Cancer Research and Treatment最新文献

Purpose: We assessed human papillomavirus (HPV) genotype-based risk stratification and the efficacy of cytology testing for cervical cancer screening in patients with atypical squamous cells of undetermined significance (ASCUS)/low-grade squamous intraepithelial lesion (LSIL).

Materials and methods: Between 2010 and 2021, we monitored 1,237 HPV-positive women with ASCUS/LSIL every 6 months for up to 60 months. HPV infections were categorized as persistent (HPV positivity consistently observed post-enrollment), negative (HPV negativity consistently observed post-enrollment), or non-persistent (neither consistently positive nor negative). HPV genotypes were grouped into high-risk (Hr) groups 1 (types 16, 18, 31, 33, 45, 52, and 58) and 2 (types 35, 39, 51, 56, 59, 66, and 68) and a low-risk group. Hr1 was subdivided into types a) 16 and 18; b) 31, 33, and 45; and c) 52 and 58. Cox regression and machine learning (ML) algorithms were used to analyze progression rates.

Results: Among 1,273 participants, 17.6% with persistent HPV infections experienced disease progression versus no progression in the HPV-negative group (p<0.001). Cox analysis revealed the highest hazard ratios (HRs) for Hr1-a (11.6, p<0.001), followed by Hr1-b (9.26, p<0.001) and Hr1-c (7.21, p<0.001). HRs peaked at 12-24 months, with Hr1-a maintaining significance at 24-36 months (10.7, p=0.034). ML analysis identified the final cytology change pattern as the most significant factor, with 14-15 months the optimal time for detecting progression from the first examination.

Conclusion: In ASCUS/LSIL cases, follow-up strategies should be based on HPV risk types. Annual follow-up was the most effective monitoring for detecting progression/regression.

Purpose: This study aimed to investigate whether levetiracetam (LEV), the most used antiepileptic drug, influences survival in patients with glioblastoma (GBM), using a national database.

Materials and methods: This study used data from the Korea Health Insurance Review and Assessment database. Patients diagnosed with GBM between 2007-2018 treated with standard therapy were included. The study population was divided into long-term (≥60 days) and short-term (<30 days) LEV groups. A separate long-term valproic acid (VPA) group (≥60 days) was identified for comparison. Demographics, disease characteristics, and treatment parameters were collected. Kaplan-Meier method and Cox regression were used to compare survival outcomes between the groups.

Results: Overall, 2,971 patients were included, with 1,319 and 1,652 in the short-term and long-term LEV groups, respectively. The median overall survival (OS) for the entire population was 19.15 months post-surgery. Kaplan-Meier analysis revealed a significantly longer median OS in the long-term LEV group versus the short-term LEV group. After adjusting for confounders, Cox proportional hazard analysis revealed an association of long-term LEV use with improved survival, which was also observed in a subgroup analysis of patients without preoperative seizure history. The long-term LEV group demonstrated longer median OS, compared with the long-term VPA group.

Conclusion: Our nationwide population-based study found an association between long-term LEV use and improved survival in patients with GBM, regardless of preoperative seizure history. Prospective studies are needed to validate these findings and investigate the potential impact of LEV on the survival outcomes of patients with GBM.

Purpose: We aim to determine whether preoperative percutaneous needle aspiration or biopsy (PCNA/Bx) increases recurrence risk and reduces survival in stage I lung cancer patients, using a nationwide lung cancer registry.

Materials and methods: We retrospectively included 3,452 patients diagnosed with stage I lung cancer who underwent curative surgery between 2014 and 2019, as recorded in the Korean Association of Lung Cancer Registry. To balance the characteristics of patients with and without PCNA/Bx, we applied inverse probability of treatment weighting. We used cumulative incidence plots and a weighted subdistribution hazard model to analyze time to recurrence. Recurrence-free survival and overall survival were analyzed using Kaplan-Meier curves and weighted Cox proportional hazard ratio models.

Results: In patients with adenocarcinoma, the use of PCNA/Bx was associated with a 1.9-fold increase (95% CI, 1.5-2.4) in the risk of recurrence and a 1.7-fold decrease (95% CI, 1.3-2.2) in recurrence-free survival. Subgroup analysis based on pathologic pleural invasion revealed that the risk of recurrence increased when PCNA/Bx was performed, with 2.1-fold (95% CI, 1.5-2.8) in patients without pleural invasion and 1.6-fold (95% CI, 1.0-2.4) in those with pleural invasion. No association was found between the use of PCNA/Bx and overall survival.

Conclusion: Preoperative PCNA/Bx was associated with increased recurrence risks in stage I adenocarcinoma, regardless of pathologic pleural invasion status. In early lung cancer cases where adenocarcinoma is strongly suspected and curative surgery is feasible, the use of transthoracic biopsy should be approached with caution.

