Untutored training pathway to achieve competence in esophagogastric endoscopic submucosal dissection in a Western center.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) has a long learning curve. The aim of this study was to assess the efficacy of an ESD unsupervised training model for experienced endoscopists. METHODS: Stepwise training included a visit to a high-volume center, unsupervised training on an ex vivo porcine model, and in vivo human upper GI cases with anatomic progression. Performance measures included en bloc resection, R0 resection, adverse event rates, and operating time. RESULTS: After observation of 30 esophagogastric ESDs and 15 untutored ex vivo ESDs, 5 human cases of distal gastric ESDs were performed, followed by 55 unselected esophagogastric cases. En bloc and R0 resection rates were 93.0% and 80.7%, respectively. Operating time was 14.0 min/cm2 in the stomach and 25.1 min/cm2 in the esophagus, with evidence of a learning curve for esophageal ESDs (first block 30.26 min/cm2 vs second block 14.81 min/cm2, P = .01). CONCLUSIONS: Untutored training for esophagogastric ESD is feasible and allows endoscopists, experienced in therapeutic endoscopy, to achieve the required standards toward competency.

The effect of procedural time on dysplasia detection rate during endoscopic surveillance of Barrett's esophagus.

BACKGROUND : Endoscopic surveillance of Barrett's esophagus (BE) with Seattle protocol biopsies is time-consuming and inadequately performed in routine practice. There is no recommended procedural time for BE surveillance. We investigated the duration of surveillance procedures with adequate tissue sampling and effect on dysplasia detection rate (DDR). METHODS : We performed post hoc analysis from the standard arm of a crossover randomized controlled trial recruiting patients with BE (≥C2 and/or ≥M3) and no clearly visible dysplastic lesions. After inspection with white-light imaging, targeted biopsies of subtle lesions and Seattle protocol biopsies were performed. Procedure duration and biopsy number were stratified by BE length. The effect of endoscopy-related variables on DDR was assessed by multivariable logistic regression. RESULTS : Of 142 patients recruited, 15 (10.6 %) had high grade dysplasia/intramucosal cancer and 15 (10.6 %) had low grade dysplasia. The median procedural time was 16.5 minutes (interquartile range 14.0-19.0). Endoscopy duration increased by 0.9 minutes for each additional 1 cm of BE length. Seattle protocol biopsies had higher sensitivity for dysplasia than targeted biopsies (86.7 % vs. 60.0 %; P = 0.045). Longer procedural time was associated with increased likelihood of dysplasia detection on quadrantic biopsies (odds ratio [OR] 1.10, 95 %CI 1.00-1.20, P = 0.04), and for patients with BE > 6 cm also on targeted biopsies (OR 1.21, 95 %CI 1.04-1.40; P = 0.01). CONCLUSIONS : In BE patients with no clearly visible dysplastic lesions, longer procedural time was associated with increased likelihood of dysplasia detection. Adequate time slots are required to perform good-quality surveillance and maximize dysplasia detection.

Image-Enhanced Endoscopy and Molecular Biomarkers Vs Seattle Protocol to Diagnose Dysplasia in Barrett's Esophagus.

