Exploration of Immune-Modulatory Effects of Amivantamab in Combination with Pembrolizumab in Lung and Head and Neck Squamous Cell Carcinoma.

Immune checkpoint inhibitors are effective first-line therapy for solid cancers. However, low response rate and acquired resistance over time has led to the need for additional therapeutic options. Here, we evaluated synergistic antitumor efficacy of EGFR × MET targeting bispecific antibody, amivantamab with PD-L1 immunotherapy, pembrolizumab in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma tumor-bearing humanized patient-derived xenograft (PDX) models. We demonstrated that pembrolizumab or amivantamab alone was ineffective and that combination treatment induced a significant reduction of tumor growth in both models (P < 0.0001 and P < 0.01, respectively). It appeared that combination of amivantamab and pembrolizumab significantly enhanced infiltration of granzyme B-producing CD8 T cells was in the TME of HNSCC PDX (P < 0.01) and enhanced neoantigen-associated central memory CD8 T cells in circulating immune cells. Analysis of single-cell RNA transcriptomics suggested that the tumor cells dramatically upregulated EGFR and MET in response to PD-L1 immunotherapy, potentially creating a metabolic state fit for tumor persistence in the tumor microenvironment (TME) and rendered pembrolizumab ineffective. We demonstrated that EGFRHIGHMETHIGH subcluster displayed an increased expression of genes implicated in production of lactate [SLC16A3 and lactate dehydrogenase A (LDHA)] compared to the EGFRLOWMETLOW cluster. Accumulation of lactate in the TME has been associated with immunosuppression by hindering the infiltration of tumor killing CD8 T and NK cells. This study proved that amivantamab reduced glycolytic markers in the EGFRHIGHMETHIGH subcluster including SLC16A3 and LDHA and highlighted remodeling of the TME by combination treatment, providing rationale for additional therapy of amivantamab with PD-1 immunotherapy. SIGNIFICANCE: Amivantamab in synergy with pembrolizumab effectively eradicated EGFRHIGHMETHIGH tumor subcluster in the tumor microenvironment of head and neck squamous cell carcinoma and overcame resistance against anti-PD-1 immunotherapy.

Exploring aryl hydrocarbon receptor expression and distribution in the tumor microenvironment, with a focus on immune cells, in various solid cancer types.

Introduction: Aryl hydrocarbon receptor (AhR) is a transcription factor that performs various functions upon ligand activation. Several studies have explored the role of AhR expression in tumor progression and immune surveillance. Nevertheless, investigations on the distribution of AhR expression, specifically in cancer or immune cells in the tumor microenvironment (TME), remain limited. Examining the AhR expression and distribution in the TME is crucial for gaining insights into the mechanism of action of AhR-targeting anticancer agents and their potential as biomarkers. Methods: Here, we used multiplexed immunohistochemistry (mIHC) and image cytometry to investigate the AhR expression and distribution in 513 patient samples, of which 292 are patients with one of five solid cancer types. Additionally, we analyzed the nuclear and cytosolic distribution of AhR expression. Results: Our findings reveal that AhR expression was primarily localized in cancer cells, followed by stromal T cells and macrophages. Furthermore, we observed a positive correlation between the nuclear and cytosolic expression of AhR, indicating that the expression of AhR as a biomarker is independent of its localization. Interestingly, the expression patterns of AhR were categorized into three clusters based on the cancer type, with high AhR expression levels being found in regulatory T cells (Tregs) in non-small cell lung cancer (NSCLC). Discussion: These findings are anticipated to serve as pivotal evidence for the design of clinical trials and the analysis of the anticancer mechanisms of AhR-targeting therapies.

CD81 and CD82 expressing tumor-infiltrating lymphocytes in the NSCLC tumor microenvironment play a crucial role in T-cell activation and cytokine production.

