Cancer Research and Treatment最新文献

Purpose: This study aims to investigate the role of cytochrome b-245 chaperone 1 (CYBC1) in glioblastoma (GBM) progression, focusing on its involvement in reactive oxygen species (ROS) production and associated signaling pathways. Understanding the molecular mechanisms driven by CYBC1 could provide new therapeutic targets and prognostic markers for GBM.

Materials and methods: Publicly available datasets were analyzed to assess CYBC1 expression in GBM and its correlation with patient survival. GBM cell lines were genetically manipulated using the CRISPR/Cas9 system to deplete CYBC1. The effects of CYBC1 deficiency on cell proliferation, migration, invasion, and cell cycle dynamics were experimentally evaluated. Additionally, the impact of CYBC1 on the expression of NOXA1, a subunit of NADPH oxidase, and downstream signaling pathways such as nuclear factor кB (NF-κB) was explored.

Results: CYBC1 expression was significantly elevated in GBM tissues and correlated with poor patient survival. CYBC1 deficiency in GBM cells resulted in reduced cell viability, migration, and invasion. Mechanistically, CYBC1 positively regulated NOXA1 expression, which in turn enhanced ROS production and activated the ERK·AKT/NF-κB pathways. The suppression of CYBC1 led to decreased ROS levels, reduced phosphorylation of NF-κB, and downregulation of genes involved in epithelial-mesenchymal transition.

Conclusion: CYBC1 is implicated in GBM progression by regulating NOXA1-mediated ROS production and activating the ERK·AKT/NF-κB pathways. This study suggests that CYBC1 could serve as a potential therapeutic target and prognostic marker in GBM, warranting further investigation into its molecular mechanisms and therapeutic potential.

Purpose: After surgery for lung adenocarcinoma, a patient may experience various states of recurrence, with multiple factors potentially influencing the transitions between these states. Our purpose was to investigate the effects of clinical and pathological factors on tumor recurrence, death, and prognosis across various metastasizing pathways.

Materials and methods: Our study group included 335 patients with all demographic and pathologic data available who underwent surgical resection for lung adenocarcinoma for more than 10 years. The following states of disease were defined: initial state, operation (OP); three intermediate states of local recurrence (LR), metastasis (Meta), and concurrent LR with metastasis (LR+Meta); and a terminal state, death. We identified eight transitions representing various pathways of tumor progression. We employed a multi-state model (MSM) to separate the impacts of multiple prognostic factors on the transitions following surgery.

Results: After surgery, approximately half of patients experienced recurrence. Specifically, 142 (42.4%), 54 (16.1%), and seven (2.1%) patients developed Meta, LR+Meta, and LR, respectively. Clinical and pathological factors associated with the transitions were different. Impact of pathological lymph node remained a risk factor for both OP to Meta (λ02, p=0.001) and OP to LR+Meta (λ03, p=0.001).

Conclusion: Lung adenocarcinoma displays a broad spectrum of clinical scenarios even after curative surgery. Incidence, risk factors, and prognosis varied across different pathways of recurrence in lung adenocarcinoma patients. The greatest implication of this MSM is its ability to predict the timing and type of clinical intervention that will have the greatest impact on survival.

B-cell lymphomas are a heterogeneous group of malignancies with a high relapse rate after conventional therapies. T-cell-mediated immunotherapies, notably chimeric antigen receptor (CAR) T-cell therapies and T-cell-engaging bispecific antibodies (BsAbs), have transformed treatment paradigms by harnessing the immune system to target malignant cells. This review analyzes the efficacy and safety profiles of several CD19-targeted CAR T-cell therapies and emerging CD20×CD3 BsAbs across various B-cell lymphoma subtypes. While these therapies have demonstrated high response rates and potential for durable remissions, challenges such as cytokine release syndrome, neurotoxicity, and infections remain significant. Understanding these mechanisms and managing adverse effects are crucial for optimizing clinical outcomes and guiding future research in personalized treatment strategies.

Purpose: Fentanyl, a highly lipophilic opioid, was developed as a sublingual fentanyl tablet (SFT) for the management of breakthrough cancer pain (BTcP), and its efficacy and safety were confirmed in a randomized, controlled study. We investigated the effectiveness and safety of SFT administered to alleviate BTcP in a real-world setting.

Materials and methods: In this prospective, open, single-cohort study, conducted in 13 referral hospitals in South Korea, opioid-tolerant cancer patients receiving around-the-clock opioids for persistent cancer pain were enrolled if the individual had BTcP ≥ 1 episode/day during the preceding week. The primary outcome was the SFT titration success rate.

