Sleeve gastrectomy improves cardiac function and glucose-lipid metabolism disorder in obese rats induced by a high-fat and high-sugar diet.

Obesity is affecting global health with multiple complications, including cardiac dysfunction. Currently, it is uncertain whether drug therapy should be applied in the early stages of obesity-induced cardiac dysfunction, with weight reduction as the first choice. Sleeve gastrectomy (SG) has been widely used to treat obesity and its complications, showing promising results. However, it remains unclear whether SG can alleviate obesity-induced cardiac dysfunction. A sudden decline in body weight and food intake was observed in both the obese and obese + SG groups, with a higher rate of increase observed in the Obese group. Elevated levels of plasma glucose, serum insulin, and glycated haemoglobin in obese rats were significantly reduced by SG. Markedly increased levels of alanine transaminase, aspartate transaminase, alkaline phosphatase albumin, total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels, elevated values of heart rate, left ventricular end-systolic pressure, left ventricular end-diastolic pressure, systolic pressure, and end diastolic pressure, and decreased value of stroke volume were observed in obese rats, which were sharply reversed by SG. Furthermore, enhanced pathological changes, including inflammatory cell infiltration and loss of cytoplasm striations, enhanced oil red O staining, increased TUNEL-positive cells, upregulated Bax and cleaved-caspase-3, and downregulated Bcl-2, were observed in obese rats, which were notably alleviated by SG. Lastly, the increased levels of relative proteins observed in obese rats were significantly reduced by SG. In conclusion, SG improved cardiac function and glucose-lipid metabolism disorders in obese rats induced by a high-fat and high-sugar diet.

Automated quantification of the pulmonary vasculature in pulmonary embolism and chronic thromboembolic pulmonary hypertension.

The shape and distribution of vascular lesions in pulmonary embolism (PE) and chronic thromboembolic pulmonary hypertension (CTEPH) are different. We investigated whether automated quantification of pulmonary vascular morphology and densitometry in arteries and veins imaged by computed tomographic pulmonary angiography (CTPA) could distinguish PE from CTEPH. We analyzed CTPA images from a cohort of 16 PE patients, 6 CTEPH patients, and 15 controls. Pulmonary vessels were extracted with a graph-cut method, and separated into arteries and veins using deep-learning classification. Vascular morphology was quantified by the slope (α) and intercept (ß) of the vessel radii distribution. To quantify lung perfusion defects, the median pulmonary vascular density was calculated. By combining these measurements with densities measured in parenchymal areas, pulmonary trunk, and descending aorta, a static perfusion curve was constructed. All separate quantifications were compared between the three groups. No vascular morphology differences were detected in contrast to vascular density values. The median vascular density (interquartile range) was -567 (113), -452 (95), and -470 (323) HU, for the control, PE, and CTEPH group. The static perfusion curves showed different patterns between groups, with a statistically significant difference in aorta-pulmonary trunk gradient between the PE and CTEPH groups (p = 0.008). In this proof of concept study, not vasculature morphology but densities differentiated between patients of three groups. Further technical improvements are needed to allow for accurate differentiation between PE and CTEPH, which in this study was only possible statistically by measuring the density gradient between aorta and pulmonary trunk.

Short-term outcomes of sleeve gastrectomy plus uncut jejunojejunal bypass (SG-uncut JJB) in patients with obesity: a preliminary prospective cohort study.

