Single-cell landscape of intratumoral heterogeneity and tumor microenvironment remolding in pre-nodal metastases of breast cancer.

BACKGROUND: The metastasis of cancer cells is influenced by both their intrinsic characteristics and the tumor microenvironment (TME). However, the molecular mechanisms underlying pre-nodal metastases of breast cancer remain unclear. METHODS: We integrated a total of 216,963 cells from 54 samples across 6 single-cell datasets to profile the cellular landscape differences between primary tumors and pre-nodal metastases. RESULTS: We revealed three distinct metastatic epithelial cell subtypes (Epi1, Epi2 and Epi3), which exhibited different metastatic mechanisms. Specifically, the marker gene KCNK15 of the Epi1 subtype exhibited increased gene expression along the cell differentiation trajectory and was specifically regulated by the transcription factor ASCL1. In the Epi3 subtype, we highlighted NR2F1 as a regulator targeting the marker gene MUCL1. Additionally, we found that the Epi2 and Epi3 subtypes shared some regulons, such as ZEB1 and NR2C1. Similarly, we identified specific subtypes of stromal and immune cells in the TME, and discovered that vascular cancer-associated fibroblasts might promote capillary formation through CXCL9+ macrophages in pre-nodal metastases. All three subtypes of metastatic epithelial cells were associated with poor prognosis. CONCLUSIONS: In summary, this study dissects the intratumoral heterogeneity and remodeling of the TME in pre-nodal metastases of breast cancer, providing novel insights into the mechanisms underlying breast cancer metastasis.

Prognostic value of platelet distribution width and mean platelet volume in patients with laryngeal cancer.

Aims: To investigate the prognostic relevance of platelet volume indices for survival in laryngeal cancer. Patients & methods: The study included 640 patients with laryngeal cancer. We analyzed the optimal cutoff values through receiver operating characteristic analysis, then analyzed the univariate factor and multivariate variables. Kaplan-Meier curves and log-rank tests were conducted to compare the overall survival (OS) and recurrence-free survival rates between the groups. Results: In multivariate analysis, elevated platelet distribution width (PDW) and PDW/platelet count ratio were significantly correlated with poor prognosis for OS; however, elevated mean platelet volume (MPV) and MPV/platelet count ratio suggested a notable correlation with favorable prognosis for OS. Meanwhile, elevated PDW and decreased MPV were significantly correlated with poor prognosis for recurrence-free survival. Conclusions: Our findings indicate that elevated PDW and decreased MPV could serve as independent biomarkers for worse survival in laryngeal cancer.

Clinical outcomes of patients taking first-generation EGFR-TKIs may predict the benefits afforded by osimertinib in EGFR T790M-mutant NSCLC patients.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used to treat patients with EGFR-mutated non-small cell lung cancers (NSCLCs). The association between the clinical outcomes of patients on first-line EGFR-TKIs and the efficacy of osimertinib as second-line treatment has not been previously assessed. This is our topic here. PATIENTS AND METHODS: We retrospectively analysed 67 patients with EGFR mutations on osimertinib after treatment with first-generation EGFR-TKIs. We evaluated patient characteristics, the EGFR T790M allele frequency in plasma samples and clinical outcomes. RESULTS: When osimertinib was given as second-line treatment, the median progression-free survival (PFS) was 6.0 months, and the response rate and disease control rate were 32.8% and 91.0%, respectively. Correlation analysis showed that the female sex and isolated (not multiple) progression on first-line EGFR-TKIs were correlated with a superior response to osimertinib. Kaplan-Meier analysis showed that patients exhibiting a partial response, isolated progression, and longer PFS on first-line EGFR-TKIs experienced prolonged PFS on osimertinib. Univariate analysis indicated that the treatment response, PFS and progression when on first-line EGFR-TKIs affected the PFS on osimertinib. Multivariate analysis showed that progression when on first-line EGFR-TKIs was independently prognostic of a response to osimertinib. The median PFS of patients with isolated progressive disease PD alone who were receiving brain radiotherapy was significantly longer than that of patients with isolated progressive disease alone who did not receive brain radiotherapy as well as patients exhibiting multiple progression. A low frequency of the EGFR T790M allele in plasma tended to predict an inferior efficacy of osimertinib and shorter PFS. CONCLUSION: We found that patients who benefited from first-line EGFR-TKIs may experience prolonged PFS and a higher response rate when subsequently given osimertinib. A low plasma frequency of the EGFR T790M allele may predict poor osimertinib efficacy and shorter PFS.

