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Abstract To date, there have been no reports on tertiary lymphoid structures (TLS) in primary adenocarcinoma of jejunum and ileum. In this study, we employed digital pathology image analysis software to classify and quantify TLS, and evaluated the maturity of TLS using immunohistochemistry. Molecular genetics and immunotherapy biomarker detection were performed using next-generation sequencing technology, such as tumor mutational burden (TMB) and microsatellite instability (MSI). The aim of this study was to investigate the presence, location, maturity, association with immunotherapy biomarkers, and prognostic value of TLS in primary adenocarcinoma of jejunum and ileum. Compared to secondary follicle-like TLS (SFL-TLS), intra-tumoral TLS (IT-TLS) were more likely to manifest as early TLS (E-TLS) (P = 0.007). Compared to IT-TLS, SFL-TLS had a higher propensity to occur at the invasive margin (IM) (P = 0.032) and showed a trend towards being more prevalent at the tumor periphery (P = 0.057). In terms of immunotherapy biomarkers, there was a higher trend of IM-TLS density in PD-L1(22C3) score CPS

Abstract Melanoma is one of the most prevalent skin cancers, with high metastatic rates and poor prognosis. Understanding its molecular pathogenesis is crucial for improving its diagnosis and treatment. Integrated analysis of multi-omics data from 207 treatment-naïve melanomas (primary-cutaneous-melanomas (CM, n = 28), primary-acral-melanomas (AM, n = 81), primary-mucosal-melanomas (MM, n = 28), metastatic-melanomas (n = 27), and nevi (n = 43)) provides insights into melanoma biology. Multivariate analysis reveals that PRKDC amplification is a prognostic molecule for melanomas. Further proteogenomic analysis combined with functional experiments reveals that the cis-effect of PRKDC amplification may lead to tumor proliferation through the activation of DNA repair and folate metabolism pathways. Proteome-based stratification of primary melanomas defines three prognosis-related subtypes, namely, the ECM subtype, angiogenesis subtype (with a high metastasis rate), and cell proliferation subtype, which provides an essential framework for the utilization of specific targeted therapies for particular melanoma subtypes. The immune classification identifies three immune subtypes. Further analysis combined with an independent anti-PD-1 treatment cohort reveals that upregulation of the MAPK7-NFKB signaling pathway may facilitate T-cell recruitment and increase the sensitivity of patients to immunotherapy. In contrast, PRKDC may reduce the sensitivity of melanoma patients to immunotherapy by promoting DNA repair in melanoma cells. These results emphasize the clinical value of multi-omics data and have the potential to improve the understanding of melanoma treatment.

Aim: To investigate the clinical features, diagnosis and treatment of lymphoepithelioma-like carcinoma (LELC).Materials & methods: The clinical data of 114 LELC patients were retrospectively analyzed.Results: Ninety-eight patients (86.0%) were Epstein-Barr virus-encoded small RNA (EBER) positive detected by situ hybridization. A 67.1% (51/76) patients had PD-L1 expression. The 5-year overall survival rate of EBER negative patients was 51.6% while the rate of positive patients was 84.8% (p = 0.015). The 5-year progression free survival rate of EBER negative patients was 40.2% while the rate of positive patients was 70.2% (p = 0.004).Conclusion: The progression of LELC is relatively slow and present a better prognosis. The occurrence of tumor is closely related to Epstein–Barr virus infection and PD-L1 is highly expressed in tumor cells.

Abstract Soft tissue sarcoma is a broad family of mesenchymal malignancies exhibiting remarkable histological diversity. We portray the proteomic landscape of 272 soft tissue sarcomas representing 12 major subtypes. Hierarchical classification finds the similarity of proteomic features between angiosarcoma and epithelial sarcoma, and elevated expression of SHC1 in AS and ES is correlated with poor prognosis. Moreover, proteomic clustering classifies patients of soft tissue sarcoma into 3 proteomic clusters with diverse driven pathways and clinical outcomes. In the proteomic cluster featured with the high cell proliferation rate, APEX1 and NPM1 are found to promote cell proliferation and drive the progression of cancer cells. The classification based on immune signatures defines three immune subtypes with distinctive tumor microenvironments. Further analysis illustrates the potential association between immune evasion markers (PD-L1 and CD80) and tumor metastasis in soft tissue sarcoma. Overall, this analysis uncovers sarcoma-type-specific changes in proteins, providing insights about relationships of soft tissue sarcoma.