OBJECTIVE: To compare the safety, weight loss, and metabolic outcomes of patients with obesity with sleeve gastrectomy (SG) or sleeve gastrectomy plus uncut jejunojejunal bypass (SG-uncut JJB). METHODS: This prospective study included patients with BMIs ≥ 32.5 kg/m2 or refractory metabolic disorders undergoing SG or SG-uncut JJB between January and December 2020 in our hospital (NCT04534504). Weight loss, metabolic outcomes, surgical results, and complaints during 1-year follow-up were compared between two groups. RESULTS: Forty-seven patients were enrolled, 26 in the SG and 21 in the SG-uncut JJB groups. A longer operative time was observed in the SG-uncut JJB than in the SG group (140 (110-180) min vs. 90 (70-180) min, P = 0.001). No significant differences were found in complications. Total weight loss (TWL%) and excess weight loss (EWL%) in both groups increased with the duration of follow-up (P = 0.001). TWL% was greater at 1 month ((11.1 ± 2.4)% vs. (8.2 ± 4.4)%, P = 0.011] and 12 months [(29.7 ± 6.9)% vs. (20.3 ± 7.2)%, P = 0.001) with SG-uncut JJB than with SG. SG-uncut JJB and SG had similar metabolic outcomes and complaints during the 1-year follow-up, but less nausea was reported with SG-uncut JJB (9.2% vs. 46.2%, P = 0.006). CONCLUSION: In short-term follow-up, SG-uncut JJB was a safe and effective bariatric surgery procedure in patients with obesity.

Active surveillance in long period of total neoadjuvant therapy in rectal cancer: Early prediction of poor regression response.

Aim: To analyze locally advanced rectal cancer (LARC) patients and tumor characteristics during the period of total neoadjuvant therapy (TNT) and explore the risk factors that may predict poor tumor regression in response to TNT. Materials and methods: The data of 120 LARC patients who received TNT from December 2016 and September 2019 in our hospital were retrospectively analyzed. The clinicopathological characteristics of patients with different tumor regression responses were compared. Then we divided patients into two groups according to the carcinoembryonic antigen (CEA) clearance pattern after chemoradiation to explore risk factors that might predict the tumor regression response. Results: Of 120 LARC patients, 34 (28.3%) exhibited poor regression. Stratified analysis by tumor response showed that patients with poor response to TNT were more likely to obtain elevated CEA during the course of TNT (all P < 0.05). For those with elevated pretreatment CEA, fewer patients with poor response obtained normal CEA after chemoradiation (13.6% vs. 72.7%, P < 0.001). Besides, less patients' CEA levels in the poor response group decreased by greater than 50% after chemoradiation when compared with that in the good response group (18.2% vs. 60.6%, P = 0.002). Stratified analysis by CEA clearance pattern after chemoradiation showed patients who obtained an elevated pretreatment CEA and decreased by less than 50% after chemoradiation were more likely to have poor response to TNT compared to others (76.2% vs. 18.2%, P < 0.001). Logistic multivariate analysis revealed that cN2 (95% CI 1.553-16.448), larger tumors (95% CI 2.250-21.428) and CEA clearance pattern after chemoradiation (95% CI 1.062-66.992) were independent risk factors for poor tumor regression response. Conclusion: Approximately one-fourth of LARC patients with TNT achieved a poor regression response. Here, cN2, larger tumor size before treatment and elevated CEA levels were considered predictive features of a poor response. Active surveillance of CEA levels during the TNT course are potentially important, and CEA levels after chemoradiation might have important implications for the tumor response to TNT.

Learning coronary artery calcium scoring in coronary CTA from non-contrast CT using unsupervised domain adaptation.

Deep learning methods have demonstrated the ability to perform accurate coronary artery calcium (CAC) scoring. However, these methods require large and representative training data hampering applicability to diverse CT scans showing the heart and the coronary arteries. Training methods that accurately score CAC in cross-domain settings remains challenging. To address this, we present an unsupervised domain adaptation method that learns to perform CAC scoring in coronary CT angiography (CCTA) from non-contrast CT (NCCT). To address the domain shift between NCCT (source) domain and CCTA (target) domain, feature distributions are aligned between two domains using adversarial learning. A CAC scoring convolutional neural network is divided into a feature generator that maps input images to features in the latent space and a classifier that estimates predictions from the extracted features. For adversarial learning, a discriminator is used to distinguish the features between source and target domains. Hence, the feature generator aims to extract features with aligned distributions to fool the discriminator. The network is trained with adversarial loss as the objective function and a classification loss on the source domain as a constraint for adversarial learning. In the experiments, three data sets were used. The network is trained with 1,687 labeled chest NCCT scans from the National Lung Screening Trial. Furthermore, 200 labeled cardiac NCCT scans and 200 unlabeled CCTA scans were used to train the generator and the discriminator for unsupervised domain adaptation. Finally, a data set containing 313 manually labeled CCTA scans was used for testing. Directly applying the CAC scoring network trained on NCCT to CCTA led to a sensitivity of 0.41 and an average false positive volume 140 mm3/scan. The proposed method improved the sensitivity to 0.80 and reduced average false positive volume of 20 mm3/scan. The results indicate that the unsupervised domain adaptation approach enables automatic CAC scoring in contrast enhanced CT while learning from a large and diverse set of CT scans without contrast. This may allow for better utilization of existing annotated data sets and extend the applicability of automatic CAC scoring to contrast-enhanced CT scans without the need for additional manual annotations. The code is publicly available at https://github.com/qurAI-amsterdam/CACscoringUsingDomainAdaptation.