BACKGROUND & AIMS: Dysplasia in Barrett's esophagus often is invisible on high-resolution white-light endoscopy (HRWLE). We compared the diagnostic accuracy for inconspicuous dysplasia of the combination of autofluorescence imaging (AFI)-guided probe-based confocal laser endomicroscopy (pCLE) and molecular biomarkers vs HRWLE with Seattle protocol biopsies. METHODS: Barrett's esophagus patients with no dysplastic lesions were block-randomized to standard endoscopy (HRWLE with the Seattle protocol) or AFI-guided pCLE with targeted biopsies for molecular biomarkers (p53 and cyclin A by immunohistochemistry; aneuploidy by image cytometry), with crossover to the other arm after 6 to 12 weeks. The primary end point was the histologic diagnosis from all study biopsies (trial histology). A sensitivity analysis was performed for overall histology, which included diagnoses within 12 months from the first study endoscopy. Endoscopists were blinded to the referral endoscopy and histology results. The primary outcome was diagnostic accuracy for dysplasia by real-time pCLE vs HRWLE biopsies. RESULTS: Of 154 patients recruited, 134 completed both arms. In the primary outcome analysis (trial histology analysis), AFI-guided pCLE had similar sensitivity for dysplasia compared with standard endoscopy (74.3%; 95% CI, 56.7-87.5 vs 80.0%; 95% CI, 63.1-91.6; P = .48). Multivariate logistic regression showed pCLE optical dysplasia, aberrant p53, and aneuploidy had the strongest correlation with dysplasia (secondary outcome). This 3-biomarker panel had higher sensitivity for any grade of dysplasia than the Seattle protocol (81.5% vs 51.9%; P < .001) in the overall histology analysis, but not in the trial histology analysis (91.4% vs 80.0%; P = .16), with an area under the receiver operating curve of 0.83. CONCLUSIONS: Seattle protocol biopsies miss dysplasia in approximately half of patients with inconspicuous neoplasia. AFI-guided pCLE has similar accuracy to the current gold standard. The addition of molecular biomarkers could improve diagnostic accuracy.

Thiopurine monotherapy is effective in ulcerative colitis but significantly less so in Crohn's disease: long-term outcomes for 11 928 patients in the UK inflammatory bowel disease bioresource.

OBJECTIVE: Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohn's disease (CD), including their impact on need for surgery. DESIGN: Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines. RESULTS: Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p<0.0001). This difference was corroborated in a multivariable analysis: after adjusting for variables including treatment era, thiopurine monotherapy was less effective in CD than UC (OR 0.47, 95% CI 0.43 to 0.51, p<0.0001). Thiopurine intolerance was associated with increased risk of surgery in UC (HR 2.44, p<0.0001); with a more modest impact on need for surgery in CD (HR=1.23, p=0.0015). CONCLUSION: Thiopurine monotherapy is an effective long-term treatment for UC but significantly less effective in CD.

Single-bite versus double-bite technique for mapping biopsies during endoscopic surveillance for hereditary diffuse gastric cancer: a single-center, randomized trial.

BACKGROUND : Endoscopic surveillance is recommended in patients with hereditary diffuse gastric cancer (HDGC) who refuse or want to delay surgery. Because early signet-ring cell carcinoma (SRCC) can be inconspicuous, the current surveillance endoscopy protocol entails 30 random biopsies, which are time-consuming. This study aimed to compare single-bite and double-bite techniques in HDGC surveillance. METHODS : Between October 2017 and December 2018, consecutive patients referred for HDGC surveillance were prospectively randomized to the single- or double-bite arm. The primary outcome was the diagnostic yield for SRCC foci. Secondary outcomes were: procedural time for random biopsies; comfort score; biopsy size; and quality of specimens, the latter assessed by the presence of muscularis mucosa, crush artifact, and proportion usable for diagnostic assessment. RESULTS : 25 patients were randomized to the single-bite arm and 23 to the double-bite arm. SRCC foci were detected in three and four patients in the single- and double-bite arms, respectively (P = 0.70). The procedural time for the double-bite arm (12 minutes, interquartile range [IQR] 4) was significantly shorter than for the single-bite arm (15 minute, IQR 6; P = 0.01), but comfort scores were similar. The size of the biopsies in the double-bite arm was significantly smaller than in single-bite arm (2.5 mm vs. 3.0 mm; P < 0.001) but this did not affect the presence of muscularis mucosa (P = 0.73), artifact level (P = 0.11), and diagnostic utility (P = 0.051). CONCLUSION : For patients undergoing HDGC surveillance, the double-bite technique is significantly faster than the single-bite technique. The diagnostic yield for SRCC and the biopsy quality were similar across both groups.

Role of angiopoietins in mesothelioma progression.

