Immune checkpoint inhibitors (ICIs) have been revolutionary in the field of cancer therapeutics. Myositis is a known rheumatic immunotherapy related adverse event with a fatality rate of 26.8% when associated with myasthenia gravis and 51.3% when associated with myocarditis. Typically, creatine kinase (CK) is elevated in ICI-myositis, thus normal CK levels in such cases may delay diagnosis and treatments in such patients. We report 2 cases of patients diagnosed with ICI-myositis after ipilimumab/nivolumab treatment for metastatic renal cell carcinoma and metastatic melanoma. Their lab studies showed normal CK values but elevated aldolase, which led to the ICI-myositis diagnosis and steroid treatment. Early recognition and treatment with steroids led to symptom improvement. These 2 cases highlight an atypical presentation of ICI-myositis with normal CK but elevated aldolase levels, suggesting aldolase may be a sensitive parameter in diagnosing ICI-myositis.

Cancer incidence is increasing, becoming a significant public health concern. Cancer arises from the uncontrolled division of cells that cannot be restrained by the anti-tumour response mounted by the immune system. Both tumour and immune cells require high levels of energy in the form of ATP and synthesis of macromolecules to support differentiation and proliferation. To support these metabolic demands, adaptations at the cell, tissue and systemic level are required. Here, we take a systemic perspective to summarise the energetic needs of the anti-tumour response and how metabolic overload and obesity affects these processes. We describe how immunotherapies that aim to reverse immune cell exhaustion have unexpected effects depending on the metabolic background of the patient and finally we propose the use of this knowledge to advance current cancer prevention and treatment strategies.

To integrate pharmacovigilance and network pharmacology methods for a comprehensive analysis of the potential adverse reactions of complement C5 inhibitors (eculizumab, ravulizumab, zilucoplan) and neonatal Fc receptor (FcRn) inhibitors (efgartigimod, rozanolixizumab), and to explore their toxicity mechanisms, thereby providing a reference for rapidly understanding the safety of these two novel classes of biologics in the treatment of myasthenia gravis (MG).

We extracted adverse event (AE) reports for these five drugs from the FDA Adverse Event Reporting System (FAERS) database, limited to the period since their FDA approval for the treatment of MG. Reports were further restricted to those where the drug was listed as the primary suspect (PS) and the indication (INDI) was "MG". Signal detection was performed using the Reporting Odds Ratio (ROR) method, the UK Medicines and Healthcare products Regulatory Agency (MHRA) method, and the Bayesian Confidence Propagation Neural Network (BCPNN) method. Additionally, network pharmacology was employed to analyze the toxicity mechanisms of the system organ categories (SOCs) specifically associated with complement C5 inhibitors and FcRn inhibitors.

Signal detection of AE reports associated with these five drugs revealed previously unlabeled positive signals, including: eculizumab (gastric cancer, embolic stroke), ravulizumab (psoriatic arthropathy, hypoacusis, peripheral vascular disorders), zilucoplan (weight increased, weight decreased), efgartigimod (metastases to liver, hepatic failure, nephrolithiasis, dysuria, Prostatitis, prostate cancer, Angina pectoris, congestive cardiac failure) and rozanolixizumab (vomiting, dyspepsia). However, the gastric cancer, liver metastasis and prostate cancer were reported within the first 30 days, causal associations cannot be established based on the data presented. Potential toxicity analysis was conducted on noteworthy SOCs for complement C5 inhibitors and FcRn inhibitors, revealing key targets and pathways.

This study elucidated the safety profiles of complement C5 inhibitors and FcRn inhibitors in clinical practice through pharmacovigilance analysis, confirming known adverse reactions and identifying several previously unreported ones. Furthermore, network pharmacology analysis revealed potential mechanisms underlying these adverse reactions. These findings provide valuable insights for monitoring and managing risks during treatment with two novel classes of biologics.

Chronic lymphocytic leukemia (CLL) has proven difficult to treat with chimeric antigen receptor (CAR) T cell therapy. CLL cells can negatively alter T cell fitness and induce a pseudohypoxic state. We hypothesized that production of CAR T cells under restricted oxygen conditions resembling physiological oxygen levels that can be encountered in tissues (i.e. 2% O₂) could promote outgrowth of hypoxia-tolerant CAR T cells.

We performed in vitro phenotypic and functional assessments of CD19-directed CAR T cells produced in either 21% (^NorCAR) or 2% (^HypCAR) O₂ derived from healthy donors (HDs) or patients with CLL.

Production of HD-derived CAR T cells in 2% O₂ promoted the enrichment of a naïve-like subset. ^HypCAR and ^NorCAR cells were functionally distinct; CD4+ ^HypCAR cells produced more IL-2 and tumor necrosis factor than CD4+ ^NorCAR cells. Production in 2% O₂ was not detrimental to viability or proliferation upon cognate antigen-stimulation and led to increased activation. After chronic stimulation in hypoxia, ^HypCAR-product remained enriched in naïve-like cells, and demonstrated cytotoxic and cytokine production capacity. In CAR T cells derived from patients with CLL, ^NorCAR and ^HypCAR subsets were functionally and phenotypically comparable, but displayed different mitochondrial metabolism.