Impact of total neoadjuvant therapy consisting of consolidation chemotherapy on locally advanced rectal cancer survival.

PURPOSE: The objective was to compare disease-free survival (DFS) and distant metastasis in patients with neoadjuvant chemoradiotherapy (NCRT) and total neoadjuvant therapy (TNT) for locally advanced rectal cancer. METHODS: Patients with cT3-4N0M0 or cTxN1-2M0 rectal cancer were included in this retrospective study. Patients who received NCRT (radiotherapy with concurrent capecitabine) or TNT (radiotherapy with two concurrent cycles of capecitabine and oxaliplatin (CAPOX) followed by another two cycles of CAPOX) during January 2011 and November 2016 at Beijing Chaoyang Hospital, Capital Medical University were included. All patients had received radical surgery. Adverse events, pathological response and survival outcomes in the two groups were compared. RESULTS: One hundred eighty-two patients were enrolled, 120 in the TNT and 62 in the NCRT groups. No significant between-group differences in neoadjuvant therapy-associated adverse events or surgical complications were found. TNT achieved a higher pathological complete response (pCR) rate (25.8%) compared with NCRT (12.9%, P = 0.044). Patients in the TNT group had a higher 3-year DFS rate (82.8% versus 75.7%, P = 0.041) and lower distant metastasis rate (19.2% versus 33.1%, P = 0.049) than those in the NCRT group. Multivariate analysis showed that NCRT was an independent risk factor for DFS (95%CI 2.023-13.415, P = 0.001) and distant metastasis (95% CI 2.149-20.082, P = 0.001). CONCLUSION: With similar adverse events and a higher pCR rate when compared with NCRT, TNT might be considered as a safe and effective therapeutic strategy to improve prognosis in patients with locally advanced rectal cancer.

Long-term outcomes after extra-levator versus conventional abdominoperineal excision for low rectal cancer.

PURPOSE: Extralevator (ELAPE) and abdominoperineal excision (APE) are two major surgical approaches for low rectal cancer patients. Although excellent short-term efficacy is achieved in patients undergoing ELAPE, the long-term benefits have not been established. In this study we evaluated the safety, pathological and survival outcomes in rectal cancer patients who underwent ELAPE and APE. METHODS: One hundred fourteen patients were enrolled, including 68 in the ELAPE group and 46 in the APE group at the Beijing Chaoyang Hospital, Capital Medical University from January 2011 to November 2020. The baseline characteristics, overall survival (OS), progression-free survival (PFS), and local recurrence-free survival (LRFS) were calculated and compared between the two groups. RESULTS: Demographics and tumor stage were comparable between the two groups. The 5-year PFS (67.2% versus 38.6%, log-rank P = 0.008) were significantly improved in the ELAPE group compared to the APE group, and the survival advantage was especially reflected in patients with pT3 tumors, positive lymph nodes or even those who have not received neoadjuvant chemoradiotherapy. Multivariate analysis showed that APE was an independent risk factor for OS (hazard ratio 3.000, 95% confidence interval 1.171 to 4.970, P = 0.004) and PFS (hazard ratio 2.730, 95% confidence interval 1.506 to 4.984, P = 0.001). CONCLUSION:  Compared with APE, ELAPE improved long-term outcomes for low rectal cancer patients, especially among patients with pT3 tumors, positive lymph nodes or those without neoadjuvant chemoradiotherapy.