Purpose: Cancer survivors are at increased risk of diabetes mellitus (DM). Additionally, the prevalence of obesity, which is also a risk factor for DM, is increasing in cancer survivors. We investigated the associations between weight change after cancer diagnosis and DM risk.

Materials and methods: This retrospective cohort study used data from the Korean National Health Insurance Service. Participants who were newly diagnosed with cancer from 2010 to 2016 and received national health screening before and after diagnosis were included and followed until 2019. Weight change status after cancer diagnosis was categorized into four groups: sustained normal weight, obese to normal weight, normal weight to obese, or sustained obese. Cox proportional hazard analyses were performed to examine associations between weight change and DM.

Results: The study population comprised 264,250 cancer survivors. DM risk was highest in sustained obese (adjusted hazard ratios, 95% confidence interval: 2.17, 2.08-2.26), followed by normal weight to obese (1.66, 1.54-1.79), obese to normal weight (1.29, 1.21-1.39), and then sustained normal weight group (reference). In subgroup analyses according to cancer type, most cancers showed the highest risks in sustained obese group.

Conclusion: Obesity at any time point was related to increased DM risk, presenting the highest risk in cancer survivors with sustained obesity. Survivors who changed from obese to normal weight had lower risk than survivors with sustained obesity. Survivors who changed from normal weight to obese showed increased risk compared to those who sustained normal weight. Our finding supports the significance of weight management among cancer survivors.

Purpose: Considering the high disease burden and unique features of Asian patients with breast cancer (BC), it is essential to have a comprehensive view of genetic characteristics in this population. An institutional targeted sequencing platform was developed through the Korea Research-Driven Hospitals project and was incorporated into clinical practice. This study explores the use of targeted next-generation sequencing (NGS) and its outcomes in patients with advanced/metastatic BC in the real world.

Materials and methods: We reviewed the results of NGS tests administered to BC patients using a customized sequencing platform - FiRST Cancer Panel (FCP) - over seven years. We systematically described clinical translation of FCP for precise diagnostics, personalized therapeutic strategies, and unraveling disease pathogenesis.

Results: NGS tests were conducted on 548 samples from 522 patients with BC. 97.6% of tested samples harbored at least one pathogenic alteration. The common alterations included mutations in TP53(56.2%), PIK3CA(31.2%), GATA3(13.8%), BRCA2(10.2%), and amplifications of CCND1(10.8%), FGF19(10.0%), and ERBB2(9.5%). NGS analysis of ERBB2 amplification correlated well with HER2 immunohistochemistry and in situ hybridization. RNA panel analyses found potentially actionable and prognostic fusion genes. FCP effectively screened for potentially germline pathogenic/likely pathogenic mutation. 10.3% of BC patients received matched therapy guided by NGS, resulting in a significant overall survival advantage (p=0.022), especially for metastatic BCs.  .

Conclusion: Clinical NGS provided multifaceted benefits, deepening our understanding of the disease, improving diagnostic precision, and paving the way for targeted therapies. The concrete advantages of FCP highlight the importance of multi-gene testing for BC, especially for metastatic conditions.

Purpose: Leptin interacts not only with leptin receptor (LEPR) but also engages with other receptors. While the pro-oncogenic effects of the adrenergic receptor β2 (ADRB2) are well-established, the role of leptin in activating ADRB2 in triple-negative breast cancer (TNBC) remains unclear.

Materials and methods: The pro-carcinogenic effects of LEPR were investigated using murine TNBC cell lines, 4T1 and EMT6, and a tumor-bearing mouse model. Expression levels of LEPR, NOX4, and ADRB2 in TNBC cells and tumor tissues were analyzed via Western blot and qPCR. Changes in reactive oxygen species (ROS) levels were assessed using flow cytometry and MitoSox staining, while immunofluorescence double-staining confirmed the co-localization of LEPR and ADRB2.

Results: LEPR activation promoted NOX4-derived ROS and mitochondrial ROS production, facilitating TNBC cell proliferation and migration, effects which were mitigated by the LEPR inhibitor Allo-aca. Co-expression of LEPR and ADRB2 was observed on cell membranes, and bioinformatics data revealed a positive correlation between the two receptors. Leptin activated both LEPR and ADRB2, enhancing intracellular ROS generation and promoting tumor progression, which was effectively countered by a specific ADRB2 inhibitor ICI118551. In vivo, leptin injection accelerated tumor growth and lung metastases without affecting appetite, while treatments with Allo-aca or ICI118551 mitigated these effects.

Conclusion: This study demonstrates that leptin stimulates the growth and metastasis of TNBC through the activation of both LEPR and ADRB2, resulting in increased ROS production. These findings highlight LEPR and ADRB2 as potential biomarkers and therapeutic targets in TNBC.

