Occult cancer in patients with unprovoked venous thromboembolism: A nested case-control study.

OBJECTIVES: Detecting occult cancer in patients with unprovoked venous thromboembolism (VTE) remains a significant challenge. Our objective was to investigate the potential predictive role of coagulation-related biomarkers in the diagnosis of occult malignancies. METHODS: We conducted a nested case-control study with a 1-year prospective cohort of 214 patients with unprovoked VTE, with a focus on identifying occult cancer. At the time of VTE diagnosis, we measured various biomarkers, including soluble P-selectin (sP-selectin), dimerized plasmin fragment D (D-dimer), platelets, leukocytes, hemoglobin, total extracellular vesicles (EVs), EVs expressing tissue factor on their surface (TF+EVs), and EVs expressing P-selectin on their surface (Psel+EVs) in all participants. RESULTS: We observed statistically significant increased levels of sP-selectin (P = .015) in patients with occult cancer. Despite an increase in Psel+EVs, TF+EVs, D-dimer, and platelets within this group, however, no significant differences were found. When sP-selectin exceeded 62 ng/mL and D-dimer surpassed 10,000 µg/L, the diagnosis of occult cancer demonstrated a specificity of up to 91% (95% CI, 79.9%-96.7%). CONCLUSIONS: The combination of sP-selectin and D-dimer can be a valuable biomarker in detecting occult cancer in patients with unprovoked VTE. Further research is necessary to ascertain whether easily measurable biomarkers such as sP-selectin and D-dimer can effectively distinguish between patients who have VTE with and without hidden malignancies.

Comparison of long-term complications in cancer patients with incidental and acute symptomatic venous thromboembolism.

Background: Clinical practice guidelines recommend that patients with incidental venous thromboembolism (VTE) receive the same anticoagulant therapy as those with symptomatic VTE. We aimed to compare the rate of complications between cancer patients with incidental and symptomatic VTE through a long-term follow-up cohort. Methods: We performed a post hoc analysis of prospective studies of cancer patients with VTE between 2008 and 2019, with the primary outcome of rates of recurrent VTE and clinically relevant bleeding (CRB) in incidental and symptomatic VTE groups. Results: In total, 796 patients were included, of which 42.8% had incidental VTE. No significant differences were noted in the rate of recurrent VTE (0.4 per 100 patients/month vs. 0.5 per 100 patients/month; p = 0.313) and in the rate of CRB (0.6 per 100 patients/month vs. 0.5 per 100 patients/month; p = 0.128) between patients with incidental VTE and symptomatic VTE, respectively. At six-month follow-ups, the cumulative incidence of CRB was significantly higher in patients with incidental VTE than that in those with symptomatic VTE (7.9% vs. 4.4%, respectively; OR: 1.8; 95% CI: 1.01-3.2). Conclusion: Cancer patients with incidental VTE had similar rates of CRB and VTE recurrence in long-term follow-up compared with patients with symptomatic VTE. At six-month follow-ups, patients with incidental VTE had a higher cumulative incidence of CRB than those with symptomatic VTE.

Prediction of serious complications in patients with pulmonary thromboembolism and solid cancer: Validation of the EPIPHANY Index in a prospective cohort of patients from the PERSEO study.

INTRODUCTION: There is currently no validated score capable of classifying cancer-associated pulmonary embolism (PE) in its full spectrum of severity. This study has validated the EPIPHANY Index, a new tool to predict serious complications in cancer patients with suspected or unsuspected PE. METHOD: The PERSEO Study prospectively recruited individuals with PE and active cancer or receiving antineoplastic therapy from 22 Spanish hospitals. The estimation of the relative frequency θ of complications based on the EPIPHANY Index categories was made using the Bayesian alternative for the binomial test. RESULTS: A total of 900 patients, who were diagnosed with PE between October 2017 and January 2020, were enrolled. The rate of serious complications at 15 days was 11.8%, 95% highest density interval [HDI], 9.8-14.1%. Of the EPIPHANY low-risk patients, 2.4% (95% HDI, 0.8-4.6%) had serious complications, as did 5.5% (95% HDI, 2.9-8.7%) of the moderate-risk participants and 21.0% (95% HDI, 17.0-24.0%) of those with high-risk episodes. The EPIPHANY Index was associated with overall survival (OS) in patients with different risk levels: median OS was 16.5, 14.4, and 4.4 months for those at low, intermediate, and high risk, respectively. Both the EPIPHANY Index and the Hestia criteria exhibited greater negative predictive value and a lower negative likelihood ratio than the remaining models. The incidence of bleeding at 6 months was 6.2% (95% HDI, 2.9-9.5%) in low/moderate-risk vs 12.7% (95% HDI, 10.1-15.4%) in high-risk (p-value = 0.037) episodes. Of the outpatients, serious complications at 15 days were recorded in 2.1% (95% HDI, 0.7-4.0%) of the cases with EPIPHANY low/intermediate-risk vs 5.3% (95% HDI, 1.7-11.8%) in high-risk cases. CONCLUSION: We have validated the EPIPHANY Index in patients with incidental or symptomatic cancer-related PE. This model can contribute to standardize decision-making in a scenario lacking quality evidence.

