Cancer Research and Treatment

Original Articles

Safety and Efficacy of Combining Metastasis-Directed Stereotactic Ablative Radiation Therapy with Tyrosine Kinase Inhibitors Versus Immune Checkpoint Inhibitors in Metastatic Hepatocellular Carcinoma: Eunyeong Yang, Jeong Il Yu, Hee Chul Park, Myung Ji Goh, Byeong Geun Song, Wonseok Kang, Dong Hyun Sinn, Geum-Youn Gwak, Yong-Han Paik, Joon Hyeok Lee, Moon Seok Choi, Jung Yong Hong, Minsuk Kwon, Nalee Kim; Received September 5, 2025 Accepted February 1, 2026 Published online February 3, 2026; DOI: https://doi.org/10.4143/crt.2025.966 [Accepted]

Abstract PDF: Purpose
Immune checkpoint inhibitors (ICIs) have become a standard therapy for metastatic hepatocellular carcinoma (HCC), often as an alternative to tyrosine kinase inhibitors (TKIs). However, safety data combining ICIs with stereotactic ablative radiotherapy (SABR) remain limited. We compared the safety and efficacy of SABR combined with ICIs versus TKIs in patients with extrahepatic metastatic HCC.
Materials and methods
This single-center retrospective study included patients with HCC who received SABR for extrahepatic metastases combined with either TKIs or ICIs within 30 days of SABR between January 2010 and June 2024. Adverse events (AEs; CTCAE v5.0) and oncologic outcomes were evaluated using logistic regression and Cox models.
Results
Among 103 patients with 128 SABR-treated lesions, 72 patients (90 lesions) received SABR+TKI and 31 patients (38 lesions) received SABR+ICI. Acute AEs occurred only in the SABR+TKI group (8.9%), predominantly grade 1. Grade 3 late AEs were rare, occurring in one case in each group, while late AEs of lower grades were more frequent with SABR+ICI (any-grade: 57.9% vs. 25.6%, p<0.001; grade ≥2: 23.7% vs. 8.9%, p=0.024). Multivariable analysis showed borderline increased risk of grade ≥2 late AEs with SABR+ICI (p=0.052). One-year local control, progression-free survival, and overall survival were 76.6%, 35.3%, and 72.3% respectively, with no significant differences between groups.
Conclusion
Metastasis-directed SABR combined with either TKIs or ICIs was generally well tolerated in patients with extrahepatic metastatic HCC, with rare grade 3 late AEs; grade ≥2 late AEs were more frequent with SABR plus ICIs, warranting prospective evaluation.

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Predictive Role of Baseline Peripheral Lung SUVmax on PET/CT for Immune-Related Pneumonitis and Adverse Events in Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Kun Ho Kim, Seong Min Kim, Jeong Eun Lee, Song Soo Kim, Da Hyun Kang, Chaeuk Chung; Received May 22, 2025 Accepted October 22, 2025 Published online October 28, 2025; DOI: https://doi.org/10.4143/crt.2025.548 [Accepted]

Abstract PDF: Purpose
Immune checkpoint inhibitors (ICIs) offer durable responses in lung cancer patients lacking actionable mutations or with resistance to prior therapies. However, predicting their efficacy and associated immune-related adverse events (irAEs), such as severe pneumonitis, remains a clinical challenge. This study investigated the predictive value of positron emission tomography/computed tomography (PET/CT)-derived metabolic parameters for pneumonitis and other irAEs in lung cancer patients treated with ICIs.
Materials and Methods
We retrospectively analyzed 151 patients with advanced non-small cell lung cancer (NSCLC) who received ICIs as first-line treatment, either as monotherapy or in combination. Pre-treatment PET/CT was used to measure SUVmax at the primary tumor, tumor-uninvolved peripheral lung, and metastatic sites. Pneumonitis and irAEs were assessed using clinical and radiological findings.
Results
Pneumonitis, severe pneumonitis (grade ≥3), and irAEs occurred in 26.5%, 19.9%, and 37.1% of patients, respectively. A peripheral SUVmax cutoff of >1.1 significantly predicted pneumonitis (area under the curve [AUC] = 0.720, p <0.001). High peripheral SUVmax was associated with higher rates of pneumonitis (42.9% vs. 12.3%, p <0.001), severe pneumonitis (31.4% vs. 9.9%, p=0.001), and irAEs (46.4% vs. 29.5%, p=0.038). In multivariate analysis, high peripheral SUVmax independently predicted pneumonitis (odds ratio [OR]: 4.621; 95% confidence interval [CI]: 1.868–11.431; p=0.001), severe pneumonitis (OR: 2.848; 95% CI: 1.043–7.779; p=0.041), and irAEs (OR: 2.509; 95% CI: 1.114–5.504; p=0.022).
Conclusion
Baseline peripheral SUVmax on PET/CT may serve as a noninvasive biomarker for predicting immune-related pneumonitis and other irAEs in NSCLC patients receiving ICIs, supporting early risk identification.

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Analysis of T Cell Subsets Using Multiplex Immunohistochemistry and Clinical Outcomes of Immune Checkpoint Inhibitors in Advanced Gastric Cancer Patients: Tae-Yong Kim, Jeesun Yoon, Dae-Won Lee, Yoonjin Kwak, Hye Seung Lee, Do-Youn Oh; Received April 28, 2025 Accepted September 7, 2025 Published online September 9, 2025; DOI: https://doi.org/10.4143/crt.2025.458 [Accepted]

