Journal of Cancer Research and Clinical Oncology最新文献

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.

Introduction: This retrospective study compared the impact of radiotherapy (RT) and immunotherapy (IO) on survival in patients with stage IV non-small cell lung cancer (NSCLC) following a diagnosis of bone metastasis.

Methods: The TriNetX database (2013-2024) was queried for adults (≥ 18 years) with NSCLC who received IO after diagnosis of bone metastases. Patients were then divided into cohorts based on whether they also received RT after bone metastasis diagnosis.

Results: A risk assessment revealed RT + IO was associated with significantly improved survival at 3 months (92% vs. 86% alive, p < 0.001), 6 months (79% vs. 72%, p = 0.002), and 1 year (59% vs. 54%, p = 0.014). In patients with adenocarcinoma, RT + IO was associated with improved survival at 3 months (92% vs. 88%, p = 0.046) but not at 6 months or 1 year. Similarly, in patients with squamous cell carcinoma, IO + RT was also associated with higher survival (94% vs. 85%, p = 0.040) at 3 months but not at 6 months or 1 year. A Cox proportional hazards model found significant lower hazard of death in the RT + IO group (hazard ratio [HR] = 0.83) and several covariates were associated with higher hazard, including adrenal metastasis (HR = 1.7), liver metastasis (HR = 1.4), lymph node metastasis (HR = 1.3), hypoalbuminemia (< 3.45 g/dL; HR = 1.5), and inpatient or observation care (HR = 1.4).

Discussion: This study highlights the potential importance of combining RT with IO, particularly in the early period after bone metastasis diagnosis.

Purpose: Primary testicular lymphoma (PTL) is a rare but aggressive form of extranodal lymphoma with a high risk of central nervous system (CNS) relapse and poor long-term survival. However, the optimal CNS prophylaxis strategy and effective prognostic models for PTL remain unclear. This study aimed to evaluate the prognostic impact of intrathecal (IT) prophylaxis and to develop a novel, simplified prognostic model in a Chinese multicenter cohort.

Methods: We retrospectively collected data from a total of 55 patients with PTL, treated at three major tertiary hospitals in China. Multivariate Cox regression identified independent prognostic factors for overall survival (OS) and progression-free survival (PFS). A new risk stratification model (BL model, based on B symptoms and LDH levels) was constructed and validated using time-dependent C-index and calibration plots, and compared with the International Prognostic Index (IPI).

Results: IT prophylaxis reduced CNS relapse rates (9.1% vs. 36.4%, p < 0.001) and was independently associated with improved OS (HR = 0.18, p < 0.001) and PFS (HR = 0.21, p < 0.001). The BL model (B symptoms and LDH), demonstrated superior predictive accuracy compared to the IPI, with higher AUCs at 1-, 3-, and 5-year OS (0.883, 0.894, 0.854 vs. 0.656, 0.804, 0.724), and a corrected C-index of 0.798. Calibration analysis confirmed good agreement between predicted and observed survival.

Conclusion: IT prophylaxis significantly improves survival and reduces CNS relapse in PTL. The BL model provides a simple yet effective tool for individualized risk stratification, outperforming IPI and aiding clinical decision-making in PTL.

Background: Although pembrolizumab has been shown to be effective, its high price has prevented it from being widely used. Especially in the real world, the application situation is still uncertain. The purpose of this study was to evaluate the cost-effectiveness of pembrolizumab on the basis of real-world studies, from the perspective of the health care system.

Methods: Retrospectively, 630 patients with advanced NSCLC treated with pembrolizumab (monotherapy or combination chemotherapy) versus chemotherapy alone from January 2020 to December 2022 at a large 3 A hospital in China were included. Confounders between groups were eliminated using propensity score matching analysis. A partitioned survival model was developed to evaluate the cost-effectiveness of pembrolizumab versus chemotherapy for the treatment of advanced NSCLC based on progression-free survival, overall survival, and the incidence of adverse effects in the two matched groups (n = 450 patients). The incremental cost-effectiveness ratio was calculated. The impact of a drug donation program on the cost-effectiveness of pembrolizumab was also evaluated.

Results: Pembrolizumab significantly improved median PFS in patients (15.5 months vs. 8.8 months). The median OS in the Pembrolizumab group has not been reached, while it was 26.2 months in the chemotherapy group. When the drug donation program is not considered, the ICER of pembrolizumab is $146,409.07/QALY. Regardless of whether the willingness-to-pay threshold is set at three times the per capita GDP of China ($36,070.2) or three times the per capita GDP of Guangdong Province ($64,523.8), the use of pembrolizumab is not cost-effective. However, after considering the drug donation program, the ICER decreased to $56,127.74/QALY. Under the willingness-to-pay threshold of three times the per capita GDP of Guangzhou in 2022 ($64,523.8), pembrolizumab became a cost-effective choice.

Conclusion: In the treatment of advanced NSCLC in China, pembrolizumab, particularly when considering the drug donation program, offers better survival outcomes and becomes cost-effective. This highlights the importance of such programs in making high-cost treatments accessible in real-world clinical settings.

Purpose: This study aimed to assess the health-related quality of life (HRQoL) in patients with locally advanced rectal cancer (LARC) undergoing total neoadjuvant therapy (TNT), comparing outcomes with the German general population and colorectal cancer (CRC) patients treated with curative intent.

Methods: In a multicenter, cross-sectional study within the "TNTox" study framework (DRKS 00033000), EORTC QLQ-C30 and QLQ-CR29 questionnaires were distributed to LARC patients who had completed TNT. Mean reference values were compared descriptively, and further exploratory comparisons based on clinical features were performed.

Results: The study included responses from 72 patients. Compared to the German general population, a reduction in mean HRQoL across most domains was observed; the strongest effect was observed for role functioning (- 28.7 points, Cohen's d = - 0.95), social functioning (- 25.3 points, d = - 0.89), and for diarrhea (+ 9.9 points, d = 0.80). General HRQoL was similar to that of CRC patients following curative treatment. However, some symptom scores, notably fecal incontinence (+ 13.4 points, d = 0.52), impotence (+ 29.0 points, d = 0.73), and dyspareunia (+ 10.4 points, d = 0.40) appeared to be higher. Significant factors associated with HRQoL included the presence of chronic treatment-related toxicity and duration of TNT; no major differences were observed between patients with or without NOM or stoma.

Conclusion: LARC patients undergoing TNT showed comparable HRQoL outcomes to CRC patients treated with curative intent, but with reductions when compared to the general population. The presence of chronic toxicity significantly impacts HRQoL. Survivors may experience HRQoL impairments post-TNT, underscoring the necessity for ongoing management of chronic toxicity tailored to their needs.