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Introduction: Despite the emergence of atezolizumab and bevacizumab (A + B) as standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC), a comprehensive understanding of the clinical significance of immune-related adverse events (irAEs) remains limited. We aimed to assess the impact of irAEs on patients with HCC undergoing A + B treatment. Methods: This multicentre retrospective study included consecutive patients with HCC who were treated with the A + B regimen from September 2020 to December 2022. Patients were categorized into three groups based on the severity of irAEs, ranging from those without any experience of irAEs to those with severe irAEs. Results: This study included 150 patients with HCC, with a mean age of 63.3 years. Among them, 93.3% of patients were classified as Barcelona Clinic Liver Cancer stage C, 52.0% had portal vein tumour thrombosis (PVTT), and 60.7% extrahepatic spread. Patients were classified as follows: group 1 (n = 84) had no irAEs, group 2 (n = 37) had mild irAEs (grade 1-2), and group 3 (n = 29) had severe irAEs (grade ≥3). The median overall survival (OS), progression-free survival (PFS), and time-to-treatment discontinuation (TTD) were 13.6, 5.7, and 3.6 months, respectively. Group 2 demonstrated significantly superior OS compared to group 1 (9.5 months) and group 3 (5.6 months), with a median OS of 23.0 months (p < 0.001). Furthermore, group 2 demonstrated significantly better outcomes in terms of PFS and TTD compared to both group 1 and group 3 (p < 0.001 for both). Multivariate analysis identified mild irAEs (hazard ratio [HR], 0.353; p = 0.010), ALBI grade 1 (HR, 0.389; p = 0.006), Child-Pugh class A (HR, 0.338; p = 0.002), and the absence of PVTT (HR, 0.556; p = 0.043) as independent predictors of better OS. Conclusion: Our study highlights the significant impact of irAE severity on the outcomes of patients with HCC receiving A + B. Notably, the occurrence of mild irAEs was independently associated with favourable survival, suggesting their potential role as surrogate indicators of HCC prognosis.
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BACKGROUND AND AIMS: Hepatic stellate cells (HSCs) contribute to hepatocellular carcinoma (HCC) progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX3CR1+ macrophages to pro-tumorigenic properties in the peritumoral area. APPROACH AND RESULTS: In single cell RNA-sequencing analysis of HCC patients, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area, and were highly enriched with retinol metabolism-related genes. Flow cytometry analysis showed significantly increased frequencies of CD14+CD11b+HLA-DRâ macrophages with CX3CR1 in the HCC adjacent region where α-SMA-expressing activated HSCs (aHSCs) showed co-localized expression of CX3CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX3CR1+Ly6C+ macrophages was mostly observed with decreased CD8+ T cells. In adoptive transfer and in vitro co-culture of myeloid cells, we demonstrated that CX3CR1+Ly6C+ macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or co-culturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX3CR1+Ly6C+ macrophages and human blood CD14+ cells, leading to the suppression of CD8+ T cell proliferation. Moreover, genetic deficiency of CX3CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development. CONCLUSION: We showed that CX3CR1+Ly6C+ macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX3CR1+Ly6C+ macrophages, subsequently depriving CD8+ T cells of arginine and promoting HCC.
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The optic nerve head (ONH) is a complex structure wherein the axons of the retinal ganglion cells extrude from the eyeball through three openings: 1) the Bruch's membrane opening (BMO) in the retinal layer, 2) the anterior scleral canal opening in the anterior scleral layer, and 3) the lamina cribrosa (LC). Eyeball expansion during growth induces an offset among openings, since the expansion affects the inner retinal and outer scleral layers differently: the posterior polar retinal structure is preserved by the preferential growth in the equatorial region, whereas no such regional difference is observed in the scleral layer. The various modes and extents of eyeball expansion result in diverse directionality and amount of offset among openings, which causes diverse ONH morphology in adults, especially in myopia. In this review, we summarize the ONH changes that occur during myopic axial elongation. These changes were observed prospectively in our previous studies, wherein LC shift and subsequent offset from the BMO center could be predicted by tracing the central retinal vascular trunk position. This offset induces the formation of γ-zone parapapillary atrophy or externally oblique border tissue. As a presumptive site of glaucomatous damage, the LC/BMO offset may render the LC pores in the opposite direction more vulnerable. To support such speculation, we also summarize the relationship between LC/BMO offset and glaucomatous damage. Indeed, LC/BMO offset is not only the cause of diverse ONH morphology in adults, but is also, potentially, an important clinical marker for assessment of glaucoma.