Risk of recurrent cancer-associated thrombosis after discontinuation of anticoagulant therapy.

Background: Clinical guidelines suggest continuing anticoagulation therapy for >6 months for patients with active cancer and venous thromboembolism (VTE). However, data regarding the safety of its discontinuation are scarce. Objectives: To valuate the risk factors and the incidence of recurrent VTE 6 months after the discontinuation of anticoagulation therapy in patients with cancer-associated thrombosis (CAT). Methods: We performed a retrospective study on consecutive patients with CAT recruited between 2008 and 2019. The primary and secondary outcomes were recurrent VTE at 6 and 12 months, respectively. Sensitivity analyses were conducted to investigate the possible heterogeneity of these effects. Results: A total of 311 patients were included, among whom 33.4% had metastases and 30.8% were still receiving oncological treatment after 6 months of anticoagulant therapy. At 6 and 12 months, the incidences of recurrent VTE were 6.1% (95% CI, 3.5-9.4%) and 8.7% (95% CI, 5.8-12.4%), respectively. Recurrent VTE was more frequent in patients with metastases at 6 (sub-distribution hazard ratio [SHR] 3.83; 95% CI, 1.54-9.52) and 12 months (SHR 5; 95% CI, 2.2-11.5). Patients with incidental VTE had fewer recurrent events at 6 (SHR 0.3; 95% CI, 0.1-0.8) and 12 months (SHR 0.3; 95% CI, 0.1-0.6) after discontinuing the anticoagulant therapy. Conclusion: The incidence of recurrent VTE at 6 and 12 months following the discontinuation of anticoagulant therapy is higher in patients with CAT. Patients with metastases were at an increased risk of recurrent VTE, whereas patients with incidental VTE were at a lower risk.

Three-Month Outcomes in Cancer Patients with Superficial or Deep Vein Thrombosis in the Lower Limbs: Results from the RIETE Registry.

BACKGROUND: The clinical characteristics and outcomes of cancer patients with lower-limb isolated superficial vein thrombosis (SVT) have not been consistently evaluated. METHODS: We used data in the RIETE registry to compare the clinical characteristics and 90-day outcomes for patients with: (1) active cancer and lower-limb SVT; (2) active cancer and lower-limb deep vein thrombosis (DVT); (3) lower-limb SVT without cancer. The primary outcomes included subsequent symptomatic SVT, DVT or pulmonary embolism (PE). Secondary outcomes were major bleeding and death. RESULTS: From March 2015 to April 2021, there were 110 patients with cancer and SVT, 1695 with cancer and DVT, and 1030 with SVT but no cancer. Most patients in all subgroups (93%, 99% and 96%, respectively) received anticoagulants, while those with SVT received lower daily doses of low-molecular-weight heparin (114 ± 58, 163 ± 44, and 106 ± 50 IU/kg, respectively). During the first 90 days, 101 patients (3.6%) developed subsequent VTE (PE 47, DVT 41, SVT 13), whereas 72 (2.5%) had major bleeding and 282 (9.9%) died. Among the three groups, 90-day events were, respectively: VTE at rates of 7.3%, 4.0% and 2.4%; major bleeding at rates of 2.7%, 3.9% and 0.3%; mortality at rates of 8.2%, 16% and 0.3%. Between D90 and D180, only one SVT recurrence and one death occurred in SVT cancer patients. In multivariable analysis, cancer was associated with subsequent VTE (HR = 2.04; 1.15-3.62), while initial presentation as SVT or DVT were not associated with a different risk. CONCLUSIONS: The risk for subsequent VTE (including symptomatic SVT, DVT or PE) was similar in cancer patients with isolated SVT than in those with isolated DVT.

