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Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment. Herein, we find that overexpression of Rac1 is associated with multi-drug resistance to the neoadjuvant chemotherapy (NAC). Mechanistically, Rac1 activates aldolase A and ERK signaling which up-regulates glycolysis and especially the non-oxidative pentose phosphate pathway (PPP). This leads to increased nucleotides metabolism which protects breast cancer cells from chemotherapeutic-induced DNA damage. To translate this finding, we develop endosomal pH-responsive nanoparticles (NPs) which deliver Rac1-targeting siRNA together with cisplatin and effectively reverses NAC-chemoresistance in PDXs from NAC-resistant breast cancer patients. Altogether, our findings demonstrate that targeting Rac1 is a potential strategy to overcome acquired chemoresistance in breast cancer. Acquired resistance to chemotherapy can lead to multi-drug resistance and poor prognosis in cancer. Here, the authors show that Rac1 increases glycolysis and non-oxidative pentose phosphate pathway activity leading to neoadjuvant chemotherapy (NAC) resistance, thus its inhibition sensitizes resistant breast cancer PDXs to NAC.

Nasopharyngeal carcinoma (NPC) is an epithelial tumor located in the nasopharynx and is highly associated with Epstein-Barr virus (EBV) infection. Although radiotherapy alone can cure ~90% of patients with early-stage disease, >70% of patients with NPC have locoregionally advanced or metastatic disease at the first diagnosis due to the insidious and aggressive nature of NPC. After comprehensive radiochemotherapy, 20-30% of patients with advanced NPC still fail treatment, mainly due to recurrence and/or metastasis (R/M). Conventional salvage treatments, such as radiotherapy, chemotherapy and surgery, are suboptimal and frequently accompanied by severe adverse effects and limited efficacy. In recent years, immunotherapy has emerged as a promising treatment modality for R/M NPC. An increasing number of clinical studies have investigated the safety and efficacy of immunotherapy for advanced NPC and have shown considerable progress. In the present review, the rationale for the use of immunotherapy to treat NPC was summarized and the current status, progress and challenges of NPC clinical research on different immunotherapeutic approaches were highlighted, including immune checkpoint inhibitors, vaccines, immunomodulators, adoptive cell transfer and EBV-specific monoclonal antibodies. The comprehensive overview of immunotherapy in NPC may provide insight for clinical practice and future investigation.

The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted. We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort. We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75–86), 62% (55–70), and 25% (20–34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)—which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories—significant associations with overall survival were noted (81% [95% CI 75–87%], 55% (44–66), and 28% (18–40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group. PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy. Samsung Biomedical Research Institute.

Chimeric antigen receptor T-cell (CAR-T) therapy has significantly improved overall survival (OS) in relapsed or refractory large B-cell lymphomas (R/R LBCL). However, factors associated with outcomes of CAR-T cell therapy in patients with R/R LBCL have not been fully elucidated. And limited evidence supports the use of early endpoints to evaluate the efficacy and long-term survival. Progression-free survival (PFS) at 6 months (PFS6) was defined as being alive and free of relapse or progression within 6 months of CAR-T cell infusion. We aimed to assessed OS stratified by PFS6 by analyzing data from 71 R/R LBCL patients treated with CAR-T therapy across 2 hospitals. Subsequent OS was defined from the time of PFS6 or progression within 6 months to death. Among them, 58% reached PFS6. Compared with patients failed to achieve PFS6, 1-year OS was 91.3% vs. 40.2% and 2-year OS was 91.3% vs. 32.1%, respectively. Patients achieving PFS6 had excellent outcome, whereas patients exhibiting earlier progression had a poor survival. Key predictors of PFS failure included older age (> 60) ( P  = 0.040, OR:3.40, 95%CI:1.06–10.93), lower pretransfusion hemoglobin level ( P  = 0.019 OR:0.27, 95%CI:0.09–0.81), and higher IFN-ʏ level ( P  = 0.022, OR:2.00, 95% CI:1.66–4.08). This insight could aid in risk stratification and support the use of PFS6 as a surrogate endpoint in clinical trials.

T-cell lymphoma is a highly invasive tumor with significant heterogeneity. Invasive tissue biopsy is the gold standard for acquiring molecular data and categorizing lymphoma patients into genetic subtypes. However, surgical intervention is unfeasible for patients who are critically ill, have unresectable tumors, or demonstrate low compliance, making tissue biopsies inaccessible to these patients. A critical need for a minimally invasive approach in T-cell lymphoma is evident, particularly in the areas of early diagnosis, prognostic monitoring, treatment response, and drug resistance. Therefore, the clinical application of liquid biopsy techniques has gained significant attention in T-cell lymphoma. Moreover, liquid biopsy requires fewer samples, exhibits good reproducibility, and enables real-time monitoring at molecular levels, thereby facilitating personalized health care. In this review, we provide a comprehensive overview of the current liquid biopsy biomarkers used for T-cell lymphoma, focusing on circulating cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), Epstein-Barr virus (EBV) DNA, antibodies, and cytokines. Additionally, we discuss their clinical application, detection methodologies, ongoing clinical trials, and the challenges faced in the field of liquid biopsy.

