Palliative Gastrectomy Improves the Survival of Patients with Metastatic Early-Onset Gastric Cancer: A Retrospective Cohort Study.

Background: Recent studies have found that patients with incurable gastric cancer might benefit from palliative gastrectomy, but the impact of palliative gastrectomy on metastatic early-onset gastric cancer (mEOGC) patients remains unclear. Methods: We analyzed mEOGC patients enrolled in the Surveillance, Epidemiology, and End Results registry from January 2004 to December 2018. Propensity score matching (PSM) analysis with 1:1 matching and the nearest-neighbor matching method were used to ensure well-balanced characteristics between the groups of patients with palliative gastrectomy and those without surgery. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to evaluate the overall survival (OS) and cause-specific survival (CSS) risk with corresponding 95% confidence intervals (CIs). Results: Of 3641 mEOGC patients, 442 (12.1%) received palliative gastrectomy. After PSM, 596 patients were included in the analysis, with 298 in each group. For the matched cohort, the median survival was 8 months, and the 5-year survival was 4.0%. The median OS of mEOGC patients undergoing palliative gastrectomy was significantly longer than that of patients without surgery (13 months vs. 6 months, p < 0.001), and palliative gastrectomy remained an independent protective factor after adjusting for confounders (HR 0.459, 95% CI 0.382-0.552, p < 0.001), and the protective effect was robust in the subgroup analysis. Similar results were indicated in CSS. Stratified analyses by treatment modality also warranted the superiority of palliative-gastrectomy-based treatment in improving OS and CSS. Conclusions: mEOGC patients with palliative gastrectomy had a significantly longer survival time than patients without surgery. Exploratory analysis confirmed that surgery-based therapy modality was superior in improving survival time.

Gastroparesis after video-assisted thoracic surgery: A case report.

BACKGROUND: Video-assisted thoracic surgery (VATS) lobectomy is a common treatment for patients with early-stage lung cancer. Some patients can experience slight gastrointestinal discomfort after lobectomy for a moment. Gastroparesis is a gastrointestinal disorder that can be severe; it is associated with an increased risk of aspiration pneumonia and impaired postoperative recovery. Here, we report a rare case of gastroparesis after VATS lobectomy. CASE SUMMARY: A 61-year-old man underwent VATS right lower lobectomy uneventfully but had an obstruction of the upper digestive tract 2 d after surgery. Acute gastroparesis was diagnosed after emergency computed tomography and oral iohexol X-ray imaging. After gastrointestinal decompression and administration of prokinetic drugs, the patient's gastrointestinal symptoms improved. Since perioperative medication was applied according to the recommended dose and there was no evidence of electrolyte imbalance, intraoperative periesophageal vagal nerve injury was the most likely underlying cause of gastroparesis. CONCLUSION: Although gastroparesis is a rare perioperative complication following VATS, clinicians should be on the alert when patients complain about gastrointestinal discomfort. When surgeons resect paraesophageal lymph nodes with electrocautery, excessive ambient heat and compression of paraesophageal hematoma might induce vagal nerve dysfunction.

Autophagy-related IFNG is a prognostic and immunochemotherapeutic biomarker of COAD patients.