Abstract PDF: Purpose
As immunotherapy has become essential in the treatment of gastric cancer (GC), there has been growing interest in T-cells, which play a key role in immunotherapy. In this study, we evaluated the impact of T-cell subsets on immune responsiveness to immune checkpoint inhibitors (ICIs) in GC using multiplex immunohistochemistry (mIHC).
Materials and Methods
Eighty-four GC patients treated with ICIs were enrolled, and we repeated the staining-scanning-stripping procedure nine times to assess different kinds of T-cells or cell-surface immune checkpoints in a single tissue section.
Results
The proportions of patients with microsatellite instability-high (MSI-H), Epstein-Barr virus (EBV), and non-MSI/non-EBV were 8.3%, 3.6% and 88.1%. A high cytotoxic T-cell (T_cyto) density was related to longer overall survival (OS). GC with a high ratio of T_cyto/total T-cells (T_total) and a low ratio of regulatory T-cells (T_reg)/T_total showed better OS. A high density of PD-1- or TIM-3- expressing T_cyto were also associated with longer OS than a low density of those. Among memory T-cells (T_mem) subsets, GC with a high ratio of memory T_cyto/T_mem and a low ratio of memory T_reg/T_mem showed prolonged OS. Better tumor responses were observed in GC with a high ratio of T_cyto/T_total and memory T_cyto/T_mem.
Conclusion
T-cell subsets within the tumor microenvironment were associated with the clinical efficacy of ICIs in GC. PD-1- or TIM-3 expressing T-cells were also associated with response to ICIs, while memory T-cells subsets were associated with survival. mIHC is a feasible method for evaluating T-cell subsets in archival gastric tumor tissue.

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Clinicopathological Factors Influencing PD-L1 Expression and the Effect of Immune Checkpoint Inhibitors on Survival Outcomes in Patients with Gastric Cancer Depending on Sex in a Tertiary Hospital in South Korea: Jeong hwan Lee, Nayoung Kim, Ji-Hyun Kim, Hyeon Jeong Oh, Yeejin Kim, Yonghoon Choi, Hyemin Jo, Ho-Kyoung Lee, Jinju Choi, Yu Kyung Jun, Hyuk Yoon, Cheol Min Shin, Young Soo Park, Dong Ho Lee, Hye Seung Lee, So Hyun Kang, Young Suk Park, Sang-Hoon Ahn, Yun-Suhk Suh, Do Joong Park, Hyung Ho Kim, Ji-Won Kim, Jin Won Kim, Keun-Wook Lee, Won Chang, Yoon Jin Lee, Kyoung Ho Lee, Young Hoon Kim, Soyeon Ahn; Received January 31, 2025 Accepted August 5, 2025 Published online August 13, 2025; DOI: https://doi.org/10.4143/crt.2025.126 [Epub ahead of print]

Abstract PDF Supplementary Material: Purpose
Programmed cell death ligand-1 (PD-L1) negatively regulates T-cell activation, and exhibits sex-based differences in expression and immune responses. This study investigated sex-related differences in clinicopathological factors influencing PD-L1 expression and the effect of immune checkpoint inhibitors (ICIs) on survival in gastric cancer (GC) patients in South Korea.
Materials and Methods
We analyzed a prospective cohort of 468 GC patients who underwent PD-L1 immunohistochemistry. Age, tumor characteristics, molecular features, and survival outcomes were compared by sex. Multivariate analyses, including Cox proportional hazards modeling with an interaction term for sex, were performed.
Results
Among 468 patients, 280 (59.8%) were PD-L1 positive. In the overall cohort, PD-L1 positivity was significantly associated with Epstein-Barr virus (EBV) infection (odds ratio [OR], 7.46; p < 0.001), antral location of GC (OR, 1.84; p=0.027), and macrosatellite instability–high (MSI-H) (OR, 5.04; p=0.027). Diffuse-type histology was inversely associated (OR, 0.22; p=0.041). In males, EBV (OR, 36.27) and antral location (OR, 2.38) were significant. In females, only MSI-H was significant (OR, 11.63). ICI-containing therapy significantly improved survival in males (p=0.012) but not in females (p=0.415). Cox regression showed a survival benefit from ICIs (hazard ratio, 0.70; p=0.080), with a borderline-significant interaction by sex (p=0.073).
Conclusion
PD-L1 expression and therapeutic efficacy of ICIs differ by sex in GC. EBV infection and antral tumor location were independent factors in males, while MSI-H status was significant in females. These findings highlight the importance of sex-based immunobiology in tailoring GC treatment strategies.

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Characteristics of Immune Checkpoint Inhibitor–Related Hepatotoxicity Based on the Baseline Liver Function: Won-Jung Jung, Eun-Jung Jo, Ye-Jee Kim, Mihyun Park, Eunji Kim, Yu-Seon Jung, Sook Ryun Park, Ji Seon Oh, So-Hui Kim, Jeongbin Park, Sun-Young Jung, Nakyung Jeon; Received January 9, 2025 Accepted July 17, 2025 Published online July 18, 2025; DOI: https://doi.org/10.4143/crt.2025.040 [Epub ahead of print]

Abstract PDF Supplementary Material

Purpose
This study estimated the incidence of immune checkpoint inhibitor–related hepatotoxicity (ICH), identified risk factors, and characterized patients who developed ICH.
Materials and Methods
Adult patients treated with immune checkpoint inhibitors (ICIs) from January 2015 to June 2022 in a tertiary hospital were included, excluding those without liver function tests or those with liver cancer but normal baseline liver function. Patients were stratified by baseline liver function status; in overall and each of stratified cohorts ICH incidence was calculated as the number of events per 100 person-years with grade 3 hepatotoxicity as the primary outcome. Patient characteristics were assessed using descriptive statistics, and risk factors were identified through multivariable Cox regression. Causality between ICI use and hepatotoxicity was assessed using the Naranjo Algorithm.
Results
Among 803 patients, the ICH incidence was 19.5 cases per 100 person-years, with a higher incidence (47.3 vs. 9.3 cases per 100 person-years) and earlier onset (13 vs. 15 days) in the abnormal compared to the normal group. Significant risk factors for ICH included female sex in the normal group and liver cancer in the abnormal group. According to the Naranjo Algorithm, all the 60 ICH cases were classified as “probable” or “possible”. Among the 60 cases, 61.7% (n=37) resulted in ICI discontinuation. The baseline liver function did not impact on the severity or the likelihood of ICI discontinuation.
Conclusion
Future studies are needed to evaluate whether the impact of ICI discontinuation on survival outcomes in patients with ICH varies based on baseline liver function abnormalities.

