YH29407 with anti-PD-1 ameliorates anti-tumor effects via increased T cell functionality and antigen presenting machinery in the tumor microenvironment.

Among cancer cells, indoleamine 2, 3-dioxygenase1 (IDO1) activity has been implicated in improving the proliferation and growth of cancer cells and suppressing immune cell activity. IDO1 is also responsible for the catabolism of tryptophan to kynurenine. Depletion of tryptophan and an increase in kynurenine exert important immunosuppressive functions by activating regulatory T cells and suppressing CD8+ T and natural killer (NK) cells. In this study, we compared the anti-tumor effects of YH29407, the best-in-class IDO1 inhibitor with improved pharmacodynamics and pharmacokinetics, with first and second-generation IDO1 inhibitors (epacadostat and BMS-986205, respectively). YH29407 treatment alone and anti-PD-1 (aPD-1) combination treatment induced significant tumor suppression compared with competing drugs. In particular, combination treatment showed the best anti-tumor effects, with most tumors reduced and complete responses. Our observations suggest that improved anti-tumor effects were caused by an increase in T cell infiltration and activity after YH29407 treatment. Notably, an immune depletion assay confirmed that YH29407 is closely related to CD8+ T cells. RNA-seq results showed that treatment with YH29407 increased the expression of genes involved in T cell function and antigen presentation in tumors expressing ZAP70, LCK, NFATC2, B2M, and MYD88 genes. Our results suggest that an IDO1 inhibitor, YH29407, has enhanced PK/PD compared to previous IDO1 inhibitors by causing a change in the population of CD8+ T cells including infiltrating T cells into the tumor. Ultimately, YH29407 overcame the limitations of the competing drugs and displayed potential as an immunotherapy strategy in combination with aPD-1.

YH25448, an Irreversible EGFR-TKI with Potent Intracranial Activity in EGFR Mutant Non-Small Cell Lung Cancer.

PURPOSE: Given that osimertinib is the only approved third-generation EGFR-TKI against EGFR activating and resistant T790M mutated non-small cell lung cancer (NSCLC), additional mutant-selective inhibitors with a higher efficacy, especially for brain metastases, with favorable toxicity profile are still needed. In this study, we investigated the antitumor efficacy of YH25448, an oral, mutant-selective, irreversible third-generation EGFR-TKI in preclinical models. EXPERIMENTAL DESIGN: Antitumor activity of YH25448 was investigated in vitro using mutant EGFR-expressing Ba/F3 cells and various lung cancer cell lines. In vivo antitumor efficacy, ability to penetrate the blood-brain barrier (BBB), and skin toxicity of YH25448 were examined and compared with those of osimertinib using cell lines and PDX model. RESULTS: Compared with osimertinib, YH25448 showed a higher selectivity and potency in kinase assay and mutant EGFR-expressing Ba/F3 cells. In various cell line models harboring EGFR activating and T790M mutation, YH25448 effectively inhibited EGFR downstream signaling pathways, leading to cellular apoptosis. When compared in vivo at equimolar concentrations, YH25448 produced significantly better tumor regression than osimertinib. Importantly, YH25448 induced profound tumor regression in brain metastasis model with excellent brain/plasma and tumor/brain area under the concentration-time curve value. YH25448 rarely suppressed the levels of p-EGFR in hair follicles, leading to less keratosis than osimertinib in animal model. The potent systemic and intracranial activity of YH25448 has been shown in an ongoing phase I/II clinical trial for advanced EGFR T790M mutated NSCLC (NCT03046992). CONCLUSIONS: Our findings suggest that YH25448 is a promising third-generation EGFR inhibitor, which may be more effective and better tolerated than the currently approved osimertinib.

ESTIMATION OF THE CUMULATIVE EXPOSURE FREQUENCY AND CUMULATIVE EFFECTIVE DOSE OF DIAGNOSTIC MEDICAL RADIATION IN THE KOREAN POPULATION FROM 2002 TO 2010.

Along with increase in the frequency and exposure dose from the diagnostic medical radiation procedures, the public's interest in radiation exposure has also been growing. In this study, in order to estimate the Cumulative Exposure Frequency and the cumulative effective dose of diagnostic medical radiation in the Korean population, we included 680 diagnostic medical radiation procedure codes of the Health Insurance Review & Assessment Service's health insurance medical expenses data and adopted the effective dose data from the 2008 report of the United Nations Scientific Committee on the Effects of Atomic Radiation. We combined the data of one million individuals in the national sample cohort database (2002-10) of the National Health Insurance Service. The results revealed that 93.2% (917 972) of the subjects were exposed to diagnostic medical radiation at least once in the past nine years, and the Cumulative Exposure Frequency was 17 286.4 per 1000 individuals with a cumulative effective dose of 5.7 (±17.8) mSv per person. Additionally, 93.1% (854 480) of the subjects had a cumulative effective dose less than 20 mSv, and 0.7% (6139) had a dose that exceeded 100 mSv (extreme), showing that the dosage level was mostly low. However, the number of individuals whose exposure exceeded 100 mSv/y increased 28-fold, from 18 in 2002 to 500 in 2010. In addition, the size of increase also grew each year, suggesting that cancer occurrence due to diagnostic medical radiation may have also increased. In order determine the causal relationship between cancer occurrence and diagnostic medical radiation and setup a guideline for exposure, it is necessary to monitor individual cumulative exposure doses nation-wide and follow up on heavily exposed individuals for an extended period of time.

Thyroid Cancer Screening in South Korea Increases Detection of Papillary Cancers with No Impact on Other Subtypes or Thyroid Cancer Mortality.

