HIST1H2BK predicts neoadjuvant-chemotherapy response and mediates 5-fluorouracil resistance of gastric cancer cells.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is routinely used to treat patients with advanced gastric cancer (AGC). However, the identification of reliable markers to determine which AGC patients would benefit from NACT remains challenging. METHODS: A systematic screening of plasma proteins between NACT-sensitive and NACT-resistant AGC patients was performed by a mass spectrometer (n = 6). The effect of the most differential plasma protein was validated in two independent cohorts with AGC patients undergoing NACT (ELISA cohort: n = 155; Validated cohort: n = 203). The expression of this candidate was examined in a cohort of AGC tissues using immunohistochemistry (n = 34). The mechanism of this candidate on 5-Fluorouracil (5-FU) resistance was explored by cell-biology experiments in vitro and vivo. RESULTS: A series of differential plasma proteins between NACT-sensitive and NACT-resistant AGC patients was identified. Among them, plasma HIST1H2BK was validated as a significant biomarker for predicting NACT response and prognosis. Moreover, HIST1H2BK was over-expression in NACT-resistant tissues compared to NACT-sensitive tissues in AGC. Mechanistically, HIST1H2BK inhibited 5-FU-induced apoptosis by upregulating A2M transcription and then activating LRP/PI3K/Akt pathway, thereby promoting 5-FU resistance in GC cells. Intriguingly, HIST1H2BK-overexpressing 5-FU-resistant GC cells propagated resistance to 5-FU-sensitive GC cells through the secretion of HIST1H2BK. CONCLUSION: This study highlights significant differences in plasma protein profiles between NACT-resistant and NACT-sensitive AGC patients. Plasma HIST1H2BK emerged as an effective biomarker for achieving more accurate NACT in AGC. The mechanism of intracellular and secreted HIST1H2BK on 5-FU resistance provided a novel insight into chemoresistance in AGC.

Evaluation of transrectal ultrasound-guided tru-cut biopsy as a complementary method for predicting pathological complete response in rectal cancer after neoadjuvant treatment: a phase II prospective and diagnostic trial.

IMPORTANCE: Patients with pathological complete response (pCR) of rectal cancer following neoadjuvant treatment had better oncological outcomes. However, reliable methods for accurately predicting pCR remain limited. OBJECTIVE: To evaluate whether transrectal ultrasound-guided tru-cut biopsy (TRUS-TCB) adds diagnostic value to conventional modalities for predicting pathological complete response in patients with rectal cancer after neoadjuvant treatment. DESIGN, SETTING, AND PARTICIPANTS: This study evaluated data of patients with rectal cancer who were treated with neoadjuvant treatment and reassessed using TRUS-TCB and conventional modalities before surgery. This study is registered with ClinicalTrials.gov. MAIN OUTCOMES AND MEASURES: The primary outcome was accuracy, along with secondary outcomes including sensitivity, specificity, negative predictive value, and positive predictive value in predicting tumour residues. Final surgical pathology was used as reference standard. RESULTS: Between June 2021 and June 2022, a total of 74 patients were enroled, with 63 patients ultimately evaluated. Among them, 17 patients (28%) exhibited a complete pathological response. TRUS-TCB demonstrated an accuracy of 0.71 (95% CI, 0.58-0.82) in predicting tumour residues. The combined use of TRUS-TCB and conventional modalities significantly improved diagnostic accuracy compared to conventional modalities alone (0.75 vs. 0.59, P =0.02). Furthermore, TRUS-TCB correctly reclassified 52% of patients erroneously classified as having a complete clinical response by conventional methods. The occurrence of only one mild adverse event was observed. CONCLUSIONS AND RELEVANCE: TRUS-TCB proves to be a safe and accessible tool for reevaluation with minimal complications. The incorporation of TRUS-TCB alongside conventional methods leads to enhanced diagnostic performance.

Intercellular adhesion molecule 2 as a novel prospective tumor suppressor induced by ERG promotes ubiquitination-mediated radixin degradation to inhibit gastric cancer tumorigenicity and metastasis.