BACKGROUND AND OBJECTIVE: Anti-angiogenic treatment has been recently shown to be clinically beneficial for mesothelioma patients. Angiopoietins-1 and -2 are key regulators of tumor angiogenesis. Ang-1 is mainly known to promote angiogenesis and vessel stability, while Ang-2 could serve as an antagonist of Ang-1 causing vessel regression and destabilization or enhance angiogenesis in a context-dependent manner. We hypothesized that Ang-1 would promote and Ang2 would halt experimental mesothelioma by affecting tumor angiogenesis. METHODS: To examine the effects of angiopoietins in mesothelioma angiogenesis and in vivo growth we constructed Ang-1 or Ang-2 overexpressing AE17 and AB1 mesothelioma cells and implanted them in the respective syngeneic animals. We also explored the clinical relevance of our observations using the human tumoral mRNAseq data available in the TCGA database. RESULTS AND CONCLUSIONS: Ang-1 promotes mesothelioma angiogenesis and growth while the effect of Ang-2 is context-dependent. Low Ang-1 levels in human mesotheliomas are associated with the epitheloid subtype. Tumors of high Ang-1, or concurrent high Ang-2 and VEGF expression present high PECAM-1 and CDH5 expression, markers of vascularity and vascular stability, respectively. Our results highlight the importance of angiopoietins in mesothelioma pathophysiology and pave the way for the clinical development of novel anti-angiogenic strategies.

Seasonal changes in epidermal ceramides are linked to impaired barrier function in acne patients.

Acne skin demonstrates increased transepidermal water loss (TEWL) compared with healthy skin, which may be due, in part, to altered ceramide (CER) levels. We analysed ceramides in the stratum corneum of healthy and acne skin, and studied seasonal variation over the course of a year. Using ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry (UPLC/ESI-MS/MS), we identified 283 ceramides. Acne-affected skin demonstrated overall lower levels of ceramides, with notable reductions in CER[NH] and CER[AH] ceramides, as well as the acylceramides CER[EOS] and CER[EOH]; these differences were more apparent in the winter months. Lower ceramide levels reflected an increase in TEWL in acne, compared with healthy skin, which partly resolves in the summer. Individual ceramide species with 18-carbon 6-hydroxysphingosine (H) bases (including CER[N(24)H(18)], CER[N(26)H(18)], CER[A(24)H(18)], CER[A(26)H(18)]) were significantly reduced in acne skin, suggesting that CER[NH] and CER[AH] species may be particularly important in a healthy skin barrier.

The Kollias legacy: Skin autofluorescence and beyond.

In a paper published at the J Invest Dermatol in 1998 Nik Kollias and coworkers described distinct changes in skin native fluorescence associated with skin aging and photoaging, using in vivo fluorescence excitation spectroscopy. The assignment of the 295 nm band to tryptophan fluorescence had a profound significance influencing many later studies from multiple groups. The reproducible changes in skin native fluorescence suggested that aging causes predictable alterations in both the epidermis and the dermis, whereas chronic UV exposure induces the appearance of new fluorophores. This seminal, but insufficiently widely appreciated work deserves re-examination as it points to important horizons in future experimental dermatology, such as cancer diagnostics, diabetes, wound healing, and understanding skin aging and photoaging mechanisms.

Assessing the clinical utility of Wnt pathway markers in colorectal cancer.

PURPOSE: ß-catenin and AXIN2 play an important role in the Wnt signaling pathway. The aim of this study was to investigate ß-catenin and AXIN2 expression in colorectal cancer (CRC) and relate these findings with patients' clinicopathological features and prognosis. METHODS: 57 consecutive patients with surgically treated CRC were included in this study. Quantitative PCR and immunohistochemistry (IHC) analyses were performed to characterize the expression of the aforementioned markers in CRC tissues. RESULTS: ß-catenin overexpression in the nucleus was associated with advanced N stage CRCs (p=0.04). Multivariate Cox regression analysis showed that ß-catenin overexpression is an independent prognostic factor for overall survival (OS). A positive correlation between ß-catenin location and AXIN2 mRNA was observed. CONCLUSIONS: Nuclear ß-catenin is a valuable prognostic factor. AXIN2 is a component of the "Destruction Complex" and also a Wnt target gene. However, the clinical importance of AXIN2 expression in CRC remains unclear.

Nutrition and skin.