Citations

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Integrative multi-omics profiling identifies infiltrative hepatocellular carcinoma as an immunotherapy-resistant subtype with distinct molecular features
Won Suk Lee, Seonjeong Woo, Sung Hwan Lee, Gae Hoon Jo, Ilhwan Kim, Hyeyeong Kim, Chansik An, Sanghoon Jung, Gwangil Kim, Haeyoun Kang, Beodeul Kang, Jung Sun Kim, Ho Yeong Lim, Incheon Kang, Hannah Yang, So Jung Kong, Dahyeon Son, Dong Jun Shin, Woo Youn
Clinical and Molecular Hepatology.2026; 32(1): 258. CrossRef

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Programmed Death-Ligand 1 Expression Across Multiple Assays in Ovarian Cancer: A Comparative Analysis: Eun Bi Jang, Kyeong A So, Wook Youn Kim, So Dug Lim, Tae Jin Kim, Heejin Bang, Wan Seop Kim; Received February 21, 2025 Accepted June 5, 2025 Published online June 9, 2025; DOI: https://doi.org/10.4143/crt.2025.202 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Purpose
Ovarian cancer presents significant treatment challenges due to its aggressive nature and poor response to immune checkpoint inhibitors (ICIs). The lack of standardized programmed cell death-ligand 1 (PD-L1) assays and cut-off values complicates clinical decision-making. We evaluated the concordance among commonly used PD-L1 assays and assessed changes in the expression of PD-L1 following chemotherapy.
Materials and Methods
Tissue samples from 29 patients with ovarian cancer were analyzed using five validated PD-L1 immunohistochemistry assays: Dako 22C3, Ventana SP263, Ventana SP142, Dako 28-8, and Ventana 22C3. PD-L1 positivity was assessed using a combined positive score (CPS), immune cell, or tumor proportion score at 1%, 5%, and 10% cut-offs. Concordance rates, including overall percent agreement and Cohen’s kappa coefficient, were analyzed. In addition, changes in the expression of PD-L1 pre- and postchemotherapy were evaluated.
Results
Positivity rates ranged from 15.8% (SP142) to 29.8% (Dako 22C3 and SP263) at the 1% CPS cut-off. SP142 consistently exhibited the lowest concordance, whereas Dako 22C3 displayed high agreement with SP263, 28-8, and Ventana 22C3. Chemotherapy increased PD-L1 positivity, with 28% of patients converting from negative to positive.
Conclusion
The expression of PD-L1 in ovarian cancer varies across assays and scoring methods, emphasizing the need for standardized testing protocols. Increased PD-L1 expression post-chemotherapy underscores the importance of assessing its status at appropriate times to guide ICI therapy. Larger studies are required to validate these findings and refine clinical applications.

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Lung and Thoracic cancer

Unraveling the Impact of Sarcopenia-Induced Lymphopenia on Treatment Response and Prognosis in Patients with Stage III Non–Small Cell Lung Cancer: Insights for Optimizing Chemoradiation and Immune Checkpoint Inhibitor: Joongyo Lee, Kyung Hwan Kim, Jina Kim, Chang Geol Lee, Jaeho Cho, Hong In Yoon, Yeona Cho; Cancer Res Treat. 2025;57(2):422-433. Published online October 30, 2024; DOI: https://doi.org/10.4143/crt.2024.493

Abstract PDF Supplementary Material PubReader ePub

Purpose
Sarcopenia is a poor prognostic factor in non–small cell lung cancer (NSCLC). However, its prognostic significance in patients with NSCLC receiving immune checkpoint inhibitors (ICIs) and its relationship with lymphopenia remain unclear. We aimed to investigate the prognostic role of sarcopenia and its effect on lymphocyte recovery in patients with stage III NSCLC treated with concurrent chemoradiotherapy (CCRT) followed by ICI.
Materials and Methods
We retrospectively evaluated 151 patients with stage III NSCLC who received definitive CCRT followed by maintenance ICI between January 2016 and June 2022. Sarcopenia was evaluated by measuring the skeletal muscle area at the L3 vertebra level using computed tomography scans. Lymphocyte level changes were assessed based on measurements taken before and during CCRT and at 1, 2, 3, 6, and 12 months post-CCRT completion.
Results
Even after adjusting for baseline absolute lymphocyte count through propensity score-matching, patients with pre-radiotherapy (RT) sarcopenia (n=86) exhibited poor lymphocyte recovery and a significantly high incidence of grade ≥ 3 lymphopenia during CCRT. Pre-RT sarcopenia and grade ≥ 3 lymphopenia during CCRT emerged as prognostic factors for overall survival and progression-free survival, respectively. Concurrent chemotherapy dose adjustments, objective response after CCRT, and discontinuation of maintenance ICI were also analyzed as independent prognostic factors.
Conclusion
Our results demonstrated an association between pre-RT sarcopenia and poor survival, concurrent chemotherapy dose adjustments, and impaired lymphocyte recovery after definitive CCRT. Moreover, CCRT-induced lymphopenia not only contributed to poor prognosis but may have also impaired the therapeutic efficacy of subsequent maintenance ICI, ultimately worsening treatment outcomes.

