Volume-based 18F-FDG PET/CT predicts prognosis and outcome of active surveillance for intra-abdominal desmoid tumor.

PURPOSE: Desmoid tumor (DT) is a rare monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Initial active surveillance is recommended by current guideline, and surgery is one of the main therapies for DT. Predicting the prognosis and outcome of active surveillance for intra-abdominal DT is pressing issue. METHODS: The study included eighteen patients with intra-abdominal DT. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum standardized uptake value (SUVmax) were measured. We analyzed their relationship with the outcome of active surveillance, as well as clinical, prognostic, and pathological data. RESULTS: The MTV and TLG of recurrent DT were significantly higher than those of non-recurrent DT (P < 0.001 and P = 0.00, respectively). The ROC curve suggested that the appropriate cutoff values for distinguishing recurrent DT from non-recurrent DT were 760.8 for MTV (sensitivity = 1, specificity = 0.857 and AUC = 0.929), and 1318.4 for TLG (sensitivity = 1, specificity = 0.786, and AUC = 0.911). The cutoff values of MTV and TLG significantly correlated with PFS using the Kaplan-Meier method (P = 0.002 and P = 0.007, respectively). MTV and TLG could distinguish DTs with subsequent progression from stable ones (P = 0.004 and P = 0.004, respectively). The ROC curve suggested that the appropriate cutoff values for distinguishing DTs with subsequent progression from stable ones were 197.1 for MTV (sensitivity = 0.9, specificity = 1, and AUC = 0.900), and 445.45 for TLG (sensitivity = 0.9, specificity = 1, and AUC = 0.900). CONCLUSION: Volume-based 18F-FDG-PET can predict prognosis of intra-abdominal DT. MTV and TLG can predict the outcome of active surveillance for intra-abdominal DT. MTV and TLG can potentially be predictors of surgical risk and difficulty.

Preoperative assessment of retroperitoneal Liposarcoma using volume-based 18F-FDG PET/CT: implications for surgical strategy and prognosis.

PURPOSE: Retroperitoneal liposarcoma (RLPS) poses a challenging scenario for surgeons due to its unpredictable biological behavior. Surgery remains the primary curative option for RLPS; however, the need for additional information to guide surgical strategies persists. Volume-based 18F-FDG PET/CT may solve this issue. METHODS: We analyzed data from 89 RLPS patients, measuring metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum standardized uptake value (SUVmax) and explored their associations with clinical, prognostic, and pathological factors. RESULTS: MTV, TLG of multifocal and recurrent RLPS were significantly higher than unifocal and primary ones (P < 0.001, P < 0.001, P = 0.003 and P = 0.002, respectively). SUVmax correlated with FNCLCC histological grade, mitotic count and Ki-67 index (P for G1/G2 = 0.005, P for G2/G3 = 0.017, and P for G1/G3 = 0.001, P < 0.001 and P = 0.024, respectively). MTG, TLG and SUVmax of WDLPS were significantly lower than DDLPS and PLPS (P for MTV were 0.009 and 0.022, P for TLG were 0.028 and 0.048, and P for SUVmax were 0.027 and < 0.001, respectively). Multivariable Cox analysis showed that MTV > 457.65 (P = 0.025), pathological subtype (P = 0.049) and FNCLCC histological grade (P = 0.033) were related to overall survival (OS). CONCLUSIONS: Our findings indicate that MTV is an independent prognostic factor for RLPS, while MTV, TLG, and SUVmax can preoperatively predict multifocal lesions, histological grade, and pathological subtype. Volume-based 18F-FDG PET/CT offers valuable information to aid in the decision-making process for RLPS surgical strategies.

High LYRM4-AS1 predicts poor prognosis in patients with glioma and correlates with immune infiltration.