Nutrition has long been associated with skin health, including all of its possible aspects from beauty to its integrity and even the aging process. Multiple pathways within skin biology are associated with the onset and clinical course of various common skin diseases, such as acne, atopic dermatitis, aging, or even photoprotection. These conditions have been shown to be critically affected by nutritional patterns and dietary interventions where well-documented studies have demonstrated beneficial effects of essential nutrients on impaired skin structural and functional integrity and have restored skin appearance and health. Although the subject could be vast, the intention of this review is to provide the most relevant and the most well-documented information on the role of nutrition in common skin conditions and its impact on skin biology.

Lymphovascular infiltration in the tumor bed is a useful marker of biological behavior in breast cancer.

PURPOSE: Tumor cells can metastasize by entering existing vessels or new vessels actively recruited into the primary tumor. Invasion of the lymphatics and blood vessels in the periphery of the tumor seems to be a prerequisite step in the metastatic process. The aim of this study was to correlate peripheral lymphatic vessel infiltration (PLI) and peripheral blood vessel infiltration (PVI) in a cohort of patients with invasive ductal carcinoma of the breast with various other prognostic parameters and outcome. METHODS: The study population consisted of 236 female patients with invasive ductal breast carcinomas, who had been operated between 2011 and 2013. The registered data included age at diagnosis, histological subtype, tumor size, TNM stage, histological grade, estrogen (ER) and progesterone receptors (PR), HER-2, p53, and PLI and PVI. RESULTS: Pathological examination revealed that 22.5% of the patients had PVI and 37.3% had PLI at the tumor front. PVI correlated with younger age (p<0.05), higher histologic grade (p<0.05), advanced TNM stage (p<0.05), higher T stage (p<0.05), higher N stage (p<0.05) and positive Ki67 expression (p<0.05). Similarly, PLI correlated with higher histologic grade (p<0.05), advanced TNM stage (p<0.05), higher T stage (p<0.05) and higher N stage (p<0.05). Statistical analysis did not reveal significant correlation between the presence of tumor blood and lymphatic vessels with infiltration in overall (OS) and disease-free survival (DFS). CONCLUSIONS: PLI and PVI are important markers of worse clinical outcome as shown by their association with other established factors, but no association with recurrence and survival could be proven.

Keratinocyte differentiation and upregulation of ceramide synthesis induced by an oat lipid extract via the activation of PPAR pathways.

Activation of peroxisome proliferator-activated receptors (PPARs) has been shown to have an important role in skin barrier function by regulating differentiation and lipid synthesis in keratinocytes. Oat (Avena sativa) has long been used as a soothing agent to relieve skin irritations, and the clinical benefits of topical oat formulations have been proven; however, the mechanistic understanding of oat's mode of action remains unknown. We investigated whether an oat lipid extract could activate PPARs and subsequently increase epidermal lipid synthesis and differentiation markers. Primary human epidermal keratinocytes and transformed cell lines were treated with PPAR agonists and oat lipid extracts to investigate the PPAR agonism. PPAR target genes and epidermal differentiation markers were analysed using quantitative real-time PCR and HPTLC analysis. Oat lipid extract demonstrated robust dual agonism for PPARα and PPARß/δ, and increased direct PPAR target gene induction in primary human keratinocytes. In addition, oat oil treatment increased both receptor expression and, consistent with the literature on PPARs, oat oil treatment resulted in a significant upregulation of differentiation genes (involucrin, SPRRs and transglutaminase 1) and ceramide processing genes (ß-glucocerebrosidase, sphingomyelinases 3 and ABCA12). Further, oat oil treatment in keratinocytes significantly increased ceramide levels (70%), suggesting a functional translation of PPAR activation by oat oil in keratinocytes. Taken together, these results demonstrate that oat lipids possess robust dual agonistic activities for PPARα and PPARß/δ, increase their gene expression and induce differentiation and ceramide synthesis in keratinocytes, which can collectively improve skin barrier function.

Temsirolimus targets multiple hallmarks of cancer to impede mesothelioma growth in vivo.

