Cancer Research and Treatment最新文献

Purpose: Investigate the role of lipid metabolism in the tumor immune microenvironment (TIME) of lung adenocarcinoma (LUAD) and identify vital lipid metabolism-related genes (LMRGs) that contribute to immunotherapy outcomes.

Materials and methods: 1130 LUAD patients were acquired utilizing public databases. Multiple algorithms were used to analyze the contribution of lipid metabolism in TIME. Importantly, cell lines, clinical samples (52 patients in surgery cohort and 36 in immunotherapy cohort), animal models, RNA-seq, experiments in protein and mRNA levels were conducted for identifying and validating key biomarker in LUAD immunotherapy.

Results: A prognostic signature comprising 33 LMRGs was developed and validated as an effective predictor of prognosis and TIME, with a C-index of 0.766 (95% CI: 0.729-0.804). Additionally, we identified Acyl-CoA Synthetase Long Chain Family Member 3 (ACSL3) as a potential biomarker for immunotherapy prognosis. The expression of ACSL3 was verified in 88 clinical tissues from LUAD patients, which indicated that elevated ACSL3 expression was correlated with worse progression-free survival (PFS) (p<0.001) and overall survival (OS) (p=0.008). Subsequent experiments revealed that knockdown of ACSL3 in vivo enhanced the efficacy of immunotherapy, potentially through increasing interferon α secretion, as indicated by Bulk RNA-seq and ELISA analysis, thereby promoting the infiltration of anti-tumor immune cells.

Conclusion: The study established a model that accurately predicts immunotherapy response, prognosis, and TIME dynamics in LUAD patients. Notably, the pivotal role of ACSL3 in driving tumor progression and immune evasion was uncovered, offering novel insights into the optimization of immunotherapy strategies for LUAD.

Purpose: To assess prognostic values of the POST-Treatment Extent of Tumor (POSTTEXT) system and clinical factors after neoadjuvant chemotherapy in hepatoblastoma patients and evaluate benefits of posttreatment imaging and clinical factors concomitant with Children's Hepatic Tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system.

Materials and methods: This single-center retrospective study of hepatoblastoma cases (2006-2022) included pediatric patients receiving ≥ 4 cycles of neoadjuvant chemotherapy, with pre- and post-treatment imaging and complete medical records. Clinical data included age, sex, and serum alpha-fetoprotein (AFP) levels. Cox regression analyses identified predictors of event-free survival (EFS). Time-dependent receiver operating characteristic curves assessed the predictive power of combining the CHIC-HS risk stratification with posttreatment factors. Inter-reader agreement was analyzed using weighted kappa.

Results: Among the 109 hepatoblastoma patients, 73 (mean age: 2.2 ± 2.7 years) met the inclusion criteria. Prognostic factors for EFS included AFP levels after the fourth cycle of neoadjuvant chemotherapy (HR, 1.233; 95% CI, 1.806-1.400; p=0.001), tumor size change ratio (HR, 0.654; 95% CI, 0.448-0.955; p=0.03), and POSTTEXT annotation factor M (HR, 5.209; 95% CI, 1.639-16.553; p=0.005). Incorporating AFP levels after the fourth cycle of neoadjuvant chemotherapy into the CHIC-HS improved predictive power (p=0.043). POSTTEXT system showed better inter-reader agreement than PRETEXT.

Conclusion: Predictors of EFS in hepatoblastoma include AFP levels after the fourth cycle of neoadjuvant chemotherapy, tumor size change ratio, and metastasis (POSTTEXT M). Combining AFP levels after the fourth cycle of neoadjuvant chemotherapy to the CHIC-HS improved the predictive ability.

Purpose: Ninjury-induced protein 1 (Ninj1) is associated with inflammation and tumor progression and shows increased expression in various cancers. This study aimed to investigate the role of Ninj1 in colitis-associated colorectal cancer (CRC) by focusing on its interaction with 17β-estradiol (E2).

Materials and methods: Using an azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model of colitis-associated CRC, wild-type (WT) and Ninj1 knockout (KO) male mice were treated with or without E2.