Good prognosis for follicular lymphoma with estrogen receptor α-positive follicular dendritic cells.

Follicular lymphoma (FL) has a meshwork of follicular dendritic cells (FDCs). We previously demonstrated the presence of estrogen receptor alpha (ERα)+ CD23+ FDCs in grades 1-2 FL. The significance of FDCs as a prognostic factor in FL remains unknown. The current study aimed to compare clinicopathological features, including prognosis, between FL with and without ERα+ FDCs. This study evaluated the clinicopathological significance of ERα expression in 70 FL patients by immunostaining. The presence of ERα mRNA on FDCs from 5 FL patients was confirmed by CD21/ERα double staining (immunohistochemistry and in situ hybridization). We defined patients with frequent ERα expression as the ERαhigh group and those with infrequent ERα expression as the ERαlow group. Thirty-two patients were assigned to the ERαhigh group (45.7%), and 38 patients were assigned to the ERαlow group (54.3%). Both overall survival (OS) and progression-free survival (PFS) were significantly better in the ERαhigh group than in the ERαlow group (OS, log-rank, P = .0465; PFS, log-rank, P = .0336). Moreover, high ERα expression on FDCs was an independent prognostic factor for OS in both the univariate ([hazard ratio] HR, 0.163; P = .0260) and multivariate (HR, 0.050; P = .0188) analyses and for PFS in both the univariate (HR, 0.232; P = .0213) and multivariate (HR, 0.084; P = .0243) analyses. ERα mRNA expression was detected in CD21+ FDCs within the neoplastic follicles of FL patients. In conclusion, a neoplastic follicular microenvironment with ERα-positive FDCs might affect the grade and presence of the follicular pattern of FL and improve patient prognosis.

Prognostic Significance of Lactate Dehydrogenase in Patients Undergoing Surgical Resection for Laryngeal Squamous Cell Carcinoma.

The aim is to estimate the prognostic value of lactate dehydrogenase (LDH) in patients undergoing surgical resection for laryngeal squamous cell carcinoma (LSCC). A total of 640 resected LSCC patients were included. Preoperative lactate dehydrogenase (LDH) was assessed. Kaplan-Meier survival analysis and Cox regression analysis were conducted for overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meier analysis, univariate analysis and multivariate analysis demonstrated significant prognostic value for preoperative LDH. Although LDH was predictor of OS, it failed to be a predictor of RFS. The univariate HR and 95% CI of LDH were 0.484 and 0.357-0.658 (P < 0.0001). The multivariate analysis showed that LDH (HR = 0.518, 95% CI: 0.380-0.705, p < 0.0001) was related to OS. Elevated preoperative LDH >132 IU/L was significantly associated with better survival. Preoperative LDH might be an independent prognostic marker of OS in LSCC patients undergoing surgical resection.

Differential expression of estrogen receptor-α on follicular dendritic cells from patients with grade 1-2 and grade 3 follicular lymphoma.