BACKGROUND AND OBJECTIVE: The mechanistic target of rapamycin (mTOR) promotes cancer cell proliferation and survival, transduces pro-angiogenic signals and regulates immune cell differentiation and function. We hypothesized that temsirolimus, an mTOR inhibitor, would curtail experimental mesothelioma progression in vivo by limiting tumour cell growth, abrogating tumour angiogenesis and modulating immune/inflammatory tumour milieu. METHODS: We produced flank and pleural syngeneic murine mesotheliomas by delivering AE17 and AB1 murine mesothelioma cells into the right flank or the pleural space of C57BL/6 and BALB/c mice, respectively. Animals were given five times/week intraperitoneal injections of 20 mg/kg temsirolimus or vehicle and were sacrificed on day 26 (flank) or on day 15 (pleural) post-tumour cell propagation. RESULTS: Temsirolimus limited mesothelioma growth in vivo by stimulating tumour cell apoptosis, inhibiting tumour angiogenesis, enhancing tumour lymphocyte abundance and blocking pro-tumour myeloid cell recruitment. Pleural fluid accumulation was significantly mitigated in AE17 but not in AB1 mesotheliomas. In vitro, temsirolimus hindered mesothelioma cell growth, NF-kappaB activation and macrophage migration. CONCLUSIONS: In conclusion, temsirolimus apart from inducing tumour cell apoptosis, targets tumour angiogenesis and influences inflammatory tumour microenvironment to halt experimental mesothelioma growth in vivo.

Evaluation of Seasonal Changes in Facial Skin With and Without Acne.

The objective of this study was to compare facial skin of adolescent males with (acne) and without acne (non-acne) over the course of 1 year. At study entry, presence of acne was determined by clinical image analysis (acne n=7, non-acne n=10). Monthly evaluations of skin condition were made using standard and fluorescent imaging, fluorescence spectroscopic analysis, sebum analysis, skin high frequency conductivity (moisture content), transepidermal water loss (TEWL), and sampling of skin bacteria (aerobic and anaerobic). Data were evaluated seasonally. Over the course of the study, subjects in the acne and non-acne groups had no significant increase in their clinical acne score. Sebum production was significantly greater in subjects with acne than in those without for each season examined (P<0.019) and was lowest in the winter and highest in the fall. TEWL was higher in those with acne than without acne across all seasons (P=0.001). Skin moisture in both groups was increased during summer and fall compared with winter (P≤0.016 for both seasons). Subjects with acne had a higher recovery of both aerobic and anaerobic bacteria compared with subjects without acne (P≤0.015). Analysis of cheek skin in the nasal area revealed significantly higher fluorescence (500-800 nm) in image-based and spectroscopic analysis from subjects with acne, suggesting the greater presence of the bacterial metabolite porphyrin in those with acne. In these cohorts of adolescent males, significant differences in sebum production, skin barrier function, moisture content, and microbial load (anaerobic and aerobic) were noted between those with and without acne. Evidence for seasonality was observed, with lower lipid production and reduced barrier function during the winter. More studies to quantify differences in skin lipid components and bacterial species among these cohorts are planned.

High Plasma Osteopontin Levels Are Associated with Serious Post-Acute-COVID-19-Related Dyspnea.

COVID-19 survivors commonly report persistent symptoms. In this observational study, we investigated the link between osteopontin (OPN) and post-acute COVID-19 symptoms and lung functional/imaging abnormalities. We recorded symptoms and lung imaging/functional data from previously hospitalized COVID-19 patients, who were followed for 4-84 weeks (122 patients/181 visits) post-symptom onset at our outpatient clinic. Circulating OPN was determined using ELISA. Plasma OPN levels were higher in symptomatic patients (compared with the asymptomatic ones); those with dyspnea (compared with those without dyspnea);those with a combination of serious symptoms, i.e., the presence of at least one of the following: dyspnea, fatigue and muscular weakness (compared with those with none of these symptoms); and those with dyspnea and m-MRC > 1 (compared with those with m-MRC = 0-1). Plasma OPN levels were inversely correlated with EQ-VAS (visual analog scale of the EQ-5D-5L health-related quality-of-life questionnaire) values. High-resolution CT or diffusion lung capacity (DLCO) findings were not related to circulating OPN. In the multiple logistic regression, the presence of symptoms, dyspnea, or the combination of serious symptoms were linked to female gender, increased BMI and pre-existing dyspnea (before the acute disease), while increased plasma OPN levels, female gender and pre-existing dyspnea with m-MRC > 1 were independently associated with severe post-COVID-19 dyspnea (m-MRC > 1). Using a correlation matrix to investigate multiple correlations between EQ-VAS, OPN and epidemiological data, we observed an inverse correlation between the OPN and EQ-VAS values. Increased circulating OPN was linked to the persistence of severe exertional dyspnea and impaired quality of life in previously hospitalized COVID-19 patients.

