Abstract
Irreversible electroporation (IRE) is a local non-thermal ablative technique currently used to treat solid tumors. Here, we investigated the clinical potency and safety of IRE with an ...endoscope in the upper gastrointestinal tract. Pigs were electroporated with recently designed endoscopic IRE catheters in the esophagus, stomach, and duodenum. Two successive strategies were introduced to optimize the electrical energy for the digestive tract. First, each organ was electroporated and the energy upscaled to confirm the upper limit energy inducing improper tissue results, including bleeding and perforation. Excluding the unacceptable energy from the first step, consecutive electroporations were performed with stepwise reductions in energy to identify the energy that damaged each layer. Inceptive research into inappropriate electrical intensity contributed to extensive hemorrhage and bowel perforation for each tissue above a certain energy threshold. However, experiments performed below the precluded energy accompanying hematoxylin and eosin staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling assays showed that damaged mucosal area and depth significantly decreased with decreased energy. Relevant histopathology showed infiltration of inflammatory cells with pyknotic nuclei at the electroporated lesion. This investigation demonstrated the possibility of endoscopic IRE in mucosal dysplasia or early malignant tumors of the hollow viscus.
Objectives
To evaluate the time-dependent incidence, risk factors and clinical significance of percutaneous lung biopsy (PLB)-related pneumothorax.
Methods
From January 2012–November 2015, 3,251 ...patients underwent 3,354 cone-beam CT-guided PLBs for lung lesions. Cox, logistic and linear regression analyses were performed to identify time-dependent risk factors of PLB-related pneumothorax, risk factors of drainage catheter insertion and those of prolonged catheter placement, respectively.
Results
Pneumothorax occurred in 915/3,354 PLBs (27.3 %), with 230/915 (25.1 %) occurring during follow-ups. Risk factors for earlier occurrence of PLB-related pneumothorax include emphysema (HR=1.624), smaller target (HR=0.922), deeper location (HR=1.175) and longer puncture time (HR=1.036), while haemoptysis (HR=0.503) showed a protective effect against earlier development of pneumothorax. Seventy-five cases (8.2 %) underwent chest catheter placement. Mean duration of catheter placement was 3.2±2.0 days. Emphysema (odds ratio OR=2.400) and longer puncture time (OR=1.053) were assessed as significant risk factors for catheter insertion, and older age (parameter estimate=1.014) was a predictive factor for prolonged catheter placement.
Conclusion
PLB-related pneumothorax occurred in 27.3 %, of which 25.1 % developed during follow-ups. Smaller target size, emphysema, deeply-located lesions were significant risk factors of PLB-related pneumothorax. Emphysema and older age were related to drainage catheter insertion and prolonged catheter placement, respectively.
Key Points
• One-fourth of percutaneous lung biopsy (PLB)-related pneumothorax occurs during follow-up.
• Smaller, deeply-located target and emphysema lead to early occurrence of pneumothorax.
• Emphysema is related to drainage catheter insertion for PLB-related pneumothorax.
• Older age may lead to prolonged catheter placement for PLB-related pneumothorax.
• Tailored management can be possible with time-dependent information of PLB-related pneumothorax.
Hypoxia has diverse stimulatory effects on human adipose-derived stem cells (ASCs). In the present study, we investigated whether hypoxic culture conditions (2% O₂) suppress spontaneous ...mineralization and osteogenic differentiation of ASCs. We also investigated signaling pathways and molecular mechanisms involved in this process. We found that hypoxia suppressed spontaneous mineralization and osteogenic differentiation of ASCs, and up-regulated mRNA and protein expression of Insulin-like growth factor binding proteins (IGFBPs) in ASCs. Although treatment with recombinant IGFBPs did not affect osteogenic differentiation of ASCs, siRNA-mediated inhibition of IGFBP3 attenuated hypoxia-suppressed osteogenic differentiation of ASCs. In contrast, overexpression of IGFBP3 via lentiviral vectors inhibited ASC osteogenic differentiation. These results indicate that hypoxia suppresses spontaneous mineralization and osteogenic differentiation of ASCs via intracellular IGFBP3 up-regulation. We determined that reactive oxygen species (ROS) generation followed by activation of the MAPK and PI3K/Akt pathways play pivotal roles in IGFBP3 expression under hypoxia. For example, ROS scavengers and inhibitors for MAPK and PI3K/Akt pathways attenuated the hypoxia-induced IGFBP3 expression. Inhibition of Elk1 and NF-κB through siRNA transfection also led to down-regulation of IGFBP3 mRNA expression. We next addressed the proliferative potential of ASCs with overexpressed IGFBP3, but IGFBP3 overexpression reduced the proliferation of ASCs. In addition, hypoxia reduced the osteogenic differentiation of bone marrow-derived clonal mesenchymal stem cells. Collectively, our results indicate that hypoxia suppresses the osteogenic differentiation of mesenchymal stem cells via IGFBP3 up-regulation.