Low-molecular-weight heparin beyond 12 months in patients with cancer-associated thrombosis.

BACKGROUND: Clinical guidelines indicate that in patients with cancer-associated thrombosis (CAT), anticoagulant treatment should be continued beyond 6 months as long as the cancer is active. We aimed to analyse the safety of low-molecular-weight heparin (LMWH) beyond 12 months in patients with CAT. METHODS: We performed a post hoc analysis of consecutive CAT patients from October 2008 to December 2019. The primary outcome was the rate of clinically relevant bleeding (CRB), and we compared two periods (1-12 vs. 12-24 months). Hazard ratio (HR), competing risk analysis and sensitivity analyses were performed. RESULTS: Of the 588 patients included, 30.1% (n = 177) received LMWH beyond 12 months. The rate of CRB in the first 12 months compared to the 12-24 month period was 3.2 per 100 patients/month (95% CI 2.5-4.1) vs. 0.9 per 100 patients/month (95% CI 0.4-1.5), (P < 0.0001). The competing risk analysis of CRB comparing both periods showed a lower sub-distribution hazard ratio (SHR) during the period 12-24 months (SHR: 0.5, 95% CI: 0.3-0.8, P < 0.001). CONCLUSION: In patients with cancer-associated thrombosis under anticoagulant treatment with LMWH, the rate of clinically relevant bleeding and major bleeding were lower beyond 12 months.

Inflammatory response in human lung cells stimulated with plasma from COPD patients.

Background: Chronic obstructive pulmonary disease (COPD) is a condition resulting from a persistent inflammatory state in the airways even after smoking cessation. Intriguingly, the reasons behind this persistence of the inflammatory influx without smoking exposure have not been fully unraveled. We aimed to explore the hypothesis that systemic inflammation in COPD patients influences lung cell inflammatory response. Methods: We cultured human lung fibroblast and human airway epithelial cell lines with plasma from COPD patients (four emphysematous-COPD, four asthma-COPD overlap, four chronic bronchitis-COPD, and four bronchiectasis- COPD), and four smokers or ex-smokers without COPD as controls. Non-stimulated cells were used as controls. We measured Interleukine-8 (IL-8), C-reactive protein (CRP) and matrix metalloproteinase-9 (MMP-9) in plasma and culture supernatants by ELISA. Results: Cells stimulated with plasma from COPD patients and non-COPD smoker subjects produced higher CRP, IL- 8 and MMP-9 levels, an increase for COPD in CRP (p=0.029) in epithelial cells and IL-8 (p=0.039) in fibroblasts and decrease for MMP-9 (p=0.039) in fibroblasts, compared with non-stimulated cells. The response was higher in epithelial cells for IL-8 (p=0.003) and in fibroblasts for MMP-9 (p=0.063). The plasma from chronic bronchitis and bronchiectasis phenotypes induced higher IL-8 in fibroblasts. Conclusions: Plasma from COPD patients increases the inflammatory response in lung epithelial cells and lung fibroblasts, with a different response depending on the cell type and clinical phenotype.

Short and Long-Term Impact of COVID-19 Infection on Previous Respiratory Diseases.

On March 11, 2020, the World Health Organization declared Coronavirus Disease 2019 (COVID-19) a pandemic. Till now, it affected 452.4 million (Spain, 11.18 million) persons all over the world with a total of 6.04 million of deaths (Spain, 100,992). It is observed that 75% of hospitalized COVID-19 patients have at least one COVID-19 associated comorbidity. It was shown that people with underlying chronic illnesses are more likely to get it and grow seriously ill. Individuals with COVID-19 who have a past medical history of cardiovascular disorder, cancer, obesity, chronic lung disease, diabetes, or neurological disease had the worst prognosis and are more likely to develop acute respiratory distress syndrome or pneumonia. COVID-19 can affect the respiratory system in a variety of ways and across a spectrum of levels of disease severity, depending on a person's immune system, age and comorbidities. Symptoms can range from mild, such as cough, shortness of breath and fever, to critical disease, including respiratory failure, shock and multi-organ system failure. So, COVID-19 infection can cause overall worsening of these previous respiratory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease, etc. This review aims to provide information on the impact of the COVID-19 disease on pre-existing lung comorbidities.

