Efficacy and Safety of Surgical Resection in Elderly Patients with Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Background/Aims: : With increased life expectancy, the management of elderly hepatocellular carcinoma (HCC) patients became a crucial issue, yet it is still challenging due to comorbidities and high surgical risks. While surgical resection is considered as primary treatment for eligible HCC patients, systematic evidence on its outcomes in elderly patients remains scarce. In this review, we aimed to analyze the efficacy and safety outcomes of surgical resection in elderly HCC patients. Methods: : The studies included in this meta-analysis were selected from Ovid-MEDLINE, Ovid-Embase, CENTRAL, KoreaMed, KMbase, and KISS databases following a predefined protocol. Efficacy outcomes included overall survival and disease-free survival, while the safety outcomes included postoperative mortality and complications. Results: : Patients in the elderly group (≥65 years) who underwent surgery exhibited non-inferior overall survival (hazard ratio [HR], 1.26; 95% confidence interval [CI], 0.92 to 1.74) and disease-free survival (HR, 1.03; 95% CI, 0.99 to 1.08) compared to the non-elderly group. Overall postoperative mortality exhibited no statistical difference (odds ratio [OR], 1.07; 95% CI, 0.87 to 1.31), but 30-day, 90-day, and in-hospital mortality were higher in the elderly group. The incidence of overall complications was higher in the elderly group (OR, 1.44; 95% CI, 1.22 to 1.69). Sensitivity analysis for the super elderly group (≥80 years) showed significantly higher in-hospital mortality compared to the non-super elderly group (OR, 2.51; 95% CI, 1.16 to 5.45). Conclusions: : The efficacy outcome of surgical resection in the elderly HCC patients was not worse than that in the non-elderly HCC patients, while in-hospital mortality and complications rates were higher. Therefore, surgical resection should be purposefully considered in the elderly population, with careful candidate selection.

An epidemic of cataract surgery in Korea: the effects of private health insurance on the National Health Insurance Service.

OBJECTIVES: In Korea, the National Health Insurance Service (NHIS) covers essential healthcare expenses, including cataract surgery. To address concerns that private health insurance (PHI) might have inflated the need for such procedures, we investigated the extent of the PHI-attributable increase in cataract surgery and its impact on NHIS-reimbursed expenses. METHODS: This retrospective, observational study uses nationwide claims data for cataract surgery from 2016 to 2020. We examined trends in utilization and cost, and we estimated the excess numbers of (1) cataract operations attributable to PHI and (2) types of intraocular lenses used for cataract surgery in 2020. RESULTS: Between 2016 and 2020, a 36.8% increase occurred in the number of cataract operations, with increases of 63.5% and 731.8% in the total healthcare costs reimbursed by NHIS and PHI, respectively. Over a 5-year period, the surgical rate per 100,000 people doubled for patients aged <65 years (from 328 in 2016 to 664 in 2020). Among the 619,771 cases in 2020 of cataract surgery reimbursed by the Korean diagnosis-related group system, more non-NHIS-covered intraocular lenses were used for patients aged <65 years than ≥65 years (68.1 vs. 14.2%). In 2020 alone, an estimated 129,311 excess operations occurred, accounting for an excess cost of US$115 million. CONCLUSIONS: A dramatic increase in the number and cost of cataract operations has occurred over the last 5 years. The PHI-related increase in operations resulted in increased costs to NHIS. Measures to curtail the non-indicated use of cataract surgery should be implemented regarding PHI.

Comparison of Cefazolin/Metronidazole to Ampicillin/Sulbactam as Preoperative Antibiotics in Colorectal Surgery: A Retrospective, Single-Center Cohort Study.

AIM: The use of prophylactic antibiotics prior to colorectal surgery reduces surgical site infections. Cefazolin and metronidazole are used as a standard regimen. Ampicillin/sulbactam may be an alternative, but current data are limited. We compared the efficacy of ampicillin/sulbactam with cefazolin and metronidazole as prophylactic antibiotics. METHODS: Patients who underwent colorectal surgery at Inha University Hospital between 2010 and 2020 were treated prophylactically with cefazolin and metronidazole or ampicillin/sulbactam, and observed for 30 days following surgery. The primary outcome was surgical site infections. The secondary outcomes were deep/organ infections and the need for drainage. RESULTS: SSIs occurred in 2.6% (17/646) of the ampicillin/sulbactam group, whose rate was not inferior to the occurrence in the group receiving cefazolin and metronidazole (3.8%, 21/556). There was no significant difference between the two groups in the secondary outcomes. CONCLUSIONS: Compared to the cefazolin and metronidazole combination, ampicillin/sulbactam is not inferior as a preoperative prophylactic antibiotic regimen for colorectal surgery.

