Search Results (152)

Background: Thymic epithelial tumors (TETs), including thymic carcinomas and thymomas, are rare malignancies originating in the mediastinum. Therapeutic options remain limited for patients experiencing disease progression following platinum-based chemotherapy. High tumor mutational burden (TMB) is uncommon in thymic malignancies but may predict response to immunotherapy. We report a patient with TMB-high TET who participated in the KOSMOS-II study in South Korea and achieved a durable response to atezolizumab without developing immune-related adverse events (irAEs). Case presentation: A 73-year-old woman who had been treated for thymoma 20 years ago presented with a left neck mass. A biopsy of the neck mass confirmed recurrent thymoma, type B3, and her disease progressed despite platinum-based chemotherapy and subsequent pemetrexed treatment. TMB-high thymoma is very rare, but based on the next-generation sequencing (NGS) results, she was diagnosed with TMB-high (20.3 mutations/Mb) thymoma. As TMB-based immunotherapy is not approved in Korea, she was enrolled in the KOSMOS-II study and initiated on atezolizumab following molecular tumor board review. She achieved stable disease after three cycles and has remained progression-free for 14 months, completing 20 cycles without significant irAEs. Notably, her underlying myasthenia gravis did not worsen during treatment. Conclusions: This case demonstrates a favorable outcome with biomarker-directed ICI treatment in recurrent thymoma with limited treatment options, highlighting the importance of appropriate molecular markers to predict drug response. Although TMB-based immunotherapy is FDA-approved in the U.S., it remains unavailable in Korea, underscoring the need to explore flexible access pathways, including the potential use of immunotherapy beyond current indications, to improve treatment options for patients with life-threatening conditions. Full article

Background: Autophagy, a self-destructive cellular mechanism with a paradoxical nature, plays a part in both tumor suppression and induction by providing cancer cells with metabolic substrates, resulting in cell proliferation and survival. In this study, we aim to investigate the clinical significance of four autophagy pathway components (BECLIN, p62/, LC3b, ATG3) in pathogenetic mechanisms of thymic epithelial tumors (TETs) with possible prognostic importance. Methods: Immunohistochemistry was used to evaluate the cytoplasmic expression of BECLIN, p62, LC3b, and ATG3 in tumor cells of 99 TETs, and possible correlations with clinicopathological parameters were examined. Results: Higher BECLIN and p62 expression was associated with male gender (p = 0.027 and p = 0.014, respectively). B3 thymomas and thymic carcinomas (TCs) displayed higher p62 expression (p = 0.019), while LC3b expression was marginally higher in non-B3/TC TETs (p = 0.098). A positive correlation between higher BECLIN expression and advanced Masaoka–Koga stage was also observed (p = 0.009). ATG3 was not associated with any of the investigated clinicopathological parameters (p > 0.05). There was also no significant correlation between any of the four examined molecules and overall survival or relapse. Conclusions: Our findings indicate autophagy activation in B3/TC and advanced Masaoka–Koga stage cases. Further studies are needed to explore the role of these autophagy related proteins as potential biomarkers and therapeutic targets in TETs. Full article

Background and Objectives: Aggressive cancer development is characterized by rapid tumor growth and progressive immune dysfunction. Tumor-derived microRNAs (miRNAs) emerge as master regulators of both malignant transformation and immune evasion, making them promising therapeutic targets. Using the highly aggressive CT-26 peritoneal adenomatosis model, this study explored the potential of selective miRNA inhibition to simultaneously suppress tumor growth and overcome immunosuppression. Methods and Results: Our results revealed that inhibition of miR-155, miR-21, and miR-17 by methylsulfonyl phosphoramidate (mesyl) oligonucleotides exhibited markedly different therapeutic profiles. miR-155 inhibition demonstrated minimal efficacy. miR-21 suppression provided early tumor regression and prevented cancer-associated thymic atrophy, translating into extended survival. miR-17 inhibition displayed delayed but superior tumor growth inhibition, significantly reducing pathologically elevated polymorphonuclear myeloid-derived suppressor cell (MDSC) populations, and nearly doubled animal lifespan. Combination therapy targeting all three miRNAs integrated these complementary mechanisms, maintaining consistent anti-tumor efficacy across early and late stages while providing thymic protection and MDSC reduction. Importantly, therapeutic responses in vivo substantially exceeded predictions based on in vitro tumor cell proliferation and motility measurements, revealing critical contributions of systemic immunomodulation. Conclusions: These findings demonstrate that miRNA inhibition reshapes tumor–immune interactions, positioning anti-miRNA therapeutics as immunomodulatory agents for effective colorectal cancer treatment. Full article