Subject(s)
Bruch Membrane , Glaucoma , Optic Disk , Humans , Optic Disk/pathology , Bruch Membrane/pathology , Glaucoma/physiopathology , Glaucoma/pathology , Retinal Ganglion Cells/pathology , Intraocular Pressure/physiology , Eye/growth & development , Eye/pathology , Optic Nerve Diseases/physiopathology , Optic Nerve Diseases/pathology , Sclera/pathology , Myopia/pathology , Myopia/physiopathologyABSTRACT
This study aims to determine the influencing factors of the participation of older individuals aged 65 years and above in South Korea's National Cancer Screening Program (NCSP) using data from the eighth wave (2019-2021) of the Korea National Health and Nutrition Examination Survey (KNHANES VIII), and discuss potential problems and coping strategies. Variables were selected based on Andersen's healthcare utilization model. "Participation in the NSCP" was considered the dependent variable, with independent variables including sociodemographic characteristics (sex, marital status, residence, education level, income level, economic activity, medical coverage type, and private insurance), health conditions (subjective health status, hypertension, and diabetes), and health behaviors (physical activity, monthly alcohol consumption, and current smoking status). The analysis revealed that higher participation rates correlated with being married, having an education level beyond elementary school, being employed, subscribing to private insurance, perceiving oneself as having average or poor health, engaging in physical activity, and not smoking. Sex, residence, income, medical coverage type, hypertension, diabetes, and monthly alcohol consumption were found to be insignificantly correlated. These findings underscore the importance of tailored promotion and health education for older individuals to boost NCSP participation rates, which could ultimately elevate public health standards.
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We investigated three-dimensional (3D) eyeball protrusion and its association with the offset between the lamina cribrosa (LC) and Bruch's membrane opening (BMO). 3D-MRI scans were taken from 93 subjects (186 eyes). An ellipsoid was fitted along the posterior 2/3 contour of each eyeball. Eyeball asymmetry with focal bulging was determined by the existence of an adjacent outward protrusion/reciprocal inward depression pair, and the angular deviation of the outermost protruded point (OPP) was measured from the nasal side of the fovea-BMO axis. The LC/BMO offset was evaluated by measuring the central retinal vascular trunk (CRVT) location from the BMO center: (1) the angular deviation and (2) the offset index as the ratio between the CRVT-BMO center distance and the BMO radius in the same direction. Seventy-nine eyes (42%) were classified as having eyeball asymmetry, which had a more superior LC/BMO offset (P < 0.001) and a larger offset index (P = 0.002). In those eyes, the angular deviation of the OPP showed a significant correlation with that of the LC/BMO offset (r = -0.724, P < 0.001), as did protrusion depth with the offset index (r = 0.291, P = 0.009). The presence of eyeball asymmetry was associated with superior LC/BMO offset (P = 0.004) and larger offset index (P = 0.009). Superior LC/BMO offset was associated with older age (P < 0.001), shorter axial length (P < 0.001) and inferior location of OPP (P < 0.001). The location and extent of focal bulging were closely associated with those of LC/BMO offset. This indicates that focal bulging during expansion might be associated with diverse directionality of LC/BMO offset.
