Increase in serum platelet-derived growth factor (PDGF)-BB reflects lymph node involvement in esophageal cancer patients independently from platelet count

Aim: To evaluate clinical significance and diagnostic utility of increase in serum PDGF-BB (sPDGF-BB) in esophageal cancer, which have not been addressed yet despite the relevance of PDGF axis in this cancer type. Methods: Immunoenzymatically assessed sPDGF-BB was related to clinicopathological features, and inflammatory, angiogenic, and lymphangiogenic indices in 84 patients with esophageal cancer and 47 controls. Its diagnostic utility was evaluated by receiver operating characteristics (ROC) curve analysis. Results: sPDGF-BB was significantly higher in esophageal cancer patients than controls (3.76 vs. 2.66 µg/l, p = 0.0001) and corresponded with the disease advancement. Of evaluated clinicopathological features, lymph node metastases and distant metastases were independently associated with an increase in sPDGF-BB; however, only the association with lymph node metastases persist adjustment to platelets. In univariate analysis, sPDGF positively correlated with platelets (r=0.70, p 2.845 µg/l cut-off, over 76% of patients had elevated sPDGF-BB. Its accuracy as lymph node metastases marker was 75%, sensitivity and specificity corresponding with >3.029 µg/l cut-off were 84 and 61%, respectively. Conclusions: sPDGF-BB owns potential as a possible lymph node metastases marker and might be considered as a diagnostic tool in preliminary evaluation of esophageal cancer patients identifying those likely to be burdened with lymph node metastases, the disease recurrence monitoring, and/or preselecting patients for PDGF-directed cancer therapies

Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency

Aim: Due to the common etiologic factor, a considerable number of esophagogastric cancer patients suffer from respiratory insufficiency in course of chronic obstructive pulmonary disease, primary to cancer. Systemic hypoxemia may account for poor oxygenation of tumor tissue-a main driving force of tumor neoangiogenesis. We hypothesized that in cancer patients with respiratory insufficiency, systemic hypoxemia may be related to enhanced aggressiveness of cancer on one side and to the elevation of angiogenic factors on the other. Methods: The levels of vascular endothelial growth factors A and C were determined with immunoenzymatic methods in patients diagnosed with esophagogastric cancer with or without co-existing respiratory insufficiency in course of chronic obstructive pulmonary disease and in healthy controls. Blood gasometry and hemoglobin levels of cancer patients were related to cancer histology and TNM status, and to circulating vascular endothelial growth factors A and C. Results: Patients with systemic hypoxemia had higher incidence rates of locally advanced tumors. Partial oxygen pressure and blood oxygen saturation were significantly lowered in patients with T4 cancers as compared to less advanced onces. Circulating vascular endothelial growth factor A, but not C, was more elevated in esophagogastric cancer patients with co-existing respiratory insufficiency, as compared to those without respiratory insufficiency. Vascular endothelial growth factor A was also strongly related to the extension of primary tumor. Conclusion: Our results show that systemic hypoxemia in esophagogastric cancer patients is associated with the extension of primary tumor and that this effect might be mediated by the up-regulation of circulating vascular endothelial growth factor A.Цель: в связи с общим этиологическим фактором заболевания , значительное количество больных гастроэзофагальным раком страдает от респираторной недостаточности в процессе хронического обструктивного легочного заболевания, кото- рое предшествует раку. Системная гип оксемия может влиять на пониженн ую оксигена цию опухолево й ткани — основной источник опухолевого неоангиогенеза. Авторы предп оложили , что у больных онкологического п рофиля с респираторно й недостаточностью системная гипоксемия может быть связана с повышенной агрессивностью опухолевого процесса, с одной стороны, и повышенным уровнем ангиогенных факторов — с другой. Методы: сод ержание факторов роста эндо- телия сосудов A и C ( VEGF ) опред еляли имму ноферментными мето дами у пациентов с гастроэзофагальным раком на фоне респираторной недостаточности в процессе хронического обструктивного заболевания легких или в отсутствие такового, а также у здоровых доноров. Анализировали д анные газометрии и сод ержания гемоглобина в зависимости от гистологии новообразования, статуса TNM и уровня VEGF A и C. Результаты: у больных с системно й гипоксемие й частота появления новообразований была выше. Парциальное давление кислоро да и насыщение крови кислоро д ом значительно снижено у пациентов с категорией T4. Повышение сод ержания циркулирующего VEGF A, но не C, более выражено у больных с респи- раторной недостаточностью, чем без нее. Содержание VEGF коррелировало с объемом первично й опухоли . Выводы: на результаты показывают, что системная гипоксемия у пациентов с гастроэзофагальным раком связана с увеличением объема первичной опухоли, и такой эффект может быть опосредован повышением содержания циркулирующего VEGF