Swelling Characteristics and Interaction Mechanism of High-Rank Coal during CO2 Injection: A Molecular Simulation Study.

In CO2-enhanced coalbed methane (CO2-ECBM) engineering, accurate knowledge of the interaction mechanism of CO2 and coal matrix is crucial for improving the recovery of CH4 and contributing to the geological sequestration of CO2. This study is performed to prove the accuracy of molecular simulation and calculate the variation characteristics of pore structure, volumetric strain, mechanical properties, Fourier transform infrared (FT-IR) spectra, and the system free energy by molecular dynamics (MD) and grand canonical Monte Carlo (GCMC) methods. According to the obtained results, a relationship between pore structure, swelling strain, mechanical properties, chemical structure, and surface free energy was established. Then, the correlation of various coal change characteristics was analyzed to elucidate the interaction mechanism between CO2 and coal. The results showed that (1) the molecular simulation method was able to estimate the swelling mechanism of CO2 and coal. However, because the adsorption capacity of the molecular simulate is greater than that of the experiment and the raw coal is softer than the macromolecular structure, the molecular results are slightly better than the experimental results. (2) As pressure increased from 0 to 4 MPa, the intramolecular pores and sorption-induced strain changed significantly, whereas when the pressure increased from 4 to 8 MPa (especially at 6-8 Mpa), there was an increase of the intermolecular pores and mechanical properties and transition from elastic to plastic. In addition, when the pressure was >8 MPa, the coal matrix changed slightly. ScCO2 with a higher adsorption capacity results in greater damage and causes larger alterations of coal mechanical properties. (3) The change of the coal matrix is essentially controlled by the surface free energy of the molecular system. E valence affects the aromatic structure and changes the volume of the intramolecular pores, thus affecting the sorption-induced strain change rate. E non affects the length of side chains and the disorder degree of coal molecules and changes the volume of the intramolecular pores, thus affecting the mechanical property change rate. Our findings shed light on the dynamic process of coal swelling and provide a theoretical basis for CO2 enhancing the recovery of CH4 gas in coal.

Transcriptome of visceral adipose tissue identifies an inflammation-related ceRNA network that regulates obesity.

Obesity is becoming an epidemic of widespread concern, but the underlying causes remain elusive. In this study, whole transcriptome RNA sequencing revealed differential profiles of noncoding (nc) RNAs and mRNAs in visceral adipose tissue from obese (BMI > 32.5 kg/m2) and lean (BMI < 20 kg/m2) individuals, with 1920 differentially expressed genes, 1466 long noncoding (lnc) RNAs, 122 micro (mi) RNAs, and 52 circular (circ) RNAs identified. Gene Set Enrichment Analysis, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis revealed that these ncRNAs were involved in inflammation-related pathways that included cytokine-cytokine receptor interaction, the tumor necrosis factor and nuclear factor kappa B signaling pathways. The results indicated a critical role of inflammation in the pathogenesis of obesity. The network interaction of lncRNA, circRNA, and miRNA revealed a competing endogenous (ce) RNA network that was associated with inflammation. The ceRNA network included circORC5/miR-197-5p/TNFRSF10D and circNTRK2/miR-760/LAT, which were dysregulated in obese patients. In conclusion, this whole transcriptome study provided a pool of data that will be useful for identifying biomarkers of obesity and identified an obesity-associated ceRNA network that is regulated by circORC5 and circNTRK2.

Effects of Pore Parameters and Functional Groups in Coal on CO2/CH4 Adsorption.