Thymic carcinoma (TC) is a rare and aggressive malignancy with poor prognosis, and its genomic landscape remains incompletely defined. Identifying the somatic alterations that shape TC biology is essential for improving diagnostic precision, developing targeted therapies, and informing early detection strategies. We performed a retrospective genomic analysis of 141 TC tumor specimens from 134 patients using de-identified data from the American Association for Cancer Research (AACR) Project GENIE^® database. Somatic mutations and copy number alterations (CNAs) were characterized, and statistical analyses were conducted to evaluate associations with patient demographics (sex, race) and tumor site (primary vs. metastatic). The cohort was predominantly male (56.7%) and White (56.7%). The most frequently altered genes were TP53 (27.7%), CYLD (17.6%), and CDKN2A (12.1%). Recurrent homozygous deletions at chromosome 9p21.3 involving CDKN2A and CDKN2B were common. Sex-stratified analysis revealed several significant male-specific alterations. Although the Pacific Islander subgroup was small (n = 2), preliminary analysis suggested enrichment of alterations in key cancer-associated genes, including TP53, BRCA1, and STAT5B, underscoring the need for diverse representation in TC genomics. Notably, MTOR mutations were significantly enriched in a subset of local recurrences and lymph node metastases (n = 3; q = 0.013), suggesting a potential role in disease progression. This large-scale genomic analysis reinforces the central involvement of TP53, cell-cycle control, and chromatin-modifying pathways in TC. The identification of sex-associated and race-associated mutational patterns, together with the enrichment of MTOR alterations in recurrent and metastatic disease, highlights biologically plausible mechanisms of progression and potential therapeutic vulnerabilities. These findings support the value of comprehensive genomic profiling in TC and emphasize the need for prospective, multi-omic studies to validate these observations and guide the development of more personalized treatment strategies. Full article

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that strongly suppress immunity and expand during tumor progression. Various antitumor chemotherapy agents can induce MDSC accumulation, reducing treatment effectiveness. We investigated the impact of the CHOP regimen and its components (cyclophosphamide (CTX), doxorubicin, vincristine, and prednisolone) on the dynamics of MDSC accumulation and the associated changes in immune cell profiles in the peripheral blood and spleen of healthy and lymphosarcoma RLS₄₀-bearing CBA mice. CHOP induced significant thymic atrophy and splenomegaly, T-cell depletion, and robust accumulation of MDSCs, primarily polymorphonuclear MDSCs. Kinetic analysis in healthy mice revealed splenic MDSC expansion and T-cell depletion peaked 10-day post-CHOP, driven mainly by CTX; whereas doxorubicin, vincristine, and prednisolone exerted minimal immunological effects. To mitigate CTX-induced MDSCs, glycyrrhizic acid (GLZ), a natural triterpenoid with known immunomodulatory properties, and febroxolone methyl (FM), its novel cyano enone derivative, were administered to CTX-treated mice. GLZ significantly attenuated splenic MDSC accumulation, partially restored T-cell function, and improved immune organ morphology. Conversely, FM exacerbated immunosuppression by expanding MDSCs, enhancing their function by upregulation of Nos1 and Ido1 in vivo, and promoting the generation of highly immunosuppressive bone marrow-derived MDSCs in vitro. Thus, our results highlight CTX’s central role in CHOP-induced MDSC expansion. The structure-dependent duality of triterpenoids, countering (GLZ) or promoting (FM) MDSC expansion, offers therapeutic potential for pathologies ranging from chemotherapy-induced side effects to autoimmunity. Full article

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Since numerous studies highlight the significance of cholinergic system components in tumor development, acetylcholine (ACh) and the differential activation of its receptors could play a crucial role in GBM progression. The aim of this study was to test this hypothesis by assessing the relevance of the cholinergic system in GBM cells and their microenvironment. We analyzed bulk RNA-seq expression data using the TIMER2.0 web server, focusing on the impact of patient survival in relation to muscarinic receptors (CHRM) and neutrophil infiltration in low-grade glioma (LGG) and GBM. Our analysis revealed a marked decrease in survival associated with all CHRMs, particularly in LGG. Moreover, GBM showed higher neutrophil infiltration and reduced survival, especially in relation to CHRM3. These findings were validated in the U251 cell line and in human GBM tumor biopsies (GBM-b), which also displayed CHRM3 expression. Additionally, we show that GBM cells exposed to cholinergic stimulation exhibited increased vascular endothelial growth factor (VEGF), IL-8 production, and PD-L1 expression, while the VEGF increase was blocked by tiotropium (Tio), a CHRM3 antagonist. Similarly, polymorphonuclear cells from GBM patients (PMN-p) displayed increased PD-L1 expression and IL-8 production upon cholinergic stimulation. Finally, as we previously reported on the relevance of thymic stromal lymphopoietin (TSLP) in GBM pathophysiology, here, we found that TSLP upregulated CHRM3 expression. Our findings highlight the importance of the cholinergic system in the tumor microenvironment, where it may act directly on tumor cells or influence neutrophil physiology, thereby modulating tumor progression. Full article