Abstract Acral melanoma (AM) is a rare subtype of melanoma characterized by a high incidence of lymph node (LN) metastasis, a critical factor in tumor dissemination and therapeutic decision-making. Here, we employ single-cell and spatial transcriptomic analyses to investigate the dynamic evolution of early AM dissemination. Our findings reveal substantial inter- and intra-tumor heterogeneity in AM, alongside a highly immunosuppressive tumor microenvironment and complex intercellular communication networks, particularly in patients with LN metastasis. Notably, we identify a strong association between MYC + Melanoma (MYC +MEL) and FGFBP2 +NKT cells with LN metastasis. Furthermore, we demonstrate that LN metastasis requires a metabolic shift towards fatty acid oxidation (FAO) induced by MITF in MYC +MEL cells. Etomoxir, a clinically approved FAO inhibitor, can effectively suppress MITF-mediated LN metastasis. This comprehensive dataset enhances our understanding of LN metastasis in AM, and provides insights into the potential therapeutic targeting for the management of early AM dissemination.

IntroductionHeat ablation is one of the key modalities in treating liver cancer, yet the residual cancer tissues suffering sublethal heat treatment possess a potential for increased malignancy. This study conducts a comprehensive analysis of cellular dynamics, metabolic shifts, and macrophage polarization within the tumor microenvironment following sublethal heat treatment.MethodsWe observed significant acidification in tumor cell supernatants, attributed to increased lactic acid production. The study focused on how this pH shift, crucial in tumor progression and resistance, influences macrophage polarization, especially towards the M2 phenotype known for tumor-promoting functions. We also examined the upregulation of MCT1 expression post sublethal heat treatment and its primary role in lactic acid transport.ResultsNotably, the study found minimal disparity in MCT1 expression between hepatocellular carcinoma patients and healthy liver tissues, highlighting the complexity of cancer biology. The research further revealed an intricate relationship between lactic acid, MCT1, and the inhibition of macrophage pyroptosis, offering significant insights for therapeutic strategies targeting the tumor immune environment. Post sublethal heat treatment, a reduction in paraspeckle under lactic acid exposure was observed, indicating diverse cellular impacts. Additionally, PKM2 was identified as a key molecule in this context, with decreased levels after sublethal heat treatment in the presence of lactic acid.DiscussionCollectively, these findings illuminate the intertwined mechanisms of sublethal heat treatments, metabolic alterations, and immune modulation in the tumor milieu, providing a deeper understanding of the complex interplay in cancer biology and treatment.

Background: Malignant mesothelioma (MM) is a tumor originating from the pleura, peritoneum, or pericardial cavity. It is divided into diffuse and localized malignant mesothelioma, with four subtypes in diffuse MM: epithelioid, sarcomatoid, desmoplastic, and biphasic, with biphasic being less common. The onset of this tumor is insidious, and the prognosis is extremely poor in some cases, with a median survival of 6–18 months and no standard treatment options in the past.Aims: We report a case of peritoneal malignant mesothelioma that was successfully treated with transformative therapy. We also review the literature in the hope of providing reference for the treatment and pathological diagnosis of such patients.Methods: The case of the peritoneal malignant mesothelioma was processed and reported in the routine manner for biopsy specimens at different stages.Results and conclusion: We report a case of a malignant tumor originating in the hepatorenal recess, which was diagnosed as biphasic malignant mesothelioma through a biopsy. Immunohistochemical testing showed PD-L1 expression. After multidisciplinary discussion, the patient received transformative treatment, including a trial of combined immunotherapy. The tumor significantly shrank, and the patient obtained a chance for curative surgical resection. Microscopic examination showed significant collagenization in the lesion area, with almost no residual tumor. After 19 months of comprehensive treatment, the patient developed multiple fluffy opacities under the pleura of both lungs. Transthoracic core needle biopsy under CT guidance, the pathology showed organizing pneumonia, considering it as delayed interstitial pneumonitis due to immunotherapy based on previous treatment history. Successful comprehensive treatment was achieved for this case of peritoneal malignant mesothelioma, and the patient has been alive without evidence of disease for 33 months, with long-term follow-up. In this process, the pathologist had three opportunities for pathological diagnosis, which required understanding the patient’s medical history, being attentive to the clinical purpose of the specimen, and providing accurate responses to morphological changes at different stages, along with corresponding descriptions and diagnoses to provide effective information for clinical treatment.