BACKGROUND: Gastric cancer (GC) is a fatal cancer with unclear pathogenesis. In this study, we explored the function and potential mechanisms of intercellular adhesion molecule 2 (ICAM2) in the development and advancement of GC. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to quantify ICAM2 expression in harvested GC tissues and cultured cell lines. Immunohistochemical analyses were conducted on a GC tissue microarray to quantify ICAM2 expression and explore its implication on the prognosis of GC patients. In vitro experiments were carried out to reveal the biological functions of ICAM2 in GC cell lines. Further, in vivo experiments were conducted using xenograft models to assess the impact of ICAM2 on GC development and metastasis. Western blot, immunofluorescence, immunoprecipitation, luciferase assay, chromatin immunoprecipitation, and ubiquitination analysis were employed to investigate the underlying mechanisms. RESULTS: ICAM2 expression was downregulated in GC, positively correlating with advanced T stage, distant metastasis, advanced clinical stage, vessel invasion, and shorter patient survival time. ICAM2 overexpression suppressed the proliferation, migration, invasion, metastasis of GC cells as well as their ability to form tumors, whereas ICAM2 knockdown yielded opposite results. Erythroblast transformation-specific-related gene (ERG) as a transcription factor promoted the transcription of ICAM2 by binding to the crucial response element localized within its promoter region. Further analysis revealed that ICAM2 reduced radixin (RDX) protein stability and expression. In these cells, ICAM2 bound to the RDX protein to promote the ubiquitination and degradation of RDX via NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L), and this post-translational modification resulted in the inhibition of GC. CONCLUSIONS: In summary, this study demonstrates that ICAM2, which is induced by ERG, suppresses GC progression by enhancing the ubiquitination and degradation of RDX in a NEDD4L-dependent manner. Therefore, these results suggest that ICAM2 is a potential prognostic marker and a therapeutic target for GC.

LAD1 promotes malignant progression by diminishing ubiquitin-dependent degradation of vimentin in gastric cancer.

BACKGROUND: Ladinin-1 (LAD1), an anchoring filament protein, has been associated with several cancer types, including cancers of the colon, lungs, and breast. However, it is still unclear how and why LAD1 causes gastric cancer (GC). METHODS: Multiple in vitro and in vivo, functional gains and loss experiments were carried out in the current study to confirm the function of LAD1. Mass spectrometry was used to find the proteins that interact with LAD1. Immunoprecipitation analyses revealed the mechanism of LAD1 involved in promoting aggressiveness. RESULTS: The results revealed that the LAD1 was overexpressed in GC tissues, and participants with increased LAD1 expression exhibited poorer disease-free survival (DFS) and overall survival (OS). Functionally, LAD1 promotes cellular invasion, migration, proliferation, and chemoresistance in vivo and in vitro in the subcutaneous patient-and cell-derived xenograft (PDX and CDX) tumor models. Mechanistically, LAD1 competitively bound to Vimentin, preventing it from interacting with the E3 ubiquitin ligase macrophage erythroblast attacher (MAEA), which led to a reduction in K48-linked ubiquitination of Vimentin and an increase in Vimentin protein levels in GC cells. CONCLUSIONS: In conclusion, the current investigation indicated that LAD1 has been predicted as a possible prognostic biomarker and therapeutic target for GC due to its ability to suppress Vimentin-MAEA interaction.

ADAMTS12 promotes oxaliplatin chemoresistance and angiogenesis in gastric cancer through VEGF upregulation.

