Immune checkpoint inhibitor score (IChIS) predicts survival benefit of immunotherapy in patients with non-small cell lung cancer.

Background: The use of immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer is increasing. Despite ongoing studies to predict the efficacy of ICIs, its use in clinical practice remains difficult. Thus, we aimed to discover a predictive marker by analyzing blood cell characteristics and developing a scoring system for patients treated with ICIs. Methods: This was a prospective multicenter study in patients with advanced non-small cell lung cancer (NSCLC) who received ICIs as second-line treatment from June 2021 to November 2022. Blood cell parameters in routine blood samples were evaluated using an automated hematology analyzer. Immune checkpoint inhibitor score (IChIS) was calculated as the sum of neutrophil count score and immature granulocyte score. Results: A total of 143 patients from 4 institutions were included. The treatment response was as follows: partial response, 8.4%; stable disease, 37.1%; and progressive disease, 44.8%. Median progression-free survival and overall survival after ICI treatment was 3.0 and 8.3 months, respectively. Median progression-free survival in patients with an IChIS of 0 was 4.0 months, which was significantly longer than 1.9 months in patients with an IChIS of 1 and 1.0 month in those with an IChIS of 2 (p = 0.001). The median overall survival in patients with an IChIS of 0 was 10.2 months, which was significantly longer than 6.8 and 1.8 months in patients with an IChIS of 1 and 2, respectively (p < 0.001). Conclusions: Baseline IChIS could be a potential biomarker for predicting survival benefit of immunotherapy in NSCLC.

Does the use of tranexamic acid intraoperatively reduce postoperative blood loss and complications following biportal endoscopic lumbosacral decompression?

Background: Biportal endoscopic spine surgery is an effective minimally invasive technique for treating common lumbar pathologies. We aim to evaluate the impact of intraoperative tranexamic acid (TXA) use on postoperative blood loss in biportal endoscopic decompression surgery. Methods: Patients undergoing biportal endoscopic lumbar discectomies and decompressions either by same day surgery or overnight stay at a single institution beginning in October 2021 were prospectively enrolled. This study was non-randomized, non-blinded with the first cohort of consecutive patients receiving 1 g of intravenous TXA intra-operatively before closure and the second cohort of consecutive patients receiving no TXA. Exclusion criteria included any revision surgery, any surgery for the diagnosis of spinal instability, infection, tumor, or trauma, any contraindication for TXA. Results: Eighty-four patients were included in the study, with 45 (54%) receiving TXA and 39 (46%) not receiving TXA. Median follow-up was 168 days [interquartile range (IQR), 85-368 days]. There were no differences in patient or surgical characteristics between cohorts. Estimated blood loss (EBL) was similar (P=0.20), while post-operative drain output was significantly lower in the TXA cohort (P=0.0028). Single level discectomies had significantly less drain output as compared to 2 level unilateral laminotomy, bilateral decompression (ULBD) cases (P<0.005). Post-operative complications were similar, with low rates of wound complication (1.2%) and transient postoperative weakness (2.4%, P>0.99 for both). Oswestry disability index (ODI), visual analog scale (VAS) back and VAS leg scores decreased significantly; the absolute decrease in scores did not differ between groups (P=0.71, 0.22, 0.86, respectively). Conclusions: Systemic intraoperative TXA administration is associated with a significant decrease in post-operative blood loss in biportal spinal endoscopy, with no impact on the improvement in patient-reported outcomes (PROs) or rate of post-operative complications. Single level biportal discectomies had significantly less postoperative drainage with TXA and may not need drains postoperatively. Larger, randomized studies are necessary to evaluate the cost-effectiveness of TXA use in biportal spinal endoscopy.

Nicotinamide in Combination with EGFR-TKIs for the Treatment of Stage IV Lung Adenocarcinoma with EGFR Mutations: A Randomized Double-Blind (Phase IIb) Trial.