Abstract Purpose This study aimed to evaluate the clinical relevance of exosomal HER2 (Exo HER2) level in assessing the tissue HER2 status and predicting the efficacy of trastuzumab treatment. Methods In this prospective study, patients with advanced gastric cancer (AGC) from three hospitals between August 2016 to November 2020 were enrolled. The Exo HER2 level was detected by enzyme‐linked immunosorbent assay. Receiver operating characteristic curve (ROC) was drawn referring to the HER2 tissue status to assess the diagnostic value of Exo HER2. Cox proportional hazards regression and logistic regression were used to evaluate the association between Exo HER2 and progression‐free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients who received trastuzumab‐based first‐line therapy. Results In this study, 242 patients with advanced or metastatic gastric adenocarcinoma were registered. Of these, 238 AGC patients were eligible for evaluating serum‐derived exosome HER2 diagnostic value, including 114 HER2‐positive. Finally, 64 were eligible for efficacy analysis. The area under the ROC curve was 0.746. The optimal cutoff value for diagnosing tissue HER2‐positive status was 729.95 ng/ml, with a sensitivity of 66.7% and a specificity of 74.2%. In 64 patients treated with trastuzumab, higher baseline Exo HER2 level indicated better prognosis. 844 ng/ml and 723 ng/ml were the right cutoffs for distinguishing the population with superior PFS (hazard ratio [HR] = 0.41, P = 0.017) and OS (HR = 0.30, P

The proteogenomic landscape of diffuse gliomas remains to be explored. Here, the authors perform proteogenomic characterisation of diffuse gliomas, investigate the functional role of genomic alterations and suggest three proteomic subgroups.

Abstract Background This study evaluated programmed cell death-ligand 1 (PD-L1) expression from pre-invasive adenocarcinoma to invasive lung adenocarcinoma, aimed to investigate the potential association of PD-L1 pathway with lung adenocarcinoma early evolution. Methods We evaluated PD-L1 expression in 1123 resected lung specimens of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) of stage IA1–IA3. PD-L1 expression was defined based on the proportion of stained tumor cells using the tumor proportion score:

Squamous cell carcinomas are an aggressive cancer type which can occur in multiple organ systems. Here, the authors analyse the proteome of SCC cancers from 17 organs and show commonly dysregulated proteins independent of location.

Abstract Background Former single center studies indicated that HER2 assessment with two primary tumor blocks (dual block HER2 assessment) could be an efficient and practical approach to overcome the adverse impact of heterogeneity and acquire a HER2 positive rate in gastric cancer (GC). This multicenter prospective clinical trial (NCT 02843412) was launched to verify its value and generality. Methods A total of 3806 participants with primary GCs have been enrolled from 8 hospitals in China. Two primary tumor blocks were selected and recorded as block 1 and block 2 after histological evaluation. An HER2 (4B5) rabbit monoclonal antibody was used for the immunohistochemistry (IHC) analysis. Results In total patients, HER2 IHC positive (3+) rate with dual block assessment (9.4%) was higher than that with single block assessment (block 1: 7.8%, block 2: 7.8%) (P