Nutriepigenomics and chronic obstructive pulmonary disease: potential role of dietary and epigenetics factors in disease development and management.

Over recent decades, a number of studies have revealed the possible role of different types of diets, as well as the nutritional elements they are made up of, in the pathogenesis of chronic obstructive pulmonary disease (COPD). To date, dietary factors have been identified to play a role in the prevention of COPD, with evidence from antioxidant nutrients, vitamins, and fiber intake. Additionally, certain dietary patterns such as the Mediterranean diet, together with other Western diets, provide evidence of the influence on COPD development, promoting lung health through nutritional approaches, and giving us an opportunity for intervention. The effect of diet on COPD is conveyed by 3 mechanisms: regulation of inflammation, oxidative stress, and carbon dioxide produced/oxygen intake. Current advances have begun to highlight the possible role of diet in modifying gene expression in certain individuals that predisposes them to COPD through epigenetic modifications. The relation between dietary intake and epigenetic factors has therefore outlined nutriepigenomics as a possible missing link in the relation between environmental exposure to smoke and the appearance of a subsequent chronic bronchial obstruction. This review summarizes the evidence regarding the influence of dietary patterns and nutrients and epigenetic regulatory mechanisms on COPD development and prevention with the aim of encouraging clinical research on the impact of dietary modifications on COPD-related clinical outcomes. This review highlights the importance of proposing and carrying out future studies focused on the modulating effects of certain nutrients on epigenetic changes in patients with specific COPD phenotypes (bronchiectasis, emphysema, asthma/COPD, chronic bronchitis), and their individual responses to cigarette smoking, environmental pollution, or other noxious particles. The objectives of these future studies must be directed to the development of novel therapeutic approaches and personalized management of COPD.

Case-Control Analysis of the Impact of Anemia on Quality of Life in Patients with Cancer: A Qca Study Analysis.

Anemia is a common condition in cancer patients and is associated with a wide variety of symptoms that impair quality of life (QoL). However, exactly how anemia affects QoL in cancer patients is unclear because of the inconsistencies in its definition in previous reports. We aimed to examine the clinical impact of anemia on the QoL of cancer patients using specific questionnaires. We performed a post-hoc analysis of a multicenter, prospective, case-control study. We included patients with cancer with (cases) or without (controls) anemia. Participants completed the European Organization for Research and Treatment of Cancer Quality of Life questionnaire version 3.0 (EORTC QLQ-C30) and Euro QoL 5-dimension 3-level (EQ-5D-3L) questionnaire. Statistically significant and clinically relevant differences in the global health status were examined. From 2015 to 2018, 365 patients were included (90 cases and 275 controls). We found minimally important differences in global health status according to the EORTC QLQ-C30 questionnaire (case vs. controls: 45.6 vs. 58%, respectively; mean difference: -12.4, p < 0.001). Regarding symptoms, cancer patients with anemia had more pronounced symptoms in six out of nine scales in comparison with those without anemia. In conclusion, cancer patients with anemia had a worse QoL both clinically and statistically.

Prognostic Significance of Incidental Deep Vein Thrombosis in Patients with Cancer Presenting with Incidental Pulmonary Embolism.

In symptomatic acute pulmonary embolism (PE), the presence of deep vein thrombosis (DVT) is a risk factor for 30- and 90-day mortality. In patients with cancer and incidental PE, the prognostic effect of concomitant incidental DVT is unknown. In this retrospective study, we examined the effect of incidental DVT on all-cause mortality in such patients. Adjusted Cox multivariate regression analysis was used for relevant covariates. From January 2010 to March 2018, we included 200 patients (mean age, 65.3 ± 12.4 years) who were followed up for 12.5 months (interquartile range 7.4-19.4 months). Of these patients, 62% had metastases, 31% had concomitant incidental DVT, and 40.1% (n = 81) died during follow-up. All-cause mortality did not increase in patients with DVT (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.43-2.75, p = 0.855). On multivariate analysis, weight (adjusted HR 0.96, 95% CI 0.92-0.99, p = 0.032), and metastasis (adjusted HR 10.26, 95% CI 2.35-44.9, p = 0.002) were predictors of all-cause mortality. In conclusion, low weight and presence of metastases were associated with all-cause mortality, while presence of concomitant DVT was unrelated to poorer survival.