Results: At week 2, Ninj1 KO mice exhibited attenuated colitis symptoms than WT mice following AOM/DSS treatment. E2 administration significantly alleviated these symptoms in both WT and Ninj1 KO mice, with reductions in the disease activity index (DAI), colon length shortening, and histopathological damage. The levels of pro-inflammatory mediators were reduced by E2 treatment in both groups, with the Ninj1 KO group showing a more pronounced response. At week 13, tumor development in Ninj1 KO mice was significantly lower than that in WT mice, particularly in the distal colon. E2 treatment inhibited tumor formation in WT mice and had a stronger inhibitory effect on distal colon tumorigenesis in Ninj1 KO mice. Immune cell populations, including the populations of macrophages and T cells, were also modulated by E2 in WT mice; however, these effects were diminished in Ninj1 KO mice.

Conclusion: These findings suggest that Ninj1 plays a role in modulating colitis and CRC progression, with E2 exerting anti-inflammatory and anti-tumorigenic effects that are influenced by Ninj1 status.

Purpose: To compare clinicopathologic features and clinical outcomes of metastatic colorectal cancer (mCRC) based on EGFR amplification status.

Materials and methods: Patients with mCRC who underwent next-generation sequencing using a targeted 244-gene panel from 2016 to 2021 were identified and screened for EGFR copy numbers. Cases with at least 5 copies were reviewed for tumor purity adjustment, and those with an adjusted copy number of ≥6 were defined as EGFR-amplified (EGFR amp+). Their clinical characteristics were compared with those without EGFR amplification (EGFR amp-).

Results: Among 2,421 patients, 35 (1.4%) were EGFR amp+. Clinical characteristics did not significantly differ according to EGFR amplification status, but EGFR amp+ cases had fewer instances of peritoneal seeding (8.6% vs. 21.8%). Overall survival (OS) tended to be better in EGFR amp+ patients compared with EGFR amp- patients (median OS 76 vs. 37 months, p=0.15). Among 572 patients who received anti-EGFR antibody-based chemotherapy (anti-EGFR CTx) during disease course, mOS tended to be better in 16 EGFR amp+ patients (79 months) compared with 556 EGFR amp- patients (39 months, p=0.048). Seven out of 35 EGFR amp+ patients were treated with front-line anti-EGFR CTx, and their progression-free survival did not differ from that of EGFR amp- patients treated with front-line anti-EGFR CTx (20 vs. 14 months, p=0.344).

Conclusion: This study may suggest a favorable predictive impact of EGFR amplification in patients treated with anti-EGFR CTx. However, the benefit of front-line anti-EGFR antibody treatment in this group was not notable.

Purpose: Smoking cessation interventions for participants in lung cancer screening are essential for increasing the effectiveness of screening to reduce lung cancer mortality. This study aimed to investigate the factors that lead to smoking cessation after lung cancer screening.

Materials and methods: The Korean National Lung Cancer Screening (KNLCS) Satisfaction Survey was conducted from 2021 to 2022 with 1,000 samples per year among participants in KNLCS targets 30 or more pack-year smokers. Factors associated with smoking cessation were analyzed based on the survey.

Results: Among 1,525 current smokers in the survey participants, 728 (47.7%) received screening result counseling from physician after screening and showed significantly higher smoking cessation rate than non-counselling participants [OR 2.17, 95% CI 1.27-3.70]. The participants who considered the counseling helpful were more likely to quit smoking [OR 3.53, 95% CI 2.00-6.22] and to reduce smoking amount [OR 2.05, 95% CI 1.54-2.71]. Similarly, those who received physicians' active recommendations to quit smoking were likely to quit smoking [OR 2.20, 95% CI 1.25-3.87] and to decrease smoking amount [OR 1.30, 95% CI 1.00-1.68]. In contrast, participants who had no abnormal findings from screening tended to have no significant change in smoking status despite the physicians' active recommendations to quit smoking.