Citations

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Effects of Sarcopenia on the Outcomes and Safety of Chemoradiotherapy Followed by Durvalumab for the Treatment of Patients With Locally Advanced Non‐Small Cell Lung Cancer
Kentaro Tamura, Hidehito Horinouchi, Mototaka Miyake, Ken Masuda, Yuki Shinno, Yusuke Okuma, Tatsuya Yoshida, Noboru Yamamoto, Yasushi Goto
Thoracic Cancer.2025;[Epub] CrossRef
Patient-related factors in advanced lung cancer: A review of ECOG-PS, malnutrition, and sarcopenia
Shun Matsuura
Respiratory Investigation.2025; 63(6): 1250. CrossRef

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Association of TP53 Mutation Status and Sex with Clinical Outcome in Non–Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study: Songji Choi, Se Hyun Kim, Sejoon Lee, Jeongmin Seo, Minsu Kang, Eun Hee Jung, Sang-A Kim, Koung Jin Suh, Ji Yun Lee, Ji-Won Kim, Jin Won Kim, Jeong-Ok Lee, Yu Jung Kim, Keun-Wook Lee, Jee Hyun Kim, Soo-Mee Bang, Jong Seok Lee; Cancer Res Treat. 2025;57(1):70-82. Published online August 7, 2024; DOI: https://doi.org/10.4143/crt.2024.046

Abstract PDF Supplementary Material PubReader ePub

Purpose
Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non–small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC.
Materials and Methods
Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of The Cancer Genome Atlas and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed.
Results
In SNUBH cohort, no statistically significant difference was observed in the median progression-free survival (PFS) according to TP53 mutation status (p=0.930); however, female patients with TP53 mutations (MT) had a significantly prolonged median PFS compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). Programmed death-ligand 1 (PD-L1) high (≥ 50%) expression was significantly enriched in female patients with TP53 MT (p=0.005). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p < 0.001). In The Cancer Genome Atlas analysis, expression of immune-related genes, and tumor mutation burden score in TP53 MT females were higher than in males without TP53 MT.
Conclusion
Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

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Association Between TP53 Mutations and Platinum Resistance in a Cohort of High-Grade Serous Ovarian Cancer Patients: Novel Implications for Personalized Therapeutics
Clelia Madeddu, Eleonora Lai, Manuela Neri, Elisabetta Sanna, Giulia Gramignano, Sonia Nemolato, Mario Scartozzi, Sabrina Giglio, Antonio Macciò
International Journal of Molecular Sciences.2025; 26(5): 2232. CrossRef
Prognostic and predictive implications of tumor suppressor gene alterations in non-small cell lung cancer
Marco Sposito, Lorenzo Belluomini, Riccardo Nocini, Jessica Insolda, Ilaria Mariangela Scaglione, Jessica Menis, Michele Simbolo, Antonio Lugini, Federica Buzzacchino, Francesco Verderame, Francesca Spinnato, Giuseppe Aprile, Lorenzo Calvetti, Mario Occhi
Scientific Reports.2025;[Epub] CrossRef
Enhanced tumor heterogeneity mediates poor prognosis in females with TP53 mutation in lung adenocarcinoma
Liudan Mai, Xinxin Yang, Chen Shao, Hongwei Yu, Fenqi Du, Jialu Liu, Yue Guan, Hao Li, Maopeng Yang, Hongxue Meng, Qiuju Zhang
International Journal of Biological Macromolecules.2025; 334: 149083. CrossRef

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Sarcoma

Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response: Jung Yong Hong, Hee Jin Cho, Kum-Hee Yun, Young Han Lee, Seung Hyun Kim, Wooyeol Baek, Sang Kyum Kim, Yurimi Lee, Yoon-La Choi, Minsuk Kwon, Hyo Song Kim, Jeeyun Lee; Cancer Res Treat. 2023;55(2):671-683. Published online September 27, 2022; DOI: https://doi.org/10.4143/crt.2022.251

Abstract PDF Supplementary Material PubReader ePub

Purpose
Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy.
Materials and Methods
We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA.
Results
Of the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10–4) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker.
Conclusion
Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies.

Citations

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A systematic review and meta-analysis of pazopanib efficacy and adverse effects in sarcomas
Fernanda Picozzi, Alessandro Ottaiano, Antonella Lucia Marretta, Mariachiara Santorsola, Lucia Cannella, Antonio Pizzolorusso, Francesco Caraglia, Giuseppina Della Vittoria Scarpati, Alessandra Bracigliano, Ottavia Clemente, Ines Simeone, Michele Caraglia
Journal of Translational Medicine.2026;[Epub] CrossRef
Musculoskeletal Diseases: Mechanisms and Therapeutic Advances
Xiao Ma, Eloy Yinwang, Xupeng Chai, Fangqian Wang, Zehao Chen, Shengdong Wang, Hao Zhou, Yucheng Xue, Jiangchu Lei, Fanglu Chen, Hengyuan Li, Shixin Chen, Shenzhi Zhao, Kelei Wang, Liang Chen, Junjie Gao, Zhaoming Ye, Nong Lin
MedComm.2025;[Epub] CrossRef
Durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial
Hee Jin Cho, Kum-Hee Yun, Su-Jin Shin, Young Han Lee, Seung Hyun Kim, Wooyeol Baek, Yoon Dae Han, Sang Kyum Kim, Hyang Joo Ryu, Joohee Lee, Iksung Cho, Heounjeong Go, Jiwon Ko, Inkyung Jung, Min Kyung Jeon, Sun Young Rha, Hyo Song Kim
Nature Communications.2024;[Epub] CrossRef
The high-density lipoprotein binding protein HDLBP is an unusual RNA-binding protein with multiple roles in cancer and disease
Jonathan Feicht, Ralf-Peter Jansen
RNA Biology.2024; 21(1): 312. CrossRef
Intracranial Relapse in Pediatric Sarcoma
Danielle E. Smith, Tyler Hamby, Kenneth Heym, Ashraf Mohamed, Kelly L. Vallance, Anish Ray
Journal of Pediatric Hematology/Oncology.2023; 45(7): e810. CrossRef

