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Journal of Applied Clinical Medical... May 2022To demonstrate the plan quality and delivery efficiency of volumetric-modulated arc therapy (VMAT) with the Halcyon Linac ring delivery system (RDS) in the treatment of...
PURPOSE
To demonstrate the plan quality and delivery efficiency of volumetric-modulated arc therapy (VMAT) with the Halcyon Linac ring delivery system (RDS) in the treatment of single-isocenter/two-lesion lung stereotactic body radiation therapy (SBRT).
MATERIALS/METHODS
Sixteen previously treated non-coplanar VMAT single-isocenter/two-lesion lung SBRT plans delivered with SBRT-dedicated C-arm TrueBeam Linac were selected. Prescribed dose was 50 Gy to each lesion over five fractions with treatment delivery every other day and AcurosXB algorithm as the final dose calculation algorithm. TrueBeam single-isocenter plans were reoptimized for Halcyon Linac with coplanar geometry. Both TrueBeam and Halcyon plans were normalized for identical combined target coverage and evaluated. Conformity indices (CIs), heterogeneity index (HI), gradient index (GI), gradient distance (GD), and D were compared. The normal lung V5Gy, V10Gy, V20Gy, mean lung dose (MLD), and dose to organs at risk (OAR) were evaluated. Treatment delivery parameters, including beam-on time, were recorded.
RESULTS
Halcyon plans were statistically similar to clinically delivered TrueBeam plans. No statistical differences in target conformity, dose heterogeneity, or intermediate-dose spillage were observed (all, p > 0.05). Halcyon plans, on average, demonstrated statistically insignificant reduced maximum dose to most adjacent OAR and normal lung. However, Halcyon yielded statistically significant lower maximal dose to the ribs (p = 0.041) and heart (p = 0.026), dose to 1 cc of ribs (p = 0.035) and dose to 5 cc of esophagus (p = 0.043). Plan complexity slightly increased as seen in the average increase of total monitor units, modulation factor, and beam-on time by 480, 0.48, and 2.78 min, respectively. However, the estimated overall treatment time was reduced by 2.22 min, on average. Mean dose delivery accuracy of clinical TrueBeam plans and the corresponding Halcyon plans was 98.9 ± 0.85% (range: 98.1%-100%) and 98.45 ± 0.99% (range: 97.9%-100%), respectively, demonstrating similar treatment delivery accuracy.
CONCLUSION
SBRT treatment of synchronous lung lesions via single-isocenter VMAT on Halcyon RDS is feasible and dosimetrically equivalent to clinically delivered TrueBeam plans. Halcyon provides excellent plan quality and shorter overall treatment time that may improve patient compliance, reduce intrafraction movement, improve clinic efficiency, and potentially offering lung SBRT treatments for underserved patients on a Halcyon only clinic.
Topics: Feasibility Studies; Humans; Lung; Lung Neoplasms; Radiosurgery; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Intensity-Modulated
PubMed: 35128795
DOI: 10.1002/acm2.13555 -
BMC Musculoskeletal Disorders Jan 2022Intraoperative proximal femoral fractures (IPFF) are relevant complications during total hip arthroplasty. Fixation using cerclage wires (CW) represents a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Intraoperative proximal femoral fractures (IPFF) are relevant complications during total hip arthroplasty. Fixation using cerclage wires (CW) represents a minimally-invasive technique to address these fractures through the same surgical approach. The goal of treatment is to mobilise the patient as early as possible, which requires high primary stability. This study aimed to compare different cerclage wire configurations fixing IPFF with regard to biomechanical primary stability.
METHODS
Standardised IPFF (type II, Modified Mallory Classification) were created in human fresh frozen femora and were fixed either by two or three CW (1.6 mm, stainless steel). All cadaveric specimens (n = 42) were randomised to different groups (quasi-static, dynamic) or subgroups (2 CW, 3 CW) stratified by bone mineral density determined by Dual Energy X-ray Absorptiometry. Using a biomechanical testing setup, quasi-static and dynamic cyclic failure tests were carried out. Cyclic loading started from 200 N to 500 N at 1 Hz with increasing peak load by 250 N every 100 cycles until failure occurred or maximum load (5250 N) reached. The change of fracture gap size was optically captured.
