Tumor-infiltrating tertiary lymphoid structures (TLS) are thought to have anti-tumor activity and are believed to indicate a favorable prognosis in cancer patients. However, the prognostic value of TLS in gastrointestinal stromal tumors (GIST) is unknown. We evaluated the prognostic value of TLS using two independent GIST cohorts. Pathological examinations identified TLS in 44.9% of patients in our discovery cohort (DC). TLS was significantly associated with smaller tumor size (P = .011), relatively well morphological classification (P < .001), lower NIH classification (P < .001), lower recurrence (P = .005), longer survival time (P < .001) and lower imatinib resistance (P = .006). Kaplan-Meier curves showed that TLS was remarkably associated with favorable survival (P = .0002) and recurrence (P = .0015) time. In addition, the presence of KIT mutations and the absence of TLS suggested worst prognosis both in terms of overall survival (OS) (P = .0029) and time to recurrence (TTR) (P = .0150), while the presence of PDGFRA mutations and TLS suggested optimal prognosis for OS and TTR. Multivariate analyzes demonstrated that TLS was an independent prognostic factor for OS (HR:0.180, P = .002) and TTR (HR:0.412, P = .023). These results were confirmed using our validation cohort. Multiplexed immunohistochemistry staining was used to determine the composition of TLS. Therapies designed to target TLS may be a novel therapeutic strategy for GIST patients with imatinib resistance.

Objective: This study intended to retrospectively analyze the data of patients with primary retroperitoneal liposarcoma in a single Asian large-volume sarcoma center and to establish nomograms focused on PRLPS for predicting progression-free survival (PFS) and overall survival (OS). Methods: A total of 211 patients treated surgically for primary, non-metastatic retroperitoneal liposarcoma during 2009–2021 were identified, and clinicopathologic variables were analyzed. PFS and OS nomograms were built based on variables selected by multivariable analysis. The discriminative and predictive ability of the nomogram was assessed by concordance index and calibration curve. Results: The median follow-up time was 25 months. A total of 117 (56%) were well-differentiated, 78 (37%) were dedifferentiated, 13 (6%) were myxoid, and 3 (1%) were pleomorphic morphology. Compared to the western population cohort reported by the Memorial Sloan-Kettering Cancer Center, the median age of patients in this cohort was younger (57 vs. 63 years), the tumor burden was lower (20 vs. 26 cm), and the proportion of patients with R0 or R1 resection was higher (97% vs. 81%). The 5-year PFS rate was 49%, and factors independently associated with PFS were symptoms at visit, preoperative needle biopsy, histologic subtypes, and postoperative hospital stay. The 5-year OS rate was 72%. American Society of Anesthesiologists Physical Status and Clavien-Dindo classification were independently associated with OS. The concordance indexes for PFS and OS nomograms were 0.702 and 0.757, respectively. The calibration plots were excellent. Conclusions: The proposed nomogram provided a favorable reference for the treatment of primary retroperitoneal liposarcoma patients.

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.