Resistance to radiotherapy is frequently encountered in clinic, leading to poor prognosis of cancer patients. Long noncoding RNAs (lncRNAs) play important roles in the development of radioresistance due to their functions in regulating the expression of target genes at both transcriptional and posttranscriptional levels. Exploring key lncRNAs and elucidating the mechanisms contributing to radioresistance are crucial for the development of effective strategies to reverse radioresistance, which however remains challenging. Here, actin filament‐associated protein 1 antisense RNA1 (lncAFAP1‐AS1) is identified as a key factor in inducing radioresistance of triple‐negative breast cancer (TNBC) via activating the Wnt/β‐catenin signaling pathway. Considering the generation of a high concentration of reduction agent glutathione (GSH) under radiation, a reduction‐responsive nanoparticle (NP) platform is engineered for effective lncAFAP1‐AS1 siRNA (siAFAP1‐AS1) delivery. Systemic delivery of siAFAP1‐AS1 with the reduction‐responsive NPs can synergistically reverse radioresistance by silencing lncAFAP1‐AS1 expression and scavenging intracellular GSH, leading to a dramatically enhanced radiotherapy effect in both xenograft and metastatic TNBC tumor models. The findings indicate that lncAFAP1‐AS1 can be used to predict the outcome of TNBC radiotherapy and combination of systemic siAFAP1‐AS1 delivery with radiotherapy can be applied for the treatment of recurrent TNBC patients. Herein, lncAFAP1‐AS1 is demonstrated as a key factor in inducing radioresistance by activating the Wnt/β‐catenin signaling pathway. Considering the generation of a high concentration of glutathione (GSH) under radiation, a reduction‐responsive nanoplatform is engineered for effective siRNA delivery, which can synergistically reverse radioresistance by silencing lncAFAP1‐AS1 expression and scavenging intracellular GSH, leading to a dramatically enhanced cancer radiotherapy effect.

This study aimed to identify key prognostic factors for Natural killer/T-cell lymphoma (NKTCL) in the context of L-asparaginase/pegaspargase-based therapy and to develop a simplified yet accurate prognostic model for risk stratification. Data from 854 NKTCL patients at the Sun Yat-sen University Cancer Center were divided into a training cohort (n = 598) and an internal validation cohort (n = 256). A further 222 patients from Sichuan Cancer Hospital & Institute were used to create an external validation cohort. Least absolute shrinkage and selection operator (LASSO) and Cox regression were used to identify independent risk factors for overall survival (OS). A nomogram (Nomogram-CA) was constructed and evaluated using the consistency index (C-index), calibration curves, time-dependent ROC (tdROC) and decision curve analysis (DCA). Kaplan–Meier survival curves were generated to show the difference in OS between groups. Age, CA stage, B symptoms and hemoglobin (Hb) level were all identified as independent risk factors for OS. Nomogram-CA was constructed based on multivariate analysis results. The DCA curves demonstrated that Nomogram-CA provided more net benefit to patients in the training, internal validation and external validation cohorts. Furthermore, analysis of the Kaplan–Meier survival curve revealed a significantly lower survival rate among patients identified as high-risk by Nomogram-CA when compared to those classified as low-risk ( P  <  0.05 ). Nomogram-CA constructed based on independent prognostic factors has better predictive ability compared to the traditional staging system, which can assist clinical doctors in evaluating patient prognosis.

BackgroundWhether primary tumor surgery is better than no surgery in patients with de novo stage IV breast cancer remains controversial.MethodsThis study combined prospective clinical trials and a multicenter cohort to evaluate the impact of locoregional surgery in de novo stage IV breast cancer. The GRADE approach was used to assess the quality of evidence in meta-analysis, and propensity score matching analysis was used in the cohort study. This study was registered with PROSPERO CRD42016043766 and ClinicalTrials.gov NCT04456855.ResultsA total of 1110 patients from six trials and 353 patients from the cohort study were included. The meta-analysis showed that compared with no surgery, locoregional surgery did not prolong overall survival (hazard ratio [HR] = 0.90, P = 0.40; moderate-quality) but had a significantly longer locoregional progression-free survival (HR = 0.23, P < 0.001; moderate-quality). The subgroup analysis of solitary bone-only metastasis (HR = 0.47, P = 0.04; high-quality) resulted in prolonged overall survival. In the cohort study, locoregional surgery showed a survival benefit (HR = 0.63, P = 0.041) before matching, but not (HR = 0.84, P = 0.579) after matching. Patients with bone-only metastasis showed a survival advantage in surgery compared with no surgery before matching (HR = 0.36, P = 0.034) as well as after matching (HR = 0.18, P = 0.017).ConclusionsThis study indicated that locoregional surgery had a significantly longer locoregional progression-free survival than no surgery in de novo stage IV breast cancer, and patients with bone-only metastasis tended to show an overall survival benefit from surgery.