Frontiers in Oncology最新文献

Background: Colorectal cancer (CRC) is a leading cause of morbidity and mortality, and timely diagnosis and intervention are crucial for cancer patients. Transfer RNA-derived fragments (tRFs) play a noncoding regulatory role in organisms. Serum EV(extracellular vesicles), as an integral mediator of intercellular transmission of genetic information vesicles in Transfer RNA-derived fragment (tRF RNA), are expected to be minimally invasive diagnostic and predictive biologic factors of CRC.

Methods: Collect serum samples from 205 CRC patients, and then isolate extracellular vesicles from the serum. Captured the physical morphology of EV through transmission electron microscopy. The particle size was detected by particle size assay, and protein expression on the surface of EV was verified by Western blot. Gene microarrays were screened for differentially expressed tRF-RNA. TRF RNAs were verified by qPCR for differential expression in 205 CRC patients and 201 healthy donors, assessing the CRC diagnostic efficiency by area under the curve (AUC).

Results: Compared with 201 healthy donors, CRC patients experienced significantly down-regulated serum EV 3'tRF-ThrCGT while significantly up-regulated 3'tRF-mtlleGAT. Serum EV 3'tRF-ThrCGT and 3'tRF-mtlleGAT predictive diagnostic efficiency: 0.669 and 0.656, and the combination of CEA and CA724 predictive diagnostic efficiency was 0.938.

Conclusion: The study data showed that 3'tRF-ThrCGT and 3'tRF-mtlelGAT can be minimally invasive diagnostic CRC indicators. The combination of tumor markers CEA and CA724 has important diagnostic significance.

Purposes: Osimertinib, one of the third-generation EGFR-tyrosine kinase inhibitors (TKIs) designed to target EGFR T790M mutation, significantly improves the prognosis of lung cancer. However, drug resistance still happens and MET amplification is responsible for one of the main causes. Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection, but fundamentally limited by observer subjectivity. Herein, we assessed the value of next-generation sequencing (NGS) method in MET amplification detection in non-small cell lung cancer (NSCLC), as well as revealed the mutation profiling of NSCLC patients with osimertinib resistance to provide some valuable clues to the mechanisms of resistance.

Methods: A total of 317 cancer tissue samples from 317 NSCLC patients at time of progression following osimertinib were submitted to NGS and only 96 tissues were tested by FISH simultaneously. With FISH results as gold standard, enumeration algorithm was applied to establish the optimal model for identifying MET amplification using gene copy number (GCN) data.

Results: The optimal model for identifying MET amplification was constructed based on the GCN of MET, BRAF, CDK6 and CYP3A4, which achieved a 74.0% overall agreement with FISH and performed well in identifying MET amplification except polysomy with a sensitivity of 85.7% and a specificity of 93.9%. The inconsistency between NGS and FISH occurred mainly in polysomy subtype, while MET GCN ≥ 5 could be reliably recognized by NGS. Moreover, the most frequently mutated genes in NSCLC patients with osimertinib resistance were EGFR (59.94%), followed by TP53 (43.85%), NRG1 (9.46%), PIK3CA (6.31%), and ATM (5.36%). The known resistance mechanisms, including MET amplification, EGFR (C797S, L718Q/R), TP53, CDK4, CDK6, CDKN2A, BRAF, KRAS, NRAS and PIK3CA mutations were also disclosed in our cohort.

Conclusions: NGS assay can achieve a high concordance with FISH in MET amplification detection and has advantages in portraying various genetic alterations, which is of worthy in clinical promotion.

Background: The medical management of DT comprises tyrosine kinase inhibitors (TKIs), hormonal agents, anti-inflammatory drugs with the recently approved gamma secretase inhibitor nirogacestat being the current standard of care. Real-world data on evolving treatment landscapes of DT remains scarce.

Methods: This is a retrospective study of patients with DT registered between 1995 and 2020 at All India Institute of Medical Sciences, New Delhi and Tata Medical Center, Kolkata. Baseline characteristics were analyzed in form of median values and interquartile range. Categorical and continuous variables were compared by chi square and independent samples T- tests respectively. Anxiety, depression and QoL were prospectively measured among 30 patients using Hospital Anxiety and Depression (HADS) and Functional Assessment of Cancer Therapy-General (FACT-G) scales respectively between 2022 to 2023.