To clarify the role of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the chimeric antigen receptor T-cell therapy era, we analyzed the clinical characteristics and outcomes of 52 ...patients treated with allo-HSCT with relapsed/refractory diffuse large B cell lymphoma. Most enrolled patients had previously undergone intensive treatments, the median number of chemotherapy lines was 4, and the median time from diagnosis to allo-HSCT was 27.1 months. Patients were divided into remission-achieved (n = 30) and active-disease (n = 22) groups before allo-HSCT. Over a median follow-up period of 38.3 months, overall survival (OS) and event-free survival (EFS) rates were 38.4% and 30.6%, respectively. The cumulative incidence of relapse (CIR) and the non-relapsed mortality (NRM) were 36.7% and 32.7%, respectively. OS, EFS, and graft-versus-host disease-free, relapse-free survival (GRFS) outcomes were significantly superior in the remission-achieved group with lower CIR. In a multivariate analysis, a shorter interval from diagnosis to allo-HSCT reflected relatively rapid disease progression and showed significantly poor OS and EFS with higher CIR. Patients with active disease had significantly lower EFS, GRFS, and higher CIR. Previous autologous stem-cell transplantation was associated with better GRFS. Allo-HSCT is an established modality with a prominent group of cured patients and still has a role in the CAR T-cell era, particularly given its acceptable clinical outcomes in young patients with chemo-susceptible disease.
Nanoparticles (NPs) have distinct pharmacokinetic (PK) properties and can potentially improve the absorption, distribution, metabolism, and elimination (ADME) of small-molecule drugs loaded therein. ...Owing to the unwanted toxicities of anticancer agents in healthy organs and tissues, their precise delivery to the tumor is an essential requirement. There have been numerous advancements in the development of nanomedicines for cancer therapy. Physiologically based PK (PBPK) models serve as excellent tools for describing and predicting the ADME properties and the efficacy and toxicity of drugs, in combination with pharmacodynamic (PD) models. The recent preliminary application of these modeling approaches to NPs demonstrated their potential benefits in research and development processes relevant to the ADME and pharmacodynamics of NPs and nanomedicines. Here, we comprehensively review the pharmacokinetics of NPs, the developed PBPK models for anticancer NPs, and the developed PD model for anticancer agents.
Aims/hypothesis
Obesity-induced inflammation is initiated by the recruitment of macrophages into adipose tissue. The recruited macrophages, called adipose tissue macrophages, secrete several ...proinflammatory cytokines that cause low-grade systemic inflammation and insulin resistance. The aim of this study was to find macrophage-recruiting factors that are thought to provide a crucial connection between obesity and insulin resistance.
Methods
We used chemotaxis assay, reverse phase HPLC and tandem MS analysis to find chemotactic factors from adipocytes. The expression of chemokines and macrophage markers was evaluated by quantitative RT-PCR, immunohistochemistry and FACS analysis.
Results
We report our finding that the chemokine (C-X-C motif) ligand 12 (CXCL12, also known as stromal cell-derived factor 1), identified from 3T3-L1 adipocyte conditioned medium, induces monocyte migration via its receptor chemokine (C-X-C motif) receptor 4 (CXCR4). Diet-induced obese mice demonstrated a robust increase of CXCL12 expression in white adipose tissue (WAT). Treatment of obese mice with a CXCR4 antagonist reduced macrophage accumulation and production of proinflammatory cytokines in WAT, and improved systemic insulin sensitivity.
Conclusions/interpretation
In this study we found that CXCL12 is an adipocyte-derived chemotactic factor that recruits macrophages, and that it is a required factor for the establishment of obesity-induced adipose tissue inflammation and systemic insulin resistance.
Background:
Blinatumomab showed a higher complete remission (CR) rate and a safe bridging to allogeneic hematopoietic cell transplantation (allo-HCT) in adults with relapsed or refractory B-cell ...precursor acute lymphoblastic leukemia (R/R BCP-ALL).