Abstract Background Gastric neoplasms with fundic gland differentiation include oxyntic gland adenomas (OGAs) and gastric adenocarcinomas of fundic gland type (GA-FGs). Due to their well-differentiated and similar morphology with normal fundic glands, it is usually challenging to identify these lesions in pathological diagnosis, especially in biopsy specimens. This study aims to explore and verify the potential role of a newly developed monoclonal antibody (McAb) NJ001 (SP70) in differentiating fundic neoplasms from non-neoplastic fundic gland lesions. Methods Twenty-three cases of histological confirmed gastric fundic gland neoplasms were obtained, including 12 cases of OGAs and 11 of GA-FGs. Fifty cases of fundic gland polyps (FGPs) were taken as the control group. Six cases of well-differentiated gastric neuroendocrine tumors (NETs) (easily misdiagnosed) were also obtained. Key clinicopathological information was collected. SP70 immunostaining was performed (with para-tumor normal fundic glands as internal control). The positive intensity and staining pattern of SP70 were analyzed and compared. Results In normal gastric mucosa, SP70 was strongly and diffusely stained on the cytoplasm in fundic glands, but not in the foveolar epithelium. Therefore, a zonal distribution of SP70 was observed in normal mucosa. FGPs (50/50, 100%) shared a similar expression pattern with normal fundic glands. In fundic gland neoplasms, a significant down-expression of SP70 was observed in both OGAs and GA-FGs. The positive rate of SP70 in fundic gland neoplasms (6/23, 26.1%) was significantly lower than that in FGPs (100%) (P0.05). In these 6 NET cases, SP70 was weak to moderate intensity in the majority of tumor cells (with a different expression pattern). Conclusion Down-expression of SP70 is a specific feature to fundic gland neoplasms including OGAs and GA-FGs. Therefore, SP70 can serve as a potential biomarker in the identification and differential diagnosis of fundic gland neoplasms.

Summary: The eye is a complex organ consisting of multiple compartments with unique and specialized properties, and small disturbances in one eye region can result in impaired vision and blindness. Although there have been advancements in ocular research, the hierarchical molecular network in region-wide resolution, indicating the division of labor and crosstalk among different eye regions, is not yet comprehensively illuminated. Here, we present an atlas of region-resolved proteome and lipidome of mouse eye. Multiphoton microscopy-guided laser microdissection combined with in-depth label-free proteomics identifies 13,536 proteins across various mouse eye regions. Further integrative analysis of spectral imaging, label-free proteome, and imaging mass spectrometry of the lipidome and phosphoproteome reveals distinctive molecular features, including proteins and lipids of various anatomical mouse eye regions. These deposited datasets and our open proteome server integrating all information provide a valuable resource for future functional and mechanistic studies of mouse eye and ocular disease.

Objective: Glomus tumor is a relatively uncommon soft tissue neoplasm predominantly occurring in upper extremity (fingers), less reported in stomach. This study aimed to discuss the clinicopathologic features of gastric glomus tumor (GGT) and then provide reference for clinical practice.Methods: A retrospective analysis of all cases pathologically diagnosed of GGT was performed, pathological findings were correlated with clinical information, immunohistochemical studies, next-generation sequencing, and patient follow-ups. A review of literature by searching similar cases was conducted to summarize previous knowledge of GGTs.Results: Our study identified 15 GGTs included 5 males and 10 females, aged between 35–75 years old (median, 49 years old). The tumor was located to the gastric corpus in 6 cases (40%) and to the antrum in 9 cases (60%). The maximum tumor diameter ranged between 1–4 cm (median, 1.5 cm). There were 11 cases (73%) of solid glomus tumor, 3 cases (20%) of mixture of solid glomus tumor and glomangioma, and 1 case (7%) of glomangiomyoma. Partial spindle cell area was observed in 3 cases (20%), moderate cellular atypia in 1 case (7%), atypical mitosis in 1 case (7%), vascular invasion in 5 cases (33%), neural invasion in 6 cases (40%) and tumor necrosis in 1 case (7%). Tumor cells expressed Collagen type IV, α-smooth muscle actin (α-SMA), and synaptophysin in most cases. The Ki67 index varied from 1% to 30%. Next-generation sequencing reported EGFR, PIK3CA, KEAP1 and TP53 mutation. The outcome information was obtained in 12 (80%) cases, followed for 6–63 months, 11 patients (92%) had tumor-free survival and 1 patient (8%) developed liver metastasis 26 months after surgery. Literature review obtained 16 previously reported malignant GGT cases. In terms of the total 31 cases, univariate analysis revealed that the atypical mitosis (OS: p = 0.009; DFS: p = 0.010) and severe cellular atypia (OS: p = 0.007; DFS: p = 0.004) were significantly associated with poor prognosis (patient death).Conclusion: GGT is indolent, while long-term close follow-up should be required in the presence of increasing number of risk factors. Malignant GGT is relatively uncommon and predisposes to liver metastasis, calling for accumulation of large-sample data and experience.