Conclusion: Physicians' active recommendations and effective counseling to quit smoking could be a key factor in increasing smoking cessation among lung cancer screening participants. Further research should be conducted to develop more effective strategies for smoking cessation to participants without abnormal findings in lung cancer screening.

Purpose: In glioblastoma, the therapeutically intractable and resistant phenotypes can be derived from glioma stem cells, which often have different underlying mechanisms from non-stem glioma cells. Aberrant signaling across the EGFR-PTEN-AKT-mTOR pathways have been shown as common drivers of glioblastoma. Revealing the inter and intra-cellular heterogeneity within glioma stem cell populations in relations to signaling patterns through these pathways may be key to precision diagnostic and therapeutic targeting of these cells.

Materials and methods: Single cell parallel proteomic heterogeneity profiling of the EGFR-PTEN-AKT-mTOR pathways was conducted in a panel of fifteen glioma stem cell models derived from patient glioblastoma biopsies.

Results: The analysis included 59,464 data points from 14,866 cells and identified forty-nine molecularly distinct signaling phenotypes. High content bioinformatics resolved two unique patient clusters diverging on EGFR expression and AKT/TORC1 activation. Phenotypic validation indicated drug responsive phenotypes to EGFR blocking in the high EGFR expressing cluster with lower tumor initiating potential in comparison to the AKT/TORC1 activated cluster. High EGFR expression trended with improved patient prognosis while AKT/TORC1 activated samples trended with poorer patient outcomes. Genetic heterogeneity was observed in both clusters with proneural, classical and mesenchymal subtypes observed.

Conclusion: Quantitative single cell heterogeneity profiling reveals divergent EGFR-PTEN-AKT-mTOR pathways of patient derived glioma stem cells, which would inform future research and personalized therapeutic strategies.

Purpose: This study focused on combining irinotecan with Poly (ADP-ribose) polymerase (PARP) inhibitors to explore the potential for novel combination therapeutics in small cell lung cancer (SCLC).

Materials and methods: We selected 10 different SCLC cell lines with diverse mutational backgrounds in DNA damage response (DDR) pathway genes to evaluate the efficacy of the combination of three PARP inhibitors and irinotecan. After the cells were exposed to the drugs for seven days, cell viability was measured, and a combination index was calculated. Apoptotic signaling was assessed via western blot, and DNA damage was evaluated using an alkaline comet assay.

Results: We assessed the synergistic effects of PARP inhibitors and irinotecan in in vitro SCLC models, which revealed increased sensitivity, particularly in cells harboring BRCA mutations. However, even in cells lacking mutations in DNA damage response pathway genes, the combination of the two drugs exhibited a synergistic effect. When treated with 50 nM irinotecan, the IC50 fold changes for PARP inhibitors were: olaparib, 1649 ± 4049; talazoparib, 25 ± 34.21; venadaparib, 336 ± 596.01. This combination enhanced apoptosis signaling and increased p-chk1 and p-p53 protein levels. Additionally, the treatment of PARP inhibitor with irinotecan increased DNA damage, as visualized by the alkaline comet assay.

Conclusion: This study provides preclinical evidence of the potential clinical benefits of combining irinotecan with PARP inhibitors in SCLC. Further clinical investigations are warranted to validate these findings for the development of more effective and personalized therapeutic strategies for SCLC patients.

Purpose: Hematopoietic stem cell transplantation (HSCT) has been an important method of treatment in the advance of pediatric acute lymphoblastic leukemia (ALL). The indications for HSCT are evolving and require updated establishment. In this study, we aimed to investigate the efficacy of HSCT on the treatment outcome of pediatric ALL, considering the indications for HSCT and subgroups.

Materials and methods: A retrospective analysis was conducted on ALL patients diagnosed and treated at a single center. Risk groups were categorized based on age at diagnosis, initial white blood cell count, disease lineage (B/T), and cytogenetic study results. Data on the patients' disease status at HSCT and indications of HSCT were collected. Indications for HSCT were categorized as upfront HSCT at 1st complete remission, relapse, and refractory disease.