Evaluation of lung parenchyma, blood vessels, and peripheral blood lymphocytes as a potential source of acute phase reactants in patients with COPD.

Background: Previous studies have shown that the arterial wall is a potential source of inflammatory markers in COPD. Here, we sought to compare the expression of acute phase reactants (APRs) in COPD patients and controls both at the local (pulmonary arteries and lung parenchyma) and systemic (peripheral blood leukocytes and plasma) compartments. Methods: Consecutive patients undergoing elective surgery for suspected primary lung cancer were eligible for the study. Patients were categorized either as COPD or control group based on the spirometry results. Pulmonary arteries and lung parenchyma sections, peripheral blood leukocytes, and plasma samples were obtained from all participants. Gene expression levels of C-reactive protein (CRP) and serum amyloid A (SAA1, SAA2, and SAA4) were evaluated in tissue samples and peripheral blood leukocytes by reverse transciption-PCR. Plasma CRP and SAA protein levels were measured by enzyme-linked immunosorbent assays. Proteins were evaluated in paraffin-embedded lung tissues by immunohistochemistry. Results: A total of 40 patients with COPD and 62 controls were enrolled. We did not find significant differences in the gene expression between COPD and control group. Both CRP and SAA were overexpressed in the lung parenchyma compared with pulmonary arteries and peripheral blood leukocytes. The expression of SAA was significantly higher in the lung parenchyma than in the pulmonary artery (2-fold higher for SAA1 and SAA4, P=0.015 and P<0.001, respectively; 8-fold higher for SAA2, P<0.001) and peripheral blood leukocytes (16-fold higher for SAA1, 439-fold higher for SAA2, and 5-fold higher for SAA4; P<0.001). No correlation between plasma levels of inflammatory markers and their expression in the lung and peripheral blood leukocytes was observed. Conclusions: The expression of SAA in lung parenchyma is higher than in pulmonary artery and peripheral blood leukocytes. Notably, no associations were noted between lung expression of APRs and their circulating plasma levels, making the leakage of inflammatory proteins from the lung to the bloodstream unlikely. Based on these results, other potential sources of systemic inflammation in COPD (eg, the liver) need further scrutiny.

D-dimer and high-sensitivity C-reactive protein levels to predict venous thromboembolism recurrence after discontinuation of anticoagulation for cancer-associated thrombosis.

BACKGROUND: Optimal duration of anticoagulation for cancer-associated thrombosis (CAT) remains unclear. This study assessed D-dimer (DD) and high-sensitivity C-reactive protein (hs-CRP) levels after the withdrawal of anticoagulation treatment to predict the risk of venous thromboembolism (VTE) recurrence among patients with CAT. METHODS: Prospective, multicentre study to evaluate CAT with ≥3 months of anticoagulation that was subsequently discontinued. Blood samples were taken when patients stopped the anticoagulation and 21 days later to determine the DD and hs-CRP levels. All patients were followed up for 6 months to detect VTE recurrence. RESULTS: Between 2013 and 2015, 325 patients were evaluated and 114 patients were ultimately enrolled in the study. The mean age was 62 ± 14 years and nearly 40% had metastasis. Ten patients developed VTE recurrence within 6 months (8.8%, 95% confidence interval [CI]: 4.3-15.5%). The DD and hs-CRP levels after 21 days were associated with VTE recurrence. The subdistribution hazard ratios were 9.82 for hs-CRP (95% CI: 19-52) and 5.81 for DD (95% CI: 1.1-31.7). CONCLUSIONS: This study identified that hs-CRP and DD were potential biomarkers of VTE recurrence after discontinuation of anticoagulation in CAT. A risk-adapted strategy could identify low-risk patients who may benefit from discontinuation of anticoagulation.

Survivin is a negative prognostic factor in malignant pleural effusion.