Steatohepatitic hepatocellular carcinoma (SH-HCC) is a distinctive histologic variant of HCC for the presence of steatohepatitis. This study intended to evaluate the contrast-enhanced imaging features and clinicopathological characteristics of 26 SH-HCCs in comparison with 26 age-and-sex-matched non-SH-HCCs. The frequency of obesity (34.6%, p = 0.048) and type 2 diabetes mellitus (23.1%, p = 0.042) were significantly higher in SH-HCC patients. As seen via B-mode ultrasound (BMUS), SH-HCCs were predominantly hyperechoic (65.4%, p = 0.002) lesions, while non-SH-HCCs were mainly hypo-echoic. As seen via contrast-enhanced ultrasound (CEUS), 96.2% of SH-HCCs exhibited hyperenhancement in the arterial phase. During the portal venous and late phase, 88.5% of SH-HCCs showed late and mild washout. Consequently, most SH-HCCs and all non-SH-HCCs were categorized as LR-4 or LR-5. As seen via magnetic resonance imaging (MRI), a signal drop in the T1WI opposed-phase was observed in 84.6% of SH-HCCs (p = 0.000). Notably, diffuse fat in mass was detected in 57.7% (15/26) SH-HCCs (p < 0.001). As seen via contrast-enhanced MRI (CEMRI), most of the SH-HCCs and non-SH-HCCs exhibited heterogeneous hyperenhancement in the arterial phase (80.8% versus 69.2%, p = 0.337). During the delayed phase, 76.9% SH-HCCs and 88.5% non-SH-HCCs exhibited hypo-enhancement. Histopathologically, the rate of microvascular invasion (MVI) was significantly lower in SH-HCCs than non-SH-HCCs (42.3% versus 73.1%, p = 0.025). The frequency of hepatic steatosis >5% in non-tumoral liver parenchyma of SH-HCCs was significantly higher than in non-SH-HCCs (88.5% versus 26.9%, p = 0.000). Additionally, the fibrotic stages of S0, S1 and S2 in SH-HCCs were significantly higher than in non-SH-HCCs (p = 0.044). During follow-up, although the PFS of SH-HCC patients was significantly longer than non-SH-HCC patients (p = 0.046), for the overall survival rate of SH-HCC and non-SH-HCC patients there was no significant difference (p = 0.162). In conclusion, the frequency of metabolism-related diseases in SH-HCC patients was significantly higher than in non-SH-HCC patients. The imaging features of SH-HCCs combined the fatty change and typical enhancement performance of standard HCC as seen via CEUS/CEMRI.

Abstract Background Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor in gastrointestinal tract, with striking features of morphology and immunohistochemistry. But GISTs in pregnancy could seldom be found. Pathogenic activating mutations of the proto‐oncogene KIT and PDGFRA are detected in majority GISTs, and adjuvant imatinib therapy targeting KIT and PDGFRA mutations is recommended for patients with high‐risk GIST. However, some rare subgroups with distinct molecular features remain uncovered and more therapeutic targets need to be revealed. Methods The DNA/RNA samples were detected using the NGS‐based YuanSu450 gene panel. After identifying the CDC42BPB‐ALK fusion by NGS, this novel fusion was further confirmed by Sanger sequencing. Subsequently, FISH analysis was performed using the Vysis ALK Break Apart FISH Probe kit to testify the ALK status. ALK protein expression was confirmed by IHC (D5F3 and 5A4). Results Herein, we reported the first case of quadruple wild‐type (WT) GIST with ALK‐CDC42BPB fusion and ALK (D5F3) overexpression. In this study, we described a 33‐year‐old pregnant patient in lactation who had a massive space occupying lesion (with the maximum diameter of 22 cm) in the stomach and was eventually diagnosed as quadruple WT GIST (KITWT/PDGFRAWT/SDHWT/RAS‐PWT). Conclusion We unexpectedly found that this GIST patient showed ALK (D5F3) overexpression and harbored a novel fusion CDC42BPB exon 24‐ALK in exon 20.