The mechanisms of CO2/CH4 adsorption in coal are the theoretical foundation for CO2 sequestration in coal seams targeted for enhanced coalbed methane recovery. Herein, by changing the model (low rank coal: WMC, middle rank coal: XM and high rank coal: CZ) with plenty of side aliphatic chains and functional groups established in the literature, the influence and mechanism of pore parameters and functional groups(-CH3, -OH, -C2O, -C=O) on the adsorption of CO2 and CH4 in different rank coals are systematically studied. Using the Connolly surface algorithm to calculate the pore volume (V F) and the specific surface area (S SA) of coal with different functional groups, it can be seen that the influence of the functional group change on the pore structure is related to the coal rank. Changing the various functional groups in the original coal structure to a unified functional group (-CH3, -OH, -C2O, or -C=O) will increase the accessible pore volume (V F) and the specific surface area (S SA), except in low-rank and middle-rank coal, where the ordered arrangement of -C=O will decrease V F and S SA. The adsorption capacities of different pore parameters and functional groups were calculated by Grand Canonical Monte Carlo simulation and density functional theory. On pure adsorption, the pore parameters exert greater influence than the functional groups. By comparing the adsorption energy of the original pore structure containing functional groups and that of modified pores without functional groups, the contributions of the pore structure and original functional groups on CO2/CH4 adsorption are 71 and 29% and 83 and 17%, respectively. Small-diameter pores and -C2O have a strong adsorption capacity. In terms of competitive adsorption, the -C=O functional groups and pore diameters ranging from 1.0 to 2.0 nm can significantly enhance the selectivity of CO2 over CH4. The CH4 and CO2 adsorption does not occur via rigorous monolayer adsorption; multilayer adsorption can occur for CH4 and CO2 with pore diameters of 1.0-2.0 and 1.0-2.2 nm, respectively, thus causing micropore filling. These quantitative results establish a foundation for the development of adsorption theory for CO2/CH4 in coal.

DNA methylation mediated down-regulation of ANGPTL4 promotes colorectal cancer metastasis by activating the ERK pathway.

Background: Colorectal cancer (CRC) imposes significant health burden and is increasing in incidence. NGPTL4 has been implicated in the development of CRC. The present study aimed to investigate the molecular mechanisms by which ANGPTL4 expression might regulate epithelial-mesenchymal transition (EMT) and the tumor microenvironment in CRC. Methods: CRC and para-carcinoma tissues were collected from 67 CRC patients. ANGPTL4 expression levels and DNA methylation of ANGPTL4 promoter region were determined. Next, the migration and invasion capacities of CRC cells were assessed. Immunofluorescence and Western blot were used to identify the signaling pathways by which ANGPTL4 mediated tumor metastasis. A tumorigenesis mice model with transplanted fibroblast cells and ANGPTL4 overexpressed CRC cells was established to investigate the effects of ANGPTL4 on the metastasis of cancer cells in vivo. Results: ANGPTL4 was significantly decreased in CRC tissues and DNA hypermethylation was involved in the regulation of ANGPTL4. Mechanistically, ANGPTL4 induced activation of cancer-associated fibroblasts in the tumor microenvironment and promoted EMT in CRC cells through the ERK signaling pathway. In vivo, the overexpression of ANGPTL4 was found to inhibit the metastasis of tumor cells in lung tissues. Conclusion: DNA hypermethylation induced ANGPTL4 downregulation promoted the activation of cancer-associated fibroblasts and epithelial mesenchymal transformation of CRC cells via the ERK signaling pathway, thereby promoting invasion and metastasis in CRC.

Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor in Caenorhabditis elegans.

During development, homeostasis, and disease, organisms must balance responses that allow adaptation to low oxygen (hypoxia) with those that protect cells from oxidative stress. The evolutionarily conserved hypoxia-inducible factors are central to these processes, as they orchestrate transcriptional responses to oxygen deprivation. Here, we employ genetic strategies in C. elegans to identify stress-responsive genes and pathways that modulate the HIF-1 hypoxia-inducible factor and facilitate oxygen homeostasis. Through a genome-wide RNAi screen, we show that RNAi-mediated mitochondrial or proteasomal dysfunction increases the expression of hypoxia-responsive reporter Pnhr-57::GFP in C. elegans. Interestingly, only a subset of these effects requires hif-1. Of particular importance, we found that skn-1 RNAi increases the expression of hypoxia-responsive reporter Pnhr-57::GFP and elevates HIF-1 protein levels. The SKN-1/NRF transcription factor has been shown to promote oxidative stress resistance. We present evidence that the crosstalk between HIF-1 and SKN-1 is mediated by EGL-9, the prolyl hydroxylase that targets HIF-1 for oxygen-dependent degradation. Treatment that induces SKN-1, such as heat or gsk-3 RNAi, increases expression of a Pegl-9::GFP reporter, and this effect requires skn-1 function and a putative SKN-1 binding site in egl-9 regulatory sequences. Collectively, these data support a model in which SKN-1 promotes egl-9 transcription, thereby inhibiting HIF-1. We propose that this interaction enables animals to adapt quickly to changes in cellular oxygenation and to better survive accompanying oxidative stress.