Respiratory insufficiency related to copd accelerates systemic inflammation, under-nutrition, and angiogenesis in esophageal malignancies

A number of esophageal cancer patients suffer from respiratory insufficiency due to the coexistence of chronic obstructive pulmonary disease (COPD). Aim: To test the hypothesis that COPD-related systemic hypoxemia may result in accelerated inflammation, malnutrition, and angiogenesis in esophageal cancer patients. Methods: Serum levels of C-reactive protein (CRP), albumin, transferrin, interleukin-1, interleukin-6, interleukin-8, TNF- a, platelet-derived growth factor (PDGF-BB), and midkine and patient BMI and weight-loss rate were determined and compared with blood oxygenation status (pO2, SaO2) in 35 esophageal cancer patients and 42 controls. Results: The incidence of cachexia tended to be higher in patients with systemic hypoxemia (67% vs 40%, p = 0.169). Mean SaO2 level was also significantly decreased in cachectic patients (90.3 vs 93.3%, p = 0.026) and pO2 exhibited a similar trend (58.0 vs 63.4 mmHg, p = 0.120). Transferrin (234 vs 316 mg/dl, p = 0.005) and albumin (31.9 vs 37.1 mg/dl, p = 0.002) concentrations were reduced and CRP was elevated (129.9 vs 54.7 mg/l, p = 0.004) in hypoxemic patients and correlated with pO2 (r = 0.47, p = 0.016; r = 0.48, p = 0.012; r = –0.37, p = 0.064) and SaO2 (r = 0.52, p = 0.006; r = 0.53, p = 0.006; r = –0.40, p = 0.042). Interleukin-6 (9.97 vs 2.21 pg/ml, p = 0.005) and midkine (2101 vs 944 pg/ml, p < 0.001) were elevated and PDGF-BB was decreased (12.2 vs 17.3 pg x 10-6/PLT, p = 0.014) in hypoxemic compared with normoxemic patients. Interleukin-6 and midkine negatively correlated with pO2 (r = –0.44, p = 0.016; r = –0.42, p = 0.011) and SaO2 (r = –0.54, p = 0.003; r = –0.57, p < 0.0001) and PDGF-BB correlated positively (r = 0.53, p = 0.003; r = 0.44, p = 0.020). Interleukin-8 level was affected by pO2 (r = -0.55, p = 0.015) and SaO2 (r = –0.55, p = 0.018) only in hypoxemic patients. Conclusions: COPD-related systemic hypoxemia negatively affects the status of esophageal cancer patients by accelerating inflammation, under-nutrition, and angiogenesis.Многие больные раком пищевода страдают от респираторной недостаточности из-за развития хронического обструктивного легочного заболевания (COPD). Цель: Проверить гипотезу о возможной связи системной гипоксемии, ассоциированной с COPD, с усилением воспалительных процессов, истощением и ангиогенезом у больных раком пищевода. Методы: у 35 больных раком пищевода и 42 здоровых доноров определяли уровень CRP, альбумина, трансферина, интерлейкина-1, интерлейкина-6, интерлейкина-8, TNF-α, PDGF-BB и мидкина в сыворотке крови, показатели BMI и потери веса больных, а также показатели уровня оксигенации крови (pO2 , SaO2 ). Результаты: частота возникновения кахексии была выше у больных с системной гипоксемией (67 против 40%, p = 0,169). Средний уровень SaO2 был также значительно снижен у больных с кахексией (90,3 против 93,3%, p = 0,026), с той же тенденцией и для уровня pO2 (58,0 против 63,4 mmHg, p = 0,120). Концентрации трансферина (234 против 316 мг/дл, p = 0,005) и альбумина (31,9 против 37,1 мг/дл, p = 0,002) были снижены, CRP повышен (129,9 против 54,7 мг/л, p = 0,004) у гипоксемических пациентов, что кореллировало с показателями pO2 (r = 0,47, p = 0,016; r = 0,48, p = 0,012; r = –0,37, p = 0,064) и SaO2 (r = 0,52, p = 0,006; r = 0,53, p = 0,006; r = –0,40, p = 0,042). Уровень интерлейкина-6 (9,97 против 2,21 pg/ml, p = 0,005) и мидкина (2101 против 944 pg/ml, p < 0,001) был также повышен, а уровень PDGF-BB понижен (12,2 против 17,3 pg × 10-6/PLT, p = 0,014) у гипоксемических больных по сравнению с показателями при нормоксемии. Уровни интерлейкина-6 и мидкина негативно кореллировали с показателями pO2 (r = –0,44, p = 0,016; r = –0,42, p = 0,011) и SaO2 (r = –0,54, p = 0,003; r = –0,57, p < 0,0001) и позитивно — с PDGF-BB (r = 0,53, p = 0,003; r = 0,44, p = 0,020). На уровень интерлейкина-8 влияли pO2 (r = –0,55, p = 0,015) и SaO2 (r = –0,55, p = 0,018) только у больных с гипоксемией. Выводы: ассоциированная с COPD системная гипоксемия негативно влияет на состояние больных раком пищевода за счет ускорения воспалительных процессов, истощения и ангиогенез