Results: 200 patients were included with a male-predominant (n=111, 55.5%) population and median age 26.5 (2.5-75) years. Extremity (n=100, 50%) and abdomen (n=65, 32.5%) were commonest primary sites and median of 2 (1-4) lines of treatment were received. First-line included surgery (n=116, 58%), systemic therapy (n=67, 33.5%), radiotherapy (10, n=5%) and active surveillance (n=7, 3.5%). First-line systemic agents included tamoxifen (n=55, 27.5%), imatinib (n=7, 3.5%), sorafenib (n=1, 0.5%) and chemotherapy (n=4, 2%). 2019 onward, 3% and 63% underwent active surveillance and surgery respectively. Best radiological response obtained with tamoxifen was stable disease (SD) (n=76, 59%) and partial response (PR) (n=31, 24.2%). Best radiological response obtained with sorafenib was PR (n=17, 60.7%) and SD (n=9, 32.1%). Thirty patients underwent HADS and FACT-G scale assessment. Mean HADS-Anxiety subscale score was 3.6 (+/-3.9 SD) and HADS-Depression sub-scale score was 2.6 (+/-3.5 SD) with clinically significant anxiety and depression in 2 (6.7%) patients each. The overall mean FACT-G score was 87.5 (+/-12.6 SD) and lower mean physical well-being (p=0.006) and emotional well-being (0.017) scores were significantly associated with higher HADS-anxiety (>/=8) scores.

Conclusions: Assessment of anxiety, depression and QoL are paramount to gauge the psychological impact of DT. This study gives an overview of clinical and management profile of patients with DT in India, with limitations of selection bias, heterogeneous population and small sample size for QoL assessment.

Introduction: This study aims to investigate the role of the m6A regulatory factor METTL3 in LUAD.

Methods: By examining the expression of METTL3 in LUAD and conducting cellular functional experiments, the biological functions of METTL3 were discussed. mRNA-seq and MeRIP-qPCR were used to identify downstream target genes and pathways.

Results: The expression level of METTL3 in LUAD is lower than that in the control group. The downregulation of METTL3 promoted the proliferation, migration, and invasion of LUAD cells, while overexpression of METTL3 results in the opposite effects. Furthermore, we found that FGF2 was negatively regulated by METTL3. Inhibiting FGF2 reversed the tumor-promoting effects caused by METTL3 downregulation in LUAD cells. Silencing METTL3 enhanced the stability of FGF2 mRNA. Silencing FGF2 resulted in reduced activity of the PI3K/AKT/mTOR signaling pathway in METTL3 knockdown LUAD cells.

Discussion: In summary, our findings unveil an intricate signaling network involving METTL3/FGF2/PI3K/AKT/mTOR in LUAD and provide valuable insights into the molecular mechanisms underlying tumor progression, thus holding significant implications for targeted therapy and advancing LUAD research.

Background: Alectinib has demonstrated promising disease-free survival (DFS) benefit for early-stage non-small cell lung cancer (NSCLC) patients with ALK rearrangement positive in phase 3 ALINA trial. However, real-world evidence for the efficacy and safety of alectinib in early-stage ALK-positive NSCLC is limited.

Materials and methods: We retrospectively reviewed 68 patients with stage IB-IIIB ALK-positive NSCLC who underwent complete pulmonary resections from April 2010 to July 2023 at a single institution. 38 (55.9%) enrolled patients had N2 lymph node metastasis, and 17 (24.9%) patients had multi-station N2 metastasis. Patients were stratified into two groups according to the adjuvant treatment regimen, with 19 patients in the alectinib group and 49 patients in the chemotherapy group. There were no significant differences in clinicopathological characteristics between the two groups. After curative resection surgery, patients in alectinib group received oral alectinib at a dose of 600 mg twice daily and patients in chemotherapy group received platinum-based doublet chemotherapy regimen every 3 weeks for 4 cycles. The primary endpoint was 3-year DFS. The Kaplan-Meier method was used to estimate DFS and overall survival (OS). Safety analyses were conducted by comparing the incidence of adverse events between the two groups.

Results: At the last follow-up date (January 22th, 2024), A total of 1 (5.3%) and 28 (57.1%) DFS events were observed in alectinib group and chemotherapy group respectively. The 3-year DFS showed significant improvement in the alectinib group compared with chemotherapy group (91.7% vs 60.7%, P=0.051). In the IIIAN2 subgroup, the 3-year DFS rate in the alectinib group reached a satisfactory 87.5%. In both groups, the majority of AEs were graded as level 1 or 2, No grade 3-4 AEs were observed in alectinib group.