Effects of depression on medication adherence in HIV/AIDS patients: Korea HIV/AIDS cohort study.

BACKGROUND: The number of people with HIV/AIDS has consistently increased in Korea since the first case of HIV/AIDS infection was reported in 1985. The depressive symptoms of patients with HIV/AIDS may lead to medication non-adherence. This study sought to investigate the cross-sectional and longitudinal association between depression and antiretroviral treatment adherence in the Korean HIV/AIDS population. METHODS: We included participants of the Korea HIV/AIDS cohort study between 2009 and 2017. All information was collected at the enrollment and every annual visit, including sociodemographic characteristics, health-related behaviors, HIV/AIDS infection-related factors, depression score, and frequency of skipped medication. We performed a cross-sectional analysis of 601 participants registered between 2009 and 2017. Longitudinal data were evaluated by panel regression analysis in 515 patients who registered from 2009 to 2013. RESULTS: In cross-sectional analysis, the HIV/AIDS patients with depressive symptoms were more likely to be non-adherent (adjusted OR = 0.52, 95 % CI 0.34, 0.79, p = 0.002). Medication adherence was significantly associated with a health-related lifestyle; the adjusted odds ratio of the non-smoking and non-drinking group was 1.75 (95 % CI 1.05, 2.90, p = 0.031). The longitudinal panel regression model revealed a significant negative impact of depression on medication adherence (adjusted OR = 0.50, 95 % CI 0.30, 0.84, p = 0.009). Non-smoking and non-drinking participants were 2.31 times more likely to adhere to antiretroviral treatment (95 % CI 1.29, 4.15, p = 0.005). CONCLUSIONS: Our finding of depression and lifestyle modifications being significant contributors underscore the importance of proactive interventions to optimize the treatment outcomes of PLWH.

Clinical evaluation of a deep-learning model for automatic scoring of the Alberta stroke program early CT score on non-contrast CT.

BACKGROUND: Automated measurement of the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) can support clinical decision making. Based on a deep learning algorithm, we developed an automated ASPECTS scoring system (Heuron ASPECTS) and validated its performance in a prespecified clinical trial. METHODS: For model training, we used non-contrast computed tomography images of 487 patients with acute ischemic stroke (AIS). For the clinical trial, 326 patients (87 with AIS, 56 with other acute brain diseases, and 183 with no brain disease) were enrolled. The results of Heuron ASPECTS were compared with the consensus generated by two stroke experts using the Bland-Altman agreement. A mean difference of less than 0.35 and a maximum allowed difference of less than 3.8 were considered the primary outcome target. The sensitivity and specificity of the model for the 10 regions of interest and dichotomized ASPECTS were calculated. RESULTS: The Bland-Altman agreement had a mean difference of 0.03 [95% confidence interval (CI): -0.08 to 0.14], and the upper and lower limits of agreement were 2.80 [95% CI: 2.62 to 2.99] and -2.74 [95% CI: -2.92 to -2.55], respectively. For ASPECTS calculation, sensitivity and specificity to detect the early ischemic change for 10 ASPECTS regions were 62.78% [95% CI: 58.50 to 67.07] and 96.63% [95% CI: 96.18 to 97.09], respectively. Furthermore, in a dichotomized analysis (ASPECTS >4 vs. ≤4), the sensitivity and specificity were 94.01% [95% CI: 91.26 to 96.77] and 61.90% [95% CI: 47.22 to 76.59], respectively. CONCLUSIONS: The current trial results show that Heuron ASPECTS reliably measures the ASPECTS for use in clinical practice.

Integrative Analyses Reveal the Anticancer Mechanisms and Sensitivity Markers of the Next-Generation Hypomethylating Agent NTX-301.