BACKGROUND: While ADAMTS12 (A disintegrin and metalloproteinase with thrombospondin motifs 12) has been established as an important regulator of gastrointestinal tumor development and angiogenic activity, the precise mechanistic functions of ADAMTS12 have yet to be fully clarified in gastric cancer (GC). Accordingly, this study was developed to explore the molecular functions of ADAMTS12 in GC and to examine its utility as a biomarker associated with chemoresistance and prognostic outcomes in this cancer type. METHODS: The ability of ADAMTS12 to modulate the proliferative, migratory, invasive, chemoresistant, and tube formation activity of tumor cells was assessed in vivo and in vitro through gain- and loss-of-function approaches. Correlations between ADAMTS12, CD31, and VEGF expression levels in GC patient tumor tissue samples from individuals that did and did not undergo neoadjuvant chemotherapy (NAC) treatment were analyzed via immunohistochemical staining. RESULTS: These analyses revealed the ability of ADAMTS12 to promote in vivo and in vitro cellular proliferative and angiogenic activity, promoting the activation of ERK and the consequent upregulation of VEGF, thereby inducing angiogenesis and decreasing GC cell oxaliplatin sensitivity. A positive correlation between ADAMTS12 levels and both the expression of VEGF as well as the density of microvessels was observed in GC patient tumor tissues. Moreover, those GC patients exhibiting higher intratumoral ADAMTS12 expression exhibited worse responses to NAC treatment and worse overall survival outcomes. CONCLUSIONS: These findings suggest that ADAMTS12 can modulate signaling via the MAPK/VEGF axis in GC cells to enhance tumor cell resistance to oxaliplatin treatment under hypoxic and normoxic conditions. Elevated ADAMTS12 levels can additionally predict vascular abnormalities, worse survival outcomes, and chemoresistance in patients with GC.

Induction of filopodia formation by α-Actinin-2 via RelA with a feedforward activation loop promoting overt bone marrow metastasis of gastric cancer.

BACKGROUND: Bone marrow metastasis (BMM) is underestimated in gastric cancer (GC). GC with BMM frequently complicate critical hematological abnormalities like diffused intravascular coagulation and microangiopathic hemolytic anemia, which constitute a highly aggressive GC (HAGC) subtype. HAGC present a very poor prognosis with peculiar clinical and pathological features when compared with not otherwise specified advanced GC (NAGC). But the molecular mechanisms underlying BMM from GC remain rudimentary. METHODS: The transcriptomic difference between HAGC and NAGC were analyzed. Genes that were specifically upregulated in HAGC were identified, and their effect on cell migration and invasion was studied. The function of ACTN2 gene were confirmed by GC cell lines, bone-metastatic animal model and patients' tissues. Furthermore, the molecular mechanism of ACTN2 derived-BMM was explored by multiple immunofluorescence staining, western blot, chromatin immunoprecipitation, and luciferase reporter assays. RESULTS: We elucidated the key mechanisms of BMM depending on the transcriptomic difference between HAGC and NAGC. Five genes specifically upregulated in HAGC were assessed their effect on cell migration and invasion. The ACTN2 gene encoding protein α-Actinin-2 was detected enhanced the metastatic capability and induced BMM of GC cells in mouse models. Mechanically, α-Actinin-2 was involved in filopodia formation where it promoted the Actin filament cross-linking by replacing α-Actinin-1 to form α-Actinin-2:α-Actinin-4 complexes in GC cells. Moreover, NF-κB subunit RelA and α-Actinin-2 formed heterotrimers in the nuclei of GC cells. As a direct target of RelA:α-Actinin-2 heterotrimers, the ACTN2 gene was a positive auto-regulatory loop for α-Actinin-2 expression. CONCLUSIONS: We demonstrated a link between filopodia, BMM and ACTN2 activation, where a feedforward activation loop between ACTN2 and RelA is established via actin in response to distant metastasis. Given the novel filopodia formation function and the new mechanism of BMM in GC, we propose ACTN2 as a druggable molecular vulnerability that may provide potential therapeutic benefit against BMM of GC.

The association between fasting blood glucose and prognosis in gastrointestinal stromal tumor patients after curable resection.