Background: Many researches proved that non-coding RNAs are important in glioma development. We screened the differentially expressed genes through The Cancer Genome Atlas (TCGA) database and identified the molecule LYRM4-AS1 associated with prognosis. As a lncRNA, the expression level and role of LYRM4-AS1 in glioma are inconclusive. Therefore, we attempted to assess the clinical significance, expression and related mechanisms of LYRM4-AS1 in glioma by employing cell experiments and an integrative in silico methodology. Methods: RNA-seq data were obtained from UCSC XENA and TCGA datasets. The Gene Expression Omnibus (GEO) database was used to download glioma-related expression profile data. The LYRM4-AS1 expression level was evaluated. Survival curves were constructed by the Kaplan-Meier method. Cox regression analysis was used to analyze independent variables. Patients were divided into high and low expression group base on the median LYRM4-AS1 expression value in glioma tissues. The DESeq2 R package was used to identify differentially expressed genes (DEGs) between two different expression LYRM4-AS1 groups. Gene set enrichment analysis (GSEA) was conducted. Next, the single-sample Gene Set Enrichment Analysis (ssGSEA) was done to quantify the immune infiltration of immune cells in glioma tissues. Gene expression profiles for glioma tumor tissues were used to quantify the relative enrichment score for each immune cell. Spearman correlation analysis was used to analyze the correlation between LYRM4-AS1 and biomarkers of immune cells as well as immune checkpoints in glioma. Finally, assays for cell apoptosis, cell viability and wound healing were conducted to evaluate the function on U87 MG and U251 cells after knocking down LYRM4-AS1. Results: We found that LYRM4-AS1 was upregulated and related to the grade and malignancy of glioma. Survival analyses showed that high expression LYRM4-AS1 patients had poor clinical outcomes (P < 0.01). Cox regression analyses demonstrated that LYRM4-AS1 was an independent risk factor for overall survival (OS) in glioma (HR: 274 1.836; CI [1.278-2.639]; P = 0.001). Enrichment and immune infiltration analysis showed interferon signaling and cytokine-cytokine receptor interaction enriched in the LYRM4-AS1 high-expression phenotype, and LYRM4-AS1 showed significantly positively related to immune infiltration as well as immune checkpoints (P < 0.01). The knockdown of LYRM4-AS1 in U87 MG and U251 cells can inhibit migration and proliferation of cells (P < 0.05). Conclusions: These findings indicated that the increased LYRM4-AS1 may be useful for the diagnosis and prognosis of glioma and might participate in the immune infiltration.

Cytoreductive surgery offers prognostic benefits in metastatic gastrointestinal stromal tumors with generalized progression following imatinib therapy: a single institute retrospective study.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Distant metastasis has been detected in approximately 50% of GIST patients at the first diagnosis. The surgical strategy for metastatic GIST with generalized progression (GP) after imatinib therapy remains unclear. METHODS: We recruited 15 patients with imatinib-resistant metastatic GIST. They received cytoreductive surgery (CRS) for tumor rupture, intestinal obstruction and gastrointestinal bleeding. We collected clinical, pathological and prognostic data for analyses. RESULTS: OS and PFS after R0/1 CRS were 56.88 ± 3.47 and 26.7 ± 4.12 months, respectively, when compared with 26 ± 5.35 and 5 ± 2.78 months after R2 CRS (P = 0.002 and P < 0.001, respectively). The OS of patients from the initiation of imatinib in the R0/1 group was 133.90 ± 15.40 months when compared with 59.80 ± 10.98 months in the R2 CRS group. There were two significant grade III complications after 15 operations (13.3%). No patient underwent reoperation. In addition, no perioperative death occurred. CONCLUSIONS: R0/1 CRS is highly probable to provide prognostic benefits for patients with metastatic GIST who experience GP following imatinib treatment. An aggressive surgical strategy for achieving R0/1 CRS can be deemed safe. If applicable, R0/1 CRS should be carefully considered in imatinib-treated patients with GP metastatic GIST.

Single-Center Preliminary Experience with Gutter-Plugging Chimney Stent-Graft for Aortic Dissection.

PURPOSE: To report the early 2-year results and experience of a novel gutter-plugging chimney stent-graft in a single center that participated in the clinical trial of Prospective Study for Aortic Arch Therapy with stENt-graft for Chimney technology. MATERIALS AND METHODS: Patients diagnosed with aortic dissection were treated with the novel chimney stent-grafts named Longuette™ for the left subclavian artery revascularization. Primary study outcomes were the incidence of freedom from major adverse events within 30 days and success rate of the operation over 12 months. RESULTS: A total of 34 patients were enrolled between September 2019 and December 2020. The immediate technical success rate (stent-grafts successfully deployed without fast-flow type Ia or type III endoleak intraoperatively) was 100%, and there were no conversions to open repair. Type Ia and type II endoleaks were noted in three patients (8.8%) and one patient (2.9%) at discharge, respectively. One patient (2.9%) with type Ia endoleak underwent coil embolization at 12 months because of false lumen dilation, and one (2.9%) case of type Ia endoleak resolved spontaneously at 24 months. One chimney stent (2.9%) was revealed with stenosis at discharge and occluded with thrombosis at 6 months postoperatively. During the 2-year follow-up, there was no death, rupture, stroke, paraplegia, left arm ischemia, retrograde dissection, stent-graft induced new entry, or stent migration. CONCLUSION: The initial results of the Longuette™ stent-graft for revascularization of the left subclavian artery are encouraging with a high technical success rate. Further multicenter follow-up outcomes are required to assess the long-term durability. LEVEL OF EVIDENCE: Level 4, Case Series.

