Journal of Cancer Research and Clinical Oncology最新文献

Purpose: This case report describes a rare occurrence of quadruple primary malignancies-specifically, bilateral primary breast cancer, ovarian cancer, and pleomorphic malignant fibrous histiocytoma/undifferentiated high-grade pleomorphic sarcoma-and explores its potential association with hereditary tumor syndromes.

Methods: We conducted a detailed clinical and histopathological analysis of the case. Repeated imaging and pathological examinations were performed to confirm the diagnosis of each primary malignancy.

Results: The patient was diagnosed with four distinct primary tumors, and pathological evaluation confirmed each malignancy.

Conclusion: This case emphasizes the importance of comprehensive pathological and genetic evaluation in patients with multiple primary malignancies. It highlights the growing incidence of such tumors among long-term cancer survivors and provides valuable insights for diagnosis and management in the context of hereditary cancer syndromes.

Aim: Vasculogenic mimicry (VM), a process in which cancer cells form endothelial cell-independent vascular networks, is a hallmark of tumor aggressiveness in lung adenocarcinoma (LUAD) and supports tumor growth and metastasis. This study aims to identify and validate key genes associated with VM formation in LUAD, and to elucidate their functional roles and clinical significance.

Methods: Transcriptomic data from LUAD samples were analyzed using differential expression analysis (DEA) and weighted gene co-expression network analysis (WGCNA) to identify VM-associated genes. Machine learning algorithms were applied to refine the selection and identify hub genes. Functional enrichment and immune infiltration analyses were performed. The role of SULF1 in VM was further validated through in vitro and in vivo experiments.

Results: We identified 10,810 differentially expressed genes. WGCNA revealed 101 VM-associated genes, predominantly within the "yellow" and "brown" modules. Machine learning pinpointed three key regulators: downregulated decorin (DCN) and upregulated nucleoplasmin 3 (NPM3) and sulfatase 1 (SULF1). Functional enrichment analysis highlighted their involvement in extracellular matrix (ECM) organization and ribosomal pathways. Immune infiltration analysis indicated a positive correlation between DCN and immune cell presence, whereas NPM3 and SULF1 showed negative correlations. Critically, SULF1 overexpression promoted VM formation in vitro by enhancing cell migration and invasion, mediated through the vascular endothelial growth factor (VEGF)/transforming growth factor beta (TGF-β)/Vimentin signaling axis, and accelerated tumor growth in vivo.

Conclusion: We identified DCN, NPM3, and SULF1 as key biomarkers of VM in LUAD. SULF1, in particular, plays a central role in driving VM formation and tumor progression. These findings offer novel mechanistic insights and highlight potential therapeutic targets for LUAD treatment.

Purpose: Extranodal extension (ENE) and positive surgical margins are recognized high-risk factors in head and neck cancers. Despite their prognostic significance, ENE was incorporated into the AJCC 8th edition staging only recently. This study evaluates survival outcomes in patients with oral cavity squamous cell carcinoma (OCSCC) based on ENE status and its association with radiological ENE and other intermediate-risk features, including lymphovascular invasion (LVI), perineural invasion (PNI), T stage, and depth of infiltration (DoI).

Methods: We retrospectively analyzed 198 patients with OCSCC treated between 2015 and 2022 with surgery followed by adjuvant radiotherapy (60 Gy in 30 fractions), with or without concurrent chemotherapy. Chemotherapy was administered in cases with ENE or margin positivity. Patients were followed at 3-month intervals with clinical evaluations and imaging as indicated. Kaplan-Meier analysis was used to estimate overall survival (OS) and disease-free survival (DFS). Differences between groups were assessed using the log-rank test, and univariate and multivariate Cox regression analyses identified prognostic factors.

Results: The mean age was 55 ± 12 years, with 86.4% male patients. The buccal mucosa (61.6%) was the most common subsite. After a median follow-up of 36 months, the 3-year OS and DFS rates were 56.0% and 53.1%, respectively. Patients with pathological ENE had significantly worse outcomes: 3-year DFS was 34.7% vs. 68.6% (HR: 0.303; p < 0.001), and OS was 35.3% vs. 74.0% (HR: 0.270; p < 0.001). Radiological node positivity, LVI, and PNI were also independently associated with poorer survival.

Conclusion: ENE significantly worsens OS and DFS in OCSCC patients, even with standard adjuvant chemoradiotherapy. These findings support the need for treatment intensification strategies, such as radiation dose escalation and/or additional systemic therapy, in this high-risk group.