Results: Among the 549 screened patients, a total of 418 patients were included in the study; B-cell ALL (n=379) and T-cell ALL (T-ALL) (n=39). HSCT was conducted on a total of 106 patients (25.4%), with a higher frequency as upfront HSCT in higher-risk groups and specific cytogenetics. The overall survival (OS) was significantly better when done upfront than in relapsed or refractory state in T-ALL patients (p=0.002). The KMT2A-rearranged ALL patients showed superior event-free survival (p=0.002) and OS (p=0.022) when HSCT was done as upfront treatment.

Conclusion: HSCT had a substantial positive effect in a specific subset of pediatric ALL. In particular, frontline HSCT for T-ALL and KMT2A-rearranged ALL offered a better prognosis than when HSCT was conducted in a relapsed or refractory setting.

Purpose: The International Association for the Study of Lung Cancer suggests further subdivision of pathologic N (pN) category in non-small-cell lung cancer (NSCLC) by incorporating the location and number of involved lymph node (LN) stations. We reclassified patients with the station-based N2b disease into single-zone and multi-zone N2b groups and compared survival outcomes between the groups.

Materials and methods: This retrospective study included patients with pN2 NSCLC who underwent lobectomy from 2006 to 2019. The N2 disease was subdivided into four categories: single-station N2 without N1 (N2a1), single-station N2 with N1 (N2a2), multiple-station N2 with single zone involvement (single-zone N2b), and multiple-station N2 with multiple zone involvement (multi-zone N2b). LN zones included in the subdivision of N2 disease were upper mediastinal, lower mediastinal, aortopulmonary, and subcarinal.

Results: Among 996 eligible patients, 211 (21.2%), 394 (39.6%), and 391 (39.3%) were confirmed to have pN2a1, pN2a2, and pN2b disease, respectively. In multivariable analysis after adjustment for sex, age, pT category, and adjuvant chemotherapy, overall survival was significantly better with single-zone N2b disease (n=125, 12.6%) than with multi-zone N2b disease (n=266, 26.7%) (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.49 to 0.90; p=0.009) and was comparable to that of N2a2 disease (HR, 1.12; 95% CI, 0.83 to 1.49; p=0.46).

Conclusion: Prognosis of single-zone LN metastasis was better than that of multiple-zone LN metastasis in patients with N2b NSCLC. Along with the station-based N descriptors, zone-based descriptors might ensure optimal staging, enabling the most appropriate decision-making on adjuvant therapy for patients with pN2 NSCLC.

Tumor microenvironment is intrinsically hypoxic with abundant hypoxia-inducible factors-1α (HIF-1α), a primary regulator of the cellular response to hypoxia and various stresses imposed on the tumor cells. HIF-1α increases radioresistance and chemoresistance by reducing DNA damage, increasing repair of DNA damage, enhancing glycolysis that increases antioxidant capacity of tumors cells, and promoting angiogenesis. In addition, HIF-1α markedly enhances drug efflux, leading to multidrug resistance. Radiotherapy and certain chemotherapy drugs evoke profound anti-tumor immunity by inducing immunologic cell death that release tumor-associated antigens together with numerous pro-immunological factors, leading to priming of cytotoxic CD8+ T cells and enhancing the cytotoxicity of macrophages and natural killer cells. Radiotherapy and chemotherapy of tumors significantly increase HIF-1α activity in tumor cells. Unfortunately, HIF-1α effectively promotes various immune suppressive pathways including secretion of immune suppressive cytokines, activation of myeloid-derived suppressor cells, activation of regulatory T cells, inhibition of T cells priming and activity, and upregulation of immune checkpoints. Consequently, the anti-tumor immunity elevated by radiotherapy and chemotherapy is counterbalanced or masked by the potent immune suppression promoted by HIF-1α. Effective inhibition of HIF-1α may significantly increase the efficacy of radiotherapy and chemotherapy by increasing radiosensitivity and chemosensitivity of tumor cells and also by upregulating anti-tumor immunity.