Objectives:
We tried to analyze the outcome of blinatumomab compared with the real-world historical data. We expected superior outcome of blinatumomab compared with historical conventional chemotherapy.
Design:
We conducted a retrospective study using real-world data in the Catholic Hematology Hospital.
Methods:
Total 197 consecutive cases of R/R BCP-ALL were treated with conventional chemotherapy (n = 113) or blinatumomab, which was available since late 2016 (n = 84). Patients who achieved CR underwent allo-HCT if donor was available. We conducted a propensity score–matched cohort analysis using 5 criteria of age, CR duration, cytogenetics, previous allo-HCT, and salvage lines between historical group and blinatumomab.
Results:
Each cohort consisted of 52 patients. In blinatumomab group, CR rate was higher (80.8% versus 53.8%, p = 0.006) and more patients proceeded to allo-HCT (80.8% versus 46.2%, p < 0.001). Among the CR patients with available minimal residual disease (MRD) results, 68.6% in blinatumomab group and 40.0% in conventional chemotherapy group were MRD-negative. Regimen-related mortality during the chemotherapy cycles was significantly higher in the conventional chemotherapy group (40.4% versus 1.9%, p < 0.001). Estimated 3-year overall survival (OS) was 33.2% (median, 26.3 months) after blinatumomab, and 15.4% (median, 8.2 months) after conventional chemotherapy (p < 0.001). Estimated 3-year non-relapse mortality were 30.3% and 51.9% (p = 0.004), respectively. In multivariate analysis, CR duration < 12 months showed more relapses and poor OS, and conventional chemotherapy showed higher non-relapse mortality and poor OS.
Conclusions:
Matched cohort analysis showed superior outcomes of blinatumomab compared with conventional chemotherapy. However, large numbers of relapses and non-relapse mortalities continue to occur even after blinatumomab followed by allo-HCT. Novel therapeutic strategies are still needed for R/R BCP-ALL.
Objectives
To evaluate the clinico-radiological findings of acute fibrinous and organizing pneumonia (AFOP) in the literature according to whether a surgical or non-surgical biopsy was performed, as ...well as to identify prognostic predictors.
Methods
We searched the Embase and OVID-MEDLINE databases to identify studies that presented CT findings of AFOP and had extractable individual patient data. We compared the clinical and CT findings of the patients depending on whether a surgical or non-surgical biopsy was performed and identified survival predictors using a multivariate logistic regression analysis.
Results
Eighty-one patients (surgical biopsy,
n
= 52; non-surgical biopsy,
n
= 29) from 63 studies were included. The surgical biopsy group frequently experienced an acute fulminant presentation (
p
= .011) and dyspnea (
p
= .001) and less frequently had a fever (
p
= .006) than the non-surgical biopsy group. The surgical biopsy group had a worse prognosis than the non-surgical biopsy group in terms of mechanical ventilation and mortality (both,
p
= .023). For survival analysis, the patients with the predominant CT finding of patchy or mass-like air-space consolidation survived more frequently (
p
< .001) than those with other CT findings. For prognostic predictors, subacute indolent presentation (
p
= .001) and patchy or mass-like air-space consolidation on CT images (
p
= .002) were independently associated with good survival.
Conclusions
Approximately one-third of alleged AFOP cases in the literature were diagnosed via non-surgical biopsy, but those cases had different symptomatic presentations and prognosis from surgically proven AFOP. Subacute indolent presentation and patchy or mass-like air-space consolidation at the presentation on CT images indicated a good prognosis in patients with AFOP.
Key Points
• Acute fibrinous and organizing pneumonia (AFOP) cases diagnosed via non-surgical biopsy had different symptomatic presentations and prognosis from surgically proven AFOP.
• Subacute indolent presentation and patchy or mass-like air-space consolidation on CT images indicated a good prognosis in patients with acute fibrinous and organizing pneumonia.
We aimed to develop a deep neural network for segmenting lung parenchyma with extensive pathological conditions on non-contrast chest computed tomography (CT) images.