Background: Numerous studies have shown autophagy affects cellular immune responses. This study aims to explore prognosis and immunotherapeutic biomarkers related to autophagy in colon adenocarcinoma (COAD). Methods: Based on R software, we performed the ssGSEA, differential expression analysis, Kaplan-Meier survival analysis, correlation analysis, and enrichment analysis. For wet experiment, we did qRT-PCR, immunohistochemistry and CCK-8 experiments. Results: Using autophagy-related genes (ARGs) and the ssGSEA, COAD patients were divided into low and high autophagy groups. For immune score, stromal score, tumor purity, tumor infiltrating immune cells, co-signaling molecules, tumor mutational burden, microsatellite instability, mismatch repair, immune-related pathways, immune signatures, somatic mutations and subtype analysis, high autophagy group might benefit more from immunotherapy. Among 232 ARGs, IFNG was generally significantly correlated with tumor immunotherapy biomarkers (PD-L1, CD8A and cytotoxic T lymphocytes (CTL)). The disease-free survival of high IFNG group was significantly longer than that of low group. On above-mentioned immune-related research, the high IFNG group reached the same conclusion. The qRT-PCR and IHC analysis confirmed that IFNG was significantly higher expressed in dMMR samples compared to pMMR samples. For chemotherapy, the autophagy and IFNG were significantly negatively related to the chemosensitivity to cisplatin; IFNG inhibitor glucosamine increased cisplatin chemoresistance while IFNG increased cisplatin chemosensitivity; IFNG could reverse glucosamine induced chemoresistance. The functional enrichment analysis of IFNG, PD-L1, CD8A and 20 similar proteins were related to the activation of the immune system. The GSEA and ceRNA network partly described interaction mechanisms of IFNG with PD-L1 and CD8A. Conclusion: Autophagy score and IFNG expression were novel immunotherapy predictive biomarkers, which might play predictive effects through the JAK-STAT signaling pathway. IFNG might be a potential targeted therapy for cisplatin resistant colon cancer. Besides, IFNG was also a prognostic indicator.

Hydrogen Sulfide Creates a Favorable Immune Microenvironment for Colon Cancer.

Immunotherapy can elicit robust anticancer responses in the clinic. However, a large proportion of patients with colorectal cancer do not benefit from treatment. Although previous studies have shown that hydrogen sulfide (H2S) is involved in colorectal cancer development and immune escape, further insights into the mechanisms and related molecules are needed to identify approaches to reverse the tumor-supportive functions of H2S. Here, we observed significantly increased H2S levels in colorectal cancer tissues. Decreasing H2S levels by using CBS+/- mice or feeding mice a sulfur amino acid-restricted diet (SARD) led to a marked decrease in differentiated CD4+CD25+Foxp3+ Tregs and an increase in the CD8+ T-cell/Treg ratio. Endogenous or exogenous H2S depletion enhanced the efficacy of anti-PD-L1 and anti-CTLA4 treatment. H2S promoted Treg activation through the persulfidation of ENO1 at cysteine 119. Furthermore, H2S inhibited the migration of CD8+ T cells by increasing the expression of AAK-1 via ELK4 persulfidation at cysteine 25. Overall, reducing H2S levels engenders a favorable immune microenvironment in colorectal cancer by decreasing the persulfidation of ENO1 in Tregs and ELK4 in CD8+ T cells. SARD represents a potential dietary approach to promote responses to immunotherapies in colorectal cancer. SIGNIFICANCE: H2S depletion increases the CD8+ T-cell/Treg ratio and enhances the efficacy of anti-PD-L1 and anti-CTLA4 treatment in colon cancer, identifying H2S as an anticancer immunotherapy target.

Defining early recurrence of locally recurrent rectal cancer.

Despite advances in rectal cancer treatments, its local recurrence rate is still 4-10 percent. And an evidence-based definition of early recurrence is lacking. Our study hopes to establish a clear threshold to distinguish early and late recurrence, and analyze risk and prognostic factors for them. Rectal cancer patients who underwent proctectomy from 2009 to 2019 were included. Patients who received neoadjuvant treatment and with incomplete records were excluded. The optimal interval was obtained using the minimum P value approach. Risk factors for early recurrence were analyzed by logistic regression models, and prognostic factors associated with additional surgery were assessed by Cox proportional hazards models. The optimal interval for the definition of early recurrence was 26 months based on the subsequent prognosis (P < 0.001). The 5-year survival rate of early and late recurrence cohort was 32.5% and 57.1%, respectively (P < 0.001). Adjuvant radiotherapy was the independent protective factor for early recurrence. And the presence of lymphovascular invasion, positive surgical margin, and no re-neoadjuvant radiotherapy were independent prognostic factors for the survival of LRRC patients under additional surgery.

Survival comparison of stage IIA rectal cancer with or without neoadjuvant therapy: a SEER database analysis with propensity score matching.