Peripheral blood CD45RO+T cells is a predictor of the effectiveness of neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

ABSTRACT: To investigate the relationship between the changes in circulating CD45RO+T lymphocyte subsets following neoadjuvant therapy for rectal cancer in patients with locally advanced rectal cancer.The clinicopathological data of 185 patients with rectal cancer who received neoadjuvant therapy in the General Surgery Department of Beijing Chaoyang Hospital affiliated to Capital Medical University from June 2015 to June 2017 were analyzed. Venous blood samples were collected 1 week before neoadjuvant therapy and 1 week before surgery, and the expression of CD45RO+T was detected by flow cytometry. The receiver operating characteristic curve analysis was used to determine the optimal cut-off point of CD45RO+ratio. Log-rank test and multivariate Cox regression were used to analyze the overall survival rate (OS) and disease-free survival rate (DFS) associated with CD45RO+ratio.Circulating CD45RO+ratio of 1.07 was determined as the optimal cut-off point and CD45RO+ratio-high was associated with lower tumor regression grade grading (P = .031), T stage (P = .001), and tumor node metastasis (TNM) stage (P = .012). The 3-year DFS and OS rate in the CD45RO+ratio-high group was significantly higher than that in the CD45RO+ratio-low group (89.2% vs 60.1%, P<.001; 94.4% vs 73.2%, P<.001). The multivariate Cox analysis revealed that elevated CD45RO+ratio was an independent factor for better DFS (OR, 0.339; 95% CI, 0.153-0.752; P = .008) and OS (OR, 0.244; 95% CI,0.082-0.726; P = .011).Circulating CD45RO+ratio could predict the tumor regression grade of neoadjuvant therapy for rectal cancer, as well as long-term prognosis. These findings could be used to stratify patients and develop alternative strategies for adjuvant therapy.

Adding Three Cycles of CAPOX after Neoadjuvant Chemoradiotherapy Increases the Rates of Complete Response for Locally Advanced Rectal Cancer.

BACKGROUND AND OBJECTIVES: the total neoadjuvant chemoradiotherapy (TNT) includes different strategies, but the most appropriate model remains uncertain. The purpose of this retrospectively study was to evaluate the safety and pathological response in the consolidation chemotherapy model. METHODS: patients with cT3/T4 or TxN + M0 rectal cancer that were receiving neoadjuvant chemoradiotherapy (CRT) (50 Gy with oral capecitabine)/TNT (CRT followed by three cycles of CAPOX) during September 2017 to September 2019 in our department were included. All of the patients were recommended to receive radical surgery. RESULTS: a total of 197 patients were included. Eighty-one patients received CRT, while one hundred and sixteen patients received TNT. Nine patients did not undergo surgery because of the distant metastases (one patient (1.2%) in CRT group, two patients (1.7%) in TNT group) or a refusal of resection (two patients in CRT group, four patients in TNT group). The pathological complete response (pCR) rate was 32.7% in TNT compared with 12.8% in CRT (p = 0.002). There was no statistically significant difference in grade 3 acute toxicities of neoadjuvant treatment and surgical complications between the two groups. CONCLUSIONS: the consolidation chemotherapy model is safe for patients with locally advanced rectal cancer and it has a high pCR rate. The long-term follow-up is necessary to be evaluated in a future prospective, randomized trial.