Purpose: Extranodal NK/T-cell lymphoma (ENKTL) predominantly manifests in East Asia and Latin America. Despite shared intrinsic factors, such as ethnic and genetic backgrounds, the progression of ENKTL can be influenced by extrinsic factors related to changing lifestyle patterns.

Materials and methods: This study collected stool samples from newly diagnosed (ND)-ENKTL patients (n=40) and conducted whole genome shotgun sequencing.

Results: ND-ENKTL revealed reduced alpha diversity in ND-ENKTL compared to healthy controls (HCs) (p=0.008), with Enterobacteriaceae abundance significantly contributing to the beta diversity difference between ENKTL and HCs (p<0.001). Functional analysis indicated upregulated aerobic metabolism and degradation of aromatic compounds in ND-ENKTL. Enterobacteriaceae were associated not only with clinical data explaining disease status (serum CRP, stage, prognosis index of natural killer cell lymphoma (PINK), and PINK-E) but also with clinical outcomes (early relapse and short progression-free survival). The relative abundance of Enterobacteriaceae at the family level was similar between ENKTL and diffuse large B-cell lymphoma (DLBCL) (p=0.140). However, the ENKTL exhibited a higher abundance of Escherichia, in contrast to the prevalence of Enterobacter and Citrobacter in DLBCL. Linear regression analysis demonstrated a significant association between Escherichia abundance and PD-L1 levels in tissue samples (p=0.025), whereas no correlation with PD-L1 was observed for Enterobacteriaceae at the family level (p=0.571).

Conclusion: ND-ENKTL exhibited an abundance of Enterobacteriaceae and a dominant presence of Escherichia. These microbial characteristics correlated with disease status, treatment outcomes, and PD-L1 expression, suggesting the potential of the ENKTL microbiome as a biomarker and cause of lymphomagenesis, which warrants further exploration.

Purpose: Given that 40~50% of primary central nervous system lymphoma (PCNSL) tissues exhibit aberrancy on 9p24.1, immune-checkpoint inhibitors (ICI) may work for the disease.

Materials and methods: To define the role of ICIs in PCNSL, we carried out a nationwide retrospect analysis for 22 patients who had been treated with nivolumab monotherapy for relapsed or refractory PCNSL.

Results: The median age at diagnosis was 66, and male: female ratio was 1:1. Patients received nivolumab after a median of 3 lines (range, 2 - 6) of therapy and at the median age of 67 (range, 37 - 82). Eleven patients (50%) were refractory to the last treatment prior to nivolumab. With a median follow-up duration of 22.3 months (95% CI, 13.1 - 31.5), nine patients (41%) had an objective response (6 complete responses, 3 partial responses), and the median duration of response was 20.9 months (95% CI, 1.7 - 40.0). The median progression-free survival and overall survival were 2.1 months (95% CI, 0.2 - 4.0) and 18.9 months (95% CI, 5.0 - 32.8), respectively. Nivolumab was generally well-tolerated as no patients required dose reduction and only 2 patients required delay of treatment.

Conclusion: Our study suggests that nivolumab can be a reasonable option with the durable response for RR PCNSL.

Purpose: Approximately 50-74% of patients with metastatic HER2-positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients.

Materials and methods: In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.

Results: From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cut-off date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% CI: 8.3-18.5). With all patients evaluated, an ORR of 38.9% (95% CI: 23.1-56.5%) and a DCR of 83.3% (95% CI: 67.2-93.6%) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs.

Conclusion: Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.

Purpose: Cancer has become a significant major public health concern, making the discovery of new cancer markers or therapeutic targets exceptionally important. Elevated expression of tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) expression has been observed in certain types of cancer. This project aims to investigate the function of TNFRSF12A in tumors and the underlying mechanisms.

Materials and methods: Various websites were utilized for conducting the bioinformatics analysis. Tumor cell lines with stable knockdown or overexpression of TNFRSF12A were established for cell phenotyping experiments and subcutaneous tumorigenesis in BALB/c mice. RNA-seq was employed to investigate the mechanism of TNFRSF12A.

Results: TNFRSF12A was upregulated in the majority of cancers and associated with a poor prognosis. Knockdown TNFRSF12A hindered the colorectal cancer progression, while overexpression facilitated malignancy both in vitro and in vivo. TNFRSF12A overexpression led to increased NF-κB signaling and significant upregulation of BIRC3, a transcription target of the NF-κB member RELA, and it was experimentally confirmed to be a critical downstream factor of TNFRSF12A. Therefore, we speculated the existence of a TNFRSF12A/RELA/BIRC3 regulatory axis in colorectal cancer.

Conclusion: TNFRSF12A is upregulated in various cancer types and associated with a poor prognosis. In colorectal cancer, elevated TNFRSF12A expression promotes tumor growth, potentially through the TNFRSF12A/RELA/BIRC3 regulatory axis.