Even a mild anemia is related to tumor aggressiveness mediated by angiogenic factors

Esophagogastric cancers have high recurrence rates with lymph nodes being a common pattern. Pre-treatment anemia has been reported an independent prognostic factor of treatment failure regardless of treatment strategy, particularly associated with poor locoregional control. A causative relationship between anemia — tumor hypoxia — tumor aggressiveness mediated by angiogenesis up-regulation is advocated, yet remains controversial. Aim: To determine whether and how the pre-treatment anemia is associated with various aspects of disease aggressiveness and to evaluate the possible involvement of angiogenesis mediators. Methods: In 111 esophagogastric cancer patients we investigated the association of pre-treatment hemoglobin concentration and anemia presence with cancer-related, patients-related features and laboratory parameters including angiogenic factors: vascular endothelial growth factors A and C, interleukin-8 and midkine. Serum levels of angiogenic factors were assessed with immunoenzymatic tests. Results: Histology, disease stage, regional metastasis and dissemination in general, malnutrition and angiogenesis represented by midkine were found to correlate with anemia presence and hemoglobin concentration, while tumor extension, patient’s age and sex accounted only for anemia presence. A tendency towards hemoglobin correlation with VEGF-A and Il-8 was also observed. Midkine, tumor histology and malnutrition were found to exert an independent effect on pre-treatment hemoglobin concentration and anemia presence in esophagogastric cancer patients. Hemoglobin level of 12 g/dL was found an optimal cut-off value for discrimination between localized and disseminated cancers. Conclusions: Even a mild pre-treatment anemia is associated with cancers metastasizing especially to regional lymph nodes, which seems to be mediated by some of studied angiogenic factors

The relationship between the insulin-like growth factor-1 axis, weight loss, an inflammation-based score and survival in patients with inoperable non-small cell lung cancer