Abstract Objective In this cohort study, we determined the clinical value of the maximum standardized uptake value (SUVmax) of primary tumors in non‐small cell lung cancer (NSCLC). Study Design A retrospective review of NSCLC patients was performed from January 2011 to December 2017. Peripheral cN0 NSCLC patients with tumor size ≤2 cm were included. SUVmax was calculated as a continuous variable for semiquantitative analyses. A receiver operating characteristic curve was analyzed to assess the cutoff threshold of SUVmax on pathological (p) nodal metastasis. We further evaluated the clinical relevance of SUVmax in peripheral cN0 NSCLC patients. Results A total of 670 peripheral NSCLC patients with tumor size ≤2 cm were deemed cN0 by preoperative PET/CT scan. Statistical analyses suggested significant correlations of SUVmax with smoking status (P = .026), tumor volume (P = .001), pathology type (P = .008), tumor differentiation (P 3.8 (odds ratio, 12.149; P

Gallbladder carcinoma (GBC) is responsible for 80%–95% of biliary tract malignancies and has a dismal prognosis. Human epidermal growth factor receptor 2 (HER2) is a promising therapeutic target of GBC. Through immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods, HER2 expression and gene amplification were identified on high-output tissue microarrays (TMAs) developed in 306 GBC cases to investigate its relationship with GBC and clinicopathological characteristics. Adenocarcinomas accounted for 223 (72.9%) of the cases, with 62 (27.8%) being papillary adenocarcinoma or having partial papillary structure. HER2 positivity was studied in 16.1% (36/223) of patients with adenocarcinoma and 41.9% (26/62) in adenocarcinoma with papillary structures. For 143 radically resected primary GBC cases with 24 HER2-positive tumors, survival data were valid; the median survival time was not reached, and the 5-year survival rate was 52.9%. All patients in stages 0–I survived, and the results of the HER2-positive group and the stage II HER2-negative group were similar (p = 0.354). However, in stage III, the mortality rate in the HER2-positive group was reduced (p = 0.005) and that in stage IV was higher (p = 0.005). In conclusion, HER2 positivity was significantly higher in patients with papillary GBC. The predictive value of HER2 varies by clinical stage, with no prediction in the early stages, better in stage III, and worse in stage IV.

Iodine is an essential micronutrient for producing thyroid hormone (TH); however, iodide excess can lead to adverse thyroidal effects. Unfortunately, the lack of a proper in vitro model system hampered the studies of the effect of iodide excess on thyroid physiology and pathology. Here, we demonstrated that excessive iodide intake downregulated the genes related to TH synthesis in the thyroids of mice. Since sodium iodide has no effect on these genes in cultured cell lines, we developed a three-dimensional (3D) culture system to enable the murine thyrocytes to form organoids in vitro with thyroid follicle-like structures and function and found that the in vivo effect of iodide excess could be mimicked in these thyroid organoids. Our data indicate that iodide excess mainly activated the XBP1-mediated unfolded protein response in both murine thyroid and thyroid organoids, while activation of XBP1 was able to mimic the sodium iodide effect on genes for the synthesis of TH in murine thyroid organoids. Lastly, our results suggest that XBP1 might transcriptionally repress the genes involved in the synthesis of TH. Based on these findings, we propose that iodide excess inhibits the transcription of genes related to TH synthesis through a mechanism involving XBP1-mediated action.

Abstract Primary pulmonary mucosa‐associated lymphoid tissue‐derived (MALT) lymphoma is a rare disease with a favorable prognosis. However, its clinical characteristics, diagnosis, treatment, and prognoses remain unclear. We retrospectively analyzed 80 patients with pathologically confirmed MALT lymphoma from 2006 to 2018. The clinical characteristics, diagnosis, treatments, and prognoses of all the 80 patients were recorded. Patients were stratified into surgery and biopsy groups, respectively, to evaluate the role of surgery in the diagnosis and treatment of MALT lymphoma. The prognoses were compared between different clinical characteristics and treatments. Pathological diagnoses were confirmed by surgery, bronchoscopy, and percutaneous biopsy. Thirty patients were treated by surgery. While MALT lymphoma was only diagnosed by bronchofiberoscopy or bercutaneous biopsy in four of 18 patients in the surgery group who underwent the procedure. Six patients received adjuvant chemotherapy and one patient received involved‐field radiotherapy in surgery group. Thirty‐one patients were treated with chemotherapy alone, one patient was treated with radiotherapy, one patient received only symptomatic and supportive treatment, and waiting and watching without treatment were recommended in 17 patients in biopsy group. Eight patients died during follow‐up and the 5‐year survival rate was 87.1%. Tumor number, treatment, and age were prognostic factors for overall survival (OS), but age was the only independent prognostic factor according to multivariate analysis. While, tumor number was the only prognostic factor in the analysis about progression‐free survival (PFS). No significant difference was found in OS or PFS between patients treated with and without surgical resection. MALT lymphoma is an indolent disease with favorable treatment outcome. Tumor number is associated with PFS and age is the only significant prognostic factor for pulmonary MALT lymphoma patients because of its indolent nature, but surgery still plays an important role in the diagnosis and treatment of MALT lymphoma.