Introduction: The exploration of lipid metabolism dysregulation may provide novel perspectives for retroperitoneal liposarcoma (RPLS). In our study, we aimed to investigate potential targets and facilitate further understanding of immune landscape in RPLS, through lipid metabolism-associated genes (LMAGs) based prognostic model.Methods: Gene expression profiles and corresponding clinical information of 234 cases were enrolled from two public databases and the largest retroperitoneal tumor research center of East China, including cohort-TCGA (n=58), cohort-GSE30929 (n=92), cohort-FD (n=50), cohort-scRNA-seq (n=4) and cohort-validation (n=30). Consensus clustering analysis was performed to identify lipid metabolism-associated molecular subtypes (LMSs). A prognostic risk model containing 13 LMAGs was established using LASSO algorithm and multivariate Cox analysis in cohort-TCGA. ESTIMATE, CIBERSORT, XCELL and MCP analyses were performed to visualize the immune landscape. WGCNA was used to identify three hub genes among the 13 model LMAGs, and preliminarily validated in both cohort-GSE30929 and cohort-FD. Moreover, TIMER was used to visualize the correlation between antigen-presenting cells and potential targets. Finally, single-cell RNA-sequencing (scRNA-seq) analysis of four RPLS and multiplexed immunohistochemistry (mIHC) were performed in cohort-validation to validate the discoveries of bioinformatics analysis.Results: LMS1 and LMS2 were characterized as immune-infiltrated and -excluded tumors, with significant differences in molecular features and clinical prognosis, respectively. Elongation of very long chain fatty acids protein 2 (ELOVL2), the enzyme that catalyzed the elongation of long chain fatty acids, involved in the maintenance of lipid metabolism and cellular homeostasis in normal cells, was identified and negatively correlated with antigen-presenting cells and identified as a potential target in RPLS. Furthermore, ELOVL2 was enriched in LMS2 with significantly lower immunoscore and unfavorable prognosis. Finally, a high-resolution dissection through scRNA-seq was performed in four RPLS, revealing the entire tumor ecosystem and validated previous findings.Discussion: The LMS subgroups and risk model based on LMAGs proposed in our study were both promising prognostic classifications for RPLS. ELOVL2 is a potential target linking lipid metabolism to immune regulations against RPLS, specifically for patients with LMS2 tumors.

Unraveling the noncoding RNA expression networks governing cancer initiation and development is essential while remains largely uncompleted in retroperitoneal liposarcoma (RLS). Through RNA-seq technologies and computational biology, deregulated long noncoding RNAs (lncRNAs) are being identified and reveal that lncRNAs are implicated in serial steps of RLS development. High-throughput sequencing with computational methods for assembling the transcriptome of five paired RLS patient’s tissues. We found that long intergenic noncoding RNA 423 (linc00423) was downregulated in RLS tissues. Gain-of-function assays revealed that overexpressed linc00423 obviously inhibited RLS cell growth in vitro and in vivo. Additionally, RNA sequence, RNA-pulldown and RIP assays evidenced that linc00423 involved in MAPK signaling pathway via destabilizing of nuclear factor of activated T-cells 3 (NFATC3). Summing up, our findings demonstrated that linc00423 acted as the tumor suppressor in RLS cells through regulating the protein level of NFATC3 at a post-transcriptional level and negatively regulated the MAPK signaling pathway at a transcriptional level. Linc00423 might serve as a candidate prognostic biomarker and a target for novel therapies of RLS patients.

Distal duodenal resections are sometimes necessary for radical surgery, but how to restore duodenal continuity is still unclear. This study aimed at determining which style of anastomosis was more suitable for the duodenojejunostomy after resection of distal duodenum. We retrospectively identified 34 patients who underwent distal duodenum resection at our center between January 2014 and December 2021. According to whether the end or the side of the proximal duodenum was involved in reconstruction, duodenojejunostomy were classified as End style (E-style) and Side style (S-style). Demographic data, clinicopathological details, and postoperative complications were analyzed between two groups. Thirteen patients (38.2%) received E-style duodenojejunostomy, and 21 patients (62.8%) received S-style duodenojejunostomy. Comparative analysis showed that in group of E-style, patients had a lower rate of multivisceral resection(5/13 vs 18/21; P = 0.008), delayed gastric emptying (DGE) (1/13 vs 11/21; P = 0.011) and intraperitoneal infection (2/13 vs 12/21; P = 0.03). In this study, the incidence of major complications was up to 35.3% (12/34) and no patient died of complication in perioperative period. In two group, there was no difference in the incidence of major complications (E-style vs S-style: 3/13 vs 9/21; P = 0.292). The E-style duodenojejunostomy for the reconstruction of distal duodenum resection is safe and feasible. The E-style anastomosis may have potential value in decreasing the occurrence of complications such as DGE and intraperitoneal infection, and the definitive advantages still need to be verified.