Purpose: T-cell immunotherapy is reshaping cancer care and offers a targeted strategy for pancreatic carcinoma (PC), yet a comprehensive map of its research trajectory is lacking. We aimed to chart the evolution of the field, identify leading contributors, and clarify the thematic shifts that are shaping clinical translation.

Methods: We systematically analyzed articles and reviews indexed in the Science Citation Index Expanded of the Web of Science Core Collection from January 2000 to December 2024. Bibliographic metadata were aggregated for descriptive trend analyses and science-mapping of co-authorship, co-citation, and keyword co-occurrence networks. Temporal trend profiling was used to highlight emerging topics.

Results: Global output on T-cell immunotherapy for PC has expanded markedly over the past two decades but remains unevenly distributed across regions. The United States leads in academic influence and translational impact, with China closely following in publication volume and contributions from high-impact institutions. Research has converged at the interface of immunotherapy, tumor-microenvironment modulation, and cellular engineering. Dominant themes include engineered T-cell approaches, immune-checkpoint modulation, and strategies leveraging tumor-infiltrating lymphocytes. Emerging fronts encompass AI-enabled target/drug discovery, biomarker-guided patient stratification, and individualized treatment designs. Persisting barriers include limited efficacy in the desmoplastic and immunosuppressive PC microenvironment, primary and acquired immune resistance, safety concerns, and regulatory and trial-design complexities.

Conclusions: T-cell immunotherapy for PC is a rapidly advancing, interdisciplinary domain led by the United States with rising contributions from China. Accelerating clinical translation will require: integrated T-cell engineering with microenvironment remodeling; rational combinations with checkpoint and stroma-targeted agents; robust predictive biomarkers with standardized endpoints; safety-engineering and risk-mitigation frameworks; and coordinated, multicenter collaboration. This bibliometric synthesis delineates the field's structure and priorities to improve outcomes for patients with PC.

Rituximab and obinutuzumab, anti-CD20 monoclonal antibodies, are widely employed for treatment of follicular lymphoma (FL) by targeting both neoplastic and normal CD20-expressing B lymphocytes, consequently inducing immunosuppression. In this condition, viral reactivations are common and represent a major cause of morbidity and mortality. In this single-center two-arm observational real-life study, we evaluated incidence, immunological and serological status, and clinical outcomes of cytomegalovirus (CMV) reactivation in FL patients treated with bendamustine + rituximab (R-BENDA; N = 23) or obinutuzumab (G-BENDA; N = 23). CMV reactivation more frequently occurred in patients treated with R-BENDA compared to G-BENDA (P = 0.022), and immune kinetics showed significant differences between the two groups, with a deeper and earlier immunosuppression in R-BENDA treated subjects. Moreover, R-BENDA group displayed a significant higher risk of CMV reactivation compared to G-BENDA (hazard ratio, 2.232; 95% confidence interval 1.107-4.500; P = 0.0249). However, G-BENDA patients tended to have a shorter 5-year overall survival (59% vs. 86.7%, G-BENDA vs. R-BENDA; P = 0.0903). By multivariate analysis, B symptoms were an independent predictor of CMV reactivation, and high baseline SUV as an additional risk factor in R-BENDA patients. In conclusion, anti-CD20 agent could increase the risk of CMV reactivation in FL patients, especially in R-BENDA treated subjects who experienced early and deep immunosuppression. Therefore, close monitoring of clinical and laboratory data may improve outcomes in FL patients by preventing CMV disease, especially in those treated with rituximab who are more prone to viral reactivation. However, larger prospective studies are required to confirm our preliminary results.

Purpose: We compared failure patterns in patients with inoperable stage III non-small cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT) alone versus CRT combined with sequential and/or concurrent immune checkpoint inhibitors (CRT-IO).

Methods: Retrospective real-world data from 221 patients across two German tertiary cancer centers were analyzed. Of these, 74 received CRT-IO, including sequential durvalumab (85%) and concurrent/sequential nivolumab (15%), while 148 received CRT alone. First failure site and time to failure were compared.