PURPOSE: RUNX3 is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced RUNX3 in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR-tyrosine kinase inhibitors (TKI) for patients with stage IV lung cancer carrying EGFR mutations. PATIENTS AND METHODS: We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. RESULTS: After a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months [95% confidence interval (CI), 10.4-18.3], while the placebo group had a PFS of 10.9 months (9.0-13.2; P = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; P = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (P = 0.01) and never-smokers (P = 0.03) treated with nicotinamide. CONCLUSIONS: The addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked (ClinicalTrials.gov Identifier: NCT02416739).

ID1high/activin Ahigh glioblastoma cells contribute to resistance to anti-angiogenesis therapy through malformed vasculature.

Although bevacizumab (BVZ), a representative drug for anti-angiogenesis therapy (AAT), is used as a first-line treatment for patients with glioblastoma (GBM), its efficacy is notably limited. Whereas several mechanisms have been proposed to explain the acquisition of AAT resistance, the specific underlying mechanisms have yet to be sufficiently ascertained. Here, we established that inhibitor of differentiation 1 (ID1)high/activin Ahigh glioblastoma cell confers resistance to BVZ. The bipotent effect of activin A during its active phase was demonstrated to reduce vasculature dependence in tumorigenesis. In response to a temporary exposure to activin A, this cytokine was found to induce endothelial-to-mesenchymal transition via the Smad3/Slug axis, whereas prolonged exposure led to endothelial apoptosis. ID1 tumors showing resistance to BVZ were established to be characterized by a hypovascular structure, hyperpermeability, and scattered hypoxic regions. Using a GBM mouse model, we demonstrated that AAT resistance can be overcome by administering therapy based on a combination of BVZ and SB431542, a Smad2/3 inhibitor, which contributed to enhancing survival. These findings offer valuable insights that could contribute to the development of new strategies for treating AAT-resistant GBM.

Collagen Meniscal Scaffold Implantation Can Provide Meniscal Regeneration in Asian Patients with Partial Meniscal Defects: A Prospective Randomized Controlled Study with Three-Dimensional Volume Analysis of the Meniscus.

Background: To date, the efficiency of collagen meniscal scaffold implantation in Asian patients with partial meniscal defects has not been evaluated. In addition, no study has quantitatively analyzed meniscal regeneration using three-dimensional (3D) volume analysis after collagen scaffold implantation. We aimed to compare meniscal regeneration using 3D volume analysis between Asian patients undergoing collagen-based meniscal scaffold implantation after partial meniscectomy and those undergoing only partial meniscectomy. Methods: Nineteen patients who underwent collagen-based meniscal scaffold implantation and 14 who underwent partial meniscectomy were analyzed with a prospective randomized control design for 12 months postoperatively. The demographic characteristics, Kellgren-Lawrence grade, and location of the injury lesion (medial or lateral meniscus) were not significantly different between the groups. Using 3D volume analysis with magnetic resonance imaging (MRI), the meniscus-removing ratio during the operative procedure and the meniscus defect-filling ratio were measured during the 12-month postoperative period. Clinically, the visual analog scale, International Knee Documentation Committee score, and Knee Injury and Osteoarthritis Outcome Score were evaluated. The Whole-Organ Magnetic Resonance Imaging Score (WORMS) and Genovese grade were also evaluated using MRI. Results: In the 3D volume analysis, the average meniscus-removing ratio during surgery was not significantly different between the groups (-9.3% vs. -9.2%, p = 0.984). The average meniscus defect-filling ratio during the postoperative 12-month period was 7.5% in the scaffold group and -0.4% in the meniscectomy group (p < 0.001). None of the clinical results were significantly different between the scaffold and meniscectomy groups at 12 months postoperatively. The average change in the total WORMS score was not significantly different between the groups (0 vs. 1.9, p = 0.399). The Genovese grade of the implanted collagen scaffold did not significantly change during the follow-up period in terms of morphology and size (p = 0.063); however, the grade significantly improved in terms of signal intensity (p = 0.001). Conclusions: Definite meniscal regeneration and stable scaffold incorporation were observed after collagen-based meniscal scaffold implantation in Asian patients during 12 months of follow-up. A long-term follow-up study with a larger cohort is required to determine the advantages of collagenous meniscal scaffold implantation in Asian patients.