Thin-section non-contrast chest ...CT images from 203 patients (115 males, 88 females; age range, 31-89 years) between January 2017 and May 2017 were included in the study, of which 150 cases had extensive lung parenchymal disease involving more than 40% of the parenchymal area. Parenchymal diseases included interstitial lung disease (ILD), emphysema, nontuberculous mycobacterial lung disease, tuberculous destroyed lung, pneumonia, lung cancer, and other diseases. Five experienced radiologists manually drew the margin of the lungs, slice by slice, on CT images. The dataset used to develop the network consisted of 157 cases for training, 20 cases for development, and 26 cases for internal validation. Two-dimensional (2D) U-Net and three-dimensional (3D) U-Net models were used for the task. The network was trained to segment the lung parenchyma as a whole and segment the right and left lung separately. The University Hospitals of Geneva ILD dataset, which contained high-resolution CT images of ILD, was used for external validation.
The Dice similarity coefficients for internal validation were 99.6 ± 0.3% (2D U-Net whole lung model), 99.5 ± 0.3% (2D U-Net separate lung model), 99.4 ± 0.5% (3D U-Net whole lung model), and 99.4 ± 0.5% (3D U-Net separate lung model). The Dice similarity coefficients for the external validation dataset were 98.4 ± 1.0% (2D U-Net whole lung model) and 98.4 ± 1.0% (2D U-Net separate lung model). In 31 cases, where the extent of ILD was larger than 75% of the lung parenchymal area, the Dice similarity coefficients were 97.9 ± 1.3% (2D U-Net whole lung model) and 98.0 ± 1.2% (2D U-Net separate lung model).
The deep neural network achieved excellent performance in automatically delineating the boundaries of lung parenchyma with extensive pathological conditions on non-contrast chest CT images.
Background
The prognostic role of increased visceral fat attenuation (VFA) remains underexplored. We investigated the long‐term prognostic implications of computed tomography (CT)‐derived VFA in a ...health check‐up population.
Methods
This study included consecutive individuals who had positron‐emission tomography/CT scans for health check‐ups between January 2004 and December 2010. The primary outcome was overall survival (OS), and the secondary outcomes were cancer‐specific survival (CSS) and non‐cancer‐specific survival (NCS). Commercially available body composition analysis software was used to obtain abdominal waist VFA, visceral fat volume index (VFI) and skeletal muscle index (SMI) at the L3 level. Sarcopenia was determined using sex‐specific SMI references. VFA and VFI were dichotomized using the thresholds for the highest quartiles. The relationship between CT‐derived body composition parameters and body mass index (BMI) was evaluated with Pearson correlation coefficients. The prognostic implications of VFA and sarcopenic obesity (SO) defined by VFA were assessed by multivariable Cox regression analysis and Kaplan–Meier plots with log‐rank tests.
Results
A total of 2720 individuals (1530 men 56.3% and 1190 women 43.7%; median age: 53 years, inter‐quartile range: 47–60 years) were included. During the median follow‐up of 138 months, 128 individuals (5%) died (cancer mortality: 2%; non‐cancer mortality: 3%), with 0.2% (5 of 2720) and 1.1% (30 of 2720) of 1‐ and 5‐year mortality rates. VFA was negatively correlated with BMI (r = −0.62; P < 0.001) and VFI (r = −0.69; P < 0.001). After adjusting for clinical variables, sarcopenia and VFI, high VFA was a negative prognostic factor for OS (hazard ratio HR: 1.05 per Hounsfield unit; 95% confidence interval CI: 1.02, 1.08; P = 0.001), CSS (HR: 1.07 per Hounsfield unit; 95% CI: 1.02, 1.12; P = 0.006) and NCS (HR: 1.03 per Hounsfield unit; 95% CI: 1.01, 1.06; P = 0.009). Individuals with high VFA had higher high‐sensitivity C‐reactive protein levels than those with low VFA (0.11 vs. 0.03 mg/dL; P < 0.001). Individuals with SO defined by VFA had worse OS (9% vs. 4%; P < 0.001), CSS (3% vs. 2%; P = 0.02) and NCS (6% vs. 3%; P < 0.001) than those without SO, even in the same BMI (underweight‐to‐normal BMI, OS: 8% vs. 4%; overweight‐to‐obese BMI, OS: 38% vs. 4%; P < 0.001 in both) or VFI category (high VFI, OS: 43% vs. 6%; low VFI, OS: 8% vs. 3%; P < 0.001 in both).
Conclusions
High VFA was associated with long‐term mortality and low‐grade inflammation. VFA can further stratify the current SO by BMI or VFI, and SO defined by VFA can identify individuals who are most vulnerable to long‐term mortality.
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