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Gastrointestinal cancer

Molecular and Immune Profiling of Syngeneic Mouse Models Predict Response to Immune Checkpoint Inhibitors in Gastric Cancer: Dagyeong Lee, Junyong Choi, Hye Jeong Oh, In-Hye Ham, Sung Hak Lee, Sachiyo Nomura, Sang-Uk Han, Hoon Hur; Cancer Res Treat. 2023;55(1):167-178. Published online May 20, 2022; DOI: https://doi.org/10.4143/crt.2022.094

Abstract PDF Supplementary Material PubReader ePub

Purpose
Appropriate preclinical mouse models are needed to evaluate the response to immunotherapeutic agents. Immunocompetent mouse models have rarely been reported for gastric cancer. Thus, we investigated immunophenotypes and responses to immune checkpoint inhibitor (ICI) in immunocompetent mouse models using various murine gastric cancer cell lines.
Materials and Methods
We constructed subcutaneous syngeneic tumors with murine gastric cancer cell lines, YTN3 and YTN16, in C57BL/6J mice. Mice were intraperitoneally treated with IgG isotype control or an anti–programmed death-ligand 1 (PD-L1) neutralizing antibody. We used immunohistochemistry to evaluate the tumor-infiltrating immune cells of formalin-fixed paraffin-embedded mouse tumor tissues. We compared the protein and RNA expression between YTN3 and YTN16 cell lines using a mouse cytokine array and RNA sequencing.
Results
The mouse tumors revealed distinct histological and molecular characteristics. YTN16 cells showed upregulation of genes and proteins related to immunosuppression, such as Ccl2 (CCL2) and Csf1 (M-CSF). Macrophages and exhausted T cells were more enriched in YTN16 tumors than in YTN3 tumors. Several YTN3 tumors were completely regressed by the PD-L1 inhibitor, whereas YTN16 tumors were unaffected. Although treatment with a PD-L1 inhibitor increased infiltration of T cells in both the tumors, the proportion of exhausted immune cells did not decrease in the non-responder group.
Conclusion
We confirmed the histological and molecular features of cancer cells with various responses to ICI. Our models can be used in preclinical research on ICI resistance mechanisms to enhance clinical efficacy.

Citations

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The Therapeutic Potential of Targeting Tumor Microenvironment and Modulation of Immunotherapy in Gastrointestinal Cancer
Saeideh Khorshid Sokhangouy, Hamid Jamialahmadi, Mahdieh Sadat Mortazavi Sani, Ghazaleh Khalili-Tanha, Arian Karimi Rouzbahani, Golnaz Mahmoudvand, Zahra Goudarzi, Arshia Fakouri, Simin Farokhi, Seyed Mahdi Hassanian, Gordon A Ferns, Elham Nazari, Amir Av
Current Cancer Drug Targets.2025; 25(10): 1222. CrossRef
Tubulointerstitial nephritis antigen-like 1 from cancer-associated fibroblasts contribute to the progression of diffuse-type gastric cancers through the interaction with integrin β1
Dagyeong Lee, In-Hye Ham, Hye Jeong Oh, Dong Min Lee, Jung Hwan Yoon, Sang-Yong Son, Tae-Min Kim, Jae-Young Kim, Sang-Uk Han, Hoon Hur
Journal of Translational Medicine.2024;[Epub] CrossRef
Safety and Efficacy of Neoadjuvant Chemoimmunotherapy in Gastric Cancer Patients with a PD-L1 Positive Status: A Case Report
Alexandra V. Avgustinovich, Olga V. Bakina, Sergey G. Afanas’ev, Liudmila V. Spirina, Alexander M. Volkov
Current Issues in Molecular Biology.2023; 45(9): 7642. CrossRef
Targeting GAS6/AXL signaling improves the response to immunotherapy by restoring the anti-immunogenic tumor microenvironment in gastric cancer
Tae Hoon Kim, Dagyeong Lee, Hye Jeong Oh, In-Hye Ham, Dong Min Lee, Yulim Lee, Zhang Zhang, Ding Ke, Hoon Hur
Life Sciences.2023; 335: 122230. CrossRef

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Histopathologic and Molecular Biomarkers of PD-1/PD-L1 Inhibitor Treatment Response among Patients with Microsatellite Instability‒High Colon Cancer: Jaewon Hyung, Eun Jeong Cho, Jihun Kim, Jwa Hoon Kim, Jeong Eun Kim, Yong Sang Hong, Tae Won Kim, Chang Ohk Sung, Sun Young Kim; Cancer Res Treat. 2022;54(4):1175-1190. Published online January 12, 2022; DOI: https://doi.org/10.4143/crt.2021.1133

Abstract PDF Supplementary Material PubReader ePub

Purpose
Recent clinical trials have reported response rates < 50% among patients treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for microsatellite instability‒high (MSI-H) colorectal cancer (CRC), and factors predicting treatment response have not been fully identified. This study aimed to identify potential biomarkers of PD-1/PD-L1 inhibitor treatment response among patients with MSI-H CRC.
Materials and Methods
MSI-H CRC patients enrolled in three clinical trials of PD-1/PD-L1 blockade at Asan Medical Center (Seoul, Republic of Korea) were screened and classified into two groups according to treatment response. Their histopathologic features and expression of 730 immune-related genes from the NanoString platform were evaluated, and a machine learning–based classification model was built to predict treatment response among MSI-H CRCs patients.
Results
A total of 27 patients (15 responders, 12 non-responders) were included. A high degree of lymphocytic/neutrophilic infiltration and an expansile tumor border were associated with treatment response and prolonged progression-free survival (PFS), while mucinous/signet-ring cell carcinoma was associated with a lack of treatment response and short PFS. Gene expression profiles revealed that the interferon-γ response pathway was enriched in the responder group. Of the top eight differentially expressed immune-related genes, PRAME had the highest fold change in the responder group. Higher expression of PRAME was independently associated with better PFS along with histologic subtypes in the multivariate analysis. The classification model using these genes showed good performance for predicting treatment response.
Conclusion
We identified histologic and immune-related gene expression characteristics associated with treatment response in MSI-H CRC, which may contribute to optimal patient stratification.

