Advances in Diagnostic Imaging of Hepatopulmonary Syndrome

Hepatopulmonary syndrome (HPS) is a serious pulmonary complication of progressive liver disease that leads to a poor clinical prognosis. Patients with HPS may develop acute respiratory failure, which requires intensive care and therapy. At present, the only effective treatment is liver transplantation; therefore, early diagnosis and timely treatment are of considerable significance. The three main features of HPS are liver disease, oxygenation disorder, and intrapulmonary vascular dilatation (IPVD). Diagnosing HPS is challenging due to the difficulty in detecting the presence or absence of IPVD. As such, imaging examination is very important for detecting IPVD. This paper reviews the imaging methods for diagnosing HPS such as ultrasound, dynamic pulmonary perfusion imaging, pulmonary angiography, and computed tomography.

Myocardial Injury as a Prognostic Factor in Mid- and Long-Term Follow-Up of COVID-19 Survivors

Myocardial injury, which is present in >20% of patients hospitalized for COVID-19, is associated with increased short-term mortality, but little is known about its mid- and long-term consequences. We evaluated the association between myocardial injury with one-year mortality and readmission in 172 COVID-19 patients discharged alive. Patients were grouped according to the presence or absence of myocardial injury (defined by hs-cTn levels) on admission and matched by age and sex. We report mortality and hospital readmission at one year after admission in all patients and echocardiographic, laboratory and clinical data at six months in a subset of 86 patients. Patients with myocardial injury had a higher prevalence of hypertension (73.3% vs. 50.0%, p = 0.003), chronic kidney disease (10.5% vs. 2.35%, p = 0.06) and chronic heart failure (9.3% vs. 1.16%, p = 0.03) on admission. They also had higher mortality or hospital readmissions at one year (11.6% vs. 1.16%, p = 0.01). Additionally, echocardiograms showed thicker walls in these patients (10 mm vs. 8 mm, p = 0.002) but without functional disorder. Myocardial injury in COVID-19 survivors is associated with poor clinical prognosis at one year, independent of age and sex, but not with echocardiographic functional abnormalities at six months.

Translational Stroke Research Review: Using the Mouse to Model Human Futile Recanalization and Reperfusion Injury in Ischemic Brain Tissue

The approach to reperfusion therapies in stroke patients is rapidly evolving, but there is still no explanation why a substantial proportion of patients have a poor clinical prognosis despite successful flow restoration. This issue of futile recanalization is explained here by three clinical cases, which, despite complete recanalization, have very different outcomes. Preclinical research is particularly suited to characterize the highly dynamic changes in acute ischemic stroke and identify potential treatment targets useful for clinical translation. This review surveys the efforts taken so far to achieve mouse models capable of investigating the neurovascular underpinnings of futile recanalization. We highlight the translational potential of targeting tissue reperfusion in fully recanalized mouse models and of investigating the underlying pathophysiological mechanisms from subcellular to tissue scale. We suggest that stroke preclinical research should increasingly drive forward a continuous and circular dialogue with clinical research. When the preclinical and the clinical stroke research are consistent, translational success will follow.

Proteomic Distributions in CD34+ Microvascular Niche Patterns of Glioblastoma

The poor clinical prognosis and microvascular patterns of glioblastoma (GBM) are of serious concern to many clinicians and researchers. However, very few studies have examined the correlation between microvascular niche patterns (MVNPs) and proteomic distribution. In this study, CD34 immunofluorescence staining and matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-IMS) technology were used to investigate the protein distributions in MVNPs. CD34+ microvascular phenotype could be divided into four types: microvascular sprouting (MS), vascular cluster (VC), vascular garland (VG), and glomeruloid vascular proliferation (GVP). Based on such characteristics, MVNPs were divided into two types by cluster analysis, namely, type I, comprising primarily MS and VC, and type II, comprising many VGs and GVPs. Survival analysis indicated the type of MVNPs to be an independent prognostic factor for progression-free and overall survival in GBM. MALDI-IMS results showed the peaks at m/z 1037 and 8960 to exhibit stronger ion signals in type II, while those at m/z 3240 and 3265 exhibited stronger ion signals in type I. The findings may assist future research on therapy and help predict prognosis in GBM. However, due to the limited number of studies, more well-designed studies are warranted to further verify our results.

Lipid Droplet Accumulation Independently Predicts Poor Clinical Prognosis in High-Grade Serous Ovarian Carcinoma

High-grade serous ovarian carcinoma (HGSOC) is an epithelial cancer that accounts for most ovarian cancer deaths. Metabolic abnormalities such as extensive aerobic glycolysis and aberrant lipid metabolism are well-known characteristics of cancer cells. Indeed, accumulation of lipid droplets (LDs) in certain types of malignant tumors has been known for more than 50 years. Here, we investigated the correlation between LD accumulation and clinical prognosis. In 96 HGSOC patients, we found that high expression of the LD marker adipophilin was associated with poor progression-free and overall survival (p = 0.0022 and p = 0.014, respectively). OVCAR-3 ovarian carcinoma cells accumulated LDs in a glucose-dependent manner, which suggested the involvement of aerobic glycolysis and subsequently enhanced lipogenesis, with a result being LD accumulation. The acyl-CoA: cholesterol acyltransferase 1 inhibitor K604 and the hydroxymethylglutaryl-CoA reductase inhibitor pitavastatin blocked LD accumulation in OVCAR-3 cells and reduced phosphorylation of the survival-related kinases Akt and ERK1/2, both of which have been implicated in malignancy. Our cell-based assays thus suggested that enhanced aerobic glycolysis resulted in LD accumulation and activation of survival-related kinases. Overall, our results support the idea that cancers with lipogenic phenotypes are associated with poor clinical prognosis, and we suggest that adipophilin may serve as an independent indicator of a poor prognosis in HGSOC.

CD276 is an important player in macrophage recruitment into the tumor and an upstream regulator for PAI-1

More than 70% of colorectal, prostate, ovarian, pancreatic and breast cancer specimens show expression of CD276 (B7–H3), a potential immune checkpoint family member. Several studies have shown that high CD276 expression in cancer cells correlates with a poor clinical prognosis. This has been associated with the presence of lower tumor infiltrating leukocytes. Among those, tumor-associated macrophages can comprise up to 50% of the tumor mass and are thought to support tumor growth through various mechanisms. However, a lack of information on CD276 function and interaction partner(s) impedes rigorous evaluation of CD276 as a therapeutic target in oncology. Therefore, we aimed to understand the relevance of CD276 in tumor-macrophage interaction by employing a 3D spheroid coculture system with human cells. Our data show a role for tumor-expressed CD276 on the macrophage recruitment into the tumor spheroid, and also in regulation of the extracellular matrix modulator PAI-1. Furthermore, our experiments focusing on macrophage-expressed CD276 suggest that the antibody-dependent CD276 engagement triggers predominantly inhibitory signaling networks in human macrophages.

Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade

Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.