Epigenetic dysregulation characterized by aberrant DNA hypermethylation is a hallmark of cancer, and it can be targeted by hypomethylating agents (HMAs). Recently, we described the superior therapeutic efficacy of a novel HMA, namely, NTX-301, when used as a monotherapy and in combination with venetoclax in the treatment of acute myeloid leukemia. Following a previous study, we further explored the therapeutic properties of NTX-301 based on experimental investigations and integrative data analyses. Comprehensive sensitivity profiling revealed that NTX-301 primarily exerted anticancer effects against blood cancers and exhibited improved potency against a wide range of solid cancers. Subsequent assays showed that the superior efficacy of NTX-301 depended on its strong effects on cell cycle arrest, apoptosis, and differentiation. Due to its superior efficacy, low doses of NTX-301 achieved sufficiently substantial tumor regression in vivo. Multiomics analyses revealed the mechanisms of action (MoAs) of NTX-301 and linked these MoAs to markers of sensitivity to NTX-301 and to the demethylation activity of NTX-301 with high concordance. In conclusion, our findings provide a rationale for currently ongoing clinical trials of NTX-301 and will help guide the development of novel therapeutic options for cancer patients.

A Deep Learning-Based Automatic Collateral Assessment in Patients with Acute Ischemic Stroke.

This study aimed to develop a supervised deep learning (DL) model for grading collateral status from dynamic susceptibility contrast magnetic resonance perfusion (DSC-MRP) images from patients with large vessel occlusion (LVO) acute ischemic stroke (AIS) and compare its performance against experts' manual grading. Among consecutive LVO-AIS at three medical center sites, DSC-MRP data were processed to generate collateral flow maps consisting of arterial, capillary, and venous phases. With the use of expert readings as a reference, a DL model was developed to analyze collateral status with output classified into good and poor grades. The resulting model was externally validated in a later-collected population from one medical center site. The model was trained on 255 patients and externally validated on 72 patients. In the all-site internal validation population, DL grading of good collateral probability yielded a c statistic of 0.91; in the external validation population, the c statistic was 0.85. In the external validation population, there was moderate agreement between the experts' grades and DL grades (kappa = 0.53, 95% CI = 0.32-0.73, p < 0.0001). Day 7 infarct growth volume was higher in DL-graded poor collateral group than good collateral group patients (median volume [26 mL vs. 6 mL], p = 0.01) in patients with successful reperfusion (modified treatment in cerebral infarction (mTICI) = 2b-3). In all patients with a 90-day modified Rankin Scale (mRS) score, there was a shift to more favorable outcomes in the good collateral group, with a common odds ratio of 2.99 (95% CI = 1.89-4.76, p < 0.0001). The DL-based collateral grading was in good agreement with expert manual grading in both development and validation populations. After exclusion of patients with large infarct volume, early reperfusion is more likely to benefit patients with the poor collateral flow, and the DL method has the potential to aid the assessment of collateral status.

The effect of Epstein-Barr virus viremia on the progression to severe COVID-19.

ABSTRACT: Epstein-Barr virus (EBV) is frequently reactivated by coronavirus 2019 (COVID-19), and a high incidence of EBV viremia has been reported in patients with severe COVID-19. However, the impact of EBV viremia on progression to severe COVID-19 is unclear. Therefore, we conducted a study to evaluate the effect of EBV on COVID-19 progression.We investigated EBV viremia at the time of admission in COVID-19 patients hospitalized between February 1, 2020, and April 11, 2021. A cross-sectional study was performed to compare the severity of COVID-19 according to the presence or absence of EBV viremia. However, since it is difficult to analyze the influence of EBV viremia on COVID-19 progression with cross-sectional studies, a retrospective cohort study, limited to patients with mild COVID-19, was additionally conducted to observe progression to severe COVID-19 according to the presence or absence of EBV viremia.Two hundred sixty-nine COVID-19 patients were tested for EBV viremia. In a cross-sectional study that included patients with both mild and severe COVID-19, the EBV viremia group had more severe pneumonia than the EBV-negative group. However, in the cohort study limited to mild cases (N = 213), EBV viremia was not associated with COVID-19 progression.COVID-19 severity may affect EBV viremia; however, there was no evidence that EBV viremia was a factor in exacerbating pneumonia in patients with mild COVID-19.

Efficacy of Intravenous Mesenchymal Stem Cells for Motor Recovery After Ischemic Stroke: A Neuroimaging Study.