Introduction: To understand the immune system within the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC), it is crucial to elucidate the characteristics of molecules associated with T cell activation. Methods: We conducted an in-depth analysis using single-cell RNA sequencing data obtained from tissue samples of 19 NSCLC patients. T cells were classified based on the Tumor Proportion Score (TPS) within the tumor region, and molecular markers associated with activation and exhaustion were analyzed in T cells from high TPS areas. Results: Notably, tetraspanins CD81 and CD82, belonging to the tetraspanin protein family, were found to be expressed in activated T cells, particularly in cytotoxic T cells. These tetraspanins showed strong correlations with activation and exhaustion markers. In vitro experiments confirmed increased expression of CD81 and CD82 in IL-2-stimulated T cells. T cells were categorized into CD81highCD82high and CD81lowCD82low groups based on their expression levels, with CD81highCD82high T cells exhibiting elevated activation markers such as CD25 and CD69 compared to CD81lowCD82low T cells. This trend was consistent across CD3+, CD8+, and CD4+ T cell subsets. Moreover, CD81highCD82high T cells, when stimulated with anti-CD3, demonstrated enhanced secretion of cytokines such as IFN-γ, TNF-α, and IL-2, along with an increase in the proportion of memory T cells. Bulk RNA sequencing results after sorting CD81highCD82high and CD81lowCD82low T cells consistently supported the roles of CD81 and CD82. Experiments with overexpressed CD81 and CD82 showed increased cytotoxicity against target cells. Discussion: These findings highlight the multifaceted roles of CD81 and CD82 in T cell activation, cytokine production, memory subset accumulation, and target cell cytolysis. Therefore, these findings suggest the potential of CD81 and CD82 as promising candidates for co-stimulatory molecules in immune therapeutic strategies for cancer treatment within the intricate TME.

Polo-like Kinase 4: A Multifaceted Marker Linking Tumor Aggressiveness and Unfavorable Prognosis, and Insights into Therapeutic Strategies.

(1) Background: This study investigated whether polo-like kinase 4 (PLK4) is a suitable therapeutic target or biomarker for lung adenocarcinoma (LUAD). (2) Methods: We acquired LUAD data from The Cancer Genome Atlas (TCGA) database through the UCSC Xena data portal. Gene expression, clinical, survival, and mutation data from multiple samples were analyzed. Gene enrichment analysis, unsupervised clustering of PLK4-related pathways, and differential gene expression analyses were performed. Additionally, correlations, t-tests, survival analyses, and statistical analyses were performed. (3) Results: PLK4 expression was higher in LUAD tissues than in normal tissues and was associated with poor prognosis for both overall and progression-free survival in LUAD. PLK4 was highly correlated with cell-proliferation-related pathways using Gene Ontology (GO) biological process terms. PLK4 expression and pathways that were highly correlated with PLK4 expression levels were upregulated in patients with LUAD with the TP53 mutation. (4) Conclusions: PLK4 expression affects the survival of patients with LUAD and is a potential therapeutic target for LUAD with TP53 mutations.

Is Routine Use of Drain Really Necessary for Posterior Lumbar Interbody Fusion Surgery? A Retrospective Case Series with a Historical Control Group.

STUDY DESIGN: A retrospective case-control study. OBJECTIVES: The usefulness of a drain in spinal surgery has always been controversial. The purposes of this study were to determine the incidence of hematoma-related complications after posterior lumbar interbody fusion (PLIF) without a drain and to evaluate its usefulness. METHODS: We included 347 consecutive patients with degenerative lumbar disease who underwent single- or double-level PLIF. The participants were divided into 2 groups by the use of a drain or not; drain group and no-drain group. RESULTS: In 165 cases of PLIF without drain, there was neither a newly developed neurological deficit due to hematoma nor reoperation for hematoma evacuation. In the no-drain group, there were 5 (3.0%) patients who suffered from surgical site infection (SSI), all superficial, and 17 (10.3%) patients who complained of postoperative transient recurred leg pain, all treated conservatively. Days from surgery to ambulation and length of hospital stay (LOS) of the no-drain group were faster than those of the drain group (P < 0.001). In a multiple regression analysis, a drain insertion was found to have a significant effect on the delayed ambulation and increased LOS. No significant differences existed between the 2 groups in additional surgery for hematoma evacuation, or SSI. CONCLUSIONS: No hematoma-related neurological deficits or reoperations caused by epidural hematoma and SSI were observed in the no-drain group. The no-drain group did not show significantly more frequent postoperative complications than the drain use group, hence the routine insertion of a drain following PLIF should be reconsidered carefully.

Treating AO Type C2-3 Distal Humerus Fractures With the Anconeus Flap Transolecranon Approach.

