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The pathology of late-onset Alzheimer’s disease (LOAD) is still poorly understood, but it is multifactorial and closely related to changes with aging. We developed a cellular platform for collecting skin fibroblasts or blood cells from LOAD patients and non-demented control individuals, which are then used in an induced pluripotent stem cell (iPSC) paradigm to produce brain cells for determining LOAD pathogenic processes in the context of age, disease, genetic background, cell development, and cell type. This model has provided evidence for an innate inefficient cellular energy management in LOAD that is associated with alterations of cellular transcriptomes and lipid compositions, and interconnected cause-and-effect linkages, such as impaired insulin/IGF-1 signaling, bioenergetic substrate deficiencies, diminished glucose metabolism, and disruption of autophagic flux, among others. In addition, a testing of compounds revealed some restoration of these altered bioenergetic and metabolic processes in LOAD cells. Altogether, our studies have identified an inherent LOAD-associated cellular metabolic phenotype as a potential risk factor for developing neurodegenerative diseases with aging. We propose that our cellular model allows for patient-oriented examination of numerous mechanisms and interactions in LOAD pathogenesis, which can be used as a basis for a personalized medicine approach to predict altered aging and risk of developing dementia, and to test or implement (customized) therapeutic or disease-preventive intervention strategies.

Sporadic or late-onset Alzheimer’s disease (LOAD) is characterized by slowly progressive deterioration and death of CNS neurons. There are currently no substantially disease-modifying therapies. LOAD pathology is closely related to changes with age and include, among others, accumulation of toxic molecules and altered metabolic, microvascular, biochemical and inflammatory processes. In addition, there is growing evidence that cellular energy deficits play a critical role in aging and LOAD pathophysiology. However, the exact mechanisms and causal relationships are largely unknown. In our studies we tested the hypothesis that altered bioenergetic and metabolic cell functions are key elements in LOAD, using a cellular platform consisting of skin fibroblasts derived from LOAD patients and AD-unaffected control individuals and therefrom generated induced pluripotent stem cells that are differentiated to brain-like cells to study LOAD pathogenic processes in context of age, disease, genetic background, cell development, and cell type. This model has revealed that LOAD cells exhibit a multitude of bioenergetic and metabolic alterations, providing evidence for an innate inefficient cellular energy management in LOAD as a prerequisite for the development of neurodegenerative disease with age. We propose that this cellular platform could ultimately be used as a conceptual basis for a personalized medicine tool to predict altered aging and risk for development of dementia, and to test or implement customized therapeutic or disease-preventive intervention strategies.

Crizotinib is an oral selective small-molecular tyrosine kinase inhibitor (TKI) that suppress the activity of anaplastic lymphoma kinase (ALK) and ROS1 kinases, as well as mesenchymal-epithelial transition. The cumulative clinical trials in patients with advanced ALK- or ROS1-rearrangement NSCLC indicate that crizotinib has significant antitumor activity and a tolerable safety profile, with mild or moderate adverse events of visual disorders, diarrhea, nausea, and vomiting. As with other TKIs, however, the occurrence of crizotinib-related interstitial lung disease (crizotinib-ILD) remains a major clinical dilemma that can lead to the permanent discontinuation of TKI during cancer treatment. When there is no suitable alternative therapy for patients who develop crizotinib-ILD, some clinicians have reported successful crizotinib retreatment in cases of ALK-rearrangement NSCLC. Unfortunately, there are no specific guidelines for the treatment or retreatment of TKI-related ILD. We herein report the first successful crizotinib retreatment after crizotinib-ILD in a patient with ROS1-rearranged NSCLC, and suggest a retreatment strategy after crizotinib-ILD based on a literature review.

Alloy 690 has been selected as a steam generator tubing material for SMART owing to a near immunity to primary water stress corrosion cracking. The steam generators of SMART are faced with a neutron flux due to the integrated arrangement inside a reactor vessel, and thus it is important to know the irradiation effects of the thermal conductivity of Alloy 690. Alloy 690 was irradiated at HANARO to fluences of (0.7−28) × 1019n/cm2 (E>0.1MeV) at 250°C, and its thermal conductivity was measured using the laser-flash equipment in the IMEF. The thermal conductivity of Alloy 690 was dependent on temperature, and it was a good fit to the Smith-Palmer equation, which modified the Wiedemann-Franz law. The irradiation at 250°C did not degrade the thermal conductivity of Alloy 690, and even showed a small increase (1%) at fluences of (0.7∼28) × 1019n/cm2 (E>0.1MeV).