Successful management of tubular colonic duplication using a laparoscopic approach: A case report and review of the literature.

BACKGROUND: Alimentary duplication is a rare congenital disease with a reported incidence of 1 per 4500 persons, although the exact incidence has been difficult to ascertain. According to previous reports, the most common site of duplication is the ileum, and colonic duplication is rare. Due to different types and locations of the duplication, the manifestations are varied, which makes establishing an accurate diagnosis before surgery a challenge. CASE SUMMARY: A 17-year-old female patient sought evaluation in our department with constipation and chronic abdominal pain for 12 years; she had difficulty defecating and had dry stools since she was a child. An abdominal computed tomography revealed two extremely enlarged loops of bowel full of stool-like intestinal contents in the left lower abdomen, which led us to consider the possibility of colonic duplication. A laparoscopic exploration was performed, which revealed a tubular duplicated colon that shared a common opening with the transverse colon. A left hemi-colectomy was performed with a side-to-side anastomosis. The pathologic results confirmed the diagnosis. At the 6-mo follow-up, the patient was doing well without constipation or abdominal pain. CONCLUSION: Colonic duplication is a rare alimentary abnormality in adults. Due to the non-specific manifestations and low incidence, it is usually difficult to make an accurate diagnosis pre-operatively. Surgery is the mainstay of treatment, even though some patients are asymptomatic.

IL36 Cooperates With Anti-CTLA-4 mAbs to Facilitate Antitumor Immune Responses.

Despite the great impact on long-term survival of some cancer patients, the immune checkpoint blockade (ICB) therapy is limited by its low response rates for most cancers. There is a pressing need for novel combination immunotherapies that overcome the resistance to current ICB therapies. Cytokines play a pivotal role in tumor immunotherapy by helping initiating and driving antitumor immune responses. Here, we demonstrated that, besides conventional CD4+ and CD8+ T cells, IL36 surprisingly increased the number of tumor-infiltrating regulatory T (Treg) cells in vivo and enhanced proliferation of Tregs in vitro. Administration of CTLA-4 monoclonal antibodies (mAbs) strongly enhanced IL36-stimulated antitumor activities through depletion of Tregs. In addition, a cancer gene therapy using the IL36-loaded nanoparticles in combination with CTLA-4 mAbs additively reduced lung metastasis of breast tumor cells. We further showed that the combined therapy of CTLA-4 mAbs and IL36 led to an increase in proliferation and IFN-γ production by CD4+ and CD8+ T cells when compared to single therapy with CTLA-4 mAbs or IL36. Collectively, our findings demonstrated a new combination therapy that could improve the clinical response to ICB immunotherapy for cancer.

Does Heterotopic Ossification in Cervical Arthroplasty Affect Clinical Outcome?

OBJECTIVE: To investigate the occurrence and progression of heterotopic ossification (HO) in patients treated by anterior cervical discectomy with arthroplasty. It was evaluated if HO affects clinical outcome and range of motion (ROM). Risk factors of HO was studied as well. METHODS: Patients who underwent anterior cervical discectomy with arthroplasty for a cervical radiculopathy because of a herniated disc from the NECK and PROCON trial were analyzed for HO at 12 and 24 months postoperatively. HO was scored according to the McAfee-Mehren classification. The index ROM was defined by a custom developed image analysis tool, and global cervical ROM was measured by Cobb's angle. Clinical outcome was evaluated by means of the Neck Disability Index and the 36-Item Short Form Health Survey. RESULTS: The occurrence of HO was 60% at 1 year, and it increased to 76% at 2-year follow-up. A total of 31% of patients were scored as high-grade HO at 1-year follow-up, and this percentage increased to 50% at 2-year follow-up. Clinical outcome does not correlate to HO grade, and no risk factor for high-grade HO could be identified. The ROM at the index level was significantly higher in low-grade HO group than those patients with high-grade HO, but in 15%-38% HO grade does not correspond to ROM. CONCLUSIONS: HO occurs in three fourths of the patients at 2 years after surgery, but does not necessarily correspond to clinical outcome, nor loss or preservation of ROM. The McAfee-Mehren classification should be combined with ROM evaluation to properly study HO.

