U-Shape Pillar Strip for 3D Cell-Lumped Organoid Model (3D-COM) Mimicking Lung Cancer Hypoxia Conditions in High-Throughput Screening (HTS).

Hypoxia is a representative tumor characteristic associated with malignant progression in clinical patients. Engineered in vitro models have led to significant advances in cancer research, allowing for the investigation of cells in physiological environments and the study of disease mechanisms and processes with enhanced relevance. In this study, we propose a U-shape pillar strip for a 3D cell-lumped organoid model (3D-COM) to study the effects of hypoxia on lung cancer in a high-throughput manner. We developed a U-pillar strip that facilitates the aggregation of PDCs mixed with an extracellular matrix to make the 3D-COM in 384-plate array form. The response to three hypoxia-activated prodrugs was higher in the 3D-COM than in the 2D culture model. The protein expression of hypoxia-inducible factor 1 alpha (HIF-1α) and HIF-2α, which are markers of hypoxia, was also higher in the 3D-COM than in the 2D culture. The results show that 3D-COM better recapitulated the hypoxic conditions of lung cancer tumors than the 2D culture. Therefore, the U-shape pillar strip for 3D-COM is a good tool to study the effects of hypoxia on lung cancer in a high-throughput manner, which can efficiently develop new drugs targeting hypoxic tumors.

Cancer organoid-based diagnosis reactivity prediction (CODRP) index-based anticancer drug sensitivity test in ALK-rearrangement positive non-small cell lung cancer (NSCLC).

BACKGROUND: Recently, cancer organoid-based drug sensitivity tests have been studied to predict patient responses to anticancer drugs. The area under curve (AUC) or IC50 value of the dose-response curve (DRC) is used to differentiate between sensitive and resistant patient's groups. This study proposes a multi-parameter analysis method (cancer organoid-based diagnosis reactivity prediction, CODRP) that considers the cancer stage and cancer cell growth rate, which represent the severity of cancer patients, in the sensitivity test. METHODS: On the CODRP platform, patient-derived organoids (PDOs) that recapitulate patients with lung cancer were implemented by applying a mechanical dissociation method capable of high yields and proliferation rates. A disposable nozzle-type cell spotter with efficient high-throughput screening (HTS) has also been developed to dispense a very small number of cells due to limited patient cells. A drug sensitivity test was performed using PDO from the patient tissue and the primary cancer characteristics of PDOs were confirmed by pathological comparision with tissue slides. RESULTS: The conventional index of drug sensitivity is the AUC of the DRC. In this study, the CODRP index for drug sensitivity test was proposed through multi-parameter analyses considering cancer cell proliferation rate, the cancer diagnosis stage, and AUC values. We tested PDOs from eight patients with lung cancer to verify the CODRP index. According to the anaplastic lymphoma kinase (ALK) rearrangement status, the conventional AUC index for the three ALK-targeted drugs (crizotinib, alectinib, and brigatinib) did not classify into sensitive and resistant groups. The proposed CODRP index-based drug sensitivity test classified ALK-targeted drug responses according to ALK rearrangement status and was verified to be consistent with the clinical drug treatment response. CONCLUSIONS: Therefore, the PDO-based HTS and CODRP index drug sensitivity tests described in this paper may be useful for predicting and analyzing promising anticancer drug efficacy for patients with lung cancer and can be applied to a precision medicine platform.

Current literature review on the tumor immune micro-environment, its heterogeneity and future perspectives in treatment of advanced non-small cell lung cancer.