Results: Between 2012 and 2022, all patients received thoracic radiotherapy (≥ 60 Gy) and at least two cycles of platinum-based chemotherapy. Induction chemotherapy was administered in 36%, and induction chemo-immunotherapy in 2%. Median follow-up was 51.7 months (95% CI 47.0-56.4). Median overall survival (OS) for the entire cohort was 37.1 months (95% CI 26.0-48.2), with OS in the CRT-IO group not reached vs. 27.1 months (95% CI 18.5-25.7) in the CRT group (p < 0.001). Median progression-free survival (PFS) was 22.8 months (95% CI 6.4-39.1) for CRT-IO versus. 9.9 months (95% CI 7.0-12.8) for CRT (p = 0.001, see Fig. 1). Failure patterns differed significantly. CRT-IO patients had lower loco-regional progression (LRP) rates (9.5% vs. 21.8%, p = 0.023) and were more frequently alive without progression (45.9% vs. 16.3%, p < 0.001). Brain metastasis (BM) as the first failure, multifocal progression (MFP) and isolated extracranial distant metastasis (ecDM) rates were comparable between the CRT and CRT-IO subgroup. Women had a higher risk of isolated BM (17.3% vs. 6.8%, p = 0.016), whereas squamous cell carcinoma (SCC) patients had higher LRP rates (25.3% vs. 13.0%, p = 0.016). Median post-progression survival (PPS) was 19.4 months (95% CI 16.8-22.0) for CRT-IO and 9.5 months (95% CI 5.8-13.1) for CRT (p = 0.207). PPS was longer after BM (19.9 months) vs. LRP (8.5 months, p = 0.076) and significantly better in women (20.7 vs. 8.9 months, p = 0.012) and adenocarcinoma/non-otherwise-specified-carcinoma (AC/NOS) vs. SCC (p < 0.001).

Conclusion: CRT-IO significantly improves OS, PFS, and LRP control compared to CRT alone. Failure patterns and survival disparities by histology and gender suggest tailored surveillance and treatment strategies are needed. Further studies should optimize management of LRP and long-term outcomes in CRT-IO-treated patients.

Background: Cellular immunotherapies, such as those utilizing T lymphocytes expressing native or engineered T cell receptors (TCRs), have demonstrated therapeutic efficacy. However, some engineered high-affinity TCRs have caused fatal off-target immunotoxicity due to targeting epitopes later found to be expressed by both tumor cells and healthy tissues. Unfortunately, TCRs can be cross-reactive to epitopes with highly distinct sequences, making prediction difficult, and the exquisite sequence specificity of TCRs means that safety studies in mice miss human-specific epitopes.

Methods: To address this issue, we developed ARDitox, a novel in silico method based on computational immunology and artificial intelligence (AI) for predicting and analyzing potential TCR off-target toxicities. We tested the performance of ARDitox on four TCRs reported to target tumor-associated antigens, two of which are known to cause clinical immunotoxicity (MAGEA3_112-120 and MAGEA3_168-176 epitopes), one of which has experimentally identified off-target antigens (AFP_158-166 epitope), and the last one for which no cross-reactive epitopes are known (NY-ESO-1_157-165).

Results: ARDitox confirmed the previously identified immunotoxic epitopes. We then expanded our analyses to a novel TCR targeting the tumor-associated antigen NLGN4X, frequently upregulated in gliomas. For this target, ARDitox identified a cross-reactive peptide that would not have been found using mouse models, highlighting the value of our computational approach.

Conclusions: Our findings underscore the value of the ARDitox in silico method for the early and reliable identification of off-target epitopes for further preclinical evaluation. This platform strongly supports the development of safer TCR-mediated immunotherapies.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a high mortality rate. For patients with metastatic PDAC (mPDAC) initially deemed unresectable, systemic chemotherapy followed by conversion surgery may offer an improvement in survival. This study aimed to compare survival between mPDAC patients undergoing conversion surgery versus chemotherapy alone, and identify factors associated with recurrence following conversion surgery.

Methods: We conducted a retrospective cohort study of patients with mPDAC treated with systemic chemotherapy at National Cheng Kung University Hospital, Taiwan, between September 2020 and January 2023. Patients who subsequently underwent conversion surgery were analyzed to identify factors associated with recurrence. Clinicopathologic, treatment, and surgical variables were extracted from medical records. Recurrence-free survival (RFS) was defined from the date of conversion surgery to recurrence or death. Survival outcomes were estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards regression with stepwise selection was applied to identify independent predictors of recurrence.

Results: Among 151 patients who underwent chemotherapy, 33 subsequently received conversion surgery. In the patients who received conversion surgery, male sex (HR 4.33, 95% CI 1.60-11.72), tumor location in the head/uncinate process (HR 2.79, 95% CI 1.03-7.58), and regression grade 2 (HR 4.65, 95% CI 1.41-15.30) were significantly associated with worse RFS.

Conclusion: Among patients with mPDAC who underwent conversion surgery after chemotherapy, several factors were independently associated with shorter RFS, including male sex, tumor location in the pancreatic head/uncinate process, and histologic regression grade 2.