RESULTS
No significant differences in failure load after quasi-static (p = 0.701) or dynamic cyclic loading (p = 0.132) were found between the experimental groups. In the quasi-static load testing, all constructs resisted 250% of the body weight (BW) of their corresponding body donor. In the dynamic cyclic load testing, all but one construct (treated by 3 CW) resisted 250% BW.
CONCLUSIONS
Based on this in vitro data, both two and three CW provided sufficient primary stability according to the predefined minimum failure load (250% BW) to resist. The authors recommend the treatment using two CW because it reduces the risk of vascular injury and shortens procedure time.
Topics: Arthroplasty, Replacement, Hip; Biomechanical Phenomena; Bone Wires; Femoral Fractures; Fracture Fixation, Internal; Humans
PubMed: 34996409
DOI: 10.1186/s12891-021-04956-5 -
Clinical, histological and molecular profiling of different stages of alcohol-related liver disease.Gut Sep 2022Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH).... (Observational Study)
Observational Study
OBJECTIVE
Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking.
DESIGN
Two large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed.
RESULTS
Age and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism.
CONCLUSIONS
Despite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients.
Topics: Fibrosis; Hepatitis, Alcoholic; Humans; Liver; Prospective Studies; Retrospective Studies
PubMed: 34992134
DOI: 10.1136/gutjnl-2021-324295 -
The FEBS Journal Feb 2023p62/Sequestosome-1 (SQSTM1) is a selective autophagy receptor that recruits and delivers intracellular substrates for bulk clearance through the autophagy lysosomal... (Review)
Review
p62/Sequestosome-1 (SQSTM1) is a selective autophagy receptor that recruits and delivers intracellular substrates for bulk clearance through the autophagy lysosomal pathway. Interestingly, p62 also serves as a signaling scaffold to participate in the regulation of multiple physiological processes, including oxidative stress response, metabolism, inflammation, and programmed cell death. Perturbation of p62 activity has been frequently found to be associated with the pathogenesis of many liver diseases. p62 has been identified as a critical component of protein aggregates in the forms of Mallory-Denk bodies (MDBs) or intracellular hyaline bodies (IHBs), which are known to be frequently detected in biopsy samples from alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC) patients. Importantly, abundance of these p62 inclusion bodies is increasingly recognized as a biomarker for NASH and HCC. Although the level of p62 bodies seems to predict the progression and prognosis of these liver diseases, understanding of the underlying mechanisms by which p62 regulates and contributes to the development and progression of these diseases remains incomplete. In this review, we will focus on the function and regulation of p62, and its pathophysiological roles in the liver, by critically reviewing the findings from preclinical models that recapitulate the pathogenesis and manifestation of these liver diseases in humans. In addition, we will also explore the suitability of p62 as a predictive biomarker and a potential therapeutic target for the treatment of liver diseases, including NASH and HCC, as well as recent development of small-molecule compounds for targeting the p62 signaling axis.
Topics: Humans; Carcinoma, Hepatocellular; Sequestosome-1 Protein; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Liver; Biomarkers; Autophagy
PubMed: 34882306
DOI: 10.1111/febs.16317 -
Biomedicines Nov 2021Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are...
Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.
PubMed: 34829876
DOI: 10.3390/biomedicines9111647 -
Annals of Translational Medicine Sep 2021The goal of the present work is to provide an overview of the differential diagnosis of Wilson disease. (Review)
Review
OBJECTIVE
The goal of the present work is to provide an overview of the differential diagnosis of Wilson disease.
BACKGROUND
Wilson disease is a rare condition due to copper accumulation primarily in the liver and brain. Although there is no definitive cure, current anti-copper treatments are associated with better outcomes if initiated early and if the diagnosis is made promptly. However, diagnostic delays are frequent and often Wilson disease represents a diagnostic challenge. The diagnosis ultimately relies on a combination of clinical, laboratory and genetic findings, and it is crucial that clinicians list Wilson disease in their differential diagnosis, especially in patients presenting with a hepatocellular pattern of liver injury. Some biochemical and liver histological features of Wilson disease overlap with those of more common conditions including nonalcoholic fatty liver disease, alcohol-associated liver disease, and autoimmune hepatitis. In particular, hepatic steatosis, hepatocyte glycogenated nuclei, ballooning degeneration, and Mallory-Denk bodies are often identified in Wilson disease as well as more common liver diseases. In addition, the natural history of liver damage in Wilson disease and the risk of developing liver cancer are largely understudied.