ARF4-mediated retrograde trafficking as a driver of chemoresistance in GBM.

BACKGROUND: Cellular functions hinge on the meticulous orchestration of protein transport, both spatially and temporally. Central to this process is retrograde trafficking, responsible for targeting proteins to the nucleus. Despite its link to many diseases, the implications of retrograde trafficking in glioblastoma (GBM) are still unclear. METHODS: To identify genetic drivers of TMZ resistance, we conducted comprehensive CRISPR-knockout screening, revealing ADP-ribosylation factor 4 (ARF4), a regulator of retrograde trafficking, as a major contributor. RESULTS: Suppressing ARF4 significantly enhanced TMZ sensitivity in GBM patient-derived xenograft (PDX) models, leading to improved survival rates (p<0.01) in both primary and recurrent lines. We also observed that TMZ exposure stimulates ARF4-mediated retrograde trafficking. Proteomics analysis of GBM cells with varying levels of ARF4 unveiled the influence of this pathway on EGFR signaling, with increased nuclear trafficking of EGFR observed in cells with ARF4 overexpression and TMZ treatment. Additionally, spatially-resolved RNA-sequencing of GBM patient tissues revealed substantial correlations between ARF4 and crucial nuclear EGFR (nEGFR) downstream targets, such as MYC, STAT1, and DNA-PK. Decreased activity of DNA-PK, a DNA repair protein downstream of nEGFR signaling that contributes to TMZ resistance, was observed in cells with suppressed ARF4 levels. Notably, treatment with DNA-PK inhibitor, KU57788, in mice with a recurrent PDX line resulted in prolonged survival (p<0.01), highlighting the promising therapeutic implications of targeting proteins reliant on ARF4-mediated retrograde trafficking. CONCLUSION: Our findings demonstrate that ARF4-mediated retrograde trafficking contributes to the development of TMZ resistance, cementing this pathway as a viable strategy to overcome chemoresistance in GBM.

Atypical post-infectious glomerulonephritis with c-ANCA positivity followed by endocarditis.

Post-infectious glomerulonephritis (PIGN), an uncommon variety of glomerulonephritis (GN), is characterized by emergence of nephritic syndrome within a few weeks following an infectious event. PIGN typically presents as a mild condition and tends to resolve by the time of diagnosis for GN. Aggregatibacter actinomycetemcomitans belongs to the HACEK group of bacteria, which constitutes less than 3% of bacteria responsible for community-acquired infective endocarditis. We present a case of 29-year-old man suspected of lymphoma with B-symptoms along with severe splenomegaly and nephromegaly. Shortly after, he developed an episode of nephritic syndrome accompanied by acute kidney injury (AKI) and high titers of cytoplasmic ANCA (c-ANCA)-positivity. Kidney biopsy revealed PIGN with tubulointerstitial nephritis. Despite treatment with antibiotics and corticosteroid, he visited the emergency room due to worsening dyspnea and multi-organ failure. An echocardiogram showed a bicuspid aortic valve with vegetation unseen on previous echocardiogram. He underwent aortic valve replacement immediately without adverse events. Four months after valve replacement, his renal function and cardiac performance have remained stable. We report a case of PIGN with AKI and high titers of c-ANCA appearing later as an infective endocarditis due to Aggregatibacter actinomycetemcomitans. With careful clinical observation and appropriate and timely management, satisfactory outcomes for patient health are possible.

Association between Weight Change and Incidence of Dyslipidemia in Young Adults: A Retrospective Cohort Study of Korean Male Soldiers.