Subject(s)
Optic Disk , Humans , Male , Female , Middle Aged , Optic Disk/diagnostic imaging , Adult , Aged , Magnetic Resonance Imaging , Eye/diagnostic imaging , Eye/pathology , Bruch Membrane/pathology , Imaging, Three-Dimensional , Young Adult , Tomography, Optical Coherence/methodsABSTRACT
PURPOSE: Given its heterogeneity and diverse clinical outcomes, precise subclassification of Barcelona Clinic Liver Cancer stage C (BCLC-C) hepatocellular carcinoma (HCC) is required for appropriately determining patient prognosis and selecting treatment. EXPERIMENTAL DESIGN: We recruited 2,626 patients with BCLC-C HCC from multiple centers, comprising training/test (n = 1,693) and validation cohorts (n = 933). The XGBoost model was chosen for maximum performance among the machine learning (ML) models. Patients were categorized into low-, intermediate-, high-, and very high-risk subgroups based on the estimated prognosis, and this subclassification was named the CLAssification via Machine learning of BCLC-C (CLAM-C). RESULTS: The areas under the receiver operating characteristic curve of the CLAM-C for predicting the 6-, 12-, and 24-month survival of patients with BCLC-C were 0.800, 0.831, and 0.715, respectively-significantly higher than those of the conventional models, which were consistent in the validation cohort. The four subgroups had significantly different median overall survivals, and this difference was maintained among various patient subgroups and treatment modalities. Immune-checkpoint inhibitors and transarterial therapies were associated with significantly better survival than tyrosine kinase inhibitors (TKI) in the low- and intermediate-risk subgroups. In cases with first-line systemic therapy, the CLAM-C identified atezolizumab-bevacizumab as the best therapy, particularly in the high-risk group. In cases with later-line systemic therapy, nivolumab had better survival than TKIs in the low-to-intermediate-risk subgroup, whereas TKIs had better survival in the high- to very high-risk subgroup. CONCLUSIONS: ML modeling effectively subclassified patients with BCLC-C HCC, potentially aiding treatment allocation. Our study underscores the potential utilization of ML modeling in terms of prognostication and treatment allocation in patients with BCLC-C HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Machine Learning , Humans , Liver Neoplasms/pathology , Liver Neoplasms/mortality , Liver Neoplasms/therapy , Liver Neoplasms/drug therapy , Liver Neoplasms/diagnosis , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/diagnosis , Female , Male , Prognosis , Middle Aged , Aged , Neoplasm Staging , Algorithms , ROC Curve , AdultABSTRACT
Background/Aims: Transarterial chemoembolization (TACE) is widely performed as a major treatment for hepatocellular carcinoma (HCC) patients, and there is a need to stratify patients for whom the most benefit from the treatment. This study aimed to develop a refined prediction model for overall survival (OS) in patients undergoing TACE as a first-line treatment in a large cohort and validate its performance. Methods: A total of 2,632 patients with HCC of Barcelona Clinic Liver Cancer stage A or B who underwent TACE between 2008 and 2017 were enrolled. The patients were randomly assigned to a training cohort (n = 1,304) or a validation cohort (n = 1,328). Independent predictors of OS were used to develop a prediction model. Results: The median age of patients in the entire cohort was 63 years, with the majority having hepatitis B virus (56.6%) and being classified as Child-Pugh class A (82.4%). We developed a new prognostic model, called the TACE-prognostic (TP) score, based on tumor burden (sum of the largest tumor diameter and tumor number), alpha-fetoprotein, and Albumin-Bilirubin grade. Patients were classified into five risk groups according to TP scores, with median survival significantly differentiated in both training and validation cohorts (P < 0.001). The new model consistently outperformed other currently available models in both the training and validation cohorts. Conclusion: This newly developed TP scoring system has the potential to be a useful tool in identifying ideal candidates of TACE and predicting OS with favorable performance and discrimination. However, further external validation is needed to confirm its effectiveness.
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We investigated optic nerve head factors associated with initial parafoveal scotoma (IPFS) in primary open-angle glaucoma. Eighty (80) patients with an IPFS and 84 patients with an initial nasal step (INS) were compared. Central retinal vascular trunk (CRVT) deviation from the Bruch's membrane opening (BMO) center was measured as a surrogate of lamina cribrosa (LC)/BMO offset, and its obliqueness was defined as the absolute value of angular deviation from the fovea-BMO axis. Proximity of retinal nerve fiber layer defect (RNFLD) was defined as the angular deviation of the inner RNFLD margin from the fovea-BMO axis. Microvasculature dropout (MvD) was defined as a focal sectoral capillary dropout with no visible microvascular network identified in the choroidal layer. Factors associated with IPFS, as compared with INS, were assessed using logistic regression analyses and conditional inference tree analysis. The IPFS group had more oblique CRVT offset (P < 0.001), RNFLD closer to the fovea (P < 0.001), more MvD (P < 0.001), and more LC defects (P < 0.001) compared to the INS group. In logistic regression analyses, obliqueness of CRVT offset (P = 0.002), RNFLD proximity (P < 0.001), and MvD (P = 0.001) were significant factors influencing the presence of IPFS. Conditional inference tree analysis showed that RNFLD closer to the fovea (P < 0.001) in the upper level, more oblique CRVT offset (P = 0.013) and presence of MvD (P = 0.001) in the lower level were associated with the probability of having IPFS. IPFS was associated with closer RNFLD location to the fovea when assessed from the BMO. Oblique LC/BMO offset may not only mask RNFLD proximity to the fovea due to a deviated funduscopic disc appearance, but also potentiate IPFS via focal LC defect and MvD.