Hormone therapy has been used for patients with estrogen receptor alpha (ERα)-positive breast cancers. Recently, some studies reported the expression of ERα on neoplastic cells from B-cell lymphomas. However, there has been only one report of ERα expression on the follicular dendritic cells (FDCs) that structurally and functionally support the microenvironment of follicular lymphomas (FLs). The objective of this study was to investigate the frequency of ERα expression on FDCs in nonneoplastic reactive lymphoid tissues and to compare the frequency of ERα expression on FDCs in the axillary lymph nodes between patients with and without antiestrogen therapy and among patients with grades 1-3 of FL. Reverse transcription-polymerase chain reaction was performed to detect ERα mRNA in FL. In nonneoplastic germinal centers (GCs) from patients with tonsillitis or reactive lymphadenitis, ERα was expressed in the light zone. ERα-positive cells strongly correlated with the width of GCs (rs  = 0.81, P < 0.01) and the CD21-positive (rs  = 0.69, P < 0.01) and CD23-positive (rs  = 0.83, P < 0.01) FDC meshwork. The axillary lymph nodes had fewer ERα-positive cells, smaller GCs, and a looser CD21- and CD23-positive FDC meshwork with hormone therapy than without hormone therapy (P < 0.01). Neoplastic follicles of G1-2 FL had more ERα-positive cells and a larger CD23+ FDC meshwork than those of G3 FL (P < 0.01). ERα mRNA was detected in both G1-2 FL and G3 FL by reverse transcription-polymerase chain reaction. In conclusion, these results suggested that antiestrogen hormone therapy may decrease the number of ERα-positive FDCs and that the responses mediated by the estrogen-ERα interaction on FDCs may differ between G1-2 FL and G3 FL.

Prevalence and Prognostic Significance of HPV in Laryngeal Squamous Cell Carcinoma in Northeast China.

BACKGROUND/AIMS: Human papillomavirus (HPV) is an etiological risk factor for a subset of head and neck squamous cell carcinomas. HPV has been proven to be a powerful prognostic biomarker for oropharyngeal cancer, but its role in the larynx has not been explored in depth. Here, we sought to evaluate the prevalence and genotype distribution of HPV in patients with laryngeal squamous cell carcinoma (LSCC) in northeast China. METHODS: HPV DNA in specimens from 211 patients diagnosed with LSCC was analyzed by the polymerase chain reaction and in situ hybridization, and p16 overexpression was evaluated by immunohistochemistry. p16 expression was scored positive if strong and diffuse nuclear and cytoplasmic staining was present in > 75% of tumor cells. RESULTS: In this study, infection with HPV and p16 expression were not absolutely consistent. Among all patients, 132 (62.6%) were positive for HPV DNA (HPV+), while 23 (10.9%) were inconsistent for HPV and p16. Multivariate analysis indicated that HPV, but not p16, is an independent prognostic factor for overall survival in LSCC. Overall survival was significantly improved in HPV+ LSCC patients compared with the HPV-negative group (hazard ratio, 0.395; 95% confidence interval, 0.185-0.843; p = 0.016). Among the 132 HPV+ patients, 28 (21.2%) were HPV-16 single infection. CONCLUSION: This study indicates that HPV DNA is a more reliable surrogate marker than p16 for the prediction of survival in patients with LSCC.

Comprehensive Analysis of the Relationship Between RAS and RAF Mutations and MSI Status of Colorectal Cancer in Northeastern China.

BACKGROUND/AIMS: Colorectal cancer (CRC) is mainly caused by chromosomal instability (CIN) and microsatellite instability (MSI). The RAS and RAF genes are essential components of the CIN pathway, and several studies have found that RAS and RAF mutations are associated with MSI status in CRC. Here, we examined these three factors in CRC in Northeast China and aimed to reveal new details of the relationship between these mutations and MSI status. METHODS: This study involved 290 patients with CRC who had RAS or RAF gene mutation detected using fluorescence-based allele-specific polymerase chain reaction or Sanger sequencing. The majority of the identified patients were found to harbor MSI (MSI status). Accurate molecular detection was carried out using formalin-fixed paraffin-embedded tissue or blood samples. RESULTS: The rates of RAS and RAF mutations were 58.5% and 4.1%, respectively. The prevalence of RAS mutation in CRC was clearly higher and that of RAF mutation was lower in Northeast China compared with previously reported cohorts in other locations. High MSI level (MSI-H status) was more complex, at around 10%. This was consistent with previous data from China. However, compared with data reported from other continents, MSI-H was higher than that of Japan or South Korea in Asia, and lower than that of Europe or the United States. CONCLUSION: RAS/RAF mutations and MSI status in CRC are closely associated with tumor location and ethnicity. Further studies investigating the relationship between these three factors can help in the development of treatment strategies for patients with CRC.