Blood glucose has been demonstrated to serve as prognostic indicators in various malignancies. This study aimed to explore the relationship between fasting blood glucose (FBG) levels and the prognosis in patients with gastrointestinal stromal tumor (GIST) undergoing complete resection. Data were retrospectively collected from 256 patients with primary GIST underwent complete surgical resection or endoscopic excision. Patients were stratified into euglycemic group and hyperglycemic group. Patients' characteristics between groups were compared. Cox regression model was conducted to identify independent prognostic factors of disease-free survival (DFS). Both univariate analysis and multivariate analyses revealed that FBG ≥ 100 mg/dl was associated with poor outcomes. Patients with FBG ≥ 100 mg/dl tended to have more adverse features, more likely to suffer recurrence and a worse 5-year DFS than patients with FBG < 100 mg/dl. Moreover, FBG levels helped distinguishing between patients with different survival outcomes in different risk categories defined by modified NIH systems. Our data provided the evidence that FBG is a useful prediction marker prognosis in patients with GIST undergoing curative surgery.

Morbidity, Mortality, and Pathologic Outcomes of Transanal Versus Laparoscopic Total Mesorectal Excision for Rectal Cancer Short-term Outcomes From a Multicenter Randomized Controlled Trial.

OBJECTIVE: To determine the morbidity, mortality, and pathologic outcomes of transanal total mesorectal resection (taTME) versus laparoscopic total mesorectal excision (laTME) among patients with rectal cancer with clinical stage I to III rectal cancer below the peritoneal reflection. BACKGROUND: Studies with sufficient numbers of patients allowing clinical acceptance of taTME for rectal cancer are lacking. Thus, we launched a randomized clinical trial to compare the safety and efficacy of taTME versus laTME. METHODS: A randomized, open-label, phase 3, noninferiority trial was performed at 16 different hospitals in 10 Chinese provinces. The primary endpoints were 3-year disease-free survival and 5-year overall survival. The morbidity and mortality within 30 days after surgery, and pathologic outcomes were compared based on a modified intention-to-treat principle; this analysis was preplanned. RESULTS: Between April 13, 2016, and June 1, 2021, 1115 patients were randomized 1:1 to receive taTME or laTME. After exclusion of 26 cases, modified intention-to-treat set of taTME versus laTME groups included 544 versus 545 patients. There were no significant differences between taTME and laTME groups in intraoperative complications [26 (4.8%) vs 33 (6.1%); difference, -1.3%; 95% confidence interval (CI), -4.2% to 1.7%; P =0.42], postoperative morbidity [73 (13.4%) vs 66 (12.1%); difference, 1.2%; 95% CI, -2.8% to 5.2%; P =0.53), or mortality [1 (0.2%) vs 1 (0.2%)]. Successful resection occurred in 538 (98.9%) versus 538 (98.7%) patients in taTME versus laTME groups (difference, 0.2%; 95% CI, -1.9% to 2.2%; P >0.99). CONCLUSIONS: Experienced surgeons can safely perform taTME in selected patients with rectal cancer.

A validated tool of combining risk factors with fecal immunochemical test for selecting colonoscopy in asymptomatic Chinese population.

Fecal immunochemical test (FIT) is often used for preselection for colonoscopy, but FIT has nonoptimal sensitivity. Selection of study participant for colonoscopy based on the result of combining FIT with risk factors could improve the sensitivity of a screening program. We aimed to develop a risk prediction system of colorectal neoplasia among asymptomatic Chinese subjects. A total of 6265 asymptomatic participants with age between 50 and 70 years were invited to undergo colonoscopy screening. They were also asked to take FIT and complete a questionnaire for collecting information on risk factors. Independent risk factors were identified by binary logistic regression for colorectal neoplasia. A risk score model was developed by using the odds ratios of significant risk factors. The scoring system was divided into two groups of risk: negative risk and positive risk. The performance of the risk score model in terms of predicting colorectal neoplasia was evaluated. Of the 1786 colonoscopy screening participants, 1546 completed FIT and questionnaires. A total of 462 cases of neoplasia were detected. Based on the scoring stratification, 966 (62.5%) participants were in negative risk tier and 580 (37.5%) were in positive risk tier. The incidence of colorectal neoplasia in negative risk and positive risk groups was 18.4 and 49.0%, respectively. Risk stratification model has better ability to discriminate those with or without colorectal neoplasia than FIT-only model. Classification improved significantly with risk stratification-based screening (net reclassification improvement = 0.064, P = 0.032). Risk stratification system increases the predictive value of FIT-based screening and is useful for preselection for colonoscopy in colorectal cancer screening program.

