- and 28-day mortality. Secondary objectives were association with sequential organ failure assessment (SOFA) score, coagulation and inflammation markers, AKI-3 and differences in prespecified subgroups. Median suPAR levels were 8.0 ng/mL 25th-75th percentile 4.3-14.4, with lower levels in ICU survivors than non-survivors (6.7 vs. 11.6 ng/mL, p < 0.001). SuPAR levels were higher in COVID-19, kidney disease, moderate-to-severe liver disease, and sepsis. ICU mortality increased by an odds ratio (OR) of 4.7 in patients with the highest compared to lowest quartile suPAR. Kaplan-Meier overall survival estimates at 3 months were 63% and 49%, in patients with suPAR below/above 12 ng/mL (log-rank p = 0.027). Due to an observed interaction between SOFA score and suPAR, we performed a random forest method identifying cutoffs. ICU mortality was 53%, 17% and 2% in patients with a SOFA score > 7, SOFA ≤ 7 & suPAR > 8 ng/mL, and SOFA score ≤ 7 & suPAR ≤ 8 ng/mL, respectively. suPAR was a significant predictor for AKI-3 occurrence (OR per doubling 1.89, 95% CI: 1.20-2.98; p = 0.006). suPAR levels at ICU admission may offer additional value for risk stratification especially in ICU patients with moderate organ dysfunction as reflected by a SOFA score ≤ 7.
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