Background: Patients with stage IIA rectal cancer have a higher survival rate but side effects from chemoradiotherapy; thus, whether neoadjuvant therapy should be performed for stage IIA rectal cancer is controversial. This study aimed to compare the survival outcomes of patients with stage IIA rectal cancer with or without neoadjuvant chemoradiotherapy. Methods: Patients with stage IIA rectal cancer between 2010 and 2015 were included through the Surveillance, Epidemiology, and End Results database. Propensity score matching was used to reduce the impact of confounding factors. Survival curves were plotted using the Kaplan-Meier method, and survival differences were assessed using the log-rank test. Results: There were no significant differences in overall survival and cancer-specific survival between the neoadjuvant chemoradiotherapy and surgery groups (P=0.973 and 0.983). Compared with the surgery group, the neoadjuvant chemoradiotherapy + surgery + chemotherapy group had a better overall survival (P=0.007). Subgroup analysis showed that the neoadjuvant chemoradiotherapy + surgery + chemotherapy group had better overall survival compared to the surgery group in the subgroup containing preoperative high-risk factors (P=0.003) but not in the low-risk subgroup (P=0.685). Conclusions: There is no evidence that neoadjuvant chemoradiotherapy + surgery can improve overall survival and cancer-specific survival compared to surgery alone in patients with stage IIA rectal cancer. Neoadjuvant chemoradiotherapy + surgery + chemotherapy can improve overall survival compared to surgery alone, but only in patients with preoperative high-risk factors. We suggest that patients with no preoperative high-risk factors may be considered for surgery alone, neoadjuvant chemoradiotherapy + surgery + chemotherapy is recommended for patients with preoperative risk factors.

Survival benefits from neoadjuvant treatment in gastric cancer: a systematic review and meta-analysis.

BACKGROUND: Surgery is the main treatment option for patients with local gastric cancer. However, surgery alone is usually not sufficient for stomach cancer patients, and combined therapies are recommended for these patients. In recent studies, some preoperative treatments have shown benefits. However, the treatment selection is still uncertain because previous studies failed to obtain a statistically significant difference between preoperative chemotherapy and preoperative chemoradiotherapy. Therefore, we plan to perform a systematic review and meta-analysis to compare the benefits among these preoperative treatments. METHODS/DESIGN: This review includes randomized controlled trials with or without blinding as well as published studies, high-quality unpublished studies, full articles and meeting abstracts with an English context if sufficient results were provided for analysis. Data sources include the Cochrane Central Register of Controlled Trials, Embase, MEDLINE, major relevant international conferences and manual screening of references. Patients with a diagnosis of resectable primary gastric or EGJ adenocarcinoma (stage II or higher) who underwent surgery alone or preoperative treatment followed by surgery and who were pathologically confirmed as proposed by the AJCC 2017 guidelines without age, sex, race, subtypes of adenocarcinoma and molecular pathology limitations will be included. The following three interventions will be included: surgery alone, neoadjuvant chemistry followed by surgery and neoadjuvant chemoradiotherapy followed by surgery. All-cause mortality, overall survival (OS, the time interval from diagnosis to death) and/or progression-free survival (PFS, the time interval from diagnosis to disease progression or death from any cause) will be defined as major results of concern. The clinical and pathological response rate (according to RECIST and tumour regression score), R0 resection rate, quality of life and grade 3 or above adverse events (according to the National Cancer Institute Common Terminology Criteria for Adverse Events, NCI-CTCAE) will be defined as the secondary outcomes. DISCUSSION: The aim of this systematic review is to compare the benefits of different preoperative treatments for patients with locoregional stomach cancer. This systematic review will improve the understanding of the relative efficacy of these treatment options by providing the latest evidence on the efficacy of various treatment options in the management of gastric cancer patients and may guide clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD4202123718.

Appendico-vesicocolonic fistula: A case report and review of literature.