Background: Neoadjuvant chemotherapy is generally recommended for locally advanced, potentially resectable thymic epithelial tumors. However, neoadjuvant chemoradiotherapy has been proposed as an alternative approach, potentially achieving higher complete resection rates. In this study, a retrospective analysis was conducted to compare the outcomes of neoadjuvant chemoradiotherapy (NCRT) and neoadjuvant chemotherapy (NCT). Methods: From 2009 to 2022, a total of 98 patients who underwent surgery following either NCRT (n = 30) or NCT (n = 68) for thymic epithelial tumors were included in this study. Propensity score matching was applied, resulting in two matched groups of 30 patients each. The primary endpoint was the comparison of complete (R0) resection rates between the groups. Results: In the matched cohort, the R0 resection rate was significantly higher in the NCRT group (93.3%) compared to the NCT group (73.3%; p = 0.038). The tumor regression grade was also significantly lower in the NCRT group (p = 0.002). However, no significant difference was observed in 5-year overall survival between the groups, either in patients with thymoma (100% for NCRT vs. 90.9% for NCT; p = 0.34) or thymic carcinoma (74.3% for NCRT vs. 63.2% for NCT; p = 0.82). For patients with initial local recurrence, both the 5-year overall survival and post-recurrence survival rates were 100%. Conclusions: The neoadjuvant chemoradiotherapy group demonstrated superior local control, as evidenced by improved tumor regression grades and complete resection rates. However, the absence of corresponding improvement in overall survival warrants further investigation with a larger patient cohort and a longer follow-up period. Full article

Background/Objectives: Thymic neuroendocrine neoplasms (t-NENs) are rare, biologically aggressive malignancies of the anterior mediastinum. Due to their low incidence, clinical evidence remains limited, and treatment recommendations are primarily based on expert opinion and extrapolation from other neuroendocrine tumors. This study aimed to analyze the clinicopathological features, treatment patterns, and survival outcomes of patients with t-NENs treated at a single comprehensive cancer center over 25 years. Methods: A retrospective review was performed on 19 adult patients diagnosed with t-NENs between 2000 and 2024. Data on demographics, histology, treatment intent, modalities used, and outcomes were collected. Survival analyses—of overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS)—were conducted using the Kaplan–Meier method. Results: The median age was 52 years; 63% of patients were male. Atypical carcinoid was the most common histologic subtype (52.6%), followed by large cell neuroendocrine carcinoma (31.6%). Paraneoplastic syndromes, including Cushing’s syndrome, were observed in 26.3% of cases. Radical surgery was performed for 8 patients, but R0 resection was achieved in only 25% of them. Postoperative radiotherapy and chemotherapy were used for 36.8% and 15.8% of patients, respectively. Disease recurrence occurred in 44.4% of curatively treated patients. The median OS for the entire cohort was 127 months; patients treated with curative intent had a significantly longer OS (170 months) compared to those after palliative treatment (33 months). Median PFS in the palliative group was 11 months. Conclusions: t-NENs are aggressive tumors with high risk of recurrence and limited systemic treatment efficacy. Complete surgical resection remains the cornerstone of curative therapy. However, the overall prognosis remains poor, emphasizing the need for novel therapeutic strategies and prospective multicenter studies. Full article

Aging is characterized by immune decline, mainly due to thymic involution—the age-related shrinkage of the thymus gland. This leads to reduced T-cell production, chronic inflammation, and increased susceptibility to age-related diseases. Thymosin alpha-1 (Tα1), a peptide hormone produced by the thymus, exhibits potent immunomodulatory, anti-inflammatory, and antioxidant properties. It helps restore immune function by stimulating T-cell differentiation, enhancing thymic output, and modulating dendritic cell and macrophage activity. Preclinical and clinical studies show that Tα1 can improve vaccine response in the elderly and mitigate immunosenescence. The hybrid drug Refnot (a fusion of tumor necrosis factor alpha (TNFα) and Tα1) combines Tα1’s immunomodulation with TNF’s antitumor activity but has reduced toxicity. It represents a promising therapeutic approach to counteract age-related immune dysfunction and inflammation, potentially by slowing the aging process. Further research is needed to validate its long-term efficacy and safety in geriatrics. Full article