We demonstrated that production in 2% O₂ is not detrimental, confers subtle but lasting functional and phenotypic changes in CAR T cells warranting further research on the impact of hypoxic production on CAR T cell functionality in hypoxic tumor microenvironments.

Mesothelin (MSLN) is a cell-surface glycoprotein overexpressed in the majority of pancreatic ductal adenocarcinoma (PDAC) cases and represents a promising immunotherapeutic target. Despite studies and clinical trials investigating MSLN-targeted immunotherapies, its biological role in PDAC carcinogenesis and influence on the tumor microenvironment remain poorly characterized. This study aims to investigate MSLN expression patterns in PDAC and assess their relationship to clinical outcomes and the immune microenvironment.

MSLN expression in 74 PDAC patients was evaluated by immunohistochemistry staining on a tissue microarray and correlated with clinicopathological features and survival outcomes. Complementary analyses of publicly available transcriptomic datasets (bulk RNA-seq and single-cell RNA-seq) were performed to characterize associations between MSLN expression and the tumor immune microenvironment with immunohistochemical validation.

High MSLN expression (H-score ≥ 62) was associated with improved relapse-free survival (p = 0.021) and with increased patient age (p = 0.036). Transcriptomic analyses revealed high MSLN expression was associated with an immunosuppressive microenvironment characterized by reduced immune reactivity and diminished cytotoxic T cell infiltration. Immunohistochemical validation confirmed a trend toward decreased stromal cytotoxic T cell abundance with increasing MSLN expression.

This study revealed an inverse relationship between MSLN expression and cytotoxic T cell infiltration in PDAC, despite a trend toward improved relapse-free survival in MSLN-high tumors. These findings have important implications for MSLN-targeted immunotherapies and suggest that addressing the immunosuppressive microenvironment may be necessary to optimize their current responses in PDAC.

Circular RNAs (circRNAs) have been reported to be important in the development and progression of breast cancer. Nevertheless, the biological functions and mechanisms underlying the action of circRNAs in triple-negative breast cancer (TNBC) remain poorly understood. The present study aimed to explore the role of hsa_circ_0001910 (also termed circWWC3) interacting with vimentin in regulating the secretion of Colony Stimulating Factor 2 (CSF2) and its effects on the malignant biological behavior of triple-negative breast cancer as well as the cytotoxic activity of NK cells.

RNA-Seq was utilized to investigate potential circRNAs involved in five pairs of breast cancer (BC) tissues and their corresponding normal tissues. Fluorescence in situ hybridization (FISH) was conducted to verify the relationship between circWWC3 expression and patient clinical pathological parameters, as well as its intracellular localization. Gain- and loss-of-function assays were conducted to investigate the biological functions of circWWC3 in TNBC. A microarray analysis of mRNA expression profiles was conducted to explore the downstream target genes of circWWC3. RNA pull-down assays, RNA immunoprecipitation (RIP), and mass spectrometry were carried out to uncover the proteins interacting with circWWC3. Rescue experiments were performed to investigate the potential regulatory role of circWWC3 in the progression of TNBC in vivo and in virto.

In our present study, Circular RNA sequencing analysis revealed that the expression of circWWC3 was significantly upregulated in breast cancer (BC). FISH assay results indicated that circWWC3 is highly expressed in TNBC, and its elevated expression is associated with the patient's T stage and lymph node metastasis, and it is primarily localized in the cytoplasm. The results of gain- and loss-of-function assays indicate that knockdown of circWWC3 significantly suppressed the proliferation, invasion, and migration of TNBC cells, while enhancing the killing efficiency of NK-92MI cells against TNBC cells. In contrast, overexpression of circWWC3 exhibited the opposite effects. The microarray analysis data indicated that CSF2 may be a downstream target of circWWC3. Interaction of circWWC3 with vimentin and their downstream target genes was confirmed by RNA pull-down, RIP, and mass spectrometry. Rescue experiments confirmed that vimentin knockdown partially counteracted the tumor-promoting effects of circWWC3. Further analysis revealed that circWWC3 upregulates CSF2 secretion mainly through its interaction with vimentin, a core component of the Epithelial-mesenchymal transition (EMT) signaling pathway, thereby facilitating the malignant progression of TNBC.

Overall, our findings reveal that elevated expression of circWWC3 serves a role in the malignant progression of TNBC by directly interacting with the S56 phosphorylation site of vimentin, an interaction that is associated with increased secretion of CSF2. Furthermore, circWWC3 emerges as a potential biomarker for breast cancer diagnosis and presents an attractive therapeutic target for the treatment of TNBC.