BACKGROUND AND PURPOSE: Stem cell-based therapy is a promising approach to repair brain damage after stroke. This study was conducted to investigate changes in neuroimaging measures using stem cell-based therapy in patients with ischemic stroke. METHODS: In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct were assigned to the autologous mesenchymal stem cell (MSC) treatment or control group. Of 54 patients who completed the intervention, 31 for the MSC and 13 for the control groups were included in this neuroimaging analysis. Motor function was assessed before the intervention and 90 days after randomization using the Fugl-Meyer assessment scale. Neuroimaging measures included fractional anisotropy values of the corticospinal tract and posterior limb of the internal capsule from diffusion tensor magnetic resonance imaging and strength of connectivity, efficiency, and density of the motor network from resting-state functional magnetic resonance imaging. RESULTS: For motor function, the improvement ratio of the Fugl-Meyer assessment score was significantly higher in the MSC group compared with the control group. In neuroimaging, corticospinal tract and posterior limb of the internal capsule fractional anisotropy did not decrease in the MSC group but significantly decreased at 90 days after randomization in the control group. Interhemispheric connectivity and ipsilesional connectivity significantly increased in the MSC group. Change in interhemispheric connectivity showed a significant group difference. CONCLUSIONS: Stem cell-based therapy can protect corticospinal tract against degeneration and enhance positive changes in network reorganization to facilitate motor recovery after stroke. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01716481.

Intracranial non-occlusive intraluminal thrombus may indicate underlying etiology of large vessel occlusion in patients undergoing endovascular therapy.

BACKGROUND: The underlying etiology of intracranial non-occlusive intraluminal thrombus (iNOT) remains unknown. This study aimed to investigate whether the presence of iNOT can indicate the underlying etiology of large vessel occlusion (LVO) in patients undergoing endovascular therapy (EVT). METHODS: Among patients who underwent EVT at three comprehensive stroke centers, we included those with intracranial LVO in the anterior circulation. The presence of iNOT was determined by pretreatment DSA. We investigated the association between iNOT and intracranial atherosclerotic stenosis (ICAS) related LVO. RESULTS: Of 546 patients, 44 (8.1%) had iNOT. Patients with iNOT were younger, had less hypertension, atrial fibrillation, and a history of antiplatelet use. In addition, the involvement of the M1 segment of the middle cerebral artery (MCA) was more frequent. However, they had a lower National Institutes of Health Stroke Scale (NIHSS) score on admission and longer onset to recanalization time compared with patients with no iNOT. In a logistic regression model adjusting for age, sex, atrial fibrillation, smoking, prior antiplatelet and anticoagulant use, intravenous tissue plasminogen activator, NIHSS on admission, number of technical trials, intraprocedural re-occlusion, and the location of LVO (p<0.10 in the univariate analysis), the presence of iNOT was significantly associated with ICAS related LVO (adjusted OR 3.04; 95% CI 1.33 to 6.90; p=0.007). CONCLUSIONS: The presence of iNOT may reflect an underlying ICAS related LVO in patients undergoing EVT.

An anti-cancer effect of Sambou bamboo saltTM in melanoma skin cancer both in vivo and in vitro models.

Bamboo salt has anti-allergic, anti-inflammatory, anti-oxidant, diabetics, anti-aging, and immune-enhancing effects, which are closely related to anti-cancer effect. The aim of this study was to investigate the anti-cancer effects of Sambou bamboo saltTM (SBS) in melanoma skin cancer in vivo and in vitro models. SBS-administered mice effectively reduced tumor growth and increased survival rate compared with B16F10 cell-inoculated mice without tissue damage, hepatotoxicity, and nephrotoxicity. SBS enhanced levels of immune-enhancing mediators, such as interferon-γ, interleukin (IL)-2, IL-6, IL-12, tumor necrosis factor-α, and IgE in serum and melanoma tissues. Furthermore, SBS enhanced activities of caspases and levels of Bax and p53, whereas decreased levels of Bcl-2. This reduction was a consequence of apoptosis signaling pathway. In conclusion, these results suggest that SBS is a potential substance for cancer therapy. SBS has the potential to be developed either as Korean traditional medicine or as a health functional food for cancer therapy. PRACTICAL APPLICATIONS: In these days cancer is one of the world's largest health problems. Bamboo salt is used as a Korean traditional food or medicine and has beneficial effect on inflammation. We have identified Sambou bamboo saltTM (SBS) is a potential substance for cancer therapy. These insights suggest that SBS can potentially be utilized for health functional foods for cancer treatment as well as improve various cancer diseases such as melanoma skin cancer.

Dp44mT regulates the levels of inflammatory mediators through blocking NF-κB nuclear translocation in LPS-stimulated RAW 264.7 macrophages.