Liposarcoma (LPS) is a rare and heterogeneous malignancy of adipocytic origin. Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are two of the most common subtypes, showing similar genetic characterizations but distinct biological behaviors and clinical prognosis. Compared to WDLPS, DDLPS is more aggressive and has the potential of metastasis, as the malignant adipocytic tumor’s metabolic changes may have taken place during the tumorigenesis of LPSs. Therefore, to investigate the lipid alterations between the two subtypes, high-resolution liquid chromatography tandem mass spectrometry (LC-MS/MS) based untargeted lipidomic analysis was performed onto LPS tissues from 6 WDLPS and 7 DDLPS patients. The lipidomic analysis showed the upregulated phosphatidylcholines and phosphoethanolamines in DDLPS, and the upregulated triglycerides and diglycerides in WDLPS, which might be due to the uncompleted adipocytic dedifferentiation leading to such tumorigenesis. Such a finding was also confirmed by the similarity comparison of two LPS subtypes to the transcriptome of stromal vascular fraction at different differentiation stages. Transcriptomic analysis also demonstrated that metabolic pathways including the pentose phosphate pathway (PPP) were upregulated in WDLPS compared to DDLPS. Therefore, the cell line LPS853 was treated with the PPP inhibitor 6-aminonicotinamide ex vivo and the proliferation and invasion of LPS853 was significantly promoted by PPP inhibition, suggesting the potential role of PPP in the development and differentiation of LPS. In conclusion, this study described the altered lipid profiles of WDLPS and DDLPS for the first time, revealing the different differentiation stages of the two subtypes and providing a potential metabolic target for LPS treatment.

Malignant glioma exhibits immune evasion characterized by highly expressing the immune checkpoint CD47. RNA 5-methylcytosine(m5C) modification plays a pivotal role in tumor pathogenesis. However, the mechanism underlying m5C-modified RNA metabolism remains unclear, as does the contribution of m5C-modified RNA to the glioma immune microenvironment. In this study, we demonstrate that the canonical 28SrRNA methyltransferase NSUN5 down-regulates β-catenin by promoting the degradation of its mRNA, leading to enhanced phagocytosis of tumor-associated macrophages (TAMs). Specifically, the NSUN5-induced suppression of β-catenin relies on its methyltransferase activity mediated by cysteine 359 (C359) and is not influenced by its localization in the nucleolus. Intriguingly, NSUN5 directly interacts with and deposits m5C on CTNNB1 caRNA (chromatin-associated RNA). NSUN5-induced recruitment of TET2 to chromatin is independent of its methyltransferase activity. The m5C modification on caRNA is subsequently oxidized into 5-hydroxymethylcytosine (5hmC) by TET2, which is dependent on its binding affinity for Fe2+ and α-KG. Furthermore, NSUN5 enhances the chromatin recruitment of RBFOX2 which acts as a 5hmC-specific reader to recognize and facilitate the degradation of 5hmC caRNA. Notably, hmeRIP-seq analysis reveals numerous mRNA substrates of NSUN5 that potentially undergo this mode of metabolism. In addition, NSUN5 is epigenetically suppressed by DNA methylation and is negatively correlated with IDH1-R132H mutation in glioma patients. Importantly, pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. Our findings unveil a general mechanism by which NSUN5/TET2/RBFOX2 signaling regulates RNA metabolism and highlight NSUN5 targeting as a potential strategy for glioma immune therapy. [ABSTRACT FROM AUTHOR]