Plasma Gelsolin Promotes Proliferation of Mesangial Cell in IgA Nephropathy.

BACKGROUND/AIMS: Plasma gelsolin (pGSN) is an actin-binding protein that plays a critical role in the pathogenesis of rheumatoid arthritis. However, whether pGSN is involved in other immunological diseases remains unknown. This study focused on the relationship between pGSN and immunoglobulin A (IgA) nephropathy (IgAN). METHODS: Two hundred patients with IgAN, 200 patients each with several other types of nephropathy and healthy controls (HCs) who underwent kidney biopsies between 2000 and 2014 were enrolled in the study. The Oxford classification system was used to predict the risk of disease progression. Serum and renal tissue were used to detect pGSN, and the correlations between pGSN and IgA, galactose-deficient IgA1 (Gd-IgA1), transforming growth factor beta1 (TGF-ß1), fibronectin (FN) content, clinical symptoms, and kidney function were analyzed. RESULTS: We found that the pGSN levels were significantly decreased in sera from IgAN patients compared to sera from patients with other forms of glomerular nephritis and HCs. Furthermore, the serum pGSN levels were negatively correlated with the serum IgA1, FN, and TGF-ß1 levels, and positively correlated with the estimated glomerular filtration rate. Conversely, the glomerular pGSN content was significantly elevated in the IgAN patients and was positively correlated with TGF-ß1 and FN levels. In renal tissue, the pGSN levels were significantly higher in IgAN patients with M1 and S1 compared to patients with M0 and S0 (p < 0.05). Meanwhile, pGSN promoted human mesangial cell (HMC) proliferation by facilitating cell mitosis in vitro. pGSN also promoted integrin α2ß1 expression in HMCs and enhanced the integrin α2ß1-pGSN interaction. CONCLUSION: Our study suggested that pGSN may play an important role in the development of IgAN by promoting the proliferation of mesangial cells and that serum and glomerular pGSN levels may be new markers for predicting IgAN progression and prognosis.

Pathological mechanisms of cold and mechanical stress in modulating cancer progression.

Environmental temperature and cellular mechanical force are the inherent factors that participate in various biological processes and regulate cancer progress, which have been hot topics worldwide. They occupy a dominant part in the cancer tissues through different approaches. However, extensive investigation regarding pathological mechanisms in the carcinogenic field. After research, we found cold stress via two means to manipulate tumors: neuroscience and mechanically sensitive ion channels (MICHs) such as TRP families to regulate the physiological and pathological activities. Excessive cold stimulation mediated neuroscience acting on every cancer stage through the hypothalamus-pituitary-adrenocorticoid (HPA) to reach the target organs. Comparatively speaking, mechanical force via Piezo of MICHs controls cancer development. The progression of cancer depends on the internal activation of proto-oncogenes and the external tumorigenic factors; the above two means eventually lead to genetic disorders at the molecular level. This review summarizes the interaction of bidirectional communication between them and the tumor. It covers the main processes from cytoplasm to nucleus related to metastasis cascade and tumor immune escape.

Radiotherapy combined with anti-PD-1 and TKI for primary cardiac angiosarcoma considering the joint assessment of TLSs and PD-L1: a case report.

BACKGROUND: Primary cardiac angiosarcoma(PCA) has a low incidence rate and poor prognosis. Currently, no unified clinical treatment standards are available. CASE PRESENTATION: We report the case of a 48-year-old man presenting chest tightness, breathlessness, and dyspnea. Imaging and postoperative histopathologic studies confirmed PCA and that the tumor had invaded the entire right atrium. The patient developed progressive disease (PD) during postoperative radiotherapy. We used immunotherapy combined with targeted therapy based on the results of molecular profile and evaluation of tertiary lymphoid structures (TLSs) and programmed cell death-ligand 1 (PD-L1). After treatment, the metastatic lymph nodes of the patient were reduced to a certain extent, indicating that combination therapy was effective. CONCLUSION: To the best of our knowledge, this is the first report of radiotherapy combined with anti-PD-1 and tyrosine kinase inhibitors(TKI) for PCA. In addition, this is the first report on immunotherapy for PCA based on new evaluation methods, including TLSs, PD-L1, and genomic profile.

