Cancer Medicine最新文献

Introduction: Gliomas remain aggressive despite current therapies, highlighting the urgent need for new biomarkers and targets. Transmembrane protein 106A (TMEM106A), implicated as a tumor suppressor in various cancers, has an unclear role in gliomas. We hypothesized that TMEM106A expression associates with tumor aggressiveness and may serve as a prognostic, microenvironmental biomarker.

Methods: We integrated TCGA and CGGA bulk RNA-seq, single-cell (GSE131928, GSE89567), spatial (Ivy Atlas, Visium), and immunohistochemistry (n = 79) to evaluate TMEM106A. Differential expression used limma. Survival used Kaplan-Meier and multivariable Cox models. Immune contexture used a 12-cell-state deconvolution and CIBERSORT. GSEA assessed hallmark pathways. Drug sensitivity was inferred using pRRophetic. Immunotherapy modeling combined TCGA expression with TCIA immunophenoscore and PD-L1.

Results: (1) TMEM106A mRNA is significantly upregulated in high-grade gliomas compared to lower-grade gliomas and normal brain. (2) In IDH-wildtype tumors, differential analyses highlight roles of TMEM106A and TMEM106C; high expression links to poorer prognosis. (3) TMEM106A is an independent prognostic factor associated with aggressive behavior, especially in IDH-wildtype astrocytomas. (4) Upregulation is confirmed by immunohistochemistry. (5) High TMEM106A associates with pro-inflammatory signatures and higher inferred fractions of myeloid cells and granulocytes. (6) Single-cell RNA-seq shows enrichment in myeloid lineages, and (7) CIBERSORT shows modest positive correlations with polarized macrophage signatures. (8) Spatial transcriptomics shows higher TMEM106A in myeloid-rich regions, consistent with a microenvironmental readout. (9) In IDH-wildtype tumors, pRRophetic predicts lower IC50 for multiple targeted agents in TMEM106A-high tumors. (10) TMEM106A-high IDH-wildtype tumors show higher IPS only when PD-1 is "on," suggesting a context-dependent, inflamed-but-suppressed state.

Conclusion: TMEM106A independently predicts survival and correlates with myeloid-enriched transcriptional states in gliomas. Given its high expression in myeloid lineages in single-cell data, bulk upregulation is potentially driven by myeloid infiltration rather than tumor-cell intrinsic mechanisms. All findings are correlative; prospective studies are needed before any clinical use is considered.

Background and methods: Non-small cell lung cancer (NSCLC) outcomes have improved remarkably with the widespread use of immune checkpoint inhibitors and small molecule inhibitors targeting driver mutations. Nevertheless, many patients continue to experience suboptimal outcomes. The prevalence of mutations in the BAF (BRG1/BRM-associated factor) chromatin remodeling complexes may represent an opportunity to help close this gap: These critical regulators of chromatin accessibility are mutated in approximately a quarter of NSCLC cases, and numerous retrospective reports have evaluated the impact of these mutations on clinical outcomes. Here, we appraise the varying and occasionally divergent evidence for BAF complex mutations as predictive and prognostic biomarkers in NSCLC.

Results: We conclude that these mutations hold promise as refinements to existing prognostic and treatment algorithms, with SMARCA4 mutations imparting poor prognosis, ARID1A mutations predicting better prognosis with immune checkpoint inhibitor therapy, and ARID1A-epithelial growth factor receptor (EGFR) comutations being associated with insensitivity to EGFR tyrosine kinase inhibitor therapy. Additional research should focus on large, prospective studies that will allow better quantification of the impact of BAF complex mutations.

Conclusions: A growing body of evidence indicates that BAF complex mutations have important prognostic implications. These may be leveraged for risk stratification and therapeutic selection in patients with non-small cell lung cancer.

Background: T-cell lymphoblastic lymphoma (T-LBL) is a rare non-Hodgkin lymphoma. The World Health Organization defines T-LBL and T-cell acute lymphoblastic leukemia (T-ALL) as the same entity. However, the clinical variations between them result in divergent treatment outcomes.