Results: Among 113 patients evaluated for effectiveness, 103 patients (91.2%) had a successful titration of SFT, with an effective dose range between 100 μg and 400 μg. The most frequent dose was 100 μg, administered to 65.0%, 72.1%, and 81.8% of the patients at week 1, 4, and 12, respectively. The proportion of patients achieving the personalized pain goal assessed in the first week was 75.2%. The mean change in pain intensity measured with a numeric rating scale at 30 and 60 minutes after taking SFT was -2.57 and -3.62, respectively (p < 0.001 for both). The incidence rate of adverse events related to SFT among 133 patients included for safety evaluation was 9.0% (12/133), which included vomiting (3.0%), nausea (2.3%), and headache (1.5%).

Conclusion: In a real-world setting, SFT provides rapid and effective analgesia in BTcP, even at the lowest dose (100 μg), and the safety profile was acceptable.

Purpose: Esophageal cancer (EC) is a rapidly progressing malignancy characterized by a low survival rate and limited treatment success, largely due to late-stage detection, frequent recurrence, and a high propensity for metastasis, despite ongoing advances in therapeutic strategies. While oxaliplatin (L-OHP) is a potent chemotherapeutic agent that induces apoptosis in EC cells, its effectiveness is significantly hindered by the development of resistance.

Materials and methods: The assessment of gene and protein expression was conducted through a combination of quantitative real-time polymerase chain reaction, Western blot, and immunohistochemical staining. Cell viability was assessed using the cell counting kit-8 assay. The interactions among ALYREF, TBL1XR1, KMT2E, and APOC1 were investigated through RNA immunoprecipitation, chromatin immunoprecipitation (ChIP), ChIP-reChIP, RNA pulldown, and dual-luciferase assays. An in vivo mouse model of EC was established.

Results: Expression levels of both APOC1 and ALYREF were elevated in L-OHP-resistant EC tissues and cell lines, and their silencing enhanced sensitivity to L-OHP. TBL1XR1 and KMT2E synergistically upregulated APOC1 expression. Moreover, ALYREF recognized the 5-methylcytosine (m5C) sites on TBL1XR1 and KMT2E mRNAs, stabilizing these transcripts and promoting APOC1 expression. The regulatory role of these interactions was further validated in vivo.

Conclusion: This study demonstrated that ALYREF interacted with the m5C sites on TBL1XR1 and KMT2E mRNAs, enhancing their stability and leading to increased transcription of APOC1, which in turn contributed to L-OHP resistance in EC. These findings suggest that targeting APOC1 could be a promising strategy for overcoming L-OHP resistance in EC.

Purpose: Acute myeloid leukemia (AML) shows significant heterogeneity in therapeutic responses. We aimed to develop a gene signature for the stratification of high-risk pediatric AML using publicly available AML datasets, with a focus on literature-based prognostic gene sets.

Materials and methods: We identified 300 genes from 12 well-validated studies on AML-related gene signatures. Clinical and gene expression data were obtained from three datasets: TCGA-LAML, TARGET-AML, and BeatAML. Least absolute shrinkage and selection operator-Cox regression analysis was used to perform the initial gene selection and to construct a prognostic model using the The Cancer Genome Atlas (TCGA) database (n=132). The final gene signature was validated with two independent cohorts: BeatAML (n=411) and TARGET-AML (n=187).

Results: We identified a six-gene signature (ETFB, ARL6IP5, PTP4A3, CSK, HS3ST3B1, PLA2G4A), referred to as the literature-based signature 6 (LBS6), that was significantly associated with lower overall survival rates across the TCGA (high-risk [HR], 4.2; 95% confidence interval [CI], 2.59 to 6.81; p < 0.001), BeatAML (HR, 1.52; 95% CI, 1.17 to 1.96; p=0.001), and TARGET (HR, 2.05; 95% CI, 1.36 to 3.08; p < 0.001) datasets. The high-LBS6 score group exhibited significantly poorer five-year event-free survival compared to the low-LBS6 score group (HR, 2.09; 95% CI, 1.38 to 3.15; p < 0.001). After adjusting for key risk factors, including gene mutations (WT1, FLT3, and NPM1), protocol-based risk group, white blood cell count, and age, the LBS6 score was independently associated with worse survival rates in validation cohorts.

Conclusion: Our literature-driven approach identified a robust gene signature that stratifies AML patients into distinct risk groups. The LBS6 score shows promise in redefining initial risk stratification and identifying high-risk AML patients.

Purpose: New nomenclature has incorporated metabolic traits and/or alcohol intake history to replace nonalcoholic fatty liver disease (NAFLD). Concerning the performance of different terminologies in Asian population, this study aimed to investigate the risk of developing hepatocellular carcinoma (HCC) in persons meeting the criteria for subclasses of fatty liver disease.

Materials and methods: Between 2002 and 2021, 28,749 participants from the cancer registry linkage, who had no prior history of HCC, were prospectively included. Fatty liver disease was defined using abdominal sonography and fatty liver index. Participants were classified as having NAFLD, metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD), steatotic liver disease with increased alcohol intake (MetALD), or alcohol-related liver disease (ALD) and their association with HCC risk was investigated using Cox regression models.