Tertiary Lymphoid Structures in Microorganism-Related Cancer.

Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues formed by the accumulation of lymphocytes and other components outside lymphoid organs. They have been shown to be widespread in cancers and have predictive effects on prognosis and immunotherapy efficacy; however, there is no standardized measurement guide. This paper provides a reference for future research. Moreover, the induction strategy for the formation mechanism of TLSs is a new direction for future cancer treatment, such as cancer vaccines for microorganisms. The effects of microorganisms on cancer are dual. The role of microorganisms, including bacteria, parasites, viruses, and fungi, in promoting cancer has been widely confirmed. However, the specific mechanism of their tumor suppressor effect, particularly the promotion of TLS formation, is currently unknown. In this review, we summarize the role of TLSs in cancer related to microbial infection and provide new ideas for further understanding their mechanisms of action in cancer.

Expression and clinical significance of NKG2A and HLA-E in advanced laryngeal carcinoma.

OBJECTIVES: The purpose was to detected features of the expression levels of NKG2A and its ligand HLA-E, a new member of the immune checkpoints, in advanced laryngeal carcinoma and their clinicopathologic significance. MATERIAL AND METHODS: We analyzed the expression levels of HLA-E and NKG2A in multiple types of tumors utilizing the Tumor Immune Estimation Resource (TIMER) database and immunohistochemistry and qRT-PCR analysis of paraffin embedded tissue samples to reveal the correlations of the clinicopathological factors with the expression of these two proteins in advanced laryngeal carcinoma as well as their prognostic significance. RESULTS: KLRC1 (the coding gene of NKG2A) and HLA-E are substantially overexpressed in various human cancers than normal tissues. HNSCC is also included. KLRC1 is differentially expressed in different HPV subgroups of patients, with higher expression in the HPV-positive group. Consistent with this, immunohistochemical results also revealed the high expression of these two proteins in tumor tissue. In addition, immunohistochemical staining also displayed a preference for the distribution of NKG2A-positive cells in tumor tissue. Clinicopathological analyses also displayed that the density of NKG2A-positive cells of the HPV-positive group infiltrating laryngeal carcinoma tissue was larger than that in the HPV-negative group. Prognostic analyses indicated that the expression of this immune checkpoint does not affect the overall survival length of patients, but the highly expressed HLA-E is significantly correlated with local recurrence in the patients. CONCLUSIONS: The findings suggest that the expression levels of HLA-E and NKG2A is upregulated in advanced laryngeal carcinoma. The NKG2A-positive cells infiltrating the tumor are mainly distributed in the cancer nest, while infiltrating cell number may be regulated by HPV. The highly expressed HLA-E may promote local recurrence in patients with advanced laryngeal carcinoma.

Neoadjuvant camrelizumab combined with paclitaxel and nedaplatin for locally advanced esophageal squamous cell carcinoma: a single-arm phase 2 study (cohort study).