Citations

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Clinicopathologic, genetic and immune cell infiltration analysis of colorectal signet ring cell carcinoma with comparison to conventional adenocarcinoma
Yang An, Jiaolin Zhou, Lan Su, Lin Cong, Xinxin Mao, Bo Chen, Yuhua Gong, Yaping Xu, Han Chen, Chentong Wang, Guole Lin, Huanwen Wu
Journal of the National Cancer Center.2026; 6(1): 30. CrossRef
Macrophage-associated immune-stromal crosstalks correlate with the tumor microenvironment in microsatellite-stable mucinous colorectal cancer
Yinjun He, Tianneng Zhu, Mingyu Zheng, Qingxin Yu, Siqin Lei, Chaoyi Chen, Dianhe Yu, Zhiyong Liang, Honghe Zhang
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Gynecologic cancer

Frequency of Mismatch Repair Deficiency/High Microsatellite Instability and Its Role as a Predictive Biomarker of Response to Immune Checkpoint Inhibitors in Gynecologic Cancers: Joseph J. Noh, Min Kyu Kim, Min Chul Choi, Jeong-Won Lee, Hyun Park, Sang Geun Jung, Won Duk Joo, Seung Hun Song, Chan Lee; Cancer Res Treat. 2022;54(4):1200-1208. Published online December 13, 2021; DOI: https://doi.org/10.4143/crt.2021.828

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study was to investigate the frequency of mismatch repair deficiency/high microsatellite instability (MMRd/MSI-H) in gynecologic malignancies and the efficacy of immune checkpoint inhibitors (ICIs) in patients with recurrent gynecologic cancers according to MMR/MSI status.
Materials and Methods
We conducted a multi-center retrospective review on the patients who were diagnosed with gynecologic cancers between 2015 and 2020. Their clinicopathologic information, results of immunohistochemistry staining for MLH1/MSH2/MSH6/PMS2 and MSI analysis, tumor response to treatment with ICIs were investigated.
Results
Among 1,093 patients included in the analysis, MMRd/MSI-H was most frequent in endometrial/uterine cancers (34.8%, 164/471), followed by ovarian, tubal, and peritoneal cancers (12.8%, 54/422) and cervical cancer (11.3%, 21/186). When assessed by histology without regard for cancer types, the frequency of MMRd/MSI-H was 11.0% (38/345) in high-grade serous adenocarcinoma, 38.6% (117/303) in endometrioid adenocarcinoma, and 30.2% (16/53) in carcinosarcoma. A total of 114 patients were treated with ICIs at least once. The objective response rate (ORR) was 21.6% (8/37) in cervical cancer, 4.7% (2/43) in ovarian cancer, and 25.8% (8/31) in endometrial/uterine cancers. Univariate regression analysis identified MMRd/MSI-H as the only significant factor associated with the ORR (28.9% [11/38] vs. 11.8% [9/76]; odds ratio, 3.033; 95% confidence interval, 1.129–8.144; p=0.028).
Conclusion
The frequency of MMRd/MSI-H is moderate to high in gynecologic cancers in the Korean population. MMRd/MSI-H could be effective predictive biomarkers in gynecologic cancers of any type.

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Yuting Sheng, Hunter E. Wujcik, Mark R. Wakefield, Yujiang Fang
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Youwen Zhu, Kun Liu, Hong Zhu
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Zhi Zhao, Yijie Peng, Yuanyuan Yang, Shuaiyu Li, Jiang Ling, Zhenyu Zhu, Chenfeng He
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Carla Eksteen, Johann Riedemann, Frederick H. van der Merwe, Matthys H. Botha, Anna-Mart Engelbrecht
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Yiliminuer Abulajiang, Yumei Wu, Yue He
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A.D. Kolina, N.V. Danilova, Yu.Yu. Andreeva
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Renata Pacholczak-Madej, Michele Bartoletti, Lucia Musacchio, Mirosława Püsküllüoglu, Paweł Blecharz, Domenica Lorusso
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Na Li, Zixuan Wan, Dongyan Lu, Ruilian Chen, Xiaowei Ye
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Guillaume Mestrallet, Matthew Brown, Cansu Cimen Bozkus, Nina Bhardwaj
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Adverse Effect of the Duration of Antibiotic Use Prior to Immune Checkpoint Inhibitors on the Overall Survival of Patients with Recurrent Gynecologic Malignancies
Hye-Ji Jung, Jong-Ho Park, Jina Oh, Sae-Mi Lee, Il-Yeo Jang, Jung-Yong Hong, Yoo-Young Lee, Hyun Jin Choi
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Yunkai Xie, Weimin Kong, Xiaoling Zhao, He Zhang, Dan Luo, Shuning Chen
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Lung and Thoracic cancer

Clinical Efficacy of Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer Patients with Liver Metastases: A Network Meta-Analysis of Nine Randomized Controlled Trials: Qing Yin, Longguo Dai, Ruizhu Sun, Ping Ke, Liya Liu, Bo Jiang; Cancer Res Treat. 2022;54(3):803-816. Published online October 25, 2021; DOI: https://doi.org/10.4143/crt.2021.764