BACKGROUND: The incidence of thyroid cancer has increased worldwide. The country where the incidence has increased most is South Korea. The goal of this study is to understand the magnitude of association between opportunistic thyroid cancer screening and thyroid cancer incidence, thyroid cancer subtype, and disease-specific mortality. METHODS: We used the 2010 Korea Community Health Survey, which queried 226,873 individuals if they had been screened for thyroid cancer in the last two years. Thyroid cancer incidence data from 2008 to 2010 were obtained from the Korea Cancer registry data, and mortality data from 2007-2010 were obtained from the Statistics Korea database. The ecological association between thyroid screening and thyroid cancer incidence and mortality by age and sex were examined across Korea's 16 administrative regions by general linear regression models. RESULTS: Between 2008 and 2010, the incidence of thyroid cancer was 64.1 per 100,000 individuals: the incidence in females was 107.3 and in males was 21.1. There was a strong positive correlation between regional thyroid cancer screening and regional thyroid cancer incidence (r = 0.77, [95% confidence interval 0.70-0.82]). The magnitude of correlation was higher for females (r = 0.88 [CI 0.83-0.92]) than in males (r = 0.76 [CI 0.67-0.84]) in any age group. Thyroid screening was only associated with increased detection of papillary thyroid cancer (r = 0.74 [CI 0.59-0.88]); and not associated with mortality (r = -0.08 [CI -0.59-0.63]) due to thyroid cancer. CONCLUSIONS: The magnitude of association between thyroid cancer screening in South Korea and the incidence of thyroid cancer strongly suggests that screening is the most important driver of the epidemic of thyroid cancer, particularly among females. Thyroid cancer screening, however, was only associated with the increase of one tumor histology, papillary thyroid cancer, and it did not have any association with thyroid cancer mortality. The extent to which opportunistic thyroid cancer screening is converting thousands of asymptomatic persons to cancer patients without any known benefit to them needs to be examined carefully.

Public Perceptions on Cancer Incidence and Survival: A Nation-wide Survey in Korea.

PURPOSE: The aim of this study was to compare the public perceptions of the incidence rates and survival rates for common cancers with the actual rates from epidemiologic data. MATERIALS AND METHODS: We conducted a survey of Korean adults without history of cancer (n=2,000). The survey consisted of questions about their perceptions regarding lifetime incidence rates and 5-year survival rates for total cancer, as well as those of eight site-specific cancers. To investigate associated factors, we included questions about cancer worry (Lerman's Cancer Worry Scale) or cared for a family member or friend with cancer as a caregiver. RESULTS: Only 19% of Korean adults had an accurate perception of incidence rates compared with the epidemiologic data on total cancer. For specific cancers, most of the respondents overestimated the incidence rates and 10%-30% of men and 6%-18% of women had an accurate perception. A high score in "cancer worry" was associated with higher estimates of incidence rates in total and specific cancers. In cancers with high actual 5-year survival rates (e.g., breast and thyroid), the majority of respondents underestimated survival rates. However, about 50% of respondents overestimated survival rates in cancers with low actual survival rates (e.g., lung and liver). There was no factor consistently associated with perceived survival rates. CONCLUSION: Widespread discrepancies were observed between perceived probability and actual epidemiological data. In order to reduce cancer worry and to increase health literacy, communication and patient education on appropriate risk is needed.

Application of social network analysis to health care sectors.

OBJECTIVES: This study aimed to examine the feasibility of social network analysis as a valuable research tool for indicating a change in research topics in health care and medicine. METHODS: Papers used in the analysis were collected from the PubMed database at the National Library of Medicine. After limiting the search to papers affiliated with the National Institutes of Health, 27,125 papers were selected for the analysis. From these papers, the top 100 non-duplicate and most studied Medical Subject Heading terms were extracted. NetMiner V.3 was used for analysis. Weighted degree centrality was applied to the analysis to compare the trends in the change of research topics. Changes in the core keywords were observed for the entire group and in three-year intervals. RESULTS: The core keyword with the highest centrality value was "Risk Factor," followed by "Molecular Sequence Data," "Neoplasms," "Signal Transduction," "Brain," and "Amino Acid Sequence." Core keywords varied between time intervals, changing from "Molecular Sequence Data" to "Risk Factors" over time. "Risk Factors" was added as a new keyword and its social network was expanded. The slope of the keywords also varied over time: "Molecular Sequence Data," with a high centrality value, had a decreasing slope at certain intervals, whereas "SNP," with a low centrality value, had an increasing slope at certain intervals. CONCLUSIONS: The social network analysis method is useful for tracking changes in research topics over time. Further research should be conducted to confirm the usefulness of this method in health care and medicine.

Survival of all cancer patients in Korea through 2-year follow-up.

Cancer is the most frequent cause of death in both developing and developed countries, including Korea. The aim of this study was to present survival rates of Korean cancer patients. Survival analysis was carried out with data collected under the Korea Central Cancer Registry Program, which included all cancer patients diagnosed from January 1, 1997 to December 31, 1997. We have analyzed the effects of age at diagnosis and sex on cancer survival from the cancer registry data of 64,240 Korean patients diagnosed of cancer in 1997. The overall survival rate of all Korean cancer patients (both men and women) was 67% at 1 yr and 57% at 2 yr. The 1- and 2-yr survival rates for all cancers in men were 58% and 47%, respectively, while those in women were 77% and 69%, respectively. Men had a lower survival rate than women in most malignancies. The pancreatic cancer was shown the lowest 1-yr survival rate.