A retrospective analysis based on multiple machine learning models to predict lymph node metastasis in early gastric cancer.

Background: Endoscopic submucosal dissection has become the primary option of treatment for early gastric cancer. However, lymph node metastasis may lead to poor prognosis. We analyzed factors related to lymph node metastasis in EGC patients, and we developed a construction prediction model with machine learning using data from a retrospective series. Methods: Two independent cohorts' series were evaluated including 305 patients with EGC from China as cohort I and 35 patients from Spain as cohort II. Five classifiers obtained from machine learning were selected to establish a robust prediction model for lymph node metastasis in EGC. Results: The clinical variables such as invasion depth, histologic type, ulceration, tumor location, tumor size, Lauren classification, and age were selected to establish the five prediction models: linear support vector classifier (Linear SVC), logistic regression model, extreme gradient boosting model (XGBoost), light gradient boosting machine model (LightGBM), and Gaussian process classification model. Interestingly, all prediction models of cohort I showed accuracy between 70 and 81%. Furthermore, the prediction models of the cohort II exhibited accuracy between 48 and 82%. The areas under curve (AUC) of the five models between cohort I and cohort II were between 0.736 and 0.830. Conclusions: Our results support that the machine learning method could be used to predict lymph node metastasis in early gastric cancer and perhaps provide another evaluation method to choose the suited treatment for patients.

The Novel Protein ADAMTS16 Promotes Gastric Carcinogenesis by Targeting IFI27 through the NF-κb Signaling Pathway.

A disintegrin and metalloproteinase with thrombospondin motifs 16 (ADAMTS16) has been reported to be involved in the pathogenesis of solid cancers. However, its role in gastric cancer (GC) is unclear. In this study, the role of ADAMTS16 in gastric cancer was investigated. The effects of ADAMTS16 on cell migration, invasion, and proliferation were investigated by functional experiments in vivo and in vitro. Downstream signal pathways of ADAMTS16 were confirmed by using bioinformatics analysis, co-immunoprecipitation, and immunofluorescence. Meanwhile, bioinformatics analysis, qRT-PCR, western blot, and dual-luciferase reporter gene analysis assays were used to identify ADAMTS16 targets. The expression of ADAMTS16 in GC was analyzed in public datasets. The expression of ADAMTS16 and its correlations with the clinical characteristics of GC were investigated by immunohistochemistry. Ectopic ADAMTS16 expression significantly promoted tumor cell migration, invasion, and growth. Bioinformatics analysis and western blot showed that ADAMTS16 upregulated the IFI27 protein through the NF-κb pathway, which was confirmed by immunofluorescence and western blot. Dual-luciferase reporter gene analysis identified a binding site between P65 and IFI27 that may be directly involved in the transcriptional regulation of IFI27. IFI27 knockdown reversed the promoting effect of ADAMTS16 on cell invasion, migration, and proliferation indicating that ADAMTS16 acts on GC cells by targeting the NF-κb/IFI27 axis. ADAMTS16 was associated with poor prognosis in clinical characteristics. ADAMTS16 promotes cell migration, invasion, and proliferation by targeting IFI27 through the NF-κB pathway and is a potential progressive and survival biomarker of GC.

ADAMTS10 inhibits aggressiveness via JAK/STAT/c-MYC pathway and reprograms macrophage to create an anti-malignant microenvironment in gastric cancer.