SM22α Loss Contributes to Apoptosis of Vascular Smooth Muscle Cells via Macrophage-Derived circRasGEF1B.

Vascular smooth muscle cell (VSMC) apoptosis is a major defining feature of abdominal aortic aneurysm (AAA) and mainly caused by inflammatory cell infiltration. Smooth muscle (SM) 22α prevents AAA formation through suppressing NF-κB activation. However, the role of SM22α in VSMC apoptosis is controversial. Here, we identified that SM22α loss contributed to apoptosis of VSMCs via activation of macrophages. Firstly, deficiency of SM22α enhanced the interaction of VSMCs with macrophages. Macrophages were retained and activated by Sm22α -/- VSMCs via upregulating VCAM-1 expression. The ratio of apoptosis was increased by 1.62-fold in VSMCs treated with the conditional media (CM) from activated RAW264.7 cells, compared to that of the control CM (P < 0.01), and apoptosis of Sm22α -/- VSMCs was higher than that of WT VSMCs (P < 0.001). Next, circRasGEF1B from activated macrophages was delivered into VSMCs promoting ZFP36 expression via stabilization of ZFP36 mRNA. Importantly, circRasGEF1B, as a scaffold, guided ZFP36 to preferentially bind to and decay Bcl-2 mRNA in a sequence-specific manner and triggered apoptosis of VSMCs, especially in Sm22α -/- VSMCs. These findings reveal a novel mechanism by which the circRasGEF1B-ZFP36 axis mediates macrophage-induced VSMC apoptosis via decay of Bcl-2 mRNA, whereas Sm22α -/- VSMCs have a higher sensitivity to apoptosis.

circ-Sirt1 controls NF-κB activation via sequence-specific interaction and enhancement of SIRT1 expression by binding to miR-132/212 in vascular smooth muscle cells.

NF-κB-mediated inflammatory phenotypic switching of vascular smooth muscle cells (VSMCs) plays a central role in atherosclerosis and neointimal formation. However, little is known about the roles of circRNAs in the regulation of NF-κB signaling. Here, we identify the involvement of circ-Sirt1 that was one of transcripts of SIRT1 host gene in VSMC inflammatory response and neointimal hyperplasia. First, in the cytoplasm, circ-Sirt1 directly interacts with and sequesters NF-κB p65 from nuclear translocation induced by TNF-α in a sequence-dependent manner. The inhibitory complex of circ-Sirt1-NF-κB p65 is not dependent on IκBα. Second, circ-Sirt1 binds to miR-132/212 that interferes with SIRT1 mRNA, and facilitates the expression of host gene SIRT1. Increased SIRT1 results in deacetylation and inactivation of the nuclear NF-κB p65. These findings illustrate that circ-Sirt1 is a novel non-coding RNA regulator of VSMC phenotype.

Automated quantification of Ki-67 index associates with pathologic grade of pulmonary neuroendocrine tumors.

BACKGROUND: Classification of the pulmonary neuroendocrine tumor (pNET) categories is a step-wise process identified by the presence of necrosis and number of mitoses per 2 mm. In neuroendocrine tumor pathology, Ki-67 was first described as a prognostic factor in the pancreas and incorporated into the grading system of digestive tract neuroendocrine neoplasms in the 2010 WHO classification. However, the significance of Ki-67 in pNETs was still a controversial issue. This study was to investigate the potentially diagnostic value of Ki-67 in pNETs. METHODS: We retrieved 159 surgical specimens of pNETs, including 35 typical carcinoids (TCs), 2 atypical carcinoid (ACs), 28 large-cell neuroendocrine carcinomas (LCNECs), 94 small-cell lung cancers (SCLCs). Manual conventional method (MCM) and computer-assisted image analysis method (CIAM) were used to calculate the Ki-67 proliferative index. In CIAM, 6 equivalent fields (500 × 500 µm) at 10× magnification were manually annotated for digital image analysis. RESULTS: The Ki-67 index among the 4 groups with ranges of 0.38% to 12.66% for TC, 4.34% to 29.48% for AC, 30.67% to 93.74% for LCNEC, and 40.71% to 96.87% for SCLC. The cutoff value of Ki-67 index to distinguish low grade with high grade was 30.07%. For the univariate survival analyses in pNETs, both the overall survival and progression-free survival correlated with Ki-67 index. In addition, the Ki-67 index performed by CIAM was proved to be of great positive correlation with MCM. CONCLUSIONS: Ki-67 index counted by CIAM is a reliable method and can be a useful adjunct to classify the low- and high-grade NETs.