METHODS
We conducted an enlarged review of published papers on Wilson disease focusing on its diagnosis and distinctive clinical and liver pathology features in relation to common non-cholestatic liver diseases with the final goal in aiding clinicians in the diagnostic process of this rare but treatable condition.
CONCLUSIONS
Aside from markedly altered copper metabolism, Wilson disease has essentially no pathognomonic features that can distinguish it from more common liver diseases. Clinicians should be aware of this challenge and consider Wilson disease in patients presenting with a hepatocellular pattern of liver injury.
PubMed: 34733946
DOI: 10.21037/atm-21-2264 -
Archives of Pathology & Laboratory... Jul 2022The histologic features in patients with acute-on-chronic liver failure (ACLF) are evolving, and histologic indicators of patients' poor prognosis are not yet fully...
CONTEXT.—
The histologic features in patients with acute-on-chronic liver failure (ACLF) are evolving, and histologic indicators of patients' poor prognosis are not yet fully established.
OBJECTIVE.—
To evaluate the independent histologic predictors of 28-day mortality in ACLF patients on core-needle liver biopsies.
DESIGN.—
Core-needle biopsies from patients with a diagnosis of ACLF (n = 152) as per the European Association for the Study of the Liver criteria were included during 8 years. Liver biopsies from 98 patients with compensated chronic liver disease were included as disease controls for histologic comparison. Features of ongoing changes, such as hepatic necrosis, hepatic apoptosis, cholestasis, hepatocyte degeneration, bile ductular proliferation, Mallory-Denk bodies, steatosis, and extent of liver fibrosis, were analyzed for predicting short-term mortality (28 days). A P value of <.05 was considered significant.
RESULTS.—
In our cohort of ACLF patients, the following etiologies for acute decompensation were identified: alcohol, 47 of 152 (30.9%); sepsis, 24 of 152 (15.7%); hepatotropic viruses, 20 of 152 (13.1%); drug-induced liver injury, 11 of 152 (7.2%); autoimmune flare, 9 of 152 (5.9%); mixed etiologies, 5 of 152 (3.2%); and cryptogenic, 36 of 152 (23.6%). On histologic examination, hepatic necrosis (P < .001), dense lobular inflammation (P = .03), cholestasis (P < .001), ductular reaction (P = .001), hepatocyte degeneration (P < .001), and absence of advanced fibrosis stages (P < .001) were identified significantly more othen in ACLF patients than in disease controls on univariate analysis. On multivariate Cox regression analysis, the absence of advanced Ishak histologic activity index fibrosis stages (P = .02) and the presence of dense lobular inflammation (P = .04) were associated with increased 28-day mortality in ACLF patients. After adjusting the clinical causes of acute decompensation, only dense lobular inflammation was found as an independent predictor of short-term mortality (P = .04) in ACLF patients.
CONCLUSIONS.—
Dense lobular necroinflammatory activity is a clinically independent histologic predictor of 28-day short-term mortality in patients with ACLF.
Topics: Acute-On-Chronic Liver Failure; Biopsy; Cholestasis; Humans; Inflammation; Liver Cirrhosis; Necrosis; Prognosis
PubMed: 34705032
DOI: 10.5858/arpa.2021-0103-OA -
Histochemistry and Cell Biology Jan 2022Adapted fixation methods for electron microscopy allowed us to study liver cell fine structure in 217 biopsies of intact human livers over the course of 10 years. The...
Adapted fixation methods for electron microscopy allowed us to study liver cell fine structure in 217 biopsies of intact human livers over the course of 10 years. The following novel observations and concepts arose: single fat droplets in parenchymal cells can grow to a volume four times larger than the original cell, thereby extremely marginalizing the cytoplasm with all organelles. Necrosis of single parenchymal cells, still containing one huge fat droplet, suggests death by fat in a process of single-cell steatonecrosis. In a later stage of single-cell steatonecrosis, neutrophils and erythrocytes surround the single fat droplet, forming an inflammatory fat follicle indicating the apparent onset of inflammation. Also, fat droplets frequently incorporate masses of filamentous fragments and other material, most probably representing Mallory substance. No other structure or material was found that could possibly represent Mallory bodies. We regularly observe the extrusion of huge fat droplets, traversing the peripheral cytoplasm of parenchymal cells, the Disse space and the endothelium. These fat droplets fill the sinusoid as a sinusoidal lipid embolus. In conclusion, adapted methods of fixation applied to human liver tissue revealed that single, huge fat droplets cause necrosis and inflammation in single parenchymal cells. Fat droplets also collect Mallory substance and give rise to sinusoidal fat emboli. Therefore, degreasing of the liver seems to be an essential therapeutic first step in the self-repairing of non-alcoholic fatty liver disease. This might directly reduce single-cell steatotic necrosis and inflammation as elements in non-alcoholic steatohepatitis progression.