&lt;b&gt;Background &#38; aims:&lt;/b&gt; The involvement of a systemic inflammatory response, as evidenced by the Glasgow Prognostic Score (GPS), is associated with weight loss and poor outcome in patients with non-small cell lung cancer. There is good evidence that nutritional and functional decline in patients with advanced malignant disease is associated with catabolic changes in metabolism. However, defects in anabolism may also contribute towards nutritional decline in patients with cancer. The aim of the present study was to examine the relationship between IGF-1 and IGFBP-3, performance status, mGPS and survival in patients with inoperable NSCLC. &lt;b&gt;Methods:&lt;/b&gt; 56 patients with inoperable NSCLC were studied. The plasma concentrations of IGF-1, IGFBP-3 and leptin were measured using ELISA and RIA. &lt;b&gt;Results:&lt;/b&gt; The patients were predominantly male (61%), over 60 years old (80%), with advanced (stage III or IV) disease (98%), with a BMI≥20 (84%), an ECOG-ps of 0 or 1 (79%), a haemoglobin (59%) and white cell count (79%) in the reference range. On follow-up 43 patients died of their cancer. On univariate analysis, BMI (p&#60;0.05), Stage (p&#60;0.05), ECOG-ps (p&#60;0.05), haemoglobin (p&#60;0.05), white cell count (p&#60;0.05) and mGPS (p&#60;0.05) were associated with cancer specific survival. There was no association between age, sex, treatment, IGF-1, IGFBP-3, IGF-1:IGFBP-3 ratio, or leptin and cancer specific survival. With an increasing mGPS concentrations of haemoglobin (p&#60;0.005) and IGFBP-3 (p&#60;0.05) decreased. mGPS was not associated with either IGF-1(p&#62;0.20), or leptin (p&#62;0.20). &lt;b&gt;Conclusions:&lt;/b&gt; In summary, the results of this study suggest that anabolism (IGF-1 axis) does not play a significant role in the relationship between nutritional and functional decline, systemic inflammation and poor survival in patients with inoperable NSCLC

Oral chondroitin sulfate and prebiotics for the treatment of canine Inflammatory Bowel Disease: a randomized, controlled clinical trial

BACKGROUND Canine inflammatory bowel disease (IBD) is a chronic enteropathy of unknown etiology, although microbiome dysbiosis, genetic susceptibility, and dietary and/or environmental factors are hypothesized to be involved in its pathogenesis. Since some of the current therapies are associated with severe side effects, novel therapeutic modalities are needed. A new oral supplement for long-term management of canine IBD containing chondroitin sulfate (CS) and prebiotics (resistant starch, β-glucans and mannaoligosaccharides) was developed to target intestinal inflammation and oxidative stress, and restore normobiosis, without exhibiting any side effects. This double-blinded, randomized, placebo-controlled trial in dogs with IBD aims to evaluate the effects of 180 days administration of this supplement together with a hydrolyzed diet on clinical signs, intestinal histology, gut microbiota, and serum biomarkers of inflammation and oxidative stress. RESULTS Twenty-seven client-owned biopsy-confirmed IBD dogs were included in the study, switched to the same hydrolyzed diet and classified into one of two groups: supplement and placebo. Initially, there were no significant differences between groups (p > 0.05) for any of the studied parameters. Final data analysis (supplement: n = 9; placebo: n = 10) showed a significant decrease in canine IBD activity index (CIBDAI) score in both groups after treatment (p < 0.001). After treatment, a significant decrease (1.53-fold; p < 0.01) in histologic score was seen only in the supplement group. When groups were compared, the supplement group showed significantly higher serum cholesterol (p < 0.05) and paraoxonase-1 (PON1) levels after 60 days of treatment (p < 0.01), and the placebo group showed significantly reduced serum total antioxidant capacity (TAC) levels after 120 days (p < 0.05). No significant differences were found between groups at any time point for CIBDAI, WSAVA histologic score and fecal microbiota evaluated by PCR-restriction fragment length polymorphism (PCR-RFLP). No side effects were reported in any group. CONCLUSIONS The combined administration of the supplement with hydrolyzed diet over 180 days was safe and induced improvements in selected serum biomarkers, possibly suggesting a reduction in disease activity. This study was likely underpowered, therefore larger studies are warranted in order to demonstrate a supplemental effect to dietary treatment of this supplement on intestinal histology and CIBDAI