Background and Objective: Immune checkpoint inhibitors (ICI) were a major clinical advancement that provided an opportunity to improve the prognosis of patients with non-small cell lung cancer (NSCLC). However, programmed death-ligand-1 (PD-L1) expression does not sufficiently predict ICI efficacy in NSCLC patients. In recent studies, the tumor immune microenvironment (TIME) was shown to have a central role in lung cancer progression and to affect clinical outcome of patients diagnosed with lung cancer. As development of new therapeutic targets to overcome ICI resistance is a priority, understanding the TIME is important. Recently, a series of studies was conducted to target each component of TIME to improve efficacy of cancer treatment. In this review, important features related to TIME, its heterogeneity and current trends in treatment targeting the component of TIME are discussed. Methods: PubMed and PMC were searched from January 1st, 2012 to August 16th, 2022 using the following key words: "NSCLC", "Tumor microenvironment", "Immune", "Metastasis" and "Heterogeneity". Key Content and Findings: Heterogeneity in the TIME can be either spatial or temporal. Subsequent to heterogeneous changes in the TIME, treatment of lung cancer can be more challenging because drug resistance is more likely to occur. In terms of the TIME, the main concept for increasing the chance of successful NSCLC treatment is to activate immune responses against tumor cells and inhibit immunosuppressive activities. In addition, relevant research is focused on normalizing an otherwise aberrant TIME in NSCLC patients. Potential therapeutic targets include immune cells, cytokine interactions, and non-immune cells such as fibroblasts or vessels. Conclusions: In management of lung cancer, understanding TIME and its heterogeneity is significant to treatment outcomes. Ongoing trials including various treatment modalities such as radiotherapy, cytotoxic chemotherapy, and anti-angiogenic treatment and regimens inhibiting other immunoinhibitory molecules are promising.

Trends and an Online Survey on the Use of Rigid Bronchoscopy in Korea.

BACKGROUND: Although almost all interventional pulmonologists agree that rigid bronchoscopy is irreplaceable in the field of interventional pulmonology, less is known about the types of diseases that the procedure is used for and what difficulties the operators face during the procedure. The purpose of this study is to evaluate what diseases rigid bronchoscopy is used for, whether it is widely used, and what challenges the operators face in Korea. METHODS: We enrolled 14 hospitals in this retrospective cohort of patients who underwent rigid bronchoscopy between 2003 and 2020. An online survey was conducted with 14 operators to investigate the difficulties associated with the procedure. RESULTS: While the number of new patients at Samsung Medical Center (SMC) increased from 189 in 2003-2005 to 468 in 2018-2020, that of other institutions increased from 0 to 238. The proportion of SMC patients in the total started at 100% and steadily decreased to 59.2%. The proportion of malignancy as the indication for the procedure steadily increased from 29.1% to 43.0%, whereas post-tuberculous stenosis (25.4% to 12.9%) and post-intubation stenosis (19.0% to 10.9%) steadily decreased (all P for trends < 0.001). In the online survey, half of the respondents stated that over the past year they performed less than one procedure per month. The fewer the procedures performed within the last year, the more likely collaboration with other departments was viewed as a recent obstacle (Spearman correlation coefficient, rs = -0.740, P = 0.003) and recent administrative difficulties were encountered (rs = -0.616, P = 0.019). CONCLUSION: This study demonstrated that the number of patients undergoing rigid bronchoscopy has been increasing, especially among cancer patients. For this procedure to be used more widely, it will be important for beginners to systematically learn about the procedure itself as well as to achieve multidisciplinary consultation.

[A case of abdominal wall actinomycosis].

Actinomycosis is a chronic suppurative granulomatous infectious disease caused by actinomyces species that is characterized by formation of characteristic clumps called as sulfur granules. Abdominal actinomycosis is a rare disease and is often difficult to diagnose before operation. Abdominal actinomycosis infiltrating into the abdominal wall and adhering to the colon is even rarer. Most abdominal actinomycosis develops after operation, trauma or inflammatory bowel disease, and is also considered as an opportunistic infection in immunocompromised patient with underlying malignancy, diabetes mellitus, human immunodeficiency virus infection, etc. Actinomycosis is diagnosed based on histologic demonstration of sulfur granules in surgically resected specimen or pus, and treatment consists of long-term penicillin based antibiotics therapy with or without surgical resection. Herein, we report an unusual case of abdominal wall actinomycosis which developed in a patient after acupuncture and presented as abdominal wall mass that was first mistaken for abdominal wall invasion of diverticulum perforation.