TRAIL inhibits platelet-induced colorectal cancer cell invasion.

OBJECTIVE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic ligand that activates the extrinsic apoptosis pathway of cell death receptors. This study aimed to evaluate the relationship between TRAIL and platelet-induced tumor metastasis in colorectal cancer. METHODS: Platelet P-selectin (CD62P) was measured by immunohistochemistry in tumor and adjacent normal tissues from 90 patients with colorectal cancer undergoing resection. Tumor cell invasion was assessed by transwell assay in the presence of platelets with or without TRAIL. The expression of TRAIL receptors DR4 and DR5 on platelets was assessed by flow cytometry, real-time polymerase chain reaction, and western blotting. RESULTS: P-selectin (CD62P) expression was significantly increased in tumor tissues compared with adjacent normal tissues. High CD62P expression was significantly correlated with tumor stage and vascular invasion. Tumor cell migration was increased by coculture with platelets, but this effect was inhibited by TRAIL. Transforming growth factor (TGF)-ß1 secretion was significantly reduced in TRAIL-treated platelets. The TRAIL receptor DR5 but not DR4 was expressed in platelets according to flow cytometry. CONCLUSIONS: TRAIL could inhibit metastasis and colon cancer cell invasion by promoting platelet apoptosis and reducing the release of TGF-ß1.

Use of 18F-FDG-PET/CT for Retroperitoneal/Intra-Abdominal Soft Tissue Sarcomas.

Rationale: To assess the diagnostic value of 18F-FDG-PET/CT for different retroperitoneal soft tissue sarcomas (STS) and other similar tumors. To analyze the predictive value of 18F-FDG-PET/CT for histological grade and main prognostic factors. Methods: 195 patients with 44 different diseases have been included. Relationship between SUVmax, Clinical, pathological, and prognostic information has been analyzed. Results: Malignant tumors do not show higher SUVmax than benign ones (P=0.443). We divided all 44 different diseases into two groups; SUVmax of group 1 is significantly higher than group 2 (P ≤ 0.001). The ROC curve suggests 4.35 is the cutoff value to distinguish groups 1 and 2 (sensitivity = 0.789; specificity = 0.736). SUVmax correlates with Ki-67 index, mitotic count, vascular resection, histological grade, and recurrent STS without considering pathological diagnosis (P=0.001, P=0.012, P=0.002, P ≤ 0.001, and P=0.037, resp.). Conclusion: 18F-FDG-PET/CT cannot simply distinguish malignant and benign tumors in retroperitoneal/intra-abdominal cavity; however, the SUVmax of malignant tumors, inflammatory pseudotumor, and PPGL group is higher than the SUVmax of benign tumors, lymph node metastasis, hematoma, and low malignant STS group. Guidance of "SUVmax location" may be helpful for biopsy and pathology dissection.

Human colorectal cancer cells induce vascular smooth muscle cell apoptosis in an exocrine manner.

Tumor vessels often lack the smooth muscle layer, and the instability is conducive to tumor invasion and metastasis. The effect of tumor microenvironment on vascular smooth muscle cells needs to be explored. In the present study, we examined the density of the tumor vessels in human colorectal cancer tissues, and used the tumor conditioned medium of human colorectal cancer HT29 cells to mimic the tumor microenvironment. We showed that the vessel density in colorectal cancer tissues increased, which displayed a decreased expression of smooth muscle α-actin, a specific marker of vascular smooth muscle cells and an attenuated or a discontinuous layer of vascular smooth muscle cells compared with the matched normal tissues. We also showed that the tumor conditioned medium decreased the cell viability, and induced the apoptosis in vascular smooth muscle cells in a concentration-dependent manner. The expression of pro-Caspase-3 was down-regulated, accompanied by increasing of cleaved-Caspase-3 in the cells treated with the tumor conditioned medium, suggesting that Caspase-3 was activated. Moreover, the expression of Bax was increased, and the ratio of Bcl-2/Bax was decreased under the same conditions. Furthermore, the treatment with the tumor conditioned medium resulted in loss of mitochondrial membrane potential in vascular smooth muscle cells. These findings suggest that HT29 cells induce apoptosis of vascular smooth muscle cells in an exocrine manner, associated with activating caspase-3 via mitochondrial apoptotic pathway. This may be one of the mechanisms underlying tumor vascular structural abnormalities.