BACKGROUND: Appendico-vesicocolonic fistulas and appendiceal-colonic fistulas are two kinds of intestinal and bladder diseases that are rarely seen in the clinic. To our knowledge, no more than 4 cases of appendico-vesicocolonic fistulas have been publicly reported throughout the world, and no more than 100 cases of appendiceal-colonic fistulas have been reported. Although the overall incidence is low, an early diagnosis is difficult due to their atypical initial symptoms, but these diseases still require our attention. CASE SUMMARY: Here, we report a case of a 77-year-old male patient diagnosed with an appendico-vesicocolonic fistula combined with an appendiceal-colonic fistula. The main manifestations were diarrhea and urine that contained fecal material. The diagnosis was confirmed by multiple laboratory and imaging examinations. A routine urinalysis showed red blood cells and white blood cells. Abdominal and pelvic computed tomography scans showed close adhesions between the bowels and the bladder, and fistulas could be seen. Colonoscopy and cystoscopy and some other imaging examinations clearly showed fistulas. The preoperative diagnoses were a colovesical fistula and an appendiceal-colonic fistula. The fistulas were repaired by laparoscopic surgical treatment. The diseased bowel and part of the bladder wall were removed, followed by a protective ileostomy. The postoperative diagnosis was an appendico-vesicocolonic fistula combined with an appendiceal-colonic fistula, and the pathology suggested inflammatory changes. The patient recovered well after surgery, and all his symptoms resolved. CONCLUSION: The final diagnosis in this case was a double fistula consisting of an appendico-vesicocolonic fistula combined with an appendiceal-colonic fistula.

Characterization of stem cell landscape and identification of stemness-relevant prognostic gene signature to aid immunotherapy in colorectal cancer.

BACKGROUND: It is generally accepted that colorectal cancer (CRC) originates from cancer stem cells (CSCs), which are responsible for CRC progression, metastasis and therapy resistance. The high heterogeneity of CSCs has precluded clinical application of CSC-targeting therapy. Here, we aimed to characterize the stemness landscapes and screen for certain patients more responsive to immunotherapy. METHODS: Twenty-six stem cell gene sets were acquired from StemChecker database. Consensus clustering algorithm was applied for stemness subtypes identification on 1,467 CRC samples from TCGA and GEO databases. The differences in prognosis, tumor microenvironment (TME) components, therapy responses were evaluated among subtypes. Then, the stemness-risk model was constructed by weighted gene correlation network analysis (WGCNA), Cox regression and random survival forest analyses, and the most important marker was experimentally verified. RESULTS: Based on single-sample gene set enrichment analysis (ssGSEA) enrichments scores, CRC patients were classified into three subtypes (C1, C2 and C3). C3 subtype exhibited the worst prognosis, highest macrophages M0 and M2 infiltrations, immune and stromal scores, and minimum sensitivity to immunotherapies, but was more sensitive to drugs like Bosutinib, Docetaxel, Elesclomol, Gefitinib, Lenalidomide, Methotrexate and Sunitinib. The turquoise module was identified by WGCNA that it was most positively correlated with C3 but most negatively with C2, and five hub genes in turquoise module were identified for stemness model construction. CRC patients with higher stemness scores exhibited worse prognosis, more immunosuppressive components in TME and lower immunotherapeutic responses. Additionally, the model's immunotherapeutic prediction efficacy was further confirmed from two immunotherapy cohorts (anti-PD-L1 in IMvigor210 cohort and anti-PD-1 in GSE78220 cohort). Mechanistically, Gene Set Enrichment Analysis (GSEA) results revealed high stemness score group was enriched in interferon gamma response, interferon alpha response, P53 pathway, coagulation, apoptosis, KRAS signaling upregulation, complement, epithelial-mesenchymal transition (EMT) and IL6-mediated JAK-STAT signaling gene sets. CONCLUSIONS: Our study characterized three stemness-related subtypes with distinct prognosis and TME patterns in CRC patients, and a 5-gene stemness-risk model was constructed by comprehensive bioinformatic analyses. We suggest our stemness model has prospective clinical implications for prognosis evaluation and might facilitate physicians selecting prospective responders for preferential use of current immune checkpoint inhibitors.

LncRNA CRART16/miR-122-5p/FOS axis promotes angiogenesis of gastric cancer by upregulating VEGFD expression.