Background: Recent lifestyle changes have increased the prevalence of dyslipidemia in Korea. Young men are known to have a low awareness of dyslipidemia and a lack of motivation to maintain their weight. However, the association between weight change and dyslipidemia in young adults has not been thoroughly examined. Methods: Data from the Armed Forces Medical Command Defense Medical Information System database were used. In this study, 15,068 soldiers who underwent private and corporal health examinations between May 2020 and April 2022 were included. The difference in weights between the two different health examinations was used to quantify weight change. Four components of the lipid profile were used to assess dyslipidemia during the corporal health examination. Results: After adjusting for relevant covariates, weight gain was associated with increased risk of dyslipidemia (adjusted odds ratio [OR], 1.38 [95% confidence interval, CI, 1.15 to 1.64] for the 5% to 10% weight gain group; and OR, 2.02 [95% CI, 1.59 to 2.55] for the ≥10% weight gain group), whereas weight loss was associated with decreased risk (adjusted OR, 0.82 [95% CI, 0.68 to 0.98] for the 5% to 10% weight loss group; and OR, 0.38 [95% CI, 0.27 to 0.53] for the ≥10% weight loss group). In subgroup analysis based on the participants' baseline body mass index, smoking status, regular exercise habits, and hypertension status, there were no significant differences between the subgroups. Conclusion: Weight change was associated with dyslipidemia in Korean male soldiers. The findings suggest that limiting weight gain in young adults by encouraging a healthy lifestyle may help prevent dyslipidemia.

Phase 1/2a Study of Rivoceranib, a Selective VEGFR-2 Angiogenesis Inhibitor, in Patients with Advanced Solid Tumors.

Purpose: To report the results from an early-phase study of rivoceranib, an oral tyrosine kinase inhibitor highly selective for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors. Materials and Methods: In this open-label, single-arm, dose-escalating, multicenter three-part phase 1/2a trial, patients had advanced solid tumors refractory to conventional therapy. Part 1 evaluated the safety and pharmacokinetics of five ascending once-daily doses of rivoceranib from 81 mg to 685 mg. Part 2 evaluated the safety and antitumor activity of once-daily rivoceranib 685 mg. Part 3 was conducted later, due to lack of MTD determination in part 1, to evaluate the safety and preliminary efficacy of once-daily rivoceranib 805 mg in patients with unresectable or advanced gastric cancer. Results: A total of 61 patients were enrolled in parts 1 (n=25), 2 (n=30), and 3 (n=6). In parts 1 and 2, patients were white (45.5%) or Asian (54.5%), and 65.6% were male. The most common grade ≥3 adverse events (AEs) were hypertension (32.7%), hyponatremia (10.9%), and hypophosphatemia (10.9%). The overall response rate (ORR) was 15.2%. In part 3, dose-limiting toxicities occurred in 2 out of 6 patients: grade 3 febrile neutropenia decreased appetite, and fatigue. The ORR was 33%. Conclusion: The recommended phase 2 dose of rivoceranib was determined to be 685 mg once daily, which showed adequate efficacy with a manageable safety profile. (NCT01497704 and NCT02711969).

Real-world outcome of crizotinib for anaplastic lymphoma kinase-positive lung cancer: Multicenter retrospective analysis in South Korea.

BACKGROUND: About 3%-5% of non-small cell lung cancer (NSCLC) presents positive anaplastic lymphoma kinase (ALK). Recently, several target agents have been approved as a treatment for ALK-positive NSCLC. This study aimed to analyze the real-world efficacy and outcome when administered crizotinib, the first approved target agent for ALK-positive NSCLC, according to first- or late-line treatment. METHODS: A total of 290 patients with ALK-positive advanced NSCLC who were treated with crizotinib in 15 institutions in South Korea from January 2009 to December 2018 were enrolled. RESULTS: The median age of patients was 57.0 years, and 50.3% were male. The median follow-up duration was 29.3 months. Among them, 113 patients received crizotinib as first-line therapy. The objective response rate (ORR) was 60.1% (57.0% for first-line recipients, 61.8% for second-/later-line). Median (95% CI) progression-free survival (PFS) was 13.7 (11.6-17.0) months. For first-line recipients, overall survival (OS) was 26.3 (17.6-35.0) months. No significant difference in ORR, PFS and OS, according to the setting of crizotinib initiation, was observed. In a multivariate Cox regression analysis, old age, male gender, initially metastatic, and number of metastatic organs were associated with poor PFS and OS. The most common adverse events were nausea and vomiting, and severe adverse event leading to dose adjustment was hepatotoxicity. CONCLUSIONS: ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials. Our findings could aid in the efficient management of ALK-positive lung cancer patients.