Subject(s)
Glaucoma, Open-Angle , Optic Disk , Retinal Diseases , Humans , Optic Disk/blood supply , Scotoma/complications , Glaucoma, Open-Angle/complications , Visual Fields , Intraocular Pressure , Vision Disorders/complications , Retinal Diseases/complications , Tomography, Optical CoherenceABSTRACT
Background/Aims: This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice. Methods: The data from genotype 1 or 2 chronic hepatitis C patients treated with GLE/PIB or sofosbuvir + ribavirin or SOF/LDV in South Korea were collected retrospectively. The analysis included the treatment completion rate, sustained virologic response at 12 weeks (SVR12) test rate, treatment effectiveness, and adverse events. Results: Seven hundred and eighty-two patients with genotype 1 or 2 chronic hepatitis C who were treated with GLE/PIB (n=575) or SOF/LDV (n=207) were included in this retrospective study. The baseline demographic and clinical characteristics revealed significant statistical differences in age, genotype, ascites, liver cirrhosis, and hepatocellular carcinoma between the GLE/PIB and SOF/LDV groups. Twenty-two patients did not complete the treatment protocol. The treatment completion rate was high for both regimens without statistical significance (97.7% vs. 95.7%, p=0.08). The overall SVR12 of intention-to-treat analysis was 81.2% vs. 80.7% without statistical significance (p=0.87). The overall SVR12 of per protocol analysis was 98.7% vs. 100% without statistical significance (p=0.14). Six patients treated with GLE/PIB experienced treatment failure. They were all male, genotype 2, and showed a negative hepatitis C virus RNA level at the end of treatment. Two patients treated with GLE/PIB stopped medication because of fever and abdominal discomfort. Conclusions: Both regimens had similar treatment completion rates, effectiveness, and safety profiles. Therefore, the SOF/LDV regimen can also be considered a viable DAA for the treatment of patients with genotype 1 or 2 chronic hepatitis C.
Subject(s)
Aminoisobutyric Acids , Benzimidazoles , Cyclopropanes , Fluorenes , Hepatitis C, Chronic , Lactams, Macrocyclic , Leucine/analogs & derivatives , Liver Neoplasms , Proline/analogs & derivatives , Pyrrolidines , Quinoxalines , Sulfonamides , Humans , Male , Sofosbuvir/therapeutic use , Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Hepacivirus/genetics , Retrospective Studies , Treatment Outcome , Liver Neoplasms/drug therapy , Genotype , Drug Therapy, CombinationABSTRACT
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid growth and uncontrolled proliferation of undifferentiated myeloid cells. Metabolic reprogramming is commonly observed in the bone marrow of AML patients, as leukemia cells require increased ATP supply to support disease progression. In this study, we examined the potential role of mesothelin as a metabolic modulator in myeloid cells in AML. Mesothelin is a well-known marker of solid tumors that promotes cancer cell proliferation and survival. We initially analyzed alterations in mesothelin expression in the myeloblast subpopulations, defined as SSC-Alow/CD45dim, obtained from the bone marrow of AML patients using flow cytometry. Our results showed overexpression of mesothelin in 34.8% of AML patients. Subsequently, metabolic changes in leukemia cells were evaluated by comparing the oxygen consumption rates (OCR) of bone marrow samples derived from adult AML patients. Notably, a higher OCR was observed in the mesothelin-positive compared to the mesothelin-low and non-expressing groups. Treatment with recombinant human mesothelin protein enhanced OCR and increased the mRNA expression of glycolytic enzymes and mitochondrial complex II in KG1α AML cells. Notably, siRNA targeting mesothelin in KG1α cells led to the reduction of glycolysis-related gene expression but had no effect on the mitochondrial complex gene. The collective results demonstrate that mesothelin induces metabolic changes in leukemia cells, facilitating the acquisition of a rapid supply of ATP for proliferation in AML. Therefore, the targeting of mesothelin presents a potentially promising approach to mitigating the progression of AML through the inhibition of glycolysis and mitochondrial respiration in myeloid cells.