Alpha-fetoprotein (AFP) is a biomarker commonly used in the diagnosis of various malignancies but may also be elevated in non-neoplastic conditions, including hypothyroidism. We report the case of a 3-year-old girl with Down syndrome (DS) and newly diagnosed hypothyroidism, who presented with a hypoechoic oval lesion adjacent to the thymic parenchyma on ultrasound and markedly elevated AFP levels (169.2 ng/mL). Further investigations, including MRI, excluded the presence of germ cell tumors. Following initiation of levothyroxine therapy, AFP levels normalized in parallel with thyroid function. No evidence of malignancy was detected despite the initial suspicion. This case underscores the association between elevated AFP and hypothyroidism, highlighting the importance of evaluating thyroid status in patients with increased AFP to avoid unnecessary oncological investigations. In particular, elevated AFP in the context of hypothyroidism and DS warrants careful thyroid assessment and follow-up to prevent redundant diagnostic procedures and reduce patient and family anxiety. Thyroid function testing should be considered before extensive oncological evaluation in children with elevated AFP. Full article

Thymic epithelial tumors (TETs) are a diverse group of rare thymic tumors that arise from thymic epithelial cells. The rarity of these tumors has limited therapeutic advancements due to difficulty to enroll patients into Phase II and III clinical trials. Historically surgery, radiotherapy, and chemotherapy have been the mainstay therapeutic options for these patients with the development of new therapeutics hindered by the rarity, histological and molecular heterogeneity, and lack of actionable mutations. However, more recently, innovations in immunotherapy, next-generation tyrosine kinase inhibitors, and hyperthermic intrathoracic chemotherapy (HITHOC) have transformed the therapeutic landscape with more promising therapies currently under investigation. In this review we evaluate the histology and molecular subtypes of TETs, and discuss the therapeutic landscape including the current standard-of-care regimen as well as drugs that are currently in clinical trials. Full article

Background/Objectives: Chronic colitis presents a growing global health burden with rising incidence. This study investigated the ameliorative effect of Dendrobium officinale polysaccharide (DOP) against dextran sulfate sodium (DSS)-induced chronic colitis in mice, specifically examining its dual modulation of gut microbiota and metabolic pathways. Methods: DOP was extracted and purified from Dendrobium officinale stems and leaves. A chronic colitis model was established in male C57BL/6J mice via DSS induction. Eighty-four mice were randomized into seven groups: control, model, low/high-dose leaf-DOP, low/high-dose stem-DOP, and sulfasalazine positive control. We assessed body weight, disease activity index (DAI), colon length, splenic/thymic indices, inflammatory cytokines, and histopathology (Hematoxylin and Eosin/Alcian blue staining), with tight junction protein and tumor necrosis factor-alpha (TNF-α) expression quantified via immunofluorescence. 16S rRNA sequencing and untargeted metabolomics evaluated microbial and metabolic shifts. Results: DOP significantly attenuated colitis severity, restored colon histoarchitecture, elevated goblet cell counts, upregulated zonula occludens-1 (ZO-1) and occludin expression, and suppressed TNF-α. Crucially, DOP remodeled dysbiosis by enriching beneficial taxa (e.g., Candidatus_Saccharimonas, Lachnoclostridium) while reducing pathogens (Mucispirillum). Metabolomics further elucidated DOP-mediated regulation of purine and nicotinate/nicotinamide metabolism—pathways mechanistically linked to its anti-inflammatory and barrier-repair effects. Conclusions: DOP effectively alleviates symptoms of DSS-induced chronic colitis in mice, protects intestinal barrier integrity, and achieves therapeutic potential through simultaneous regulation of the gut microbiome and metabolome. Full article