Similar Midterm Outcomes of Total Knee Arthroplasties with Anterior and Posterior Tibial Slopes Performed on Paired Knees at a Minimum Follow-up of 5 Years.

A small posterior tibial slope (PTS) is generally recommended in posterior stabilized (PS) total knee arthroplasty (TKA). An unwanted anterior tibial slope (ATS), which can affect postoperative results, may be created in PS TKA because of the inaccuracy of surgical instruments and techniques, as well as high interpatient variability. We compared midterm clinical and radiographic results of PS TKAs with ATS and PTS performed on paired knees using the same prosthesis. One-hundred-twenty-four patients who underwent TKAs with ATS and PTS on paired knees using ATTUNE posterior-stabilized prostheses were retrospectively reviewed after a minimum follow-up period of 5 years. The mean follow-up period was 5.4 years. The Knee Society Knee and Function scores, Western Ontario and McMaster Universities Osteoarthritis Index, Feller and Kujalar scores, and range of motion (ROM) were evaluated. The preferred TKA out of ATS and PTS was also investigated. The hip-knee-ankle angle, component positions, tibial slope, posterior femoral offset, Insall-Salvati ratio, and knee sagittal angle were measured by radiography. There were no significant differences in the clinical results, including ROM, between TKAs with ATS and PTS preoperatively and at the last follow-up. Regarding patient preference, 58 patients (46.8%) were satisfied with bilateral knees, 30 (24.2%) preferred knees with ATS, and 36 (29%) preferred knees with PTS. There was no significant difference in the rate of preference between TKAs with ATS and PTS (p = 0.539). Except for the postoperative tibial slope (-1.8 vs. 2.5 degrees, p < 0.001), there were also no significant differences in the radiographic results, including the knee sagittal angle, preoperatively and at the last follow-up. The midterm outcomes were similar between PS TKAs with ATS and PTS performed on paired knees at a minimum of 5 years of follow-up. Nonsevere ATS did not affect midterm outcomes in PS TKA with proper soft tissue balancing and the current prosthesis of improved design. However, a long-term follow-up study is required to confirm the safety of nonsevere ATS in PS TKA. LEVEL OF EVIDENCE:: III.

Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth.

Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8). We hypothesized that TAMCs provide creatine to tumors, promoting GBM progression. Isotopic tracing demonstrated that TAMC-secreted creatine is taken up by tumor cells. Creatine supplementation protected tumors from hypoxia-induced stress, which was abrogated with genetic ablation or pharmacologic inhibition of SLC6A8. Lastly, inhibition of creatine transport using the clinically relevant compound, RGX-202-01, blunted tumor growth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche.

Evaluation of adrenal masses using 18 F-FDOPA PET/CT in patients suspected with pheochromocytoma.

OBJECTIVE: Pheochromocytomas (PHEOs) are chromaffin cell-derived adrenal tumors. 6-[ 18 F]-L-fluoro-L-3, 4-dihydroxyphenylalanine ( 18 F-FDOPA) is a radiotracer taken up in neuroendocrine chromaffin cells via the L-type amino-acid transporter. 18 F-FDOPA is useful in patients with PHEO. However, more information about the use of 18 F-FDOPA PET/CT scan is needed. Thus, the current study investigated various PET parameters on preoperative 18 F-FDOPA PET/CT scan. METHODS: The 18 F-FDOPA PET/CT scan findings of 29 patients who underwent adrenalectomy after PET/CT scans were evaluated according to their pathologic diagnosis. Thereafter, the patients were classified under different risk groups which were compared based on the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP). RESULTS: In terms of histopathologic results after surgery, 24 patients presented with PHEO. The remaining 5 patients were diagnosed with adrenal cortical adenomas or adrenal medullary hyperplasia. The maximum standardized uptake value, mean standardized uptake value, tumor-to-liver ratio, and tumor-to-contralateral adrenal gland ratio of PHEOs on preoperative 18 F-FDOPA PET/CT scan were higher than those of other tumors. The metabolic tumor volume (MTV) and total lesion uptake of PHEOs in the intermediate-risk group (n = 19) were higher than those in the low-risk group (n = 5). The MTV and total lesion uptake were significantly correlated with the GAPP score. CONCLUSION: Preoperative 18 F-FDOPA PET/CT is helpful to identifying PHEOs. In addition, imaging interpretation using the standardized uptake value of the suspected tumor or the tumor-to-liver/contralateral adrenal gland ratio can be effective. The metabolic parameters of PHEOs are positively correlated with the GAPP score.