Abstract PDF Supplementary Material PubReader ePub

Purpose
This network meta-analysis (NMA) was conducted to compare the efficacy of immune checkpoint inhibitors in advanced non–small cell lung cancer (NSCLC) patients with liver metastases.
Materials and Methods
English literature was retrieved from the PubMed, American Society of Clinical Oncology, and European Society for Medical Oncology databases from January 2015 to January 2021. We pooled the overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) using an NMA and ranked treatments by the surface under the cumulative ranking curve. Publication bias was evaluated by Begg’s and Egger’s tests. STATA 15.0 was used for the sensitivity analysis, and the remaining statistical analyses were performed using R 4.0.2.
Results
Nine eligible phase III randomized controlled trials were included, including 1,141 patients with liver metastases. Pembrolizumab+chemotherapy ranked highest, followed by atezolizumab+bevacizumab+chemotherapy and nivolumab. However, no significant difference in OS rates was observed across these three treatments (HR, 0.98; 95% confidence interval [CI], 0.43 to 2.22 for pembrolizumab+chemotherapy vs. atezolizumab+bevacizumab+chemotherapy; HR, 0.91; 95% CI, 0.52 to 1.57 for pembrolizumab+chemotherapy vs. nivolumab). Regarding the PFS rate, atezolizumab+bevacizumab+chemotherapy and pembro-lizumab+chemotherapy ranked highest and no significant difference was observed between them (HR, 0.79; 95% CI, 0.36 to 1.70 for atezolizumab+bevacizumab+chemotherapy vs. pembrolizumab+chemotherapy).
Conclusion
Pembrolizumab+chemotherapy, atezolizumab+bevacizumab+chemotherapy, and nivolumab were superior to other treatments in NSCLC patients with liver metastases. These new findings may help clinicians better select therapeutic strategies for NSCLC patients with liver metastases.

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Immune checkpoint inhibitor-related efficacy in non-small cell lung cancer: real-world incidence and management practices of 208 patients
Yufang Lu, Pengcheng Liu, Changxiu Ma, Hui Liu, Ying Zhang, Dahai Zhao
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红艳刘
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BMC Cancer.2025;[Epub] CrossRef
VEGF-A splicing variant in plasma is a predictive potential biomarker of bevacizumab in advanced non-squamous non-small cell lung cancer
Akira Matsui, Masahiro Morise, Ryosuke Kikuchi, Fumie Kinoshita, Atsuo Suzuki, Ichidai Tanaka, Makoto Ishii, Shingo Matsumoto, Koichi Goto
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Turkish Journal of Ophthalmology.2025; 55(6): 352. CrossRef
Progress of immune checkpoint inhibitors therapy for non-small cell lung cancer with liver metastases
Fan-jie Qu, Yi Zhou, Shuang Wu
British Journal of Cancer.2024; 130(2): 165. CrossRef
Effectiveness and Safety of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in Pulmonary Sarcomatoid Carcinoma
Daisuke Hazama, Kenji Nakahama, Hiroaki Kodama, Akito Miyazaki, Koichi Azuma, Yosuke Kawashima, Yuki Sato, Kentaro Ito, Yoshimasa Shiraishi, Keita Miura, Takayuki Takahama, Satoshi Oizumi, Yoshinobu Namba, Satoshi Ikeda, Hiroshige Yoshioka, Asuka Tsuya, Y
JTO Clinical and Research Reports.2024; 5(1): 100613. CrossRef
Evolving landscape of treatments targeting the microenvironment of liver metastases in non-small cell lung cancer
Lingling Zhu, Xianzhe Yu, Xiaojun Tang, Chenggong Hu, Lei Wu, Yanyang Liu, Qinghua Zhou
Chinese Medical Journal.2024; 137(9): 1019. CrossRef
Treatment Options for Patients with Non-Small Cell Lung Cancer and Liver Metastases
Vesna Ćeriman Krstić, Natalija Samardžić, Milija Gajić, Milan Savić, Biljana Šeha, Marina Roksandić Milenković, Dragana Jovanović
Current Issues in Molecular Biology.2024; 46(12): 13443. CrossRef
Assessing the Relationship Between Liver Metastases and the Survival of Patients With Non-Small Cell Lung Cancer After Immune Checkpoint Inhibitors Treatment: A Systematic Review and Meta-Analysis
Huilin Xu, Pingpo Ming, Zhenyu Zhao, Nan Zhao, Dingjie Zhou, Xixian Tang, Dedong Cao
Integrative Cancer Therapies.2023;[Epub] CrossRef
Liver metastases and the efficacy of immune checkpoint inhibitors in advanced lung cancer: A systematic review and meta-analysis
Handai Xia, Wengang Zhang, Yuqing Zhang, Xiaoling Shang, Yanguo Liu, Xiuwen Wang
Frontiers in Oncology.2022;[Epub] CrossRef

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274 Download
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11 Crossref

Comparison of the Predictive Power of a Combination versus Individual Biomarker Testing in Non–Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Hyojin Kim, Hyun Jung Kwon, Eun Sun Kim, Soohyeon Kwon, Kyoung Jin Suh, Se Hyun Kim, Yu Jung Kim, Jong Seok Lee, Jin-Haeng Chung; Cancer Res Treat. 2022;54(2):424-433. Published online July 7, 2021; DOI: https://doi.org/10.4143/crt.2021.583

Abstract PDF Supplementary Material PubReader ePub

Purpose
Since tumor mutational burden (TMB) and gene expression profiling (GEP) have complementary effects, they may have improved predictive power when used in combination. Here, we investigated the ability of TMB and GEP to predict the immunotherapy response in patients with non–small cell lung cancer (NSCLC) and assessed if this combination can improve predictive power compared to that when used individually.
Materials and Methods
This retrospective cohort study included 30 patients with NSCLC who received immune checkpoint inhibitors (ICI) therapy at the Seoul National University Bundang Hospital. programmed cell death-ligand-1 (PD-L1) protein expression was assessed using immunohistochemistry, and TMB was measured by targeted deep sequencing. Gene expression was determined using NanoString nCounter analysis for the PanCancer IO360 panel, and enrichment analysis were performed.
Results
Eleven patients (36.7%) showed a durable clinical benefit (DCB), whereas 19 (63.3%) showed no durable benefit (NDB). TMB and enrichment scores (ES) showed significant differences between the DCB and NDB groups (p=0.044 and p=0.017, respectively); however, no significant correlations were observed among TMB, ES, and PD-L1. ES was the best single biomarker for predicting DCB (area under the curve [AUC], 0.794), followed by TMB (AUC, 0.679) and PD-L1 (AUC, 0.622). TMB and ES showed the highest AUC (0.837) among other combinations (AUC [TMB and PD-L1], 0.777; AUC [PD-L1 and ES], 0.763) and was similar to that of all biomarkers used together (0.832).
Conclusion
The combination of TMB and ES may be an effective predictive tool to identify patients with NSCLC patients who would possibly benefit from ICI therapies.