BACKGROUND: A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10) plays a role in extracellular matrix and correlates with Weill-Marchesani syndrome. However, its role in gastric cancer remains unknown. Thus, we started this research to unveil the role of ADAMTS10 in gastric cancer (GC). METHODS: The expression of ADAMTS10 in GC was analyzed by immunohistochemical staining and quantitative RT-PCR (qRT-PCR). The effects of ADAMTS10 inhibiting GC cell progression were conducted by functional experiments in vitro and in vivo. Flow cytometry was used to discover changing of cell cycle, apoptosis and ROS by ADAMTS10 in GC cell. Western blot was applied to identify targets of ADAMTS10. Western blot, qRT-PCR and flow cytometry were applied to discover the effect of ADAMT10 on THP1. RESULTS: ADAMTS10 expression was downregulated in GC tissue and patients with low ADAMTS10 levels had poorer overall survival. ADAMTS10 overexpression altered cell cycle, promoted apoptosis, and inhibited proliferation, migration, and invasion in vitro and in vivo. ADAMTS10 regulated TXNIP and ROS through the JAK/STAT/c-MYC pathway. Decreasing TXNIP and ROS reversed the inhibitory effect of ADAMTS10 on cell migration and invasion in vitro. ADAMTS10 secreted by GC cells was absorbed by THP1 and regulated TXNIP and ROS in THP1. ADAMTS10 secreted by GC cells inhibited macrophage M2 polarization. CONCLUSIONS: These results suggest that ADAMTS10 targets TXNIP and ROS via the JAK/STAT/c-MYC pathway and that may play important roles in GC progression and macrophage polarization which indicates that ADAMTS10 can be a potential survival marker for gastric cancer.

NGFR Increases the Chemosensitivity of Colorectal Cancer Cells by Enhancing the Apoptotic and Autophagic Effects of 5-fluorouracil via the Activation of S100A9.

Colorectal cancer (CRC) is currently the third leading cause of cancer-related deaths worldwide, and 5-fluorouracil (5-FU)-based chemotherapies serve as important adjuvant therapies before and after surgery for CRC. However, the efficacy of CRC chemotherapy is limited by chemoresistance, and therefore the discovery of novel markers to indicate chemosensitivity is essential. Nerve growth factor receptor (NGFR), a cell surface receptor, is involved in cell death and survival. Our previous study indicated that NGFR acts as a tumor suppressor, and high expression is associated with better outcomes in patients receiving 5-FU-based adjuvant chemotherapy after surgery. The aim of this study was to investigate the effect of NGFR on the chemotherapeutic response in CRC. Chemosensitivity was investigated using DLD1 and HCT8 cells after NGFR transfection. Apoptosis was investigated by flow cytometry. Autophagy was assessed using GFP-LC3B transient transfection. Gene expression was measured using an mRNA microarray. Beclin-1 and Bcl-2 protein expressions were assessed by western blot. NGFR and S100 calcium-binding protein A9 (S100A9) expressions in CRC patients were investigated by immunohistochemistry. The results showed that the half maximal inhibitory concentration of NGFR-transfected cells was lower than that of controls in DLD1 and HCT8 cells after 5-FU treatment, and cell viability was lower than in empty-vector cells. Tumor sizes were also smaller than in empty-vector cells in vivo. The percentages of apoptotic and autophagic cells were higher in NGFR-transfected cells. NGFR elevated the expression of S100A9 after 5-FU treatment. The combination of Bcl-2 and Beclin-1 was significantly suppressed by overexpressed NGFR. Five-year overall and disease-free survival in NGFR+/S100A9+ patients was better than in NGFR-/S100A9- patients. This study's findings suggest that NGFR may serve as a marker predicting CRC patients' chemosensitivity.

ADAMTS19 Suppresses Cell Migration and Invasion by Targeting S100A16 via the NF-κB Pathway in Human Gastric Cancer.