Background: Early-stage lung cancers detected by low-dose computed tomography (CT) often require confirmation through invasive procedures due to the absence of endobronchial lesions. This study assesses the diagnostic utility of bronchial washing fluid (BW) sequencing, a less invasive alternative, aiming to identify patient characteristics most suited for this approach. Methods: From June 2017 to March 2018, we conducted a prospective cohort study by enrolling patients with incidental lung lesions suspected of early-stage lung cancer at two independent hospitals, and 114 were diagnosed with lung cancer while 50 were diagnosed with benign lesions. BW sequencing was performed using a targeted gene panel, and the clinical characteristics of patients detected with cancer through sequencing were identified. Results: Malignant cells were detected in 33 patients (28.9 %) through BW cytology. By applying specificity-focused mutation criteria, BW sequencing classified 42 patients (36.8 %) as having cancer. Among the cancer patients who were BW sequencing positive and BW cytology negative, 15 patients (75.0 %) showed necrosis on CT. The sensitivity of BW sequencing was particularly enhanced in patients with necrotic tumors, reaching 75 %. Conclusions: BW sequencing presents a viable, non-invasive diagnostic option for early-stage lung cancer, especially valuable in patients with necrotic lesions. By potentially reducing the reliance on more invasive diagnostic procedures, this method could streamline clinical workflows, decrease patient burden, and improve overall diagnostic efficiency.

Abstract Current guidelines recommend that cytotoxic chemotherapy be considered first in non-small cell lung cancer (NSCLC) patients with multiple metastases, and whole-brain radiotherapy (WBRT) is not initially recommended even if brain metastases are present. However, cytotoxic chemotherapeutic agents are less effective in brain metastases due to poor blood–brain barrier permeability. We investigated the effect of WBRT in combination with cytotoxic chemotherapy on survival in NSCLC patients who were EGFR, ALK, and PD-L1 negative, had an ECOG PS of 2, and had multiple metastases including brain metastases. From January 2005 to December 2018, histologically confirmed NSCLC patients who were EGFR, ALK, and PD-L1 negative, had an ECOG PS of 2, and had multiple metastases including brain metastases were included in this study. Patients were classified into two groups based on receiving WBRT prior to or concurrently with administration of first-line chemotherapeutic agents or receiving chemotherapy only. We compared intracranial progression-free survival (iPFS) and overall survival (OS). Of the 240 NSCLC patients with brain metastases at diagnosis and an ECOG PS of 2, 67 patients were EGFR, ALK, and PD-L1 negative with multiple metastases including brain metastases. Among those patients, 43 (64.2%) received WBRT prior to or concurrently with platinum-based chemotherapy. Patients who received WBRT prior to or concurrently with chemotherapy had better iPFS (7.7 months [4.8–10.6] vs. 3.5 months [2.1–4.9], p = 0.009) and OS (10.8 months [5.9–15.7] vs. 6.1 months [1.9–10.3], p = 0.038) than those who did not receive WBRT. In multivariate analyses, WBRT was significantly associated with iPFS (HR: 1.94 and 95% CI 1.11–3.40, p = 0.020) and OS (HR: 1.92 and 95% CI 1.08–3.42, p = 0.027). In NSCLC patients who are EGFR, ALK, and PD-L1 negative, have an ECOG PS of 2, and have multiple metastases including brain metastases, WBRT prior to or concurrently with chemotherapy could improve iPFS and OS. Therefore, the combination of WBRT with cytotoxic chemotherapy should be considered in these patients.

Background and Objectives: The mechanisms involved in the development of brain metastasis (BM) remain elusive. Here, we investigated whether BM is associated with spine involvement in patients with non-small-cell lung cancer (NSCLC). Materials and Methods: A consecutive 902 patients with metastatic NSCLC were included from the Inha Lung Cancer Cohort. Patients with BM at diagnosis or subsequent BM development were evaluated for both spine involvement in NSCLC and anatomic proximity of BM to the cerebrospinal fluid (CSF) space. Results: At diagnosis, BM was found in 238 patients (26.4%) and bone metastasis was found in 393 patients (43.6%). In patients with bone metastasis, spine involvement was present in 280 patients. BM subsequently developed in 82 (28.9%) of 284 patients without BM at diagnosis. The presence of spine metastasis was associated with BM at diagnosis and subsequent BM development (adjusted odd ratios and 95% confidence intervals = 2.42 and 1.74–3.37, p < 0.001; 1.94 and 1.19–3.18, p = 0.008, respectively). Most patients with spine metastasis, either with BM at diagnosis or subsequent BM, showed BM lesions located adjacent (within 5mm) to the CSF space (93.8% of BM at the diagnosis, 100% of subsequent BM). Conclusions: These findings suggest that the presence of spine involvement is a risk factor for BM development in NSCLC patients with bone metastasis.