BACKGROUND: Neoadjuvant administration of immune checkpoint inhibitors (ICIs) combined with chemotherapy demonstrated promising efficacy and manageable safety in locally advanced esophageal squamous cell carcinoma (ESCC). This prospective, single-arm, phase 2 study evaluated the efficacy and safety of neoadjuvant therapy with camrelizumab plus paclitaxel and nedaplatin for 2-4 cycles in ESCC. METHODS: Patients with locally advanced stage IIa-IIIb ESCC were enrolled in the study and received camrelizumab (200 mg), paclitaxel (155 mg/m 2 ), and nedaplatin (80 mg/m 2 ) intravenously on day one every 3 weeks. Patients underwent surgery after 2-4 cycles of treatment. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the major pathological response (MPR) rate, R0 resection rate, tumor regression, objective response rate (ORR), and disease-free survival (DFS). Programmed cell death 1 ligand 1 (PD-L1) expression in tumor tissues was measured and quantified using immunohistochemistry staining and combined positive score (CPS), respectively. RESULTS: In total, 75 patients were enrolled and received neoadjuvant treatment. Of them, 45 (60%) received two cycles, 18 (24%) received three cycles, and 10 patients (13.3%) received four cycles of neoadjuvant therapy. Ultimately, 62 patients (82.7%) underwent surgery. The patients achieved a pCR of 27.4% (95% CI: 16.9-40.2), an MPR of 45.2% (95% CI: 33.1-59.2), and an ORR of 48.4% (95% CI: 35.5-61.4); all patients had an R0 resection. T and N downstaging occurred in 39 (62.9%) and 19 (30.6%) patients Moreover, patients with CPS ≥10 tended to have enhanced ORR, pCR, and MPR compared to those with CPS <10. Treatment-related adverse events (TRAEs) of grade 1-2 occurred in 59 (78.7%) patients, grade 3 TRAEs in four (5.3%), and one patient (1.3%) experienced a grade 4 TRAE. CONCLUSIONS: Neoadjuvant camrelizumab combined with chemotherapy showed promising efficacy in locally advanced ESCC, with a manageable safety profile, when administered flexibly in two to four cycles.

The prediction of pCR and chemosensitivity for breast cancer patients using DLG3, RADL and Pathomics signatures based on machine learning and deep learning.

BACKGROUND: Limited studies have investigated the predictive value of multiomics signatures (radiomics, deep learning features, pathological features and DLG3) in breast cancer patients who underwent neoadjuvant chemotherapy (NAC). However, no study has explored the relationships among radiomic, pathomic signatures and chemosensitivity. This study aimed to predict pathological complete response (pCR) using multiomics signatures, and to evaluate the predictive utility of radiomic and pathomic signatures for guiding chemotherapy selection. METHODS: The oncogenic function of DLG3 was explored in breast cancer cells via DLG3 knockdown. Immunohistochemistry (IHC) was used to evaluate the relationship between DLG3 expression and docetaxel/epirubin sensitivity. Machine learning (ML) and deep learning (DL) algorithms were used to develop multiomics signatures. Survival analysis was conducted by K-M curves and log-rank. Multivariate logistic regression analysis was used to develop nomograms. RESULTS: A total of 311 patients with malignant breast tumours who underwent NAC were retrospectively included in this multicentre study. Multiomics (DLG3, RADL and PATHO) signatures could accurately predict pCR (AUC: training: 0.900; testing: 0.814; external validation: 0.792). Its performance is also superior to that of clinical TNM staging and the single RADL signature in different cohorts. Patients in the low DLG3 group more easily achieved pCR, and those in the high RADL Signature_pCR and PATHO_Signature_pCR (OR = 7.93, 95 % CI: 3.49-18, P < 0.001) groups more easily achieved pCR. In the TEC regimen NAC group, patients who achieved pCR had a lower DLG3 score (4.00 ± 2.33 vs. 6.43 ± 3.01, P < 0.05). Patients in the low RADL_Signature_DLG3 and PATHO_Signature_DLG3 groups had lower DLG3 IHC scores (P < 0.05). Patients in the high RADL signature, PATHO signature and DLG3 signature groups had worse DFS and OS. CONCLUSIONS: Multiomics signatures (RADL, PATHO and DLG3) demonstrated great potential in predicting the pCR of breast cancer patients who underwent NAC. The RADL and PATHO signatures are associated with DLG3 status and could help doctors or patients choose proper neoadjuvant chemotherapy regimens (TEC regimens). This simple, structured, convenient and inexpensive multiomics model could help clinicians and patients make treatment decisions.