Sex-stratified patterns of emergency cardiovascular admissions prior and during the COVID-19 pandemic

The COVID-19 pandemic has had a significant impact on global public health, with long-term consequences that are still largely unknown. This study aimed to assess the data regarding acute cardiovascular hospital admissions in five European centers before and during the pandemic. A multicenter, multinational observational registry was created, comparing admissions to the emergency departments during a 3-months period in 2020 (during the pandemic) with the corresponding period in 2019 (pre-pandemic). Data on patient demographics, COVID-19 test results, primary diagnosis, comorbidities, heart failure profile, medication use, and laboratory results were collected. A total of 8778 patients were included in the analysis, with 4447 patients in 2019 and 4331 patients in 2020. The results showed significant differences in the distribution of cardiovascular diseases between the two years. The frequency of pulmonary embolism (PE) increased in 2020 compared to 2019, while acute heart failure (AHF) and other cardiovascular diseases decreased. The odds of PE incidence among hospitalized patients in 2020 were 1.316-fold greater than in 2019. The incidence of AHF was 50.83% less likely to be observed in 2020, and the odds for other cardiovascular diseases increased by 17.42% between the 2 years. Regarding acute coronary syndrome (ACS), the distribution of its types differed between 2019 and 2020, with an increase in the odds of ST-segment elevation myocardial infarction (STEMI) in 2020. Stratification based on sex revealed further insights. Among men, the incidence of AHF decreased in 2020, while other cardiovascular diseases increased. In women, only the incidence of STEMI showed a significant increase. When analyzing the influence of SARS-CoV-2 infection, COVID-positive patients had a higher incidence of PE compared to COVID-negative patients. COVID-positive patients with ACS also exhibited symptoms of heart failure more frequently than COVID-negative patients. These findings provide valuable information on the impact of the COVID-19 pandemic on acute cardiovascular hospital admissions. The increased incidence of PE and changes in the distribution of other cardiovascular diseases highlight the importance of monitoring and managing cardiovascular health during and post pandemic period. The differences observed between sexes emphasize the need for further research to understand potential sex-specific effects of COVID-19 on cardiovascular outcomes

Evolutionary Dynamics of Co-Segregating Gene Clusters Associated with Complex Diseases

BACKGROUND: The distribution of human disease-associated mutations is not random across the human genome. Despite the fact that natural selection continually removes disease-associated mutations, an enrichment of these variants can be observed in regions of low recombination. There are a number of mechanisms by which such a clustering could occur, including genetic perturbations or demographic effects within different populations. Recent genome-wide association studies (GWAS) suggest that single nucleotide polymorphisms (SNPs) associated with complex disease traits are not randomly distributed throughout the genome, but tend to cluster in regions of low recombination. PRINCIPAL FINDINGS: Here we investigated whether deleterious mutations have accumulated in regions of low recombination due to the impact of recent positive selection and genetic hitchhiking. Using publicly available data on common complex diseases and population demography, we observed an enrichment of hitchhiked disease associations in conserved gene clusters subject to selection pressure. Evolutionary analysis revealed that these conserved gene clusters arose by multiple concerted rearrangements events across the vertebrate lineage. We observed distinct clustering of disease-associated SNPs in evolutionary rearranged regions of low recombination and high gene density, which harbor genes involved in immunity, that is, the interleukin cluster on 5q31 or RhoA on 3p21. CONCLUSIONS: Our results suggest that multiple lineage specific rearrangements led to a physical clustering of functionally related and linked genes exhibiting an enrichment of susceptibility loci for complex traits. This implies that besides recent evolutionary adaptations other evolutionary dynamics have played a role in the formation of linked gene clusters associated with complex disease traits