Real-World Treatment Outcomes and Safety of Afatinib in Advanced Squamous Cell Lung Cancer Progressed after Platinum-Based Doublet Chemotherapy and Immunotherapy (SPACE Study).

This study aimed to evaluate treatment outcomes and safety of afatinib in patients with squamous cell carcinoma of the lung (LSCC) who progressed after chemotherapy and immunotherapy. We recruited patients both retrospectively and prospectively and collected the outcomes and safety data. Additionally, we performed next-generation sequencing using tumor tissue and/or plasma to explore potential molecular biomarkers. Altogether, 42 patients were included in the final analysis. The median number of prior treatments was three (range 1-8), and the median TTF was 2.1 months. Objective response rate and disease control rate were 16.2% and 59.5%, respectively, and median duration of response was 4.0 months among response evaluable patients (n = 37). Treatment-related adverse events (TRAEs, including diarrhea, stomatitis, and paronychia) occurred in 22 (52.3%) patients; however, most were grade 2 or lower, and only 5 cases were grade 3. TRAEs led to dose modification in 17 (40.5%) and discontinuation in 4 (9.5%) patients. The TTF in patients with ERBB2 mutations was significantly longer than that in patients without (6.8 vs. 2.1 months, p = 0.045). Our results highlight that afatinib is a reasonable treatment option in terms of effectiveness and safety, and ERBB2 mutation can be used as a predictive biomarker in clinical settings.

Surgical accuracy of coronal and sagittal alignment in conventional closed-wedge high tibial osteotomy after computer-assisted surgery experience.

BACKGROUND: Although intraoperative navigation can improve the surgeon's proficiency, no studies have analyzed postoperative outcomes of high tibial osteotomy (HTO) after computer-assisted surgery (CAS) experience. The present study compared the clinical and radiographic results between conventional and CAS closed-wedge (CW) HTOs after CAS experience. METHODS: Each of the 50 conventional and CAS CW HTOs performed by single surgeon between 2015 and 2017 were included. The surgeon had experience of 140 cases of CAS CW HTOs before the study period. The groups were not different in terms of demographics. Clinically, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and range of motion (ROM) were investigated. Radiographically, the mechanical axis (MA), change in posterior tibial slope angle (PTS), and parallel angle were evaluated. The proportions of inlier groups for the postoperative MA (within valgus 2° ± 3°), change in the PTS (within ± 3°), and parallel angle (< 3°) were compared. RESULTS: There were no significant differences in postoperative clinical results between the conventional and CAS groups. The MA was appropriately corrected in both groups (2.4° versus 2.9°, p = 0.317). The amount of change in PTS was significantly greater in the conventional group (-2.2° versus -0.8°, p = 0.018). The parallel angle was 5.3° in the conventional groups and 3.1° in the CAS group (p = 0.003). The proportion of inlier group was not significantly different in the postoperative MA (72% versus 78%) and change in the PTS (52% versus 66%). The proportion of inlier for the parallel angle was significantly lower in the conventional group (36% versus 60%, p = 0.027). CONCLUSIONS: The surgical proficiency after CAS experience could cover the advantages of an intraoperative navigation in coronal adjustment, not in the sagittal adjustments in CW HTOs. A larger cohort with multiple surgeons in multiple centers would be required to identify the general trend. STUDY DESIGN: Level of evidence III.