Subject(s)
Leukemia, Myeloid, Acute , Mesothelin , Adult , Humans , Granulocyte Precursor Cells/metabolism , Succinate Dehydrogenase/metabolism , Cell Line, Tumor , Leukemia, Myeloid, Acute/genetics , Cell Proliferation , Respiration , Glycolysis , Adenosine Triphosphate/metabolismABSTRACT
Acute gastric dilatation (AGD) is one of the most prevalent and life-threatening diseases in nonhuman primates worldwide. However, the etiology of this syndrome has not been determined. Recently, sudden death occurred in a 7-year-old female cynomolgus monkey with a history of fecal microbiota transplantation using diarrheic stools. The monkey had undergone surgery previously. On necropsy, gastric dilatation and rupture demonstrated a tetrad arrangement on histopathologic examination. On 16S rRNA sequencing, a high population of Clostridium ventriculi was identified in the duodenum adjacent to stomach but not in the colon. This paper is the first report of Clostridium ventriculi infection in a cynomolgus macaque with acute gastric dilatation and rupture.
Subject(s)
Clostridium , Gastric Dilatation , Female , Animals , Macaca fascicularis , Gastric Dilatation/veterinary , Gastric Dilatation/pathology , RNA, Ribosomal, 16SABSTRACT
This study aimed to compare the treatment outcomes of atezolizumab-plus-bevacizumab (Ate/Bev) therapy with those of transarterial chemoembolization plus radiotherapy (TACE + RT) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) and without metastasis. Between June 2016 and October 2022, we consecutively enrolled 855 HCC patients with PVTT. After excluding 758 patients, 97 patients (n = 37 in the Ate/Bev group; n = 60 in the TACE + RT group) were analyzed. The two groups showed no significant differences in baseline characteristics and had similar objective response and disease control rates. However, the Ate/Bev group showed a significantly higher one-year survival rate (p = 0.041) compared to the TACE + RT group, which was constantly displayed in patients with extensive HCC burden. Meanwhile, the clinical outcomes were comparable between the two groups in patients with unilobar intrahepatic HCC. In Cox-regression analysis, Ate/Bev treatment emerged as a significant factor for better one-year survival (p = 0.049). Finally, in propensity-score matching, the Ate/Bev group demonstrated a better one-year survival (p = 0.02) and PFS (p = 0.01) than the TACE + RT group. In conclusion, Ate/Bev treatment demonstrated superior clinical outcomes compared to TACE + RT treatment in HCC patients with PVTT. Meanwhile, in patients with unilobar intrahepatic HCC, TACE + RT could also be considered as an alternative treatment option alongside Ate/Bev therapy.
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PURPOSE: To compare refractive prediction errors between phacotrabeculectomy and phacoemulsification. METHODS: Refractive prediction error was defined as the difference in spherical equivalent between the predicted value using the Barrett Universal II formula and the actual value obtained at postoperative one month. Forty-eight eyes that had undergone phacotrabeculectomy (19 eyes, open-angle glaucoma; 29 eyes, angle-closure glaucoma) were matched with 48 eyes that had undergone phacoemulsification by age, average keratometry value and axial length (AL), and their prediction errors were compared. The factors associated with prediction errors were analyzed by multivariable regression analyses. RESULTS: The phacotrabeculectomy group showed a larger absolute prediction error than the phacoemulsification group (0.51 ± 0.37 Diopters vs. 0.38 ± 0.22 Diopters, p = 0.033). Larger absolute prediction error was associated with longer AL (p = 0.010) and higher intraocular pressure (IOP) difference (p = 0.012). Hyperopic shift (prediction error > 0) was associated with shallower preoperative anterior chamber depth (ACD) (p = 0.024) and larger IOP difference (p = 0.031). In the phacotrabeculectomy group, the prediction error was inversely correlated with AL: long eyes showed myopic shift and short eyes hyperopic shift (p = 0.002). CONCLUSIONS: Surgeons should be aware of the possibility of worse refractive outcomes when planning phacotrabeculectomy, especially in eyes with high preoperative IOP, shallow ACD, and/or extreme AL.
