Prognostic factors in Hodgkin lymphoma

During the last decades, the prognosis of Hodgkin lymphoma (HL) has been improved significantly with the introduction of effective chemotherapy and the implementation of risk-adapted treatment approaches. Identification of reliable risk factors is crucial to guide treatment over the course of disease. Both clinical and biological factors have been implicated in the prognosis of HL and are often used in prognostic scores to discriminate risk groups. To prevent under- or overtreatment, patients are usually assigned to one of the three widely established risk groups for first-line treatment, based solely on clinical risk factors. To further individualize therapeutic approaches, functional imaging with positron emission tomography (PET) is becoming more widely implemented and precisely investigated within clinical trials. Biological prognostic factors have been widely evaluated but are still not a part of standard prognostication. This review will discuss the currently established factors and risk models at first diagnosis and in the setting of relapsed/refractory disease and also focus on biological factors and PET, summarizing current standards and future perspectives. (C) 2016 Elsevier Inc. All rights reserved

Serum Procalcitonin Levels in Newly Diagnosed Hodgkin Lymphoma: Correlation with Other Inflammatory Biomarkers

Background and Objectives: Procalcitonin (PCT) is a useful biomarker for the diagnosis of sepsis. Inflammatory markers are elevated in patients with Hodgkin lymphoma (HL), and yet ongoing infection rarely coexists at diagnosis. PCT levels might be helpful in differentiating bacterial from disease-related inflammation. Materials and Methods: We evaluated serum PCT levels and other inflammation markers in newly diagnosed HL patients. Values < 0.50 ng/mL were considered normal (0.10–0.50 ng/mL: detectable, <0.10 ng/mL: undetectable), while values ≥ 0.50 ng/L were considered elevated. Results: Among 137 patients, 55 had B symptoms (40%), 77/130 (59%) had elevated Erythrocyte Sedimentation Rate (ESR) and 116 (85%) had elevated C-Reactive Protein (CRP) (median 38.1 mg/L (range; 2.97–328)). PCT levels were normal in most patients (undetectable 94/137 (68.5%) and detectable 41/137(30%)) with median value < 0.10 ng/mL (range; <0.10–15.90). Elevated PCT was recorded in only two patients (1.5%). Patients with PCT < 0.10 ng/mL had significantly lower median CRP (25.75; range (2.97–203.0)) compared to patients with PCT ≥ 0.1 ng/mL (median CRP 92.50 mg/L; range (3.34–328.0)). Almost all patients (40/41, 97.6%) with detectable PCT had elevated CRP. Conclusions: This is the first study showing that the inflammation characterizing HL is not associated with PCT elevations, although CRP levels are elevated in 85% of the patients. Normal PCT levels may rule out the possibility of occult infection, thus preventing extensive evaluation, which may delay treatment initiation

Oxidants Regulated Diaphragm Proteolysis during Mechanical Ventilation in Rats

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Diaphragm dysfunction and atrophy develop during controlled mechanical ventilation. Although oxidative stress injures muscle during controlled mechanical ventilation, it is unclear whether it causes autophagy or fiber atrophy. WHAT THIS ARTICLE TELLS US THAT IS NEW: Pretreatment of rats undergoing 24 h of mechanical ventilation with N-acetylcysteine prevents decreases in diaphragm contractility, inhibits the autophagy and proteasome pathways, but has no influence on the development of diaphragm fiber atrophy. BACKGROUND: Diaphragm dysfunction and atrophy develop during prolonged controlled mechanical ventilation. Fiber atrophy has been attributed to activation of the proteasome and autophagy proteolytic pathways. Oxidative stress activates the proteasome during controlled mechanical ventilation, but it is unclear whether it also activates autophagy. This study investigated whether pretreatment with the antioxidant N-acetylcysteine affects controlled mechanical ventilation-induced diaphragm contractile dysfunction, fiber atrophy, and proteasomal and autophagic pathway activation. The study also explored whether proteolytic pathway activity during controlled mechanical ventilation is mediated by microRNAs that negatively regulate ubiquitin E3 ligases and autophagy-related genes. METHODS: Three groups of adult male rats were studied (n = 10 per group). The animals in the first group were anesthetized and allowed to spontaneously breathe. Animals in the second group were pretreated with saline before undergoing controlled mechanical ventilation for 24 h. The animals in the third group were pretreated with N-acetylcysteine (150 mg/kg) before undergoing controlled mechanical ventilation for 24 h. Diaphragm contractility and activation of the proteasome and autophagy pathways were measured. Expressions of microRNAs that negatively regulate ubiquitin E3 ligases and autophagy-related genes were measured with quantitative polymerase chain reaction. RESULTS: Controlled mechanical ventilation decreased diaphragm twitch force from 428 ± 104 g/cm (mean ± SD) to 313 ± 50 g/cm and tetanic force from 2,491 ± 411 g/cm to 1,618 ± 177 g/cm. Controlled mechanical ventilation also decreased diaphragm fiber size, increased expression of several autophagy genes, and augmented Atrogin-1, MuRF1, and Nedd4 expressions by 36-, 41-, and 8-fold, respectively. Controlled mechanical ventilation decreased the expressions of six microRNAs (miR-20a, miR-106b, miR-376, miR-101a, miR-204, and miR-93) that regulate autophagy genes. Pretreatment with N-acetylcysteine prevented diaphragm contractile dysfunction, attenuated protein ubiquitination, and downregulated E3 ligase and autophagy gene expression. It also reversed controlled mechanical ventilation-induced microRNA expression decreases. N-Acetylcysteine pretreatment had no affect on fiber atrophy. CONCLUSIONS: Prolonged controlled mechanical ventilation activates the proteasome and autophagy pathways in the diaphragm through oxidative stress. Pathway activation is accomplished, in part, through inhibition of microRNAs that negatively regulate autophagy-related genes.status: publishe