Nutritional clinical studies in dermatology.

BACKGROUND & AIMS: Nutrition has long been associated with skin health, beauty, integrity and aging through multiple pathways and cofactors implicated in skin biology. The onset and clinical course of various common skin diseases, especially acne, psoriasis, atopic dermatitis, and hair loss, have been suggested to be critically affected by nutrition patterns and habits. The relationship between acne and diet, predominantly the role of high glycemic load diets and dairy consumption have recently gained increased interest. Abnormal nutritional conditions such as obesity or malnutrition often manifest themselves by specific cutaneous features and altered skin function. Skin photoprotection, rendered by various nutrients, is well documented and appropriate nutritional supplementation has been shown to exert beneficial effects upon impaired skin integrity, restore its appearance and promote skin health. It is our intention to provide a comprehensive review of the most recent information on the role of nutrition for common skin diseases and regulation of skin biology. METHODS: Nutritional clinical studies in dermatology have been reviewed using the MedLine literature source and the terms "diet" or "nutrition" and "skin". RESULTS & CONCLUSIONS: The data on the relationship between nutrition and skin are until now controversial and much more work is needed to be done to clarify possible etiological correlations.

MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma.

BACKGROUND: MTH1 protects tumor cells and their supporting endothelium from lethal DNA damage triggered by oxidative stress in the tumor microenvironment, thus promoting tumor growth. The impact of MTH1 on the tumor-related immune compartment remains unknown. We hypothesized that MTH1 regulates immune fitness and therefore enhances the activity of currently used immunotherapeutic regimens. METHODS: Our hypotheses were validated in two syngeneic murine mesothelioma models using the clinically relevant MTH1 inhibitor, karonudib. We also examined the effect of combined MTH1 and PD-L1 blockade in mesothelioma progression, focusing on the main immune players. RESULTS: Karonudib administration enhances M1 macrophage polarization, stimulates CD8 expansion and promotes the activation of DC and T cells. Combined administration of PD-L1 and MTH1 inhibitors impairs mesothelioma tumor growth and mesothelioma-associated pleural effusion accumulation more effectively compared to each monotherapy. CONCLUSIONS: Combined MTH1 and PD-L1 inhibition holds promise for the successful clinical management of mesothelioma.

Predictors of high flow oxygen therapy failure in COVID-19-related severe hypoxemic respiratory failure.

Background: During COVID-19 pandemic, people who developed pneumonia and needed supplemental oxygen, where treated with low-flow oxygen therapy systems and non-invasive methods, including oxygen therapy using high flow nasal cannula (HFNC) and the application of bi-level or continuous positive airway pressure (BiPAP or CPAP). We aimed to investigate the outcomes of critical COVID-19 patients treated with HFNC and unveil predictors of HFNC failure. Methods: We retrospectively enrolled patients admitted to COVID-19 wards and treated with HFNC for COVID-19-related severe hypoxemic respiratory failure. The primary outcome of this study was treatment failure, such as the composite of intubation or death during hospital stay. The association between treatment failure and clinical features was evaluated using logistic regression models. Results: One hundred thirty-two patients with a median (IQR) PaO2/FiO2 ratio 96 (63-173) mmHg at HFNC initiation were studied. Overall, 45.4% of the patients were intubated. Hospital mortality was 31.8%. Treatment failure (intubation or death) occurred in 50.75% and after adjustment for age, gender, Charlson Comorbidity index (CCI) score and National Early Warning Score 2 (NEWS2) score on admission and PaO2/FiO2 ratio and acute respiratory distress syndrome (ARDS) severity at the time of HFNO initiation, it was significantly associated with the presence of dyspnea [adjusted OR 2.48 (95% CI: 1.01-6.12)], and higher Urea serum levels [adjusted OR 1.25 (95% CI: 1.03-1.51) mg/dL]. Conclusions: HFNC treatment was successful in almost half of the patients with severe COVID-19-related acute hypoxemic respiratory failure (AHRF). The presence of dyspnea and high serum Urea levels on admission are closely related to HFNC failure.