We evaluated the outcomes of precontoured locking plate fixation with the anconeus flap transolecranon (AFT) approach to treating AO type C2-3 comminuted intra-articular distal humerus (IDH) fractures among active patients. Thirty-six patients (age <65 years) with IDH fractures treated with precontoured distal humerus locking plate fixation were divided into 2 groups: group 1 (n=18; transolecranon [TO] approach) and group 2 (n=18; AFT approach). The radiographic examination included assessments of implant failure, fracture site union, and olecranon osteotomy site union. Clinical examination included assessments of operating time, range of motion (ROM), Mayo Elbow Performance Score (MEPS), Disability of the Arm, Shoulder and Hand (DASH) score, and complications. The mean follow-up time was 25.2 months (range, 18-79 months). The mean operating time was 134.3 minutes and was significantly longer for group 2 (AFT; 141.2 minutes) than for group 1 (TO; 124.2 minutes). The mean olecranon osteotomy site union time was significantly longer in group 2 (7.4 weeks) than in group 2 (4.0 weeks). Olecranon osteotomy site resorption occurred among 6 of 18 patients only in group 2. No significant difference in ROM (flexion, 130°; extension, -0.7°), MEPS (85.7 points), DASH score (20.0 points), or frequency of major complications (TO, 5; AFT, 6) was observed between the groups. Our results showed no advantage of the AFT approach over the TO approach, despite preserving the anconeus. Prospective randomized trials will be necessary to compare the AFT and TO approaches for treating comminuted IDH fractures. [Orthopedics. 2022;45(6):e326-e334.].

Pathologic Fracture of Femoral Neck in a Patient with Tumoral Calcinosis.

Tumoral calcinosis is a rare disease characterized by massive subcutaneous soft tissue deposits of calcium phosphate around large joints in patients with chronic kidney disease. Invasion of bone by tumoral calcinosis is rare. We experienced a case involving a femoral neck pathologic fracture due to bony invasion of tumoral calcinosis in a 46-year-old female with chronic kidney disease who had been on dialysis for 15 years. Successful outcomes were obtained by performance of total hip arthroplasty for treatment of the pathologic fracture of the femoral neck. Careful precaution is necessary to prevent pathologic fractures in patients with tumoral calcinosis around the hip joint.

Associations of walking and resistance training with chronic low back pain in older adults: A cross-sectional analysis of Korean National Health and Nutrition Examination Survey data.

ABSTRACT: Physical activities, such as resistance training and walking, are known to be effective against chronic low back pain (CLBP). However, few studies have examined the associations of walking and resistance training with CLBP in the general older population. Therefore, this study analyzed these relationships in the older Korean population (aged ≥65 years), with the goal of determining which exercise is better for CLBP.This cross-sectional study analyzed Korean National Health and Nutrition Examination Survey data for the period 2012 to 2015. The Korean National Health and Nutrition Examination Survey, which provides representative data for the Korean population, uses a clustered, multistage, random sampling method with stratification based on geographic area, age, and sex. Three multiple logistic regression models were generated in this study to determine the associations of walking and resistance training with CLBP.A total of 5233 participants were enrolled, 3641 (69.6%) of whom were free from CLBP; the remaining 1592 (30.4%) had CLBP. 78.4% and 64.8% of the non-CLBP and CLBP group patients, respectively, walked at least once a week. Also, 23.5% and 11.6% of the participants in the non-CLBP and CLBP groups, respectively, engaged in resistance training at least once a week. In the multiple logistic regression analysis, which was adjusted for all potential confounders, walking was significantly associated with a lower risk of CLBP (1-2d/wk: odds ratio [OR] = 0.65, P = .002; 3-4d/wk: OR = 0.69, P = .004; ≥5 d/wk: OR = 0.57, P < .001). However, resistance training showed no association with the risk of CLBP.In this cross-sectional study, walking was associated with a lower risk of CLBP. In particular, walking >5days per week had the maximum benefit in a lower risk of CLBP. Therefore, clinicians can consider recommending walking to patients with CLBP for optimal pain improvement.

Association between Chronic Knee Pain and Psychological Stress in Those over 50 Years of Age: A Nationwide Cross-Sectional Study Based on the Sixth Korea National Health and Nutrition Examination Survey (KNHANES 2013-2015).

Chronic knee pain (CKP) can degrade the quality of life and cause dysfunction, resulting in the loss of independence. Psychological stress not only affects physical and mental health but is also a risk factor for CKP. In this cross-sectional study, we analyzed data from the sixth Korea National Health and Nutrition Examination Survey (2013-2015), and investigated the association between CKP and psychological stress of the Korean general population. The CKP status was determined based on survey responses of self-reported knee pain lasting for more than 30 days during the last 3 months. Psychological stress was classified as none, mild, moderate, or severe. The association between CKP and psychological stress was analyzed using multiple logistic regression analysis considering co-variables and demographic data. Logistic regression analysis adjusting for co-variables indicated that the risk of CKP increased with an increasing degree of stress, from mild (OR = 1.65, 95% CI 1.35-2.03, p < 0.001) to moderate (OR = 2.00, 95% CI 1.56-2.57, p < 0.001) and severe (OR = 3.02, 95% CI 2.08-4.37, p < 0.001). A significant association between the risk of CKP and psychological stress was identified. Therefore, when evaluating patients with CKP, it may be helpful for clinicians to check the degree of stress.