Inflammation is increased by infection with pathogens such as viruses, bacteria, and parasites. High levels of inflammatory mediators and infiltration of macrophages into inflammatory lesions were reported in severe inflammatory diseases. Here, the aim of this study was to evaluate an anti-inflammatory activity of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Dp44mT (1-100 ng/mL) had no effect on viability of RAW 264.7 macrophages. Dp44mT (100 ng/mL) significantly reduced LPS-induced release of nitric oxide and expression of inducible nitric oxide synthase and cyclooxygenase-2. A significant upregulation of tumor necrosis factor (TNF)-α and interleukin (IL)-6 by LPS stimulation was downregulated by treatment with Dp44mT. Dp44mT blocked activation of nuclear factor-κB by the interruption of IκBα phosphorylation. Dp44mT suppressed the phagocytosis. Furthermore, administration of Dp44mT significantly reduced the serum levels of TNF-α and IL-6 in LPS-treated mice without side effects. In conclusion, these results indicate that Dp44mT has an anti-inflammatory activity and may be of therapeutic significant for the prevention and treatment of inflammatory diseases.

The immune-enhancing effect of anthocyanin-fucoidan nanocomplex in RAW264.7 macrophages and cyclophosphamide-induced immunosuppressed mice.

Aronia, a healthy fruit well known as black chokeberry, has health-promoting effects on hypertension, oxidative stress, and diabetes. Despite many reports of bioactivities of aronia, there is little scientific research on the potential for immune-enhancement. So, anthocyanin-fucoidan nanocomplex (AFNC, a nanocomplex of aronia extract and fucoidan) has been developed to improve immune-enhancement. This study aimed to identify immunomodulatory effects and underlying mechanisms of AFNC using RAW264.7 macrophages and cyclophosphamide-induced immunosuppressed mice. As a result, AFNC-treated RAW264.7 macrophages elevated the production of IL-2, IL-6, tumor necrosis factor (TNF)-α, and nitric oxide (NO). AFNC-enhanced inducible NO synthase expression via nuclear factor-κB signaling pathways. AFNC dose-dependently increased levels of IL-2, IL-6, TNF-α, IL-10, IL-12, interferon-γ, or IL-4 in the serum and spleen of immunosuppressed mice. Taken together, AFNC encourages the immune-enhancing activity through immunostimulatory cytokine production by activation of macrophage. Therefore, these results suggest that AFNC is useful for immunodeficiency-related disorders. PRACTICAL APPLICATIONS: In these days of prevalence of infectious diseases, individual immunity is very important. AFNC has the immune-enhancing effects through immunostimulatory cytokine production by activation of macrophage. Therefore, AFNC could be widely applied to ameliorate a variety of diseases caused by immunosuppression such as infectious diseases.

Efficacy and Safety of Intravenous Mesenchymal Stem Cells for Ischemic Stroke.

OBJECTIVE: To test whether autologous modified mesenchymal stem cells (MSCs) improve recovery in patients with chronic major stroke. METHODS: In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct within 90 days of symptom onset were assigned, in a 2:1 ratio, to receive preconditioned autologous MSC injections (MSC group) or standard treatment alone (control group). The primary outcome was the score on the modified Rankin Scale (mRS) at 3 months. The secondary outcome was to further demonstrate motor recovery. RESULTS: A total of 39 and 15 patients were included in the MSC and control groups, respectively, for the final intention-to-treat analysis. Mean age of patients was 68 (range 28-83) years, and mean interval between stroke onset to randomization was 20.2 (range 5-89) days. Baseline characteristics were not different between groups. There was no significant difference between the groups in the mRS score shift at 3 months (p = 0.732). However, secondary analyses showed significant improvements in lower extremity motor function in the MSC group compared to the control group (change in the leg score of the Motricity Index, p = 0.023), which was notable among patients with low predicted recovery potential. There were no serious treatment-related adverse events. CONCLUSIONS: IV application of preconditioned, autologous MSCs with autologous serum was feasible and safe in patients with chronic major stroke. MSC treatment was not associated with improvements in the 3-month mRS score, but we did observe leg motor improvement in detailed functional analyses. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that autologous MSCs do not improve 90-day outcomes in patients with chronic stroke. CLINICALTRIALSGOV IDENTIFIER: NCT01716481.

Phase II Study of Pemetrexed as a Salvage Chemotherapy for Thymidylate Synthase-Low Squamous Cell Lung Cancer.