Conclusion: Alectinib, as adjuvant therapy, demonstrated favorable efficacy and manageable safety in patients with completely resected ALK-positive stage I B-IIIB non-small cell lung cancer. A limitation of this study is the small sample size, and a larger-scale real-world sample study is needed to further evaluate the efficacy and safety of alectinib as adjuvant therapy.

YB1 (Y box binding protein 1), a multifunctional protein capable of binding to DNA/RNA, is present in most cells and acts as a splicing factor. It is involved in numerous cellular processes such as transcription, translation, and DNA repair, significantly affecting cell proliferation, differentiation, and apoptosis. Abnormal expression of this protein is closely linked to the formation of various malignancies (osteosarcoma, nasopharyngeal carcinoma, breast cancer, etc.). This review examines the multifaceted functions of YB1 and its critical role in osteosarcoma progression, providing new perspectives for potential therapeutic strategies.

Background: The advent of antibody-drug conjugates (ADCs) represents a landmark advance in cancer therapy, permitting targeted delivery of a potent cytotoxic agent to tumor cells with minimal damage to surrounding cells. Although ADCs can induce sustained therapeutic responses in heavily pretreated patients, they can also cause significant toxicity and thus require careful monitoring. The prototype ADC, ado-trastuzumab emtansine (T-DM1) is comprised of a humanized, monoclonal human epidermal growth factor receptor 2 (HER2)-directed antibody, trastuzumab, linked to the cytotoxic agent, DM1, and is used for the treatment of early-stage and advanced HER2-positive breast cancer. Liver toxicities, including transaminitis and nodular regenerative hyperplasia resulting in portal hypertension have been described. We report a case series of four patients who developed hepatopulmonary syndrome (HPS) during treatment with T-DM1. HPS is characterized by hypoxemia, portal hypertension, and intrapulmonary shunting, and it can be associated with severe hypoxic respiratory failure. HPS secondary to noncirrhotic portal hypertension occurring with long-term exposure to T-DM1 has not previously been reported.

Case series presentation: Four patients who received T-DM1 in our institutional cohort (n=230) developed HPS, which can be associated with severe hypoxic respiratory failure. Each patient diagnosed with HPS received >50 doses of T-DM1. Only one patient at diagnosis had resting hypoxia, while the other three patients became hypoxic with exertion only. Discontinuation of T-DM1 led to clinical improvement in hypoxia in three of the four patients. The spectrum of liver injury that occurs with long-term use of T-DM1 remains incompletely defined.

Conclusions: As T-DM1 is approved for use in the management of early-stage operable and advanced breast cancer, awareness of HPS as a potential complication of long-term administration of T-DM1 is necessary. The emergence of dyspnea alone or combined with low oxygen saturation and signs of hypoxemia (clubbing or elevated hemoglobin) should raise clinical suspicion and prompt evaluation for HPS. Cancer care team members should be vigilant regarding the potential for new and serious side effects associated with novel targeted therapies, which may emerge years beyond initial regulatory approval.

Bladder cancer (BC) is the most common malignancy of the urinary tract. About 75% of all BC patients present with non-muscle-invasive BC (NMIBC), of which up to 70% will recur, and 15% will progress in stage and grade. As the recurrence and progression rates of NMIBC are strongly associated with some clinical and pathological factors, several risk stratification models have been developed to individually predict the short- and long-term risks of disease recurrence and progression. The NMIBC patients are stratified into four risk groups as low-, intermediate-, high-risk, and very high-risk by the European Association of Urology (EAU). Significant heterogeneity in terms of oncological outcomes and prognosis has been observed among NMIBC patients within the same EAU risk group, which has been partly attributed to the intrinsic heterogeneity of BC at the molecular level. Currently, we have a poor understanding of how to distinguish intermediate- and (very-)high-risk NMIBC with poor outcomes from those with a more benign disease course and lack predictive/prognostic tools that can specifically stratify them according to their pathologic and molecular properties. There is an unmet need for developing a more accurate scoring system that considers the treatment they receive after TURBT to enable their better stratification for further follow-up regimens and treatment selection, based also on a better response prediction to the treatment. Based on these facts, by employing a multi-layered -omics (namely, genomics, epigenetics, transcriptomics, proteomics, lipidomics, metabolomics) and immunohistopathology approach, we hypothesize to decipher molecular heterogeneity of intermediate- and (very-)high-risk NMIBC and to better stratify the patients with this disease. A combination of different -omics will provide a more detailed and multi-dimensional characterization of the tumor and represent the broad spectrum of NMIBC phenotypes, which will help to decipher the molecular heterogeneity of intermediate- and (very-)high-risk NMIBC. We think that this combinatorial multi-omics approach has the potential to improve the prediction of recurrence and progression with higher precision and to develop a molecular feature-based algorithm for stratifying the patients properly and guiding their therapeutic interventions in a personalized manner.