Colorectal medullary carcinoma: a pathological subtype with intense immune response and potential to benefit from immune checkpoint inhibitors.

INTRODUCTION: Different pathological types of colorectal cancer have distinguished immune landscape, and the efficacy of immunotherapy will be completely different. Colorectal medullary carcinoma, accounting for 2.2-3.2%, is characterized by massive lymphocyte infiltration. However, the attention to the immune characteristics of colorectal medullary carcinoma is insufficient. AREA COVERED: We searched the literature about colorectal medullary carcinoma on PubMed through November 2023to investigate the hallmarks of colorectal medullary carcinoma's immune landscape, compare medullary carcinoma originating from different organs and provide theoretical evidence for precise treatment, including applying immunotherapy and BRAF inhibitors. EXPERT OPINION: Colorectal medullary carcinoma is a pathological subtype with intense immune response, with six immune characteristics and has the potential to benefit from immunotherapy. Mismatch repair deficiency, ARID1A missing and BRAF V600E mutation often occurs. IFN-γ pathway is activated and PD-L1 expression is increased. Abundant lymphocyte infiltration performs tumor killing function. In addition, BRAF mutation plays an important role in the occurrence and development, and we can consider the combination of BRAF inhibitors and immunotherapy in patients with BRAF mutant. The exploration of colorectal medullary carcinoma will arouse researchers' attention to the correlation between pathological subtypes and immune response, and promote the process of precise immunotherapy.

Stage-specificity of STING activation in intrahepatic cholangiocarcinoma determines the efficacy of its agonism.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer with an extremely poor prognosis, and new treatment options are needed. Recently, immunotherapy has emerged as an efficient treatment against malignant tumors, but less effective in iCCA. Activation of stimulator of interferon genes (STING) signaling could reignite immunologically inert tumors, but the expression and role of STING in iCCA remains to be determined. Here, we show STING is expressed in iCCA, and patients with high expression of STING in early-stage iCCA have a longer overall survival than those have low expression. Increased immune cell infiltration in early-stage iCCA corresponds to elevated STING expression. In mice iCCA models, treatment with the STING agonist MSA-2 show stage-specific inhibitory effects on tumors, with beneficial effects in early-stage tumors but not with advanced-stage cancer. This discrepancy was associated with greater programmed cell death ligand 1 (PD-L1) expression in advanced-stage tumors. Combination therapy targeting PD-L1 and MSA-2 strikingly reduced tumor burden in such tumors compared to either monotherapy. Cumulatively, these data demonstrate that STING agonism monotherapy improves the immune landscape of the tumor microenvironment in early-stage iCCA, while combination therapy ameliorates advanced-stage iCCA.

Xanthine oxidase promotes hepatic lipid accumulation through high fat absorption by the small intestine.

Background & Aims: There are no studies investigating the direct effects of elevated xanthine oxidase (XO) on lipid metabolism disorders. Here, we aimed to clarify the role of XO in lipid metabolism in a prospective cohort study and elucidate the underlying mechanisms. Methods: The association between serum XO activity and metabolic associated steatotic liver disease (MASLD) was examined in Cox proportional hazard models in a population-based cohort of 3,358 participants (20-75 years) at baseline. In addition, mouse models were used to investigate the underlying mechanism for the association between overexpression of XO and the lipid metabolism disorders. Results: After an average 5.8 years of follow up, we found elevated serum XO activity was associated with an increased risk of developing MASLD (hazard ratio [HR]: 2.08; 95% CI: 1.44-3.01; p-trend <0.001). Moreover, serum XO activity was significantly associated with serum triglyceride levels (r = 0.68, p <0.001). We demonstrated that hepatic XO expression increased in liver samples from patients with MASLD. Using tissue-specific Xdh knockin mice, we observed rapid lipid metabolism disorders under a high-fat diet rather than a normal chow diet. We found that XO overexpression promotes the absorption of excess dietary fat in the small intestine. Inhibition of XO also significantly reduced the absorption of fat in mice fed a high-fat diet. Conclusions: Our study clarified the association between serum XO activity levels and the development of MASLD in a large population-based prospective cohort study. Furthermore, our mouse models demonstrated that XO overexpression promotes lipid accumulation through mechanisms involving excessive fat absorption by the small intestine. Impact and implications: Using a prospective population-based cohort and various animal models, we have identified novel mechanisms by which xanthine oxidase regulates lipid metabolism. Our findings indicate that xanthine oxidase overexpression promotes lipid accumulation by increasing the absorption of excess dietary fat and possibly facilitating lipid transport in vivo. These results could be important for the development of therapies to treat diseases associated with lipid metabolism disorders.