PURPOSE: Squamous cell carcinomas (SqCC) of the lung often express high levels of thymidylate synthase (TS), which is associated with primary resistance to pemetrexed. We explored the efficacy of pemetrexed in a selected population of patients with lung SqCC with low TS expression. MATERIALS AND METHODS: In this single-arm phase II trial, we enrolled 32 previously-treated patients with advanced lung SqCC exhibiting low immunohistochemical staining for TS (i.e., in 10% or less of tumor cells). The primary endpoint was 12-week progression-free survival (PFS) rate. RESULTS: Of 32 patients, eight patients (25%) had an Eastern Cooperative Oncology Group performance status of 2, and seven patients (22%) had previously received three or more lines of chemotherapy. The disease control rate from pemetrexed treatment was 30%, and no objective response was observed. The 12-week PFS rate was 24.5% (95% confidence interval [CI], 13.0 to 46.1). Median PFS was 1.3 months (95% CI, 1.3 to 2.7), and median overall survival was 11.8 months (95% CI, 8.1 to not applicable). Most of adverse events were grade 1 or 2. CONCLUSION: Pemetrexed demonstrated modest activity as a salvage chemotherapy in patients with advanced lung SqCC with low TS expression, although its toxicity was generally manageable.

The Clinical Usefulness of Targeted Temperature Management in Acute Ischemic Stroke with Malignant Trait After Endovascular Thrombectomy.

BACKGROUND/OBJECTIVE: Targeted temperature management (TTM) may be more beneficial after endovascular treatment (EVT) in patients with a large ischemic core. Therefore, we assessed the usefulness of TTM for such patients from a multicenter endovascular registry. METHODS: Anterior circulation stroke patients who underwent endovascular recanalization were included; acute ischemic stroke with malignant traits was designated as (1) baseline Alberta Stroke Program Early CT Score (ASPECTS) below 6 and (2) diffusion-weighted imaging (DWI) lesion volume measurement (> 82 ml) or National Institutes of Health Stroke Scale score > 20 and item Ia > 0. TTM (34.5 °C) was maintained for at least 48 h. RESULTS: We evaluated baseline demographics, risk factors, EVT parameters, and clinical outcomes between the TTM and non-TTM groups. Among the 548 patients, the TTM group (n = 91) significantly had a lower baseline ASPECTS (p < 0.001) and a higher DWI volume (p < 0.001) than the non-TTM group (n = 457). TTM group had a lower prevalence of favorable outcome (0-2 of modified Rankin Scale at 3 months; p = 0.008) than the non-TTM group. In a subgroup analysis of malignant trait patients (n = 80), TTM patients (n = 28) had more favorable outcome (32.1% vs. 7.7% p = 0.009) and less hemorrhagic transformation (none vs. any hemorrhage, p = 0.007) than non-TTM patients (n = 52). After adjusting for potential outcome predictors, TTM (odds ratio [OR] 4.63; confidence interval [CI] 1.20-17.89; p = 0.026) and hypertension (OR 0.18; CI 0.04-0.74; p = 0.018) were found to be independent determinants. CONCLUSIONS: Our data suggest that TTM attenuates impending hemorrhagic transformation and leads to favorable clinical outcomes in EVT patients with malignant trait.

Sequential Treatment with an Immune Checkpoint Inhibitor Followed by a Small-Molecule Targeted Agent Increases Drug-Induced Pneumonitis.

PURPOSE: Immune checkpoint inhibitors (ICI) and targeted small-molecule drugs are mainstay elements of lung cancer chemotherapy. However, they are associated with development of pneumonitis, a rare, but potentially life-threatening event. We analyzed lung cancer patients treated with ICI to evaluate the effect of sequential therapeutic administration on the incidence of pneumonitis. MATERIALS AND METHODS: In this retrospective study, 242 patients were included. Serial radiologic findings taken during and immediately after ICI treatment were reviewed. Factors that increased pneumonitis and the relationship between peri-ICI chemotherapy and the development of pneumonitis were evaluated. RESULTS: Pneumonitis developed in 23 patients (9.5%); severe pneumonitis (grade ≥ 3) occurred in 13 of 23 patients (56%); pneumonitis-related death occurred in six. High-dose thoracic radiation (≥ 6,000 cGy) revealed a tendency toward high risk of pneumonitis (odds ratio, 2.642; 95% confidence interval, 0.932 to 7.490; p=0.068). Among 149 patients followed for ≥ 8 weeks after the final ICI dose, more patients who received targeted agents within 8-weeks post-ICI experienced pneumonitis (3/16, 18.8%) compared with patients who received cytotoxic agents (4/54, 7.4%) or no chemotherapy (4/79, 5.1%) (p=0.162). Targeted therapy was associated with earlier-onset pneumonitis than treatment with cytotoxic agents (35 vs. 62 days post-ICI, p=0.007); the resulting pneumonitis was more severe (grade ≥ 3, 100% vs. 0%, p=0.031). CONCLUSION: Sequential administration of small-molecule targeted agents immediately after ICI may increase the risk of severe pneumonitis. The sequence of chemotherapy regimens that include ICI and targeted agents should be carefully planned to reduce the risk of pneumonitis in lung cancer patients.