Objectives: The aim of this study was to compare the outcomes of patients with T-LBL and T-ALL and identify ideal candidates for autologous hematopoietic stem cell transplantation (auto-HSCT) or allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Study design: This retrospective analysis included 148 patients diagnosed with T-LBL (67 [45.3%]) or T-ALL (81 [54.7%]) between November 2009 and December 2022 in seven hospitals in the Republic of Korea. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method, and allo-HSCT, auto-HSCT, and chemotherapy-only treatment modalities were compared. Cox proportional hazards models were used to identify risk factors for survival, and survival decision trees were used for risk stratification.

Results: The median follow-up duration was 60 months. The 5-year OS rates were 43.5% and 52.8% in the T-LBL and T-ALL groups, respectively (p = 0.111). The T-LBL group had lower PFS than the T-ALL group (p < 0.001). The 5-year OS rates for allo-HSCT, auto-HSCT, and chemotherapy-only were 62.8%, 62.4%, and 13%, respectively. Two or more extranodal sites, large masses > 6 cm, axial bone involvement, and non-complete remission after chemotherapy were poor prognostic factors for OS.

Conclusions: In this multicenter retrospective analysis, hematopoietic stem-cell transplantation (allo- or auto-HSCT) was associated with better survival than chemotherapy alone. For T-LBL, an exploratory signal from our prognostic model suggests that selected high-risk patients may be considered for upfront allo-HSCT. However, overall survival was comparable between allo- and auto-HSCT in this cohort, and durable outcomes after transplant were largely observed in patients who achieved complete remission. These findings are hypothesis-generating and support individualized, response-adapted strategies that warrant prospective validation.

Background: Cancer persists as a leading cause of global mortality, largely due to the immunosuppressive tumor microenvironment (TME) that facilitates tumor progression and therapy resistance. M2 macrophages dominate this immunosuppressive landscape, and emerging evidence highlights tumor-derived exosomes (TEXs) as critical mediators of macrophage M2 polarization via delivery of noncoding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs. These TEX-ncRNA networks activate key signaling pathways (e.g., JAK/STAT, PI3K/AKT, NF-κB) to sustain immunosuppression and pro-tumorigenic responses. Understanding the molecular intricacies of TEX-driven M2 polarization is essential for advancing immunotherapeutic strategies.

Methods: This review systematically analyzes literature (2019-2024, from PubMed and Web of Science) on the molecular mechanisms by which TEX-derived ncRNAs drive M2 polarization and their interplay with immunotherapies.

Results and conclusion: This review contains 142 citations, 60 of which are detailed examples of this mechanism. Our analysis of the literature shows that TEXs deliver specific ncRNAs to macrophages, reprogramming them toward an M2 phenotype via pathways such as PTEN/PI3Kγ, Wnt/β-catenin, and STAT3. This polarization amplifies immunosuppressive factor secretion and promotes tumor metastasis, chemoresistance, and immune evasion. These insights provide a theoretical foundation for novel TME-targeted therapies, potentially improving outcomes in refractory cancers.

Background: Cancer cells reprogram their metabolism to sustain energy production and biosynthesis for malignant proliferation; however, their metabolic phenotypes vary significantly across different growth environments, creating discrepancies between in vitro and in vivo findings. These inconsistencies pose challenges for translating metabolic research into clinical applications. The emergence of 3D culture models as in vitro systems that accurately mimic the in vivo environment can mitigate these challenges by providing conditions that reflect physiological architecture and metabolic interactions. Therefore, we investigated the impact of the purine metabolism enzyme hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT1) on the proliferation and metabolism of SCLC cells using 2D and 3D culture models, with the goal of identifying context-specific metabolic regulation not captured in conventional 2D cultures.

Methods: We evaluated cell proliferation and performed metabolomic profiling of HPRT1-knockout (KO) SCLC cells grown in 2D cultures, two 3D culture systems, and mouse xenograft models. Metabolomic profiling was performed using CE-TOFMS, followed by PCA and pathway analysis. The expression of β-alanine (β-Ala) metabolism-related genes, including carnosine synthase 1 (CARNS1), was assessed by RNA-seq and RT-PCR. CARNS1 expression was further evaluated in publicly available lung cancer datasets, including both cell line and clinical tumor cohorts, to determine its association with patient prognosis and its correlation with HPRT1 expression.