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Introduction: Adipokines are proteins that are secreted by the adipose tissue. Although they are associated with obesity-related metabolic disorders, most studies have focused on adipokines expressed by visceral adipose tissue (VAT). This study aimed to identify the adipokine potentially derived from subcutaneous adipose tissue (SAT) and its clinical significance. Methods: Samples of SAT and VAT were obtained from six adult male patients who underwent laparoscopic surgery for benign gall bladder disease. Differentially expressed genes were analyzed by subjecting the samples to RNA sequencing. The serum concentration of selected proteins according to body mass index (BMI) was analyzed in 58 individuals. Results: GDF10 showed significantly higher expression in the SAT, as per RNA sequencing (fold change = 5.8, adjusted P value = 0.009). Genes related to insulin response, glucose homeostasis, lipid homeostasis, and fatty acid metabolism were suppressed when GDF10 expression was high in SAT, as per genotype-tissue expression data. The serum GDF10 concentration was higher in participants with BMI ≥ 25 kg/m2 (n = 35, 2674 ± 441 pg/mL) than in those with BMI < 25 kg/m2 (n = 23, 2339 ± 639 pg/mL; P = 0.022). There was a positive correlation between BMI and serum GDF10 concentration (r = 0.308, P = 0.019). Conclusions: GDF10 expression was higher in SAT than in VAT. Serum GDF10 concentration was high in patients with obesity. Therefore, GDF10 could be a SAT-derived protein related to obesity.
Subject(s)
Adipokines , Obesity , Adult , Humans , Male , Adipokines/metabolism , Obesity/genetics , Obesity/metabolism , Subcutaneous Fat/metabolism , Adipose Tissue/metabolism , Insulin/metabolism , Growth Differentiation Factor 10/metabolismABSTRACT
BACKGROUND: Classic laparoscopic cholecystectomy) using multiple ports is a widely used method with excellent surgical outcomes. However, the resulting wounds do not meet the cosmetic needs of patients. Therefore, this study aimed to find a new minimally invasive surgical method for invisible wounds while maintaining surgical safety through a new port site. METHODS: In this prospective cohort study, we used propensity score matching analysis to evaluate the perioperative outcomes of multiport laparoscopic cholecystectomy using articulating devices with the lower abdominal approach. We performed a propensity score matching analysis of prospectively maintained data from 228 patients who underwent classic laparoscopic cholecystectomy using straight instruments and laparoscopic cholecystectomy with a lower abdominal approach using articulating devices between January and October 2022. A single surgeon performed all operations included in the study. We evaluated several perioperative outcomes. RESULTS: No differences were found in potential confounding factors, such as sex, age, admission type, previous abdominal surgery, and medical comorbidities, between the 2 groups after propensity score matching. In the classic laparoscopic cholecystectomy group, the mean operation time was shorter (43.73 ± 23.71 vs 50.60 ± 9.75 min; P < .04). No significant difference was noted in the 2 groups' numerical rating scale scores for pain, body mass index, and incidence of postoperative complications. The mean length of hospital stay was longer for patients who underwent classic laparoscopic cholecystectomy (4.27 vs 2.07 days; P = .064). The lower abdominal laparoscopic cholecystectomy group had delayed defecation after surgery. CONCLUSION: Regarding surgical outcomes and minimal invasiveness, lower abdominal laparoscopic cholecystectomy is a feasible cholecystectomy method.
Subject(s)
Cholecystectomy, Laparoscopic , Humans , Cholecystectomy, Laparoscopic/adverse effects , Cholecystectomy, Laparoscopic/methods , Propensity Score , Prospective Studies , Cholecystectomy , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Treatment OutcomeABSTRACT
Obesity-mediated hypoxic stress underlies inflammation, including interferon (IFN)-γ production by natural killer (NK) cells in white adipose tissue. However, the effects of obesity on NK cell IFN-γ production remain obscure. Here, we show that hypoxia promotes xCT-mediated glutamate excretion and C-X-C motif chemokine ligand 12 (CXCL12) expression in white adipocytes, resulting in CXCR4+ NK cell recruitment. Interestingly, this spatial proximity between adipocytes and NK cells induces IFN-γ production in NK cells by stimulating metabotropic glutamate receptor 5 (mGluR5). IFN-γ then triggers inflammatory activation of macrophages and augments xCT and CXCL12 expression in adipocytes, forming a bidirectional pathway. Genetic or pharmacological inhibition of xCT, mGluR5, or IFN-γ receptor in adipocytes or NK cells alleviates obesity-related metabolic disorders in mice. Consistently, patients with obesity showed elevated levels of glutamate/mGluR5 and CXCL12/CXCR4 axes, suggesting that a bidirectional pathway between adipocytes and NK cells could be a viable therapeutic target in obesity-related metabolic disorders.