BACKGROUND: We previously identified a novel lncRNA, CRART16, that could induce cetuximab resistance in colorectal cancer cells. This study explored the relationship of CRART16 expression to gastric cancer progression and the molecular mechanisms involved. METHODS: We evaluated CRART16 expression in gastric cancer tissues and adjacent normal tissues from the TCGA database and our hospital. Besides, we assessed its relationship with the overall survival (OS) of patients with gastric cancer. The effects of CRART16 on gastric cancer angiogenesis were determined by endothelial tube formation assay, spheroid sprouting assay, HUVEC invasion assay, and chick embryo chorioallantoic membrane (CAM) assay. The involvement of the lncRNA CRART16/miR-122-5p/FOS axis was analyzed by western blotting and dual-luciferase reporter assay. The functions of CRART16 were confirmed in xenograft mouse models. RESULTS: We found that CRART16 was substantially overexpressed in gastric cancer tissues compared with normal tissues, based on the TCGA database and our clinical samples. High expression of CRART16 correlated with more advanced tumor stages and poor prognosis. Overexpression of CRART16 in gastric cancer cells promoted proliferation, colony formation, angiogenesis, and bevacizumab resistance in vitro, and it promoted tumor growth and angiogenesis in vivo, and vice versa. CRART16 was found to downregulate miR-122-5p by acting as a sponge, upregulating the target oncogene FOS. Afterward, the increased FOS expression led to the upregulation of VEGFD. CONCLUSION: Our findings demonstrate that CRART16 promotes angiogenesis in vitro and in vivo, and CRART16 is a prognostic marker and therapeutic target in gastric cancer.

Is a Distal Resection Margin of ≤ 1 cm Safe in Patients with Intermediate- to Low-Lying Rectal Cancer? A Systematic Review and Meta-Analysis.

BACKGROUND: It is generally accepted that the distal resection margin of intermediate- to low-lying rectal cancer should be greater than 2 cm and at least 1 cm in special cases. This study intends to investigate whether a distal resection margin ≤ 1 cm affects tumor outcomes for patients with intermediate- to low-lying rectal cancer. METHODS: A systematic review of the literature was conducted. Sixteen studies included data for distal resection margins ≤ 1 cm (1684 cases) and > 1 cm (5877 cases), and 5 studies included survival data. Meta-analysis was used to compare the local recurrence rate and long-term survival of patients with distal resection margins > or ≤ 1 cm. RESULTS: The local recurrence rate in the ≤ 1-cm margin group (9.5%) was 2.3% higher than that in the > 1-cm margin group (7.2%) according to a fixed-effects model (RR [95% CI] 1.42 [1.18, 1.70], P < 0.001). The overall survival results of the five 1-cm margin studies showed an HR (95% CI) of 0.96 (0.75, 1.24) (P = 0.78). Subgroup analysis showed that the local recurrence rate in the subgroup with perioperative treatment was 1.2% lower in the ≤ 1-cm margin group (8.3%) than in the > 1-cm margin group (9.5%) (RR [95% CI] 0.97 [0.63, 1.49], P = 0.90). In the surgery alone subgroup, the local recurrence rate was 4.7% higher in the ≤ 1-cm margin group (12.4%) than in the > 1-cm group (7.7%) (RR [95% CI] 1.76 [1.09, 2.83], P = 0.02). CONCLUSIONS: For patients with intermediate- to low-lying rectal cancer undergoing surgery alone, a distal resection margin ≤ 1 cm may be not safe.

Anatomic variations of the anterosuperior pancreaticoduodenal veins encountered during laparoscopic right hemicolectomy: a retrospective single-center analysis.