Results: The knockout of HPRT1 significantly reduced cell proliferation in 3D cultures and in vivo but had a minimal impact in 2D cultures. Comprehensive metabolomic analyses of HPRT1-KO cells revealed extensive alterations in amino acid and purine metabolism both in vitro and in vivo. Notably, the effect of HPRT1 KO on β-Ala metabolism differed between 2D and 3D cultures. In 3D cultures, HPRT1 KO led to increased expression of the endogenous antitumor metabolite carnosine and its biosynthetic enzyme CARNS1 within the β-Ala metabolic pathway. Furthermore, analysis of clinical databases showed that high CARNS1 expression correlated with improved prognosis in patients with lung cancer and negatively correlated with HPRT1 expression in tumor tissues.

Conclusion: This study highlights the potential of 3D culture systems to elucidate context-specific mechanisms of metabolic regulation, such as the suppressive effect of HPRT1 on carnosine production. Our findings demonstrate that metabolic phenotypes observed in 2D cultures may not fully capture the complexity of in vivo metabolism, whereas 3D models can reveal regulatory pathways that are otherwise overlooked, including context-dependent regulation of carnosine metabolism by HPRT1.

Introduction: Gastrointestinal stromal tumors (GISTs) originate from mesenchymal precursor cells of the gastrointestinal wall and account for approximately 3% of all gastrointestinal malignancies. In adults, these tumors most commonly harbor mutually exclusive activating mutations in KIT, PDGFRA, BRAF, or SDH-family genes. KIT and PDGFRA mutations are well-established predictive biomarkers for response to tyrosine kinase inhibitors (TKIs). The advent of Next Generation Sequencing (NGS) has accelerated the identification of novel genetic alterations, improving disease characterization, providing prognostic and predictive information, and enabling detection of rare germline variants.

Methods: We conducted a retrospective analysis of 31 patients with GIST to evaluate the implementation of NGS testing and the interpretation of pathogenicity in real-life clinical practice. Identified mutations were compared with publicly available databases, and rare KIT exon 11 variants underwent computational modeling to assess their impact on protein conformation and imatinib interaction. Germline testing was performed when indicated.

Results: In addition to common primary and secondary mutations in KIT and PDGFRA, three patients carried rare KIT exon 11 variants not previously classified in public databases: p.Gln556del (upstream of codons 557/559) and p.Asn566_Pro573del and p.Val569_Leu576_del (downstream), all located within the juxtamembrane (JM) domain. One patient harbored an SDHB c.287-1G⟩C alteration resulting in aberrant splicing, also detected in the germline. The structural modeling predicted that all rare KIT exon 11 variants affected protein conformation and influenced imatinib interaction. Clinically, all three variants were associated with response to imatinib and met ACMG-AMP criteria for pathogenicity as well as ASCO-CAP tier 1 classification.

Conclusions: Our findings highlight the clinical relevance of integrating NGS into routine GIST management, particularly for the identification and interpretation of rare genetic variants. The study underscores the importance of data sharing and collective variant annotation to support accurate molecular classification, prognostic assessment, and therapeutic decision-making for individual patients.

Objective: To evaluate the difference in the characteristics and prognosis between kidney transplantation (KT) recipients and normal patients with urothelial carcinoma.

Method: We retrospectively reviewed the characteristics of the kidney-transplanted patients and the general patients who were diagnosed with urothelial carcinoma between 2013 and 2021. The non-kidney transplantation (NKT) group is matched with the KT group through propensity score matching (PSM) to adjust for confounders. We evaluated the prognosis including overall survival (OS), relapse-free survival (RFS), and progression-free survival (PFS). We compared the difference in the prognosis between the two groups using Kaplan-Meier analysis and the log-rank test.