Topics: Hepatocytes; Humans; Inflammation; Liver; Necrosis; Non-alcoholic Fatty Liver Disease
PubMed: 34524512
DOI: 10.1007/s00418-021-02030-8 -
Current Biology : CB Sep 2021Each winter, the North Atlantic Ocean is the stage for numerous cyclones, the most severe ones leading to seabird mass-mortality events called "winter wrecks." During...
Each winter, the North Atlantic Ocean is the stage for numerous cyclones, the most severe ones leading to seabird mass-mortality events called "winter wrecks." During these, thousands of emaciated seabird carcasses are washed ashore along European and North American coasts. Winter cyclones can therefore shape seabird population dynamics by affecting survival rates as well as the body condition of surviving individuals and thus their future reproduction. However, most often the geographic origins of impacted seabirds and the causes of their deaths remain unclear. We performed the first ocean-basin scale assessment of cyclone exposure in a seabird community by coupling winter tracking data for ∼1,500 individuals of five key North Atlantic seabird species (Alle alle, Fratercula arctica, Uria aalge, Uria lomvia, and Rissa tridactyla) and cyclone locations. We then explored the energetic consequences of different cyclonic conditions using a mechanistic bioenergetics model and tested the hypothesis that cyclones dramatically increase seabird energy requirements. We demonstrated that cyclones of high intensity impacted birds from all studied species and breeding colonies during winter but especially those aggregating in the Labrador Sea, the Davis Strait, the surroundings of Iceland, and the Barents Sea. Our broad-scale analyses suggested that cyclonic conditions do not increase seabird energy requirements, implying that they die because of the unavailability of their prey and/or their inability to feed during cyclones. Our study provides essential information on seabird cyclone exposure in a context of marked cyclone regime changes due to global warming..
Topics: Animals; Atlantic Ocean; Birds; Charadriiformes; Cyclonic Storms; Humans; Seasons
PubMed: 34520704
DOI: 10.1016/j.cub.2021.06.059 -
Journal of Clinical and Experimental... 2021The presence of macrovesicular steatosis on liver biopsy is the commonest histopathological finding. Nonalcoholic fatty liver disease (NAFLD) is the presence of ≥5%...
BACKGROUND
The presence of macrovesicular steatosis on liver biopsy is the commonest histopathological finding. Nonalcoholic fatty liver disease (NAFLD) is the presence of ≥5% macrovesicular steatosis without significant alcohol use. It is subdivided into primary and secondary NAFLD; information on their differences is limited.
AIM
To determine the histopathological differences between primary and secondary NAFLD and establish whether the prevalence of advanced fibrosis varies between the two types.
METHODOLOGY
Three years of retrospective study of 90 liver biopsies with ≥5% macrovesicular steatosis. Age, gender, clinical history, serum transaminase levels were noted. The biopsy was reviewed for steatosis, inflammation, and fibrosis. Differences between primary and secondary NAFLD for age, gender, AST/ALT ratio, histopathological features were determined. Descriptive statistical analysis, 2-tailed Student's test, Chi-square test, Fisher's exact test were used, where p < was considered significant.
RESULT
Primary and secondary NAFLD were 42 (46.7%) and 48 (53.3%), respectively. Inflammation was noted in 50 (55.5%) and fibrosis in 31 (34.4%). The prevalence of advanced fibrosis was 24.4%. Primary and secondary NAFLD differed significantly on ballooning degeneration, Mallory Denk bodies (MDBs), glycogenated nuclei, and fibrosis stage (p < 0.05). There were no significant differences among AST/ALT ratio, steatosis, and inflammation grade.
CONCLUSION
Primary NAFLD is a more severe type of liver disease. On histopathology, ballooning degeneration, MDBs, glycogenated nuclei, and advanced fibrosis was more prevalent in primary than secondary NAFLD.
PubMed: 34511816
DOI: 10.1016/j.jceh.2020.12.009