Biomarkers to Predict Response to Immunotherapy for Refractory Hepatocellular Carcinoma

A team led by Professor Jason Kyungha Sa (co-first author) from Korea University Graduate School of Medicine identified the molecular properties that determine the response to immune checkpoint inhibitors in liver cancer patients.

Hepatocellular carcinoma accounts for the majority of primary liver malignancy and is the fourth leading cause of cancer-related mortalities worldwide and it is known to have a high incidence in Asia.

Pembrolizumab, an immune checkpoint inhibitor, has been approved as a second-line treatment for hepatocellular carcinoma, but the identification of reliable biomarkers to predict the response to the treatment remained a major challenge.

The research team conducted an integrated multi-omics analyses of 60 hepatocellular carcinoma patients who received pembrolizumab to identify distinct genomic correlates that distinguish responders from non-responders.

Patients’ cancer tissue specimens were collected and genomic properties were characterized such as tumor microenvironment by assessing the results from whole-exome sequencing (WES), RNA and single-cell RNA sequencing.

This is to identify the primary cause of different effects of immunotherapy during treatment and to distinguish molecular biomarkers that can help identify those who are likely to benefit from the therapy.

The research team examined the differences by observing the patients' treatment process based on the results of high-precision analysis of the patients' genome. According to the research team, six out of the 60 hepatocellular carcinoma patients who received immunotherapy demonstrated partial response to the treatment, with an overall response rate of 10%. Clinical pathological analysis confirmed that female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were contributing factors to immunotherapy response.

On the other hand, somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that responders demonstrated T cell receptor (TCR) signaling activation, indicating increased levels of T cell cytotoxicity induced response to immunotherapy.

In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, non-responders showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways. Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells and down-regulation of neutrophil-associated markers, significantly benefited from immunotherapy.

Professor Sa said, "The results of this study will help discover the next generation of immunotherapeutics for cancer patients who do not respond to the existing treatment modalities."

The study entitled "Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial" was conducted along with Samsung Medical Center with support from the Research-Oriented Hospital Development R&D Project of the Ministry of Health and Welfare, and was published in the January issue of the international renowned journal, Genome Medicine (IF 11.117).

Korea University College of Medicine Selected as the Host Organization for the Convergent Physician-Scientist Training Program

KUCM Nominated for the Second Time in a Row Since 2019

Golden Line-up as Research-Centered Hospital with Innovative Physician-Scientists

Korea University College of Medicine (KUCM) has been selected as the host organization for the 2022 Program to Foster Convergent Physician-Scientists supported by the Ministry of Health and Welfare and the Korea Health Industry Development Institute.

Launched in 2019, the Program was implemented to promote the innovation and continued growth of the biomedical industry in South Korea by providing opportunities for clinical doctors to conduct medical research. Resident doctors interested in research are provided with opportunities to engage in research that is aligned with their clinical training, and they are encouraged to take the MD-PhD course to become physician-scientists.

KUCM has formed a consortium with Yeungnam, Chung-Ang, and Hanyang Universities in addition to KIST as host organizations, and will receive a subsidy totaling KRW 2.5 billion from the government over the next three years to carry out various projects to support research activities that engage residents, build infrastructure to train medical scientists, and develop educational programs. KUCM has already successfully carried out the first phase of the program, which was launched in 2019, and won a consecutive nomination this year. The results of the first phase were presented at the 2021 Convergent Doctor-Scientist Program Meeting, and three KUCM participants, Se-Kwang Lee, Won-Ki Min, and Dong-Hoon Kim, received the Minister of Health and Welfare Award. 

Led by Anam and Guro Hospitals, KUCM will take a leading role in the future of medical research and be the main driving force behind important programs: the Innovative Doctor-Scientist Joint Research Project, which was also launched in 2019, and the Program to Foster Convergent Physician-Scientists.

Dean Young-Wook Yoon said, "At a time when the role of medical scientists is becoming more important than ever, I am pleased that we have once again been selected as the host organization following our selection in 2019. Our research capabilities as the nation's top research-oriented medical school will help us foster medical scientists who serve as an important bridge between basic and clinical medicine.”

Dance Intervention Reduces Motor Dysfunction and Improves Depression in Patients with PD

Revealed for the first time by a research team led by professor Seong-Beom Koh from the Department of Neurology at Korea University Guro Hospital
Need to develop exercise programs tailored for the special circumstances of limited physical exercise during COVID-19

A research team led by professor Seong-Beom Koh from the Department of Neurology at Korea University Guro Hospital, together with a professional dance center (instructor So-jeong Park) demonstrated for the first time in Korea that dance intervention improves symptoms, depression, and quality of life in patients with Parkinson’s disease. Dr. Koh’s research team and Jinhee Kim from Naeu Hospital in Incheon confirmed through gait analysis for the first time in the world that dancing is beneficial for patients suffering from Parkinson’s disease.

In addition to dementia and stroke, Parkinson’s Disease (PD) is one of the top three diseases that affect the elderly. This neurodegenerative disorder affects 1-1.5% of Koreans 60 years or older, and as the overall population ages, the prevalence of this disease is on the rise. Chinese politician Deng Xiaoping, actor Robin Williams, and Pope John Paul II are well-known figures with PD. Parkinson's signs and symptoms include slowed movement, tremors, and rigid muscles, especially in the limbs. Posture may become stooped, and the patients may also suffer from memory loss, depression, or sleep disorders. Parkinson's disease symptoms worsen as the condition progresses over time. Depression is also common and complications of the disease can cause pain, making consistent management necessary as it can significantly impact quality of life.