Neuroimmuno-oncology is an emerging interdisciplinary field that explores the complex interactions among the nervous system, the immune system, and tumor cells within the tumor microenvironment (TME). Recent studies have underscored the critical role of neurons in gliomas, where synaptic signaling and the release of neurotrophic factors contribute not only to tumor progression but also to mechanisms of immune evasion. Neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA), along with neuron-derived factors including brain-derived neurotrophic factor (BDNF) and neuroligin-3 (NLGN3), have been shown to modulate immune cell function and promote the formation of an immunosuppressive TME. In particular, neuronal electrical activity mediated through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) signaling facilitates immune escape in glioma cells, leading to the development of an "immune-excluded" phenotype that compromises the efficacy of immunotherapy. Therapeutic strategies that combine AMPAR antagonists with immune checkpoint inhibitors-alongside neuromodulatory techniques such as repetitive transcranial magnetic stimulation (rTMS) or deep brain stimulation (DBS)-hold potential to reprogram the neuro-immune-tumor axis, remodel the immune landscape, and improve immunotherapy responses in central nervous system malignancies. Advancing our understanding of how neuronal activity regulates the glioma immune microenvironment may open new avenues for precision-targeted therapeutic approaches in neuro-oncology.

Periodontal disease (PD) is one of the most common chronic diseases in the oral cavity, typically referring to chronic inflammation caused by infection with pathogenic microorganisms in the oral cavity. PD primarily affects the tissues surrounding the teeth, leading to inflammation of the gums and periodontal tissues, destruction of the alveolar bone, and even loosening of the teeth. Numerous studies have shown that PD is not limited to the oral cavity but is also associated with the occurrence of diseases in multiple systems throughout the body. In recent years, increasing attention has been directed toward the interaction between PD and prostate diseases. This article reviews the potential associations between PD and prostate conditions such as chronic prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa). It explores the pathological mechanisms underlying this interaction and its clinical implications. Additionally, this article aims to identify potential pathogenic mechanisms and propose possible approaches for preventing and treating prostate diseases through the management of PD.

Mature T-cell and natural killer (NK) cell lymphomas are uncommon. Their epidemiological data are mainly derived from Western and Eastern countries, some with significant variations. These differences may be related to genetic susceptibilities, prevalence of oncogenic viruses and other environmental factors. Nodal mature T-cell lymphomas are most common, with their incidences varying ethnically/geographically. Extranodal T-cell lymphomas have very different epidemiologic features. Adult T-cell leukaemia/lymphoma, due to human T-cell leukaemia virus type-1 (HTLV-1) infection, is found mainly in HTLV-1 endemic areas. Mycosis fungoides, the most common cutaneous T-cell lymphoma in the West, accounts for <2% of T-cell lymphomas in Asia. Epstein-Barr virus (EBV) related T-cell lymphomas are common in Asia and Central/South America but exceptional in the West. Germline polymorphisms of HLA-DPB1, IL18RAP and HLA-DRB1 genes have been defined in Chinese NK/T-cell lymphoma patients, potentially affecting susceptibility to EBV-related lymphomagenesis. This review explores these epidemiological differences and how they may impact on management.

Advanced/recurrent endometrial cancer (EC) patients has a poor prognosis, with higher recurrence and mortality than early-stage. However, as the real-world disease burden in these patients remains unclear, we aimed to investigate systemic anticancer therapy (SACT) patterns, healthcare resource utilization (HCRU), and costs in advanced/recurrent EC patients.

This nationwide population-based study used Korean claims data from 2008 to 2022. Adult patients with advanced/recurrent EC who received first-line SACT were included. For advanced EC, first-line SACT was defined as the initial therapy following EC diagnosis, while for recurrent EC it was defined as the initial therapy after recurrence following completion of primary therapy. We analyzed SACT patterns, prognosis, all cause- and EC-related HCRU, and costs.

A total of 2,704 EC patients were included. The most commonly used SACT was platinum-based regimen. From the first to third line, median values of SACT-free interval (18.40, 5.03, and 3.22 months) and time to next treatment (TTNT, 25.43, 9.27 and 6.44 months) showed decreasing trends. All-cause/EC-related HCRU and costs were increased with SACT progression; all-cause inpatient visits and total costs increased from 0.58 to 1.04 times per-patient-per-month (PPPM) and from $1,197.96 to $2,354.37 USD PPPM.

This study demonstrated significant variability in SACT regimen sequence, highlighting the lack of consensus on standard treatment after disease relapse. Shorter TTNT and SACT-free intervals and higher HCRU and costs in later lines indicate worsening prognosis and increasing disease burden. These findings suggest the urgent need for more effective treatments, including new therapeutic agents, to address the unmet clinical needs of advanced/recurrent EC patients.