Novel Findings of Polypoidal Choroidal Vasculopathy via Optical Coherence Tomography Angiography.

PURPOSE: To introduce novel findings of polypoidal choroidal vasculopathy (PCV) via optical coherence tomography angiography (OCTA). METHODS: This study is a retrospective chart review of 16 patients (16 eyes) with PCV. OCTA (Avanti RTVue XR) findings were evaluated and selected for analysis after agreement by two retina specialists . RESULTS: Twenty one polyps in 16 eyes (16 patients) with PCV were included in this study. The mean patient age was 67 years (13 men and three women). The shape of polypoidal lesions on OCTA at initial were halo (five polyps), rosette (seven polyps), and vascular network (nine polyps). Eight months after anti-vascular endothelial growth factor treatment, in a total of four eyes, seven polyps could be followed up completely, the two halo type polypoidal lesions changed to rosette and vascular network type. The lesions of three rosette and two vascular network type lesions did not change in shape. In addition, the size of the polypoidal lesions (one among two halo types, two among three rosette types, and two among two vascular network types) decreased, but one halo type did not change and one rosette type increased in size on OCTA. CONCLUSIONS: En-face OCTA enabled us to categorize novel types of PCV with polypoidal lesions.

Short-duration multiple-session subthreshold micropulse yellow laser (577 nm) for chronic central serous chorioretinopathy: results at 3 years.

OBJECTIVES: To review the 3-year follow-up results of subthreshold micropulse yellow laser (SMYL) delivered by a short-duration multiple-session method for treatment of chronic central serous chorioretinopathy (CSC). METHODS: A total of 27 eyes from 27 patients with chronic CSC available for 3 years of follow-up were enrolled in this retrospective and interventional study. Patients were treated with 577-nm SMYL photocoagulation at a 15% duty cycle over multiple sessions, with low power ranging from 200 to 400 mW that was increased in 100 mW increments according to resolution of subretinal fluid at monthly follow-up. Laser titration was not performed. A treatment duration of 20 ms rather than the conventional duration (100-300 ms) was applied over the area of retinal pigment epithelium leakage and all areas of serous retinal detachment, including the fovea. RESULTS: The mean follow-up period was 3.7 ± 0.8 years (range, 3-6 years). A total of 22 out of 27 eyes (81.5%) including six cases of recurrence during the follow-up period exhibited complete resolution of subretinal detachment at final follow-up, whereas only five eyes (15.5%) had either a partial or null response to SMYL treatment. The baseline best-corrected visual acuity was 0.26 ± 0.24 logarithm of the minimum angle of resolution (logMAR), which was improved to 0.08 ± 0.15 logMAR at 1-year (p = 0.005) and 3-year (p = 0.01) follow-up. The central macular thickness at baseline was 389.6 ± 103.4 µm, which was changed to 197.2 ± 40.0 µm (p < 0.001) at 1-year follow-up, 196.4 ± 40.2 µm (p < 0.001) at 3-year follow-up. CONCLUSION: Short-duration multiple-session SMYL therapy may be effective for long-term treatment of chronic CSC.

A case of ocular toxocariasis successfully treated with albendazole and triamcinolon.

We present a case of ocular toxocariasis treated successfully with oral albendazole in combination with steroids. A 26-year-old male visited the authors' clinic with the chief complaint of flying flies in his right eye. The fundus photograph showed a whitish epiretinal scar, and the fluorescein angiography revealed a hypofluorescein lesion of the scar and late leakage at the margin. An elevated retinal surface and posterior acoustic shadowing of the scar were observed in the optical coherence tomography, and Toxocara IgG was positive. The patient was diagnosed with toxocariasis, and the condition was treated with albendazole (400 mg twice a day) for a month and oral triamcinolone (16 mg for 2 weeks, once a day, and then 8 mg for 1 week, once a day) from day 13 of the albendazole treatment. The lesions decreased after the treatment. Based on this study, oral albendazole combined with steroids can be a simple and effective regimen for treating ocular toxocariasis.