The study recruited subjects with PD who visited the movement disorder clinic at Korea University Guro Hospital in Seoul, South Korea in 2019. The mean age was 69 and the average duration of disease was 5.3 years. Dance intervention (using the Feldenkrais method) was offered to these patients over a period of 6 months. In addition to traditional medication, the dance intervention was performed once a week over a 6-month period. Multiple scales were used to evaluate motor and non-motor symptoms at 3, 6, and 12 months, which was 6 months following the completion of treatment.

The Unified Parkinson’s Disease Rating Scale, a motor scale, showed that symptoms improved without increasing medication dosage during the 6-month dance intervention. Six months following the dance intervention, the symptoms worsened. The Gate Assessment Test showed better outcomes in terms of improved gait velocity and step length. The Tinetti test was used to measure balance, which was maintained during the period of dance intervention. However, once the intervention was completed, the symptoms deteriorated. In addition, dancing had a positive impact on non-motor functions, which are closely related to quality of life in patients with PD. Results on the Non-Motor Symptoms Scale (NMSS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Parkinson’s Disease Questionnaire-39 (PDQ-39) steadily improved during the intervention and started to deteriorate dramatically once the intervention stopped.

Professor Seong-Beom Koh said, “This is the world’s first study showing the effects of dancing on reducing major symptoms of stiffness and slow movement. It led to better motor scale scores, balance, and non-motor scores as well as improved depression and quality of life scale outcomes in patients with PD. Findings from the study indicate that dance intervention may be a complementary tool to manage various PD symptoms.“

He added, “This study indicates that exercise therapy done consistently can improve PD symptoms. The pandemic makes it difficult for patients to engage in physical activities. This means that PD patients may suffer from degrading motor and non-motor symptoms. Developing exercise programs and online training programs can be of great help to our patients especially during the pandemic.”

The paper was published in the November issue of Journal of Movement Disorders (JMD), an SCI-indexed journal.

https://pubmed.ncbi.nlm.nih.gov/34724780/

Yang-Hyun Kim from Korea University Anam Hospital Demonstrates Correlation between Obesity and Sleep Mismatch between Weekends and Weekdays in the Korean Population

Retired Males aged 60 or older 2.89 times are more likely to be obese
Engaging in economic activities and correcting sleep mismatch may lower the risk of obesity
Findings of value for enacting policies for the elderly

In Korea, the prevalence of obesity has been steadily increasing, and the obesity rate is predicted to reach 62% for men and 37% for women by 2030. This can pose a serious threat to Korean society as well as the health of individuals.

A research team led by professor Yang-Hyun Kim from the Department of Family Medicine at Korea University Anam Hospital (Minsung Sohn, Minhee Seo, Jaeman Park, Sojeong Kim, Heewon Jung) found that Koreans with sleep irregularity, especially males aged 60 years or older who are retired and not working, have a 2.89 times greater risk of suffering from obesity. This finding indicates that engagement in economic activities is correlated with the risk of obesity.

This study was conducted using data from the Korea National Health and Nutritional Examination Survey (KNHANES) in 2016. The subjects in the study were divided into subgroups according to sex (2,453 males and 3,231 females), age, and working status. The association between obesity and sleep mismatch was analyzed in each of the subgroups (those who had a sleep mismatch of over 90 min between weekdays and weekends) and expressed in terms of odds ratios.

The study revealed that males who are not economically active and have sleep irregularity have an increased risk of obesity. Moreover, sleep mismatch is associated with a 2.89 times increased risk of obesity in men over 60 years of age who were not working. Females over 60 years of age are also more likely to be obese, but the risk is not statistically significant.

The study is meaningful in that it does not simply study the correlation between sleep irregularity and obesity. Rather it analyzes the issue in a socioeconomic context to reveal the correlation between sleep and obesity. The study team recommended that efforts should be made to give retired elderly people a chance to work again or delay retirement in addition to correcting their sleep irregularity. This can be beneficial in that it can lower the prevalence of obesity in Korean men considering working status is correlated with obesity along with sleep patterns.

Professor Yang-Hyun Kim said, “This study showed the connection between sleep irregularity and obesity by extending the concept of sleep irregularity from daily sleep irregularity to sleep irregularity between weekends and weekdays. From a socioeconomic point of view, the results of this study imply that if elderly people can engage in economic activities, it could be helpful for not only their personal health but also for the overall health of society.

Professor Kim added, “In Korea, the number of elderly people has increased the fastest compared to other OECD countries, and this can become a huge socioeconomic burden. The findings from this study suggest new directions for future studies and new policies that support the elderly population.“

In this study, “obesity” is defined as BMI ≥ 25 kg/m2 in accordance with the Korean Society for the Study of Obesity’s 2020 Guidelines. Several studies have demonstrated that sleep variability over 90 min is associated with a high risk of cardiovascular disease. This study was conducted with support from the student research organization at KUCM and was published in an international academic journal.

https://pubmed.ncbi.nlm.nih.gov/33358214/