Evaluation of automated capillary complete blood counts for routine clinical decision making in a large cohort of hematological patients, using Mindray BC-3000 Plus Auto and Sysmex XE-5000 hematology analyzers

Introduction Venous blood (VB) sampling for complete blood count (CBC) via venipuncture is the basic method for the daily evaluation of hematological patients. However, several issues during this process, such as venipuncture difficulty and repetitive attempts, may cause pain, phlebitis, hematomas, inadequate sampling, and patient discomfort. Capillary blood (CB) sampling could be an alternative and less painful solution for the patient. The purpose of this study was the comparative evaluation of basic CBC parameters, as counted from venous and capillary blood samples. Methods During the period 06/2016-06/2019 in which the study was conducted, 1634 automated counts of VB or CB were performed, derived from 425 hematological hospitalized patients. Bland-Altman plots were performed to show the agreement of VB and CB counts of common hematological parameters (Hb, Hct, WBC, absolute neutrophil count-[ANC], RBC, Plt, MCV, MCH), using two different hematology analyzers (Mindray BC-3000 Plus Auto and Sysmex XE-5000). Clinical significance of CB sampling was assessed by applying specific clinically significant cutoffs for Hb, ANC, and Plt. Results All measured parameters revealed a significant correlation (r > .9) between CB and VB samples, irrelatively of the hematology analyzer used. CB measurements of Hb, ANC, and Plt, at different clinically important cutoff levels, showed excellent sensitivity (87%-100%), specificity (95%-100%), positive predictive value, and negative predictive value (87%-100% and 90%-100%, respectively). Conclusion Capillary blood and VB counts in hematological patients were equivalent for most basic hematological parameters. Hb, ANC, and Plt CB counts revealed clinically significant performance, indicating that they can reliably substitute VB sampling in the day work

Oxidants Regulated Diaphragm Proteolysis during Mechanical Ventilation in Rats

Background: Diaphragm dysfunction and atrophy develop during prolonged controlled mechanical ventilation. Fiber atrophy has been attributed to activation of the proteasome and autophagy proteolytic pathways. Oxidative stress activates the proteasome during controlled mechanical ventilation, but it is unclear whether it also activates autophagy. This study investigated whether pretreatment with the antioxidant N-acetylcysteine affects controlled mechanical ventilation-induced diaphragm contractile dysfunction, fiber atrophy, and proteasomal and autophagic pathway activation. The study also explored whether proteolytic pathway activity during controlled mechanical ventilation is mediated by microRNAs that negatively regulate ubiquitin E3 ligases and autophagy-related genes. Methods: Three groups of adult male rats were studied (n = 10 per group). The animals in the first group were anesthetized and allowed to spontaneously breathe. Animals in the second group were pretreated with saline before undergoing controlled mechanical ventilation for 24 h. The animals in the third group were pretreated with N-acetylcysteine (150 mg/kg) before undergoing controlled mechanical ventilation for 24 h. Diaphragm contractility and activation of the proteasome and autophagy pathways were measured. Expressions of microRNAs that negatively regulate ubiquitin E3 ligases and autophagy-related genes were measured with quantitative polymerase chain reaction. Results: Controlled mechanical ventilation decreased diaphragm twitch force from 428 +/- 104 g/cm(2) (mean +/- SD) to 313 +/- 50 g/cm(2) and tetanic force from 2,491 +/- 411 g/cm(2) to 1,618 +/- 177 g/cm(2). Controlled mechanical ventilation also decreased diaphragm fiber size, increased expression of several autophagy genes, and augmented Atrogin-1, MuRF1, and Nedd4 expressions by 36-, 41-, and 8-fold, respectively. Controlled mechanical ventilation decreased the expressions of six microRNAs (miR-20a, miR-106b, miR-376, miR-101a, miR-204, and miR-93) that regulate autophagy genes. Pretreatment with N-acetylcysteine prevented diaphragm contractile dysfunction, attenuated protein ubiquitination, and downregulated E3 ligase and autophagy gene expression. It also reversed controlled mechanical ventilation-induced microRNA expression decreases. N-Acetylcysteine pretreatment had no affect on fiber atrophy. Conclusions: Prolonged controlled mechanical ventilation activates the proteasome and autophagy pathways in the diaphragm through oxidative stress. Pathway activation is accomplished, in part, through inhibition of microRNAs that negatively regulate autophagy-related genes