OBJECTIVE: The vascular anatomic variations of the right colon present a challenge for colorectal surgeons. However, there have been few detailed studies of the variations in the anterosuperior pancreaticoduodenal vein (ASPDV). METHODS: We studied consecutive patients with right colon cancer who underwent laparoscopic right hemicolectomy at Peking University First Hospital (N = 117) between January 2018 and June 2021. RESULTS: The variations in the ASPDV were classified as type I (n = 101, (86.3%)), defined as ASPDVs draining into the gastrocolic trunk of Henle (GCT); type II (n = 10, (8.5%)), defined as ASPDVs draining into the superior mesenteric vein (SMV); or type III, defined as ASPDVs draining into both the GCT and SMV. For type I, subtypes were defined according to the branching of the ASPDVs: subtype a, with one branch (n = 87, (86.1%)); subtype b, with two branches (n = 12, (11.9%)); and subtype c, with more than two branches (n = 2, (2.0%)). Type I was also subtyped according to the confluence of the ASPDV and GCT, with subtype 1 being defined by a proximal site (n = 96, 95%) and subtype 2 by a distal site (n = 5, 5.0%). CONCLUSIONS: We have characterized the variations in ASPDVs encountered during laparoscopic right hemicolectomy, which should provide a reference for colorectal surgeons.

Overexpression of CBS/H2S inhibits proliferation and metastasis of colon cancer cells through downregulation of CD44.

BACKGROUND: The role of hydrogen sulfide (H2S) in cancer biology is controversial, including colorectal cancer. The bell-shaped effect of H2S refers to pro-cancer action at lower doses and anti-cancer effect at higher concentrations. We hypothesized that overexpression of cystathionine-beta-synthase (CBS)/H2S exerts an inhibitory effect on colon cancer cell proliferation and metastasis. METHODS: Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8), clone-formation and sphere formation assay. Cell migration was evaluated by transwell migration assay. Intracellular H2S was detected by H2S probe. Chromatin immunoprecipitation (ChIP) analysis was carried out to examine DNA-protein interaction. Cell experiments also included western blotting, flow cytometry, immunohistochemistry (IHC) and immunofluorescence analysis. We further conducted in vivo experiments to confirm our conclusions. RESULTS: Overexpression of CBS and exogenous H2S inhibited colon cancer cell proliferation and migration in vitro. In addition, overexpression of CBS attenuated tumor growth and liver metastasis in vivo. Furthermore, CD44 and the transcription factor SP-1 was probably involved in the inhibitory effect of CBS/H2S axis on colon cancer cells. CONCLUSIONS: Overexpression of CBS and exogenous provision of H2S inhibited colon cancer cell proliferation and migration both in vivo and in vitro. Molecular mechanisms might involve the participation of CD44 and the transcription factor SP-1.

The CBS-H2S axis promotes liver metastasis of colon cancer by upregulating VEGF through AP-1 activation.

BACKGROUND: The main therapy for colon cancer with liver metastasis is chemotherapy based on 5-fluorouracil combined with targeted drugs. However, acquired drug resistance and severe adverse reactions limit patients' benefit from standard chemotherapy. Here, we investigate the involvement of endogenous hydrogen sulfide (H2S) in liver metastasis of colon cancer and its potential value as a novel therapeutic target. METHODS: We used the CRISPR/Cas9 system to knockdown CBS gene expression in colon cancer cell lines. PCR arrays and proteome arrays were applied to detect the transcription and protein expression levels, respectively, of angiogenesis-related genes after knockdown. The molecular mechanism was investigated by western blot analysis, RT-qPCR, immunofluorescence staining, ChIP assays and dual-luciferase reporter assays. A liver metastasis mouse model was adopted to investigate the effect of targeting CBS on tumour metastasis in vivo. RESULTS: Knockdown of CBS decreased the metastasis and invasion of colon cancer cells and inhibited angiogenesis both in vivo and in vitro. Tissue microarray analysis showed a positive correlation between CBS and VEGF expression in colon cancer tissues. Further analysis at the molecular level validated a positive feedback loop between the CBS-H2S axis and VEGF. CONCLUSIONS: Endogenous H2S promotes angiogenesis and metastasis in colon cancer, and targeting the positive feedback loop between the CBS-H2S axis and VEGF can effectively intervene in liver metastasis of colon cancer.

CAF promotes chemoresistance through NRP2 in gastric cancer.