Elucidating the clonal relationship of esophageal second primary tumors in patients with laryngeal squamous cell carcinoma.

Laryngeal cancer ranks as the second most prevalent upper airway malignancy, following Lung cancer. Although some progress has been made in managing laryngeal cancer, the 5-year survival rate is disappointing. The gradual increase in the incidence of second primary tumors (SPTs) plays a crucial role in determining survival outcomes during long-term follow-up, and the esophagus was the most common site with a worse prognosis. In clinical practice, the treatment of esophageal second primary tumors (ESPT) in patients with laryngeal squamous cell carcinoma (LSCC) has always been challenging. For patients with synchronous tumors, several treatment modalities, such as radiotherapy, chemotherapy and potentially curative surgery are necessary but are typically poorly tolerated. Secondary cancer therapy options for metachronous patients are always constrained by index cancer treatment indications. Therefore, understanding the clonal origin of the second primary tumor may be an important issue in the treatment of patients. LSCC cells demonstrate genetic instability because of two distinct aetiologies (human papillomavirus (HPV)-negative and HPV-positive) disease. Various etiologies exhibit distinct oncogenic mechanisms, which subsequently impact the tissue microenvironment. The condition of the tissue microenvironment plays a crucial role in determining the destiny and clonal makeup of mutant cells during the initial stages of tumorigenesis. This review focuses on the genetic advances of LSCC, the current research status of SPT, and the influence of key carcinogenesis of HPV-positive and HPV-negative LSCC on clonal evolution of ESPT cells. The objective is to gain a comprehensive understanding of the molecular basis underlying the clonal origins of SPT, thereby offering novel perspectives for future investigations in this field.

Recent advances and pathological mechanisms in photodynamic and sonodynamic therapy in the treatment of bone tumors (Review).

Given the recent advances that have been made with photodynamic therapy (PDT) combined with sonodynamic therapy (SDT) (PDT/SDT; also known as SPDT), the application of this combination therapy in the clinic has provided another major breakthrough in the medical field, especially with regard to the treatment of deep tumors. Concerning its application in the treatment of bone tumors, numerous pathological mechanisms have been taken advantage of to overcome the barrier of tissue hypoxia, and SPDT is expected to achieve radical effects, with high penetration depth and low aggressiveness. In the present review, it is comprehensively shown how, according to the histoanatomy of bone tumors, PDT and SDT target cells in a coordinated manner, affecting such processes as necrotizing apoptosis, pyroptosis, autophagy and ferroptosis on the macroscopic level, and crucially, thrombosis at the vascular level, which leads to the triggering of immunogenic cell death in local and distant locations. Additionally, PDT and SDT have been shown to have roles in: i) degrading the extracellular matrix; ii) influencing the receptor activator of nuclear factor­κB (RANK)/RANK ligand signaling pathway; iii) disrupting the equilibrium between glutathione peroxidase 4 and reactive oxygen species (ROS); and iv) destroying the microscopic structure of the bone tumor. Upon PDT/SDT stimulation, several mechanisms act in concert to ensure that the targeted bone tumor is eliminated. Furthermore, widely distributed ROS have been revealed to promote osteoclast formation and osteogenic mineralization through the regulation of macrophages, processes that greatly improve the effects of postoperative repair. Finally, the developmental prospects of bone tumor engineering in the future are discussed in the present review.