Regulation of breathing pattern by IL-10

Proinflammatory cytokines like interleukin-1 beta (IL-1 beta) affect the control of breathing. Our aim is to determine the effect of the anti-inflammatory cytokine IL-10 on the control of breathing. IL-10 knockout mice (IL-10(-/-), n = 10) and wild-type mice (IL-10(+/+), n = 10) were exposed to the following test gases: hyperoxic hypercapnia 7% CO2-93% O-2, normoxic hypercapnia 7% CO2-21% O-2, hypoxic hypercapnia 7% CO2-10% O-2, and hypoxic normocapnia 3% CO2-10% O-2. The ventilatory function was assessed using whole body plethysmography. Recombinant mouse IL-10 (rIL-10; 10 mu/kg) was administered intraperitoneally to wild-type mice (n = 10) 30 min before the onset of gas challenge. IL-10 was administered in neonatal medullary slices (10-30 ng/ml, n = 8). We found that IL-10(-/-) mice exhibited consistently increased frequency and reduced tidal volume compared with IL-10(+/+) mice during room air breathing and in all test gases (by 23.62 to 33.2%, P < 0.05 and -36.23 to -41.69%, P < 0.05, respectively). In all inspired gases, the minute ventilation of IL-10(-/-) mice was lower than IL-10(+/+) (by -15.67 to -22.74%, P < 0.05). The rapid shallow breathing index was higher in IL-10(-/-) mice compared with IL-10(+/+) mice in all inspired gases (by 50.25 to 57.5%, P < 0.05). The intraperitoneal injection of rIL-10 caused reduction of the respiratory rate and augmentation of the tidal volume in room air and also in all inspired gases (by -12.22 to -29.53 and 32.18 to 45.11%, P < 0.05, respectively). IL-10 administration in neonatal rat (n = 8) in vitro rhythmically active medullary slice preparations did not affect either rhythmicity or peak amplitude of hypoglossal nerve discharge. In conclusion, IL-10 may induce a slower and deeper pattern of breathing

Mechanical Ventilation-induced Diaphragm Disuse in Humans Triggers Autophagy

Rationale: Controlled mechanical ventilation (CMV) results in atrophy of the human diaphragm. The autophagy-lysosome pathway (ALP) contributes to skeletal muscle proteolysis, but its contribution to diaphragmatic protein degradation in mechanically ventilated patients is unknown. Objectives: To evaluate the autophagy pathway responses to CMV in the diaphragm and limb muscles of humans and to identify the roles of FOXO transcription factors in these responses. Methods: Muscle biopsies were obtained from nine control subjects and nine brain-dead organ donors. Subjects were mechanically ventilated for 2 to 4 hours and 15 to 276 hours, respectively. Activation of the ubiquitin-proteasome system was detected by measuring mRNA expressions of Atrogin-1, MURF1, and protein expressions of UBC2, UBC4, and the alpha subunits of the 20S proteasome (MCP231). Activation of the ALP was detected by electron microscopy and by measuring the expressions of several autophagy-related genes. Total carbonyl content and HNE-protein adduct formation were measured to assess oxidative stress. Total AKT, phosphorylated and total FOXO1, and FOXO3A protein levels were also measured. Measurements and Main Results: Prolonged CMV triggered activation of the ALP as measured by the appearance of autophagosomes in the diaphragm and increased expressions of autophagy-related genes, as compared with controls. Induction of autophagy was associated with increased protein oxidation and enhanced expression of the FOXO1 gene, but not the FOXO3A gene. CMV also triggered the inhibition of both AKT expression and FOXO1 phosphorylation. Conclusions: We propose that prolonged CMV causes diaphragm disuse, which, in turn, leads to activation of the ALP through oxidative stress and the induction of the FOXO1 transcription factor