A fusion of CD63-BCAR4 identified in lung adenocarcinoma promotes tumorigenicity and metastasis.

BACKGROUND: Recently, fusion variants of the breast cancer anti-oestrogen-resistance 4 (BCAR4) gene were recurrently discovered in lung adenocarcinoma from the genome-wide studies. However, the functional characterisation of BCAR4 fusion has not been investigated. METHODS: Based on the analysis of RNA-sequencing data, we identified a fusion transcript of CD63-BCAR4 in a Korean patient with lung adenocarcinoma who did not harbour any known activating mutations in EGFR and KRAS genes. To investigate the oncogenic effect of CD63-BCAR4, in vitro and in vivo animal experiments were performed. RESULTS: In vitro experiments showed strongly enhanced cell migration and proliferation by the exogenous expression of CD63-BCAR4 protein in bronchial epithelial cells. Cell migration was notably reduced after knockdown of BCAR4 fusion by small-interfering RNA. The tumorigenic and metastatic capability of the CD63-BCAR4 fusion was confirmed by using the mouse xenograft model. Fusion-overexpressed cells result in metastasis to the liver and lung as well as the primary tumours after subcutaneous injection into mice. Cyclin D1, MMP1, Slug and mesenchymal markers were significantly increased after CD63-BCAR4 overexpression in the in vitro and in vivo experiments. CONCLUSIONS: Taken together, our results suggest a newly identified fusion gene, CD63-BCAR4 as a potential novel oncogene in lung adenocarcinoma.

Randomized phase II study of platinum-based chemotherapy plus controlled diet with or without metformin in patients with advanced non-small cell lung cancer.

OBJECTIVES: Accumulating evidence indicates anti-diabetic drug metformin has anti-cancer effect by controlling cancer metabolism. We evaluated whether addition of metformin to chemotherapy improved survival of lung cancer patients. MATERIALS AND METHODS: This randomized phase II study enrolled 164 patients with chemo-native, EGFR-ALK wild-type, stage IIIB/IV non-small-cell lung cancer (NSCLC). Patients were randomized to receive chemotherapy either with metformin (1000 mg twice daily) or alone every 3 weeks for six cycles. The patients received gemcitabine (1000 mg/m2) on days 1 and 8 and carboplatin (5 area under the curve) on day 1. Exploratory studies included serum metabolic panels, positron-emission tomography (PET) imaging, and genetic mutation tests for metabolism-related genes. RESULTS: Metformin group showed no significant difference in the risk of progression and death compared to control group (progression: hazard ratio [HR] = 1.01 [95% confidence interval (CI) = 0.72 - 1.42], P = 0.935; death: HR = 0.95 [95% CI = 0.67-1.34], P = 0.757). Squamous cell carcinoma (SqCC) had significantly higher fluorodeoxyglucose (FDG) uptake on baseline PET image than non-SqCC NSCLC (P = 0.004). In the SqCC with high FDG uptake, the addition of metformin significantly decreased the risk of progression and death (progression: HR = 0.31 [95% CI = 0.12-0.78], P = 0.013; death: HR = 0.42 [95% CI = 0.18-0.94], P = 0.035). The HDL-cholesterol level was significantly increased after the treatment in metformin group compared to control group (P = 0.011). The metformin group showed no survival benefit in the patients with hyperinsulinemia or patients whose insulin level was decreased after treatment. CONCLUSIONS: Addition of metformin to chemotherapy provided no survival benefit in unselected NSCLC patients. However, it significantly improved the survival of the selected patients with SqCC showing high FDG uptake. It suggests metformin shows the synergistic anti-tumor effect in the tumor which are highly dependent on glucose metabolism.