CSF1/CSF1R signaling mediates malignant pleural effusion formation.

Malignant pleural effusion (MPE) is an incurable common manifestation of many malignancies. Its formation is orchestrated by complex interactions among tumor cells, inflammatory cells, and the vasculature. Tumor-associated macrophages present the dominant inflammatory population of MPE, and M2 macrophage numbers account for dismal prognosis. M2 polarization is known to be triggered by CSF1/CSF1 receptor (CSF1R) signaling. We hypothesized that CSF1R+ M2 macrophages favor MPE formation and could be therapeutically targeted to limit MPE. We generated mice with CSF1R-deficient macrophages and induced lung and colon adenocarcinoma-associated MPE. We also examined the therapeutic potential of a clinically relevant CSF1R inhibitor (BLZ945) in lung and colon adenocarcinoma-induced experimental MPE. We showed that CSF1R+ macrophages promoted pleural fluid accumulation by enhancing vascular permeability, destabilizing tumor vessels, and favoring immune suppression. We also showed that CSF1R inhibition limited MPE in vivo by reducing vascular permeability and neoangiogenesis and impeding tumor progression. This was because apart from macrophages, CSF1R signals in cancer-associated fibroblasts leading to macrophage inflammatory protein 2 secretion triggered the manifestation of suppressive and angiogenic properties in macrophages upon CXCR2 paracrine activation. Pharmacological targeting of the CSF1/CSF1R axis can therefore be a vital strategy for limiting MPE.

Moderate COVID-19: Clinical Trajectories and Predictors of Progression and Outcomes.

BACKGROUND: Patients with COVID-19 commonly present at healthcare facilities with moderate disease, i.e., pneumonia without a need for oxygen therapy. AIM: To identify clinical/laboratory characteristics of patients with moderate COVID-19, which could predict disease progression. METHODS: 384 adult patients presented with moderate COVID-19 and admitted to two hospitals were retrospectively evaluated. In a multivariate analysis gender, age, BMI, Charlson Comorbidity Index (CCI) and National Early Weaning Score 2 were treated as co-variates. The development of hypoxemic respiratory failure, intubation rate and risk of death were considered as dependent variables. Estimated values are presented as odds-ratio (OR) with 95% confidence interval (CI). RESULTS: Most of the patients were male (63.28%) with a mean (standard deviation) age of 59 (16.04) years. Median (interquartile range) CCI was 2 (1-4). A total of 58.85% of the patients developed respiratory failure; 6.51% were intubated, and 8.85% died. The extent of pneumonia in chest X-ray (involvement of all four quartiles) [OR 3.96 (1.18-13.27), p = 0.026], respiratory rate [OR 1.17 (1.05-1.3), p = 0.004], SatO2 [OR 0.72 (0.58-0.88), p = 0.002], systolic blood pressure [OR 1.02 (1-1.04), p = 0.041] and lymphocyte count [OR 0.9993 (0.9986-0.9999), p = 0.026] at presentation were associated with the development of respiratory failure. The extent of pneumonia [OR 26.49 (1.81-387.18), p = 0.017] was associated with intubation risk. Age [OR 1.14 (1.03-1.26), p = 0.014] and the extent of pneumonia [OR 22.47 (1.59-316.97), p = 0.021] were associated with increased risk of death. CONCLUSION: Older age, the extent of pneumonia, tachypnea, lower SatO2, higher systolic blood pressure and lymphopenia are associated with dismal outcomes in patients presenting with moderate COVID-19.