Extracellular Superoxide Dismutase Attenuates Hepatic Oxidative Stress in Nonalcoholic Fatty Liver Disease through the Adenosine Monophosphate-Activated Protein Kinase Activation.

Oxidative stress is key in type 2 diabetes-associated nonalcoholic fatty liver disease (NAFLD). We explored whether extracellular superoxide dismutase (EC-SOD) activates adenosine monophosphate-activated protein kinase (AMPK) to enhance antioxidant synthesis and lipid metabolism in NAFLD. Human recombinant EC-SOD (hEC-SOD) was administered to 8-week-old male C57BLKS/J db/db mice through intraperitoneal injection once a week for 8 weeks. Target molecules involved in oxidative stress and lipid metabolism were investigated. hEC-SOD improved insulin resistance and systemic and hepatic oxidative stress characterized by increases in urinary 8-hydroxy-deoxyguanosine and 8-isoprostane levels in db/db mice and a decrease in DHE expression in the liver, respectively. Hepatic SOD3 expression in db/db mice was reversed by hEC-SOD, which improved hepatic steatosis, inflammation with M2 polarization, apoptosis, autophagy, fibrosis and lipid metabolism in db/db mice, as reflected by the changes in serum and hepatic markers, monocyte chemoattractant protein-1, tumor necrosis factor-α, TUNEL-positive cells, Bcl-2/BAX ratio, beclin1 and LC3-II/LC3-1. At the molecular level, hEC-SOD increased phosphorylated-AMPK related to CaMKKß, activation of peroxisome proliferative-activated receptor-gamma coactivator (PGC)-1α and dephosphorylation of forkhead box O (FoxO)1 and their subsequent downstream signaling. In HepG2Cs cells using AMPKα1 and AMPKα2 siRNA, hEC-SOD demonstrated a protective effect via the direct activation of both AMPK-PGC-1α and AMPK-FoxO1. EC-SOD might be a potential therapeutic agent for NAFLD through the activation of AMPK-PGC-1α and AMPK-FoxO1 signaling in hepatocytes, which modulates lipid metabolism, leading to anti-inflammatory, antioxidative and antiapoptotic effects and improving autophagy in the liver.

Predictors of Recurrent Flexion Contracture after Total Knee Arthroplasty in Osteoarthritic Knees with Greater Than 15° Flexion Contracture.

Background: This study aimed to analyze the risk factors that predict recurrent flexion contracture (FC) after total knee arthroplasty (TKA) in osteoarthritic knees with FC ≥ 15°. Methods: Data from a consecutive cohort comprising 237 TKAs in 187 patients with degenerative osteoarthritis, preoperative FC ≥ 15°, and a minimum follow-up period of 2 years were retrospectively reviewed. Preoperative FC was corrected intraoperatively from 0° to 5°. The incidence of recurrent FC (FC ≥ 10°) at 2 years postoperatively was investigated. Potential risk factors predicting recurrent FC including age, sex, body mass index, unilateral TKA, severity of preoperative FC, 3-month postoperative residual FC, γ angle, change in posterior femoral offset ratio, and lumbar degenerative kyphosis (LDK) were analyzed using logistic regression analysis. The post-hoc powers for the identified factors were then determined. Results: Forty-one knees (17.3%) with recurrent FC were identified. Risk factors with sufficient power for recurrent FC were unilateral TKA, severity of preoperative FC, residual FC at 3 months postoperatively, and LDK (odds ratios of 3.579, 1.115, 1.274, and 3.096, respectively; p < 0.05; power ≥ 86.1). Conclusions: Recurrent FC can occur in TKAs with the risk factors including unilateral TKA, severe preoperative FC, residual FC at 3 months postoperative, and LDK despite appropriate intraoperative correction. Surgical strategies and rehabilitation protocols used in managing FC should be applied in TKA cases with risk factors for recurrent FC.

Learning curve for robot-assisted knee arthroplasty; optimizing the learning curve to improve efficiency.