Thymic carcinoma (TC) is a rare, aggressive cancer that originates from thymus’s epithelial cells. It distinguishes itself from other thymic epithelial tumors with its unique pathological structure, clinical behavior, and immune characteristics. Immune checkpoint inhibitors (ICIs) targeting the Programmed cell death protein 1/Programmed cell death protein ligand 1 (PD-1/PD-L1) pathway have shown promise in advanced TC, potentially benefiting from frequent PD-L1 overexpression and abundant CD8⁺ tumor-infiltrating lymphocytes (TILs), despite typically low tumor mutational burden (TMB). While ICI monotherapy can achieve disease control in some patients, its overall efficacy is limited and it is associated with a distinct profile of immune-related adverse events (irAEs) which occur less often than in thymomas. The predictive value of biomarkers—particularly PD-L1 expression—remains uncertain, underscoring the importance of consistent assessment criteria. In this review, we summarize evidence on ICI monotherapy as well as combination approaches that incorporate anti-angiogenic agents, chemotherapy, or dual checkpoint blockade. Emerging therapeutic targets—such as CD70, TIM-3, and B7-H4—are also considered in the context of their potential clinical relevance. Finally, we discuss future directions aimed at improving efficacy, extending response durability, and reducing treatment-related toxicity through biomarker-based patient selection and tailored therapeutic strategies. Full article

Background/Objectives: T cell dysfunction represents a fundamental barrier to effective cancer immunotherapy. Although immune checkpoint blockades and adoptive cell transfer have achieved clinical success, therapeutic resistance remains prevalent across cancer types. Thymopentin (TP5), a synthetic immunomodulatory pentapeptide (Arg-Lys-Asp-Val-Tyr), has demonstrated immunostimulatory properties, yet its anticancer potential remains unexplored. The aim of this study was to investigate TP5’s antitumor efficacy and underlying immunological mechanisms. Methods: We evaluated TP5’s therapeutic effects in multiple murine tumor models, including B16-F10 melanoma, MC38 colorectal carcinoma, Hepa 1-6, and LM3 hepatocellular carcinoma. Immune cell populations and functional states were characterized using flow cytometry, ELISAs, and immunofluorescence analyses. The potential of TP5 as an adjuvant for T cell-based therapies was also systematically assessed. Results: The TP5 treatment markedly suppressed tumor growth across caner models through strictly T cell-dependent mechanisms. Critically, TP5 promoted thymic rejuvenation under immunocompromised conditions, restoring the thymus–tumor immunological balance and revitalizing peripheral T cell immunity. TP5 functionally reprogrammed T cell states, preserving effector function while ameliorating exhaustion. Furthermore, TP5 demonstrated synergistic efficacy when combined with adoptive T cell therapies, enhancing both proliferation and effector functions. Conclusions: TP5 represents a promising immunomodulator that addresses fundamental limitations of current T cell therapies by simultaneously enhancing T cell function and reversing thymic involution under immunocompromised conditions. Our findings provide compelling evidence for TP5’s clinical translation in cancer treatment. Full article

Background: Thymoma is a malignant tumor originating from the thymic epithelium and can be associated with over 100 paraneoplastic syndromes (PNSs). Due to the low incidence of thymoma and the relative rarity of alopecia areata (AA) as an associated autoimmune disease, patients with thymoma combined with AA are relatively uncommon in clinical practice. As a result, the clinicopathological features and pathogenesis of such patients have been rarely investigated. Methods: This study retrospectively analyzed the clinical records of thymoma patients who underwent surgical treatment at Peking Union Medical College Hospital and Beijing Tongren Hospital from August 2014 to July 2019, with a focus on the clinicopathological features of thymoma patients with AA. Propensity score matching (PSM) was employed to create a 1:5 matched comparison group with thymoma patients without AA. Results: A total of 428 thymoma patients were included, among which 9 had AA. Using PSM, we matched 45 control patients without AA based on age and gender. The analysis revealed that thymoma patients with AA had a significantly higher proportion of myasthenia gravis (MG) [100.00% (9/9) vs. 66.67% (30/45), p = 0.049], although there were no significant differences between the AChR antibodies, Titin antibodies, MG severity, and the incidence of postoperative myasthenic crisis. However, the proportion of thymoma patients with AA who also had other PNSs besides MG was significantly higher [88.89% (8/9) vs. 6.67% (3/45), p < 0.001]. Additionally, CD4⁺/CD8⁺ T-cell inversion in the serum was observed at a much higher rate in thymoma patients with AA [100.00% (9/9) vs. 24.44% (11/45), p < 0.001]. Conclusions: We hypothesize that the pathogenesis of thymoma with AA differs from that of thymoma with MG, though there may be a correlation. The etiology of thymoma with AA may be attributed to abnormal autoimmune CD8⁺ T lymphocytes produced by the thymoma, which can also lead to other cytotoxic T-cell-mediated autoimmune diseases. Full article