Abstract Background A heterogeneous radiological response is frequently observed in cancer patients and could reflect tumor heterogeneity. We investigated the prognostic impact of heterogeneous radiological responses in patients with advanced non‐small‐cell lung cancer (NSCLC) who received platinum‐based chemotherapy. Methods The treatment response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria was evaluated in 212 patients with advanced NSCLC who received platinum‐based chemotherapy. Patients with partial response (PR) or stable disease (SD) were classified into “PR homo,” “PR hetero,” “SD homo,” and “SD hetero” by the presence of a heterogeneous radiological response, and survival was compared between groups. We also compared survival based on the presence of metabolic responses in lesions with heterogeneous radiological responses. Results Fifty‐two patients (24.5%) were classified as PR, 112 patients (52.8%) as SD, and 48 patients (22.7%) as progressive disease (PD). There was no significant difference in progression‐free survival (PFS) and overall survival (OS) between the PR homo and PR hetero groups. The SD homo group had a longer PFS and OS than the SD hetero group. In the SD hetero group, patients with increased maximum standardized uptake value (SUVmax) in lesions with heterogeneous radiological responses had a shorter PFS than those with a stable SUVmax. Conclusions The presence of lesions with radiological heterogeneity was associated with disease progression and poor prognosis in the SD group. Patients with heterogeneous radiological responses require careful monitoring.

The major sites of metastasis in non-small cell lung cancer (NSCLC) are bones, the brain, adrenal glands, the liver, the contralateral lung, and distant lymph nodes. Solitary metastasis in an uncommon site is very rare; therefore, it has not often been reported. Identifying whether a solitary lesion is a metastatic lesion is important because it decisively influences the stage and treatment decisions. We report a series of cases of NSCLC diagnosis with uncommon solitary metastasis. (1) A 71-year-old man was diagnosed with poorly differentiated NSCLC after a bronchoscopic biopsy of a tumor in the bronchus of the right middle lobe. A hypermetabolic lesion was observed in the tail of the pancreas using positron emission tomography/computed tomography (PET/CT), and metastasis of NSCLC was confirmed using endoscopic ultrasound fine-needle aspiration (EUS-FNA). (2) A 77-year-old man was diagnosed with squamous cell carcinoma after a bronchoscopic biopsy of a tumor in the bronchus of the left upper lobe. A hypermetabolic lesion was observed in the bilateral lobes of the thyroid gland using PET/CT, and metastasis of the squamous cell carcinoma was confirmed by FNA and cytology. (3) A 79-year-old woman was diagnosed with adenocarcinoma by brushing cytology performed on the apicoposterior segmental bronchus of the left upper lobe. Hypermetabolic lesions were observed using PET/CT in the subcutaneous layer of the right back and the left breast, and metastases of adenocarcinoma were confirmed by biopsies in each lesion. These three patients were treated with platinum-based chemotherapy for stage IV lung cancer. With this case series, we recommend that, when a solitary lesion is observed in NSCLC patients, a tissue biopsy should be performed, even if the lesion is located in an organ where lung cancer metastasis is uncommon.

The cumulative results indicate that the neutrophil to lymphocyte ratio of peripheral blood (pbNLR) is a useful prognostic factor in patients with various cancers. In contrast to peripheral blood, the bronchoalveolar lavage (BAL) fluid is in direct contact with the lung lesion. However, no study has reported on the clinical utility of the NLR of BAL fluid (bNLR) for patients with lung cancer. To investigate the clinical utility of the bNLR as a prognostic factor in patients with lung cancer, we conducted a retrospective review of the prospectively collected data. A total of 45 patients were classified into high bNLR (n = 29) and low bNLR (n = 16) groups. A high pbNLR and high bNLR were associated with a shorter overall survival (p < 0.001 and p = 0.011, respectively). A multivariable analysis confirmed that ECOG PS (p = 0.023), M stage (p = 0.035), pbNLR (p = 0.008), and bNLR (p = 0.0160) were independent predictors of overall survival. Similar to the pbNLR, a high bNLR value was associated with a poor prognosis in patients with lung cancer. Although further studies are required to apply our results clinically, this is the first study to show the clinical value of the bNLR in patients with lung cancer.

Strong enhancement in proton energy was investigated from a two-dimensional particle-in-cell simulation where an ultraintense laser pulse irradiates a 2-μm thick metal foil coated with a low density, 1-μm thick PMMA (polymethylmathacrylate - C5H8O2) on the rear surface. The reduction of PMMA density effectively increases resistivity of hot electrons, which results in the generation of a strong electrostatic field at the metal-PMMA interface in addition to the sheath electrostatic field at the PMMA-vacuum boundary. The interaction of each proton beam accelerated by the two electrostatic fields leads to the enhancement of energy for the protons originated from the PMMA-vacuum side. With a laser intensity of 1×1020 W/cm2, maximum proton energy of 80 MeV was investigated with a modulation in energy spectrum, which is 2.2 times higher than those from a metal-contamination layer target or a metal-high density PMMA target. It is also interesting that there is an energy peak around 18 MeV, which is caused by an interaction with heavier ions.