BACKGROUND: Fibroblasts are the predominant cell type in the stroma of tumor, and cancer-associated fibroblasts (CAFs) promote cancer chemoresistance by secreting various bioactive molecules. However, the differential expression between CAFs and normal fibroblasts (NFs) and how can CAFs uniquely impact cancer cells are still unexplored. METHODS: Primary CAFs and NFs were cultured from gastric cancer specimens, and their variant expression was analyzed by RNA-sequencing. Chemoresistance was evaluated by measuring cell viability, apoptosis, and 3D-coculture techniques. RESULTS: CAFs were isolated from gastric cancers and defined by specific cell-surface markers. CAFs decreased the sensitivity of gastric cancer cells to 5-FU. RNA-sequencing showed that CAFs expressed a higher level of NRP2 than NFs. And the high expression of NRP2 was correlated with worse oncological outcomes in gastric cancer patients. Further study showed that the knockdown of NRP2 eradicated the resistance to 5-FU. And the secretion of stromal cell-derived factor-1 (SDF-1) was reduced following NRP2 knockdown. Furthermore, we found that the increased sensitivity to 5-FU was induced by DNA damage. And this process was mediated by predominant effectors of the Hippo pathway, YAP/TAZ. CONCLUSIONS: The present study indicated that CAFs within gastric cancers promote chemoresistance through the expression of NRP2. The secretion of SDF-1 that mediated by VEGF/NRP2 signaling in CAFs and the activation of Hippo pathway in cancer cells in large part participated in this project.

Single-Cell DNA Sequencing Reveals Punctuated and Gradual Clonal Evolution in Hepatocellular Carcinoma.

BACKGROUND & AIMS: Copy number alterations (CNAs), elicited by genome instability, are a major source of intratumor heterogeneity. How CNAs evolve in hepatocellular carcinoma (HCC) remains unknown. METHODS: We performed single-cell DNA sequencing (scDNA-seq) on 1275 cells isolated from 10 patients with HCC, ploidy-resolved scDNA-seq on 356 cells from 1 additional patient, and single-cell RNA sequencing on 27,344 cells from 3 additional patients. Three statistical fitting models were compared to investigate the CNA accumulation pattern. RESULTS: Cells in the tumor were categorized into the following 3 subpopulations: euploid, pseudoeuploid, and aneuploid. Our scDNA-seq analysis revealed that CNA accumulation followed a dual-phase copy number evolution model, that is, a punctuated phase followed by a gradual phase. Patients who exhibited prolonged gradual phase showed higher intratumor heterogeneity and worse disease-free survival. Integrating bulk RNA sequencing of 17 patients with HCC, published datasets of 1196 liver tumors, and immunohistochemical staining of 202 HCC tumors, we found that high expression of CAD, a gene involved in pyrimidine synthesis, was correlated with rapid tumorigenesis and reduced survival. The dual-phase copy number evolution model was validated by our single-cell RNA sequencing data and published scDNA-seq datasets of other cancer types. Furthermore, ploidy-resolved scDNA-seq revealed the common clonal origin of diploid- and polyploid-aneuploid cells, suggesting that polyploid tumor cells were generated by whole genome doubling of diploid tumor cells. CONCLUSIONS: Our work revealed a novel dual-phase copy number evolution model, showed HCC with longer gradual phase was more severe, identified CAD as a promising biomarker for early recurrence of HCC, and supported the diploid origin of polyploid HCC.

Proliferation Cycle Transcriptomic Signatures are Strongly associated With Gastric Cancer Patient Survival.

Gastric cancer is one of the most heterogeneous tumors with multi-level molecular disturbances. Sustaining proliferative signaling and evading growth suppressors are two important hallmarks that enable the cancer cells to become tumorigenic and ultimately malignant, which enable tumor growth. Discovering and understanding the difference in tumor proliferation cycle phenotypes can be used to better classify tumors, and provide classification schemes for disease diagnosis and treatment options, which are more in line with the requirements of today's precision medicine. We collected 691 eligible samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, combined with transcriptome data, to explore different heterogeneous proliferation cycle phenotypes, and further study the potential genomic changes that may lead to these different phenotypes in this study. Interestingly, two subtypes with different clinical and biological characteristics were identified through cluster analysis of gastric cancer transcriptome data. The repeatability of the classification was confirmed in an independent Gene Expression Omnibus validation cohort, and consistent phenotypes were observed. These two phenotypes showed different clinical outcomes, and tumor mutation burden. This classification helped us to better classify gastric cancer patients and provide targeted treatment based on specific transcriptome data.