Results: During a median follow-up of 14.5 years, 143 HCC cases were newly diagnosed. The prevalences of NAFLD and MASLD were 19.7% and 18.7%, respectively, whereas MAFLD was observed in 32.3% of the study population. Given the low proportion of excessive alcohol consumption, we identified 3.3% MetALD and 3.5% ALD cases. Overall, MAFLD was suggestively associated with HCC risk (hazard ratio, 1.40; 95% confidence interval, 0.99 to 1.98). In contrast, the results for other nomenclature were not significant.

Conclusion: Our results suggest the importance of both fatty liver and the presence of metabolic dysfunction in relation to HCC risk and the need to reconsider alcohol intake thresholds in the diagnostic criteria for NAFLD and MASLD within the Korean population.

Purpose: This study evaluates the experiences and satisfaction levels of Korean medical oncologists with the prior authorization system for the off-label use of anti-cancer drugs. Conducted by the Korean Society of Medical Oncology (KSMO), the survey aimed to identify challenges and areas for improvement in the current regulatory framework.

Materials and methods: A cross-sectional web-based survey was carried out between May 4 and May 14, 2023, targeting 261 active KSMO medical oncologists. Invitations were sent via email, and the survey, comprising 19 questions, was hosted on Microsoft Forms. The questions covered personal characteristics, work environment, experiences with the pre-application process, and post-approval experiences.

Results: For the 261 invitations sent, 110 responses (42.1%) were received. Most respondents had over 10 years of experience and worked in tertiary hospitals. Although 93.6% were familiar with the pre-application system, 67.3% expressed moderate to high dissatisfaction. The key issues included complex applications, long approval period, stringent criteria, and inconsistent reviews. Additionally, 74.4% of respondents spent over 3 hours on first-time applications, with 68.3% experiencing rejections. Emotional responses to rejections were largely negative, with many feeling disregarded. Post-approval, patients of 96.8% of respondents faced financial burdens leading to treatment discontinuation. Most oncologists (86.0%) supported selective reimbursement if the disease was controlled for a certain period.

Conclusion: The survey highlights significant dissatisfaction with the current system, suggesting the need for streamlining the application process, easing approval criteria, and reconsidering the financial aspects of post-approval treatments to support patient care and oncologists' decision-making autonomy.

Purpose: We compared the local control rate and toxicity of stereotactic ablative radiotherapy (SABR) versus wedge resection for colorectal pulmonary metastases.

Materials and methods: We retrospectively reviewed medical charts and imaging of patients treated with SABR or wedge resection between 2010 and 2017 at a single institution.

Results: A total of 404 patients were treated with local therapy for 528 pulmonary metastatic lesions. While surgery was frequently used upfront for smaller, solitary metastases without other site involvement, SABR was often used for larger, multiple lesions and disease burdens beyond the lungs. The 3-year local control rate was 88.6% following surgery, which was not significantly different from that with SABR at 86.7% (p=0.174). No major postoperative complications or mortality were observed in the surgery group, and 2.8% of patients in the SABR group experienced grade 3-4 radiation pneumonitis.

Conclusion: SABR was used in patients with a higher risk of progression compared to those undergoing surgery, yet it has similar local control rates to wedge resection.

Purpose: We aimed to develop a preoperative risk scoring system to predict early recurrence (ER) of intrahepatic cholangiocarcinoma (ICCA) after resection, utilizing clinical and computed tomography (CT) features.

Materials and methods: This multicenter study included 365 patients who underwent curative-intent surgical resection for ICCA at six institutions between 2009 and 2016. Of these, 264 patients from one institution constituted the development cohort, while 101 patients from the other institutions constituted the external validation cohort. Logistic regression models were constructed to predict ER based on preoperative variables and were subsequently translated into a risk scoring system. The discrimination performance of the risk scoring system was validated using external data and compared to the American Joint Committee on Cancer (AJCC) TNM staging system.

Results: Among the 365 patients (mean age, 62±10 years), 153 had ER. A preoperative risk scoring system that incorporated both clinical and CT features demonstrated superior discriminatory performance compared to the postoperative AJCC TNM staging system in both the development (area under the curve [AUC], 0.78 vs. 0.68; p=0.002) and validation cohorts (AUC, 0.69 vs. 0.66; p=0.641). The preoperative risk scoring system effectively stratified patients based on their risk for ER: the 1-year recurrence-free survival rates for the low, intermediate, and high-risk groups were 85.5%, 56.6%, and 15.6%, respectively (p < 0.001) in the development cohort, and 87.5%, 58.5%, and 25.0%, respectively (p < 0.001) in the validation cohort.

Conclusion: A preoperative risk scoring system that incorporates clinical and CT imaging features was valuable in identifying high-risk patients with ICCA for ER following resection.