Purpose: The overall survival of patients with pancreatic cancer is extremely low. We aimed to establish machine learning (ML) based model to accurately predict three-year survival and prognosis of pancreatic cancer patients.

Methods: We analyzed pancreatic cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2021. Univariate and multivariate logistic analysis were employed to select variables. Recursive Feature Elimination (RFE) method based on 6 ML algorithms was utilized in feature selection. To construct predictive model, 13 ML algorithms were evaluated by area under the curve (AUC), area under precision-recall curve (PRAUC), accuracy, sensitivity, specificity, precision, cross-entropy, Brier scores and Balanced Accuracy (bacc) and F Beta Score (fbeta). An optimal ML model was constructed to predict three-year survival, and the predictive results were explained by SHapley Additive exPlanations (SHAP) framework. Meanwhile, 101 ML algorithm combinations were developed to select the best model with highest C-index to predict prognosis of pancreatic cancer patients.

Results: A total of 20,064 pancreatic cancer patients from SEER database was consecutively enrolled. We utilized eight clinical variables to establish prediction model for three-year survival. CatBoost model was selected as the best prediction model, and AUC was 0.932 [0.924, 0.939], 0.899 [0.873, 0.934] and 0.826 [0.735, 0.919] in training, internal test and external test sets, with 0.839 [0.831, 0.847] accuracy, 0.872 [0.858, 0.887] sensitivity, 0.803 [0.784, 0.825] specificity and 0.832 [0.821, 0.853] precision. Surgery type had the greatest effects on three-year survival according to SHAP results. For prognosis prediction, "RSF+GBM" algorithm was the best prognostic model with C-index of 0.774, 0.722 and 0.674 in training, internal test and external test sets.

Conclusions: Our ML models demonstrate excellent accuracy and reliability, offering more precise personalized prognostic prediction to pancreatic cancer patients.

Background: Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy (ETC) offers more advantages for patients with EGFR-positive non-small cell lung cancer (NSCLC) than using EGFR TKIs alone (ET). However, whether this conclusion applies to patients with brain metastases (BM) remains controversial. This meta-analysis was performed to evaluate the benefits and risks of the two groups.

Methods: Six databases were systematically searched for relevant literatures comparing ETC versus ET in treating EGFR-positive NSCLC patients with BM. The primary outcome assessed was overall survival (OS), while secondary outcomes included progression-free survival (PFS), and central nervous system (CNS)-PFS, responses, progression status and safety.

Results: Seven studies based on five randomized clinical trials with 550 patients were included. The ETC group exhibited better OS (hazard ratio [HR]: 0.64 [0.48, 0.87]), PFS (HR: 0.42 [0.34, 0.52]), and CNS-PFS (HR: 0.42 [0.31, 0.57]). The benefits in survival for OS, PFS, and CNS-PFS were validated in nearly all subgroups. Meanwhile, the overall objective response rate (ORR) (risk ratio [RR]: 1.25 [1.02, 1.52]) and CNS-ORR (RR: 1.19 [0.93, 1.51]) also tended to favor the ETC group. However, the addition of chemotherapy also brought about more grade 3-5/serious adverse events (AEs). The top five grade 3-5 AEs in the ETC group were alanine aminotransferase increase (11.25%), neutropenia (7.5%), nausea (7.5%), anorexia (5%), and diarrhea (5%).

Conclusions: ETC appears to be better than ET in treating EGFR-positive NSCLC patients with BM, with better OS, PFS, CNS-PFS, and responses. However, its poorer safety profile also needs to be taken into consideration.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024551073.