M2 Macrophage-Based Prognostic Nomogram for Gastric Cancer After Surgical Resection.

A good prediction model is useful to accurately predict patient prognosis. Tumor-node-metastasis (TNM) staging often cannot accurately predict prognosis when used alone. Some researchers have shown that the infiltration of M2 macrophages in many tumors indicates poor prognosis. This approach has the potential to predict prognosis more accurately when used in combination with TNM staging, but there is less research in gastric cancer. A multivariate analysis demonstrated that CD163 expression, TNM staging, age, and gender were independent risk factors for overall survival. Thus, these parameters were assessed to develop the nomogram in the training data set, which was tested in the validation and whole data sets. The model showed a high degree of discrimination, calibration, and good clinical benefit in the training, validation, and whole data sets. In conclusion, we combined CD163 expression in macrophages, TNM staging, age, and gender to develop a nomogram to predict 3- and 5-year overall survivals after curative resection for gastric cancer. This model has the potential to provide further diagnostic and prognostic value for patients with gastric cancer.

Two Similar Signatures for Predicting the Prognosis and Immunotherapy Efficacy of Stomach Adenocarcinoma Patients.

BACKGROUND: Globally, stomach adenocarcinoma (STAD)'s high morbidity and mortality should arouse our urgent attention. How long can STAD patients survive after surgery and whether novel immunotherapy is effective are questions that our clinicians cannot escape. METHODS: Various R packages, GSEA software, Metascape, STRING, Cytoscape, Venn diagram, TIMER2.0 website, TCGA, and GEO databases were used in our study. RESULTS: In the TCGA and GEO, macrophage abundance of STAD tissues was significantly higher than that of adjacent tissues and was an independent prognostic factor, significantly related to the overall survival (OS) of STAD patients. Between the high- and low- macrophage abundance, we conducted differential expression, univariate and multivariate Cox analysis, and obtained 12 candidate genes, and finally constructed a 3-gene signature. Both low macrophage abundance group and group D had higher TMB and PD-L1 expression. Furthermore, top 5 common gene-mutated STAD tissues had lower macrophage abundance. Macrophage abundance and 3 key genes expression were also lower in the Epstein-Barr Virus (EBV) and HM-indel STAD subtypes and significantly correlated with the tumor microenvironment score. The functional enrichment and ssGSEA revealed 2 signatures were similar and closely related to BOQUEST_STEM_CELL_UP, including genes up-regulated in proliferative stromal stem cells. Hsa-miR-335-5p simultaneously regulated 3 key genes and significantly related to the expression of PD-L1, CD8A and PDCD1. CONCLUSION: macrophage abundance and 3-gene signature could simultaneously predict the OS and immunotherapy efficacy, and both 2 signatures had remarkable similarities. Hsa-miR-335-5p and BOQUEST_STEM_CELL_UP might be novel immunotherapy targets.

Methylome profiling identifies TCHH methylation in CfDNA as a noninvasive marker of liver metastasis in colorectal cancer.

Methylation of circulating free DNA (CfDNA) has emerged as an efficient marker of tumor screening and prognostics. However, no efficient methylation marker has been developed for monitoring liver metastasis (LM) in colorectal cancer (CRC). Utilizing methylome profiling and bisulfite sequencing polymerase chain reaction of paired primary and LM sites, significantly increased methylation of TCHH was identified in the process of LM in CRC in the present study. Methylight analysis of TCHH methylation in CfDNA displayed a promisingly discriminative power between CRC with and without LM. Besides, significant coefficient of TCHH methylation and LM tumor volume was also validated. Together, these results indicated the potential of TCHH methylation in CfDNA as a monitoring marker of LM in CRC.