BACKGROUND: Survivin is a well-known member of the inhibitor of apoptosis family, and has been related to increased tumour aggressivity, both in tissue and in pleural fluid. OBJECTIVES: In patients with malignant pleural effusion, we sought to investigate the changes in pleural fluid survivin concentrations induced by talc instillation into the pleural space. Those changes were also examined in relation to pleurodesis outcome and patient survival. METHODS: We investigated 84 patients with malignant pleural effusion who underwent talc pleurodesis. Of them, 32 had breast cancer, 25 lung cancer and 27 had mesothelioma. Serial samples of pleural fluid were obtained before thoracoscopy (baseline) and 24 hours thereafter. RESULTS: Survivin levels were successfully quantified in all pleural fluid samples, and they were significantly higher in samples obtained after thoracoscopic talc poudrage compared with baseline (P < .001). Patients with higher pleural fluid survivin levels at baseline had a significantly poorer pleurodesis outcome (P = .004). A 30 pg/mL cut-off for baseline survivin in pleural fluid predicted failure of pleurodesis with a 54% sensitivity and 79% specificity (P = .009). Moreover, median postpleurodesis survival of patients with baseline survivin levels ≥30 pg/mL was 4 months (range: 0.1-38), compared with 13 months (range: 0.1-259) in patients below that cut-off (P < .001). CONCLUSION: Elevated pleural fluid survivin concentrations are useful to predict failure of pleurodesis and are associated with shorter survival in patients with malignant pleural effusion.

[Predictive Khorana's model in patients with venous thromboembolic disease and cancer]. / La escala predictiva de Khorana en pacientes con enfermedad tromboembólica venosa y cáncer.

BACKGROUND AND OBJECTIVE: The predictive Khorana's model was developed to score the thromboembolic disease risk in cancer patients on chemotherapy and to identify which patients would benefit from thromboprophylaxis. We analized the results and applied the predictive Khorana's model in patients with cancer and who were diagnosed with deep vein thrombosis. MATERIAL AND METHODS: Retrospective analysis of prognostic characteristics of Khorana's model in 122 patients based on a prospective analysis. RESULTS: Seventy-nine percent of the total were in the low and intermediate risk category and 21% had high risk according to the Khorana's predictive model. This model had a sensitivity and prognostic precision of 20.8% (95% confidence interval [95% CI]: 14.6-28.7) and a false negatives proportion of 79.2% (95% CI: 1.3-85.4). CONCLUSIONS: Application of this model in our patients would not be enough as the unique tool to identify cancer patients who should receive tromboprophylaxis. The use of both biomarkers and clinical models seems to be the best cost-effective strategy for this purpose. Future, randomized, prospective, placebo-controlled studies are needed for find better treatment strategies in cancer patients.

Gender differences in lung cancer mortality trends in Andalusia 1975-2008: a joinpoint regression analysis.

Death rates from lung cancer in men are higher in Andalusia than in other Spanish regions. This study describes lung cancer mortality rates and their trends in Andalusia from 1975 through 2008. Data on lung cancer mortality were obtained from the Death Registry of Andalusia. For each gender, age group-specific and standardized (overall and truncated) rates were calculated by the direct method using the world standard population. Joinpoint regression analysis was used to identify points where a significant change in trends occurred. In men, short-term trends for age-standardized mortality rates (ASMRs) declined significantly from 2004 through 2008 for each age group < 80 years old. In women, the segmented joinpoint analysis showed a decrease from 1975 through 1998 in ASMRs (overall) (-0.6%, P < 0.05), followed by a marked increase (4.6%, P < 0.05). A decrease in male versus female mortality due to lung cancer is evident in Andalusia (Spain).

Chronic thromboembolic pulmonary hypertension due to upper-extremity deep vein thrombosis caused by thoracic outlet syndrome.

We report on a 20 year-old woman diagnosed with pulmonary embolism (PE) and right subclavian vein thrombosis attributable to stasis caused by right clavicular prominence. At the 10-months follow-up, the patient had developed chronic thromboembolic pulmonary hypertension (CTEPH), and treatment was begun with a dual endothelin receptor antagonist. Very few cases of deep venous thrombosis of upper limb have been reported in relation to anatomical abnormalities. This case is also exceptional because the patient developed a chronic thromboembolic pulmonary hypertension, whose incidence is estimated at 0.5% of all symptomatic PE.