The introduction of robot-assisted (RA) systems in knee arthroplasty has challenged surgeons to adopt the new technology in their customized surgical techniques, learn system controls, and adjust to automated processes. Despite the potential advantages of RA knee arthroplasty, some surgeons remain hesitant to adopt this novel technology owing to concerns regarding the cumbersome adaptation process. This narrative review addresses the learning-curve issues in RA knee arthroplasty based on the existing literature. Learning curves exist in terms of the operative time and stress level of the surgical team but not in the final implant positions. The factors that reduce the learning curve are previous experience with computer-assisted surgery (including robot or navigation systems), specialization in knee surgery, high volume of knee arthroplasty, optimization of the RA workflow, sequential implementation of RA surgery, and consistency of the surgical team. Worse clinical outcomes may occur in the early postoperative period, but not in the later period, in RA knee arthroplasty performed during the learning phase. No significant differences were observed in implant survival or complication rates between the RA knee arthroplasties performed during the learning and proficiency phases.

Serum KL-6 levels predict the occurrence and severity of treatment-related interstitial lung disease in lung cancer.

In this study, we aimed to investigate the feasibility of serum Krebs von den Lungen-6 (KL-6) as a potential biomarker for treatment-related ILD (TR-ILD) in lung cancer. We recruited patients with lung cancer in whom KL-6 was measured to differentiate between pneumonia and ILD (category 1), diagnose and assess the severity of suspicious ILD (category 2), or evaluate baseline levels before cancer treatment (category 3). Among 1,297 patients who underwent KL-6 testing, 422 had lung cancer, and TR-ILD was detected in 195 patients. In categories 1-2, median KL-6 level was higher in drug-induced ILD or acute exacerbation of underlying ILD than in no ILD or radiation-induced pneumonitis, and it was correlated with the severity of TR-ILD. High KL-6 level (cut-off: > 436U/mL) was an independent risk factor for severe TR-ILD, and low KL-6 level with high procalcitonin level (> 0.5 ng/mL) could exclude severe TR-ILD. Patients with severe TR-ILD had worse overall survival than those without, whereas high baseline KL-6 level was associated with worse survival, especially in patients without severe TR-ILD. Therefore, serum KL-6 may be a surrogate marker for predicting the occurrence and assessing the severity of TR-ILD at the time of suspected ILD and before lung cancer treatment.

Biportal Endoscopic Approach for Lumbar Degenerative Disease in the Ambulatory Outpatient vs Inpatient Setting: A Comparative Study.

BACKGROUND: Biportal spinal endoscopy is increasingly utilized for lumbar disc herniations and lumbar stenosis. The objective was to investigate the safety and effectiveness of the technique in the outpatient vs inpatient setting. METHODS: This is a comparative study of consecutive patients who underwent biportal spinal endoscopy by a single surgeon at a single institution. Demographics, surgical complications, and patient-reported outcomes were prospectively collected and retrospectively analyzed. Statistics were calculated among treatment groups using unpaired t test and χ 2 analysis where appropriate. Statistical significance was determined as P < 0.05. RESULTS: Eighty-four patients were included, 58 (69.0%) as outpatient, 26 (31.0%) as inpatient. Mean follow-up was 7.5 months. Statistically significant differences in age, American Society of Anesthesiologists classification, and Charleston Comorbidity Index scores were reported between cohorts, with younger and healthier patients undergoing outpatient surgery (P < 0.0001). Outpatients were more likely to have discectomies while inpatients were more likely to have decompressions for stenosis. No significant differences in postoperative complications were found between groups.Both cohorts demonstrated significant improvement in visual analog scale (VAS) back and leg pain scores and Oswestry Disability Index scores (P < 0.001). Outpatients had significantly lower postoperative VAS back pain (P = 0.001) and Oswestry Disability Index scores (P = 0.004) at 5-8 weeks compared with inpatients, but there was no significant difference for VAS leg pain scores at all time points between the cohorts. CONCLUSIONS: Early results demonstrate that biportal spinal endoscopy can safely and effectively be performed in both inpatient and outpatient settings. CLINICAL RELEVANCE: Outpatient biportal spinal endoscopy can be performed successfully in well selected patients, which may reduce the financial burden of spine surgery to the U.S. healthcare system.