Subject(s)
Adipocytes, White , Glutamic Acid , Interferon-gamma , Obesity , Animals , Humans , Mice , Adipocytes, White/metabolism , Glutamic Acid/metabolism , Interferon-gamma/metabolism , Killer Cells, Natural/metabolism , Obesity/metabolism , Amino Acid Transport System y+/metabolismABSTRACT
BACKGROUND: Few studies have compared the therapeutic outcomes in patients with HCC who underwent laparoscopic radiofrequency ablation (LRFA) versus percutaneous radiofrequency ablation (PRFA) for hepatocellular carcinoma (HCC). Therefore, this study compared the recurrence and survival outcomes of the two RFA methods in patients with HCC. METHODS: Recurrence and overall survival outcomes were evaluated in 307 patients who underwent LRFA (n = 151) or PRFA (n = 156) as a treatment method for de novo HCC. Inverse probability of treatment weighting (IPTW) analysis was performed to reduce the impact of treatment selection bias. RESULTS: There were no significant differences in major baseline characteristics between the LRFA and PRFA groups. However, the proportion of cirrhotic patients was higher in the LRFA group, whereas the LRFA group had more tumors and a more advanced tumor-node-metastasis stage. Moreover, the mean tumor size was significantly larger in the LRFA group than in the PRFA group. In a multivariate analysis, serum albumin level, more than three tumors, and the RFA method were identified as significant predictors of recurrence-free survival. Moreover, for the overall survival of HCC patients, serum albumin levels, days of hospital stay during RFA, and the RFA method were independent predictors. In the IPTW-adjusted analysis, the LRFA group showed significantly higher recurrence-free survival and overall survival. CONCLUSIONS: Our study revealed that compared with PRFA, LRFA was associated with longer recurrence-free survival and favorable overall survival in patients with HCC. Therefore, LRFA should be considered the primary therapy in patients with HCC eligible for RFA.
Subject(s)
Carcinoma, Hepatocellular , Catheter Ablation , Laparoscopy , Liver Neoplasms , Radiofrequency Ablation , Humans , Carcinoma, Hepatocellular/surgery , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Catheter Ablation/methods , Neoplasm Recurrence, Local/surgery , Retrospective Studies , Radiofrequency Ablation/methods , Laparoscopy/methods , Serum Albumin , Treatment OutcomeABSTRACT
Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the ß2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.
Subject(s)
Kupffer Cells , Liver Diseases, Alcoholic , Mice , Animals , Kupffer Cells/metabolism , Growth Differentiation Factor 15/metabolism , Growth Differentiation Factor 15/pharmacology , Lipopolysaccharides/metabolism , Liver Diseases, Alcoholic/genetics , Liver Diseases, Alcoholic/metabolism , Liver/metabolism , Ethanol/toxicity , Ethanol/metabolism , Inflammation/metabolism , ApoptosisABSTRACT
PURPOSE: The purpose of the study was to investigate whether the position of the central retinal vascular trunk (CRVT), as a surrogate for lamina cribrosa (LC) offset, is associated with the dominant hemisphere of visual field defect in primary angle-closure glaucoma (PACG) eyes. METHODS: Central retinal vascular trunk deviation was measured from Bruch's membrane opening (BMO) centre, which was delineated by OCT imaging, using the horizontal midline as a reference. The dominant hemisphere developing visual field defect was defined as three connected abnormal points (having a p-value < 5% probability of being normal) appearing in only one hemisphere or each point of the hemisphere having a statistically worse value compared with its mirrored point in the opposite hemisphere on pattern deviation plots. RESULTS: One hundred five (80%) of 132 eyes with PACG had dominant hemisphere of visual field defect initially: 70 eyes (67%) in the superior and 35 eyes (33%) in the inferior hemisphere. The CRVT was located superiorly in the dominant superior visual field defect group (p < 0.001). A logistic regression analysis revealed that superior deviation of the CRVT was the only factor associated with dominant superior visual field defect (p < 0.001). Externally oblique border (EOB) presence was associated with larger BMO (p = 0.005) and angular deviation of CRVT (p = 0.002). CONCLUSIONS: Central retinal vascular trunk deviation was associated with the dominant hemisphere of visual field defect in PACG eyes. This finding implies that the LC position relative to the BMO centre (LC/BMO offset) may incur structural vulnerability in the optic nerve head of PACG eyes.