Result: The characteristics of 344 NKT patients and 42 KT recipients with urothelial carcinoma were included in this research. The percentage of females was significantly higher in the KT group than in the NKT group (p < 0.001). Tumors mostly occurred in the upper tract in the KT group and in the bladder cancer (BC) in the NKT group. After propensity score matching (PSM), overall survival (OS) was significantly longer in the KT group with upper tract urothelial carcinoma (UTUC) than in the NKT group (p = 0.001), whereas recurrence-free survival and progression-free survival (PFS) were significantly lower in the KT group with UTUC+BC than in the NKT group (p = 0.028, 0.044).

Conclusion: Patients with tumors that occur in both the bladder and upper urinary tract have a worse prognosis. Kidney transplantation recipients with only bladder or upper urinary tract UC have a prognosis that is no worse or even better than that of NKT patients.

Background: Few treatment options are available for patients with epidermal growth factor receptor (EGFR) mutation-positive metastatic non-squamous non-small cell lung cancer (NSCLC) who failed treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). We aimed to assess the efficacy and safety of atezolizumab plus bevacizumab in these patients.

Methods: We conducted a single-arm, Simon's minimax two-stage adapted phase II study. Patients received atezolizumab 1200 mg plus bevacizumab 15 mg/kg once every 3 weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety.

Results: Between 14 August 2020 and 18 January 2021, 23 patients from seven sites in China were enrolled; all received study treatment. Twenty-two patients were evaluable for ORR. At data cut-off, median follow-up was 16.4 months. The confirmed ORR was 18.2% (4/22) per RECIST v1.1. The number of responders did not cross the predefined threshold (> 6 patients) for stage II enrollment. For the four responding patients, the median TTR and DOR were 1.4 and 6.4 months, respectively. Median PFS and OS were 2.8 and 14.1 months, respectively. Atezolizumab plus bevacizumab had acceptable tolerability without any new safety signals identified. All patients experienced at least one treatment-emergent adverse event (TEAE); four patients experienced serious TEAEs and one patient died of an unknown cause.

Conclusions: The chemotherapy-free atezolizumab plus bevacizumab regimen had limited efficacy but an acceptable safety profile in this exploratory study. Although current data suggest that chemotherapy may still be important for patients who failed EGFR-TKIs, more treatment regimens with lower toxicity and higher efficacy for these patients, such as antibody-drug conjugates and bispecific antibodies, need to be explored in the future.

Trial registration: ClinicalTrials.gov identifier: NCT04426825.

Background: Pancreatic cancer (PC) presents a significant challenge for prevention and treatment, posing a serious threat to the health and lives of patients. The five East Asian countries (China, Japan, North Korea, South Korea, and Mongolia) represent one of the most significant regions globally in terms of PC burden.

Methods: We retrieved data from the Global Burden of Disease (GBD) Study 2021 regarding the prevalence, incidence, mortality, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life years (DALYs) associated with PC in these five East Asian countries from 1990 to 2021. We employed joinpoint, age-period-cohort (APC), and decomposition analysis methods to assess the epidemiological characteristics of PC. To project the future burden of PC through 2036, we applied two prediction models: Autoregressive Integrated Moving Average (ARIMA) and Bayesian age-period-cohort (BAPC) models.

Results: China recorded the highest incidence, prevalence, mortality, YLLs, YLDs, and DALYs among the five East Asian countries in both 1990 and 2021. Japan exhibited the highest age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), age-standardized prevalence rate (ASPR), and age-standardized YLDs rate in both 1990 and 2021. Mongolia experienced significant increases in the number and rates of incidence, prevalence, death, YLLs, YLDs, and DALYs from 1990 to 2021. The age group with the highest prevalence, incidence, mortality, YLDs, YLLs, and DALYs rates across the five East Asian countries was consistently those aged 70 and older. The incidence rate across the five countries is influenced by aging populations, surpassing global averages. Projections for 2030 and 2036 suggest that Japan will have the highest ASPR (13.23 in 2030 and 13.85 in 2036), ASIR (12.14 in 2030 and 12.53 in 2036), and ASMR (10.97 in 2030 and 11.39 in 2036) among the countries.

Conclusion: The disease burden of PC in the five East Asian countries has steadily increased over the past three decades, particularly among older adults due to population aging.