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Mo Cheng, Xiufeng Zheng, Jing Wei, Ming Liu
Experimental and Therapeutic Medicine.2023;[Epub] CrossRef

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Rare Cancer

Clinical Experience of Male Primary Choriocarcinoma at the Samsung Medical Center: Young Sok Ji, Se Hoon Park; Cancer Res Treat. 2021;53(3):874-880. Published online December 7, 2020; DOI: https://doi.org/10.4143/crt.2020.1066

Abstract PDF PubReader ePub

Purpose
The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020.
Materials and Methods
We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes.
Results
The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, eight (8/12, 67%) achieved an objective response, and four (4/12, 33%) achieved stable disease response as the best response during chemotherapy.
Conclusion
It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients.

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Immunotherapy

The Pattern of Time to Onset and Resolution of Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitors in Cancer: A Pooled Analysis of 23 Clinical Trials and 8,436 Patients: Si-Qi Tang, Ling-Long Tang, Yan-Ping Mao, Wen-Fei Li, Lei Chen, Yuan Zhang, Ying Guo, Qing Liu, Ying Sun, Cheng Xu, Jun Ma; Cancer Res Treat. 2021;53(2):339-354. Published online November 6, 2020; DOI: https://doi.org/10.4143/crt.2020.790

Abstract PDF Supplementary Material PubReader ePub

Purpose
The occurrence pattern of immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) in cancer treatment remains unclear.
Materials and Methods
Phase II-III clinical trials that evaluated ICI-based treatments in cancer and were published between January 2007 and December 2019 were retrieved from public electronic databases. The pooled median time to onset (PMT-O), resolution (PMT-R), and immune-modulation resolution (PMT-IMR) of irAEs were generated using the metamedian package of R software.
Results
Twenty-two eligible studies involving 23 clinical trials and 8,436 patients were included. The PMT-O of all-grade irAEs ranged from 2.2 to 14.8 weeks, with the longest in renal events. The PMT-O of grade ≥ 3 irAEs was significantly longer than that of all-grade irAEs induced by programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) inhibitors (27.5 weeks vs. 8.4 weeks, p < 0.001) and treatment of nivolumab (NIV) plus ipilimumab (IPI) (7.9 weeks vs. 6.0 weeks, p < 0.001). The PMT-R of all-grade irAEs ranged from 0.1 to 54.3 weeks, with the shortest and longest in hypersensitivity/infusion reaction and endocrine events, respectively. The PMT-IMR of grade ≥ 3 irAEs was significantly shorter than that of all-grade irAEs caused by PD-1/PD-L1 blockade (6.9 weeks vs. 40.6 weeks, p=0.002) and NIV+IPI treatment (3.1 weeks vs. 5.9 weeks, p=0.031).
Conclusion
This study revealed the general and specific occurrence pattern of ICI-induced irAEs in pan-cancers, which was deemed to aid the comprehensive understanding, timely detection, and effective management of ICI-induced irAEs.

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JCO Oncology Practice.2024; 20(12): 1663. CrossRef
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Frontiers in Endocrinology.2024;[Epub] CrossRef
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Brain Sciences.2024; 14(8): 764. CrossRef
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The American Journal of Medicine.2024; 137(12): 1200. CrossRef
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Journal of Controlled Release.2024; 375: 285. CrossRef
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International Journal of Molecular Sciences.2024; 25(21): 11676. CrossRef
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International Journal of Molecular Sciences.2024; 25(22): 12241. CrossRef
Real world comparison of immune-related adverse events with nivolumab-relatlimab versus ipilimumab-nivolumab in patients with advanced cutaneous melanoma
Brooke Kielkowski, Diana Mansour, Brooke Ebbert, Kelsea Seago, Sijin Wen, Hang Li, Christine Barrett
Journal of Oncology Pharmacy Practice.2024;[Epub] CrossRef
The effects of anti-PD-1 therapy on programmed death-ligand 1 expression and glucose metabolism of normal organs in patients with advanced non-small cell lung cancer
Matthew Severyn, Eunice H L Lee, Gitasha Chand, Jessica Johnson, Damion Bailey, Kathryn Adamson, Vicky Goh, Daniel Johnathan Hughes, Gary J R Cook
BJR|Open.2024;[Epub] CrossRef
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Journal of Cancer Research and Clinical Oncology.2023; 149(6): 2375. CrossRef
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Journal of Cancer Research and Clinical Oncology.2023; 149(4): 1659. CrossRef
Immune checkpoint inhibitor-induced pure red cell aplasia: Case series and large‐scale pharmacovigilance analysis
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International Immunopharmacology.2023; 114: 109490. CrossRef
Prognostic Significance of the Severity of Immune-Related Adverse Events in Advanced Cancer Patients Treated with PD-1/PD-L1 Inhibitors: A Real-World Data Analysis
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Frontiers in Pharmacology.2023;[Epub] CrossRef
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Frontiers in Immunology.2023;[Epub] CrossRef
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Gynecologic Oncology Reports.2023; 47: 101174. CrossRef
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Frontiers in Medicine.2021;[Epub] CrossRef

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