Maintaining range of motion after cervical discectomy does not prevent adjacent segment degeneration.

BACKGROUND: Motion preservation prostheses were introduced to prevent adjacent disc degeneration (ASD) and to diminish neck disability in the postsurgical follow-up. However, it is still a controversial issue, and the relationship between range of motion (ROM) and ASD has not been studied. PURPOSE: To compare the correlation between ROM of the cervical spine and the presence of radiological ASD after anterior discectomy. Clinical outcome was also correlated to ROM and ASD. STUDY DESIGN: Retrospective cohort study. METHODS: In all, 253 patients who underwent anterior discectomy for cervical radiculopathy due to a herniated disc were analyzed for segmental and global cervical ROM and the presence of ASD both preoperatively, and 12 and 24 months postoperatively. Patients who were included in two randomized, double-blinded trials comparing anterior cervical discectomy with arthroplasty, anterior cervical discectomy with intervertebral cage, or anterior cervical discectomy without intervertebral cage for one level disc herniation were analyzed. ROM was defined by a custom-developed image analysis tool. ASD was defined by decrease in disc height and anterior osteophyte formation on X-rays. Clinical outcome was evaluated by means of the Neck Disability Index (NDI). RESULTS: Two years postoperatively, no correlation was demonstrated between ROM and ASD. The incidence of ASD was comparable in the three groups, being 34% at baseline, and 58% at 2-year follow-up. Likewise, ASD progression was comparable in the three treatment arms. No correlation was demonstrated between ROM and NDI or ASD and NDI. CONCLUSIONS: Since ROM is not correlated to ASD, and clinical outcome is not correlated to ROM either, the relevance of continued ROM at the target level seems absent.

Automatic quantitative analysis of pulmonary vascular morphology in CT images.

PURPOSE: Vascular remodeling is a significant pathological feature of various pulmonary diseases, which may be assessed by quantitative computed tomography (CT) imaging. The purpose of this study was therefore to develop and validate an automatic method for quantifying pulmonary vascular morphology in CT images. METHODS: The proposed method consists of pulmonary vessel extraction and quantification. For extracting pulmonary vessels, a graph-cuts-based method is proposed which considers appearance (CT intensity) and shape (vesselness from a Hessian-based filter) features, and incorporates distance to the airways into the cost function to prevent false detection of airway walls. For quantifying the extracted pulmonary vessels, a radius histogram is generated by counting the occurrence of vessel radii, calculated from a distance transform-based method. Subsequently, two biomarkers, slope α and intercept ß, are calculated by linear regression on the radius histogram. A public data set from the VESSEL12 challenge was used to independently evaluate the vessel extraction. The quantitative analysis method was validated using images of a three-dimensional (3D) printed vessel phantom, scanned by a clinical CT scanner and a micro-CT scanner (to obtain a gold standard). To confirm the association between imaging biomarkers and pulmonary function, 77 scleroderma patients were investigated with the proposed method. RESULTS: In the independent evaluation with the public data set, our vessel segmentation method obtained an area under the receiver operating characteristic (ROC) curve of 0.976. The median radius difference between clinical and micro-CT scans of a 3D printed vessel phantom was 0.062 ± 0.020 mm, with interquartile range of 0.199 ± 0.050 mm. In the studied patient group, a significant correlation between diffusion capacity for carbon monoxide and the biomarkers, α (R = -0.27, P = 0.018) and ß (R = 0.321, P = 0.004), was obtained. CONCLUSION: In conclusion, the proposed method was validated independently using a public data set resulting in an area under the ROC curve of 0.976 and using a 3D printed vessel phantom data set, showing a vessel sizing error of 0.062 mm (0.16 in-plane pixel units). The correlation between imaging biomarkers and diffusion capacity in a clinical data set confirmed an association between lung structure and function. This quantification of pulmonary vascular morphology may be helpful in understanding the pathophysiology of pulmonary vascular diseases.