A Disintegrin and Metalloproteinase with Thrombospondin motifs 19 (ADAMTS19) has been reported to participate in the pathogenesis of solid cancers. However, its role in gastric cancer (GC) remains undocumented. Using immunohistochemistry (IHC) staining and quantitative real-time polymerase chain reaction (qRT-PCR) on GC tissues and adjacent normal tissues, we found that ADAMTS19 was downregulated in GC tissues (IHC: p < 0.001; qRT-PCR: p = 0.017). Further investigation revealed that ADAMTS19 correlated with distant metastasis (p = 0.008) and perineural invasion (p = 0.018) and that patients with low ADAMTS19 had worse overall survival (p = 0.021). Gain- and loss-of-function assays showed that ADAMTS19 suppressed cell migration and invasion in vitro. Using bioinformatics analysis and co-immunoprecipitation, immunofluorescence, and dual-luciferase reporter gene assays, we confirmed that ADAMTS19 binds with cytoplasm P65, decreasing the nucleus phosphorylation of P65, a crucial transcription factor in the nuclear factor kappa-B (NF-κB) pathway, thereby downregulating S100 calcium-binding protein A16 (S100A16) expression. S100A16 acted as the downstream of ADAMTS19, reversing the suppression of cell migration and invasion by ADAMTS19 in vitro. A combination of ADAMTS19 and S100A16 expression provided the optimal prognostic indicator for GC. Patients with ADAMTS19high-S100A16low had better overall survival than ADAMTS19low-S100A16high patients (p = 0.006). These results suggest that ADAMTS19 suppresses cell migration and invasion by targeting S100A16 via the NF-κB pathway and that ADAMTS19 and S100A16 are potential metastasis and survival biomarkers for GC.

College of American Pathologists Tumor Regression Grading System for Long-Term Outcome in Patients with Locally Advanced Rectal Cancer.

BACKGROUND: The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined. MATERIALS AND METHODS: This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model. RESULTS: The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1-3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate. CONCLUSION: AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC. IMPLICATIONS FOR PRACTICE: The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1-3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.

Functional jejunal interposition versus Roux-en-Y anastomosis after total gastrectomy for gastric cancer: A prospective randomized clinical trial.

BACKGROUND: Nutritional status and quality of life deteriorate significantly after total gastrectomy for patients with gastric cancer. The numerous types of reconstruction proposed by medical researchers around the world have limited effect. This prospective, randomized clinical trial compared functional jejunal interposition with Roux-en-Y anastomosis to identify the optimal reconstruction procedure. METHODS: This was a multi-center, prospective, randomized control trial. The enrolled patients were randomly assigned into the functional jejunal interposition group and the Roux-en-Y group. All patients were followed up at regular intervals after surgery. The endpoints were postoperative nutritional status, quality of life, and long-term postoperative complications. RESULTS: A total of 113 patients were enrolled from August 2012 to September 2017. Until March 2018, the median follow-up period was 18 months. At 12 months after surgery, food intake per meal (P = 0.021), Prognosis Nutritional Index (P = 0.015), weight loss (P = 0.019), and Gastrointestinal Symptom Rating Scale score (P = 0.015) of the functional jejunal interposition group were significantly worse than those of the Roux-en-Y group. There was no significant difference in operative time, intraoperative blood loss, perioperative complications, time of first flatus and defecation after surgery, postoperative plasma nutritional parameters, Visick score, Eastern Cooperative Group physical condition score, and survival rate. CONCLUSION: For patients with long-term survival after total gastrectomy for gastric cancer, the Roux-en-Y anastomosis is a better choice compared with functional jejunal interposition.

ADAMTS5 acts as a tumor suppressor by inhibiting migration, invasion and angiogenesis in human gastric cancer.

BACKGROUND: ADAMTS5 has been reported to be involved in the progression of several human tumors. Nevertheless, the role of ADAMTS5 in gastric cancer (GC) remains poorly defined. METHODS: ADAMTS5 expression levels were analyzed by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) in GC cell lines and tissues, and the correlations between ADAMTS5 expression and clinicopathological features and survival were also examined. In vitro assays, including transwell assays, wound healing assays and cell adhesion assays, were employed to further explore the biological functions of ADAMTS5. A MAP kinase pathway microarray was used to identify the underlying mechanisms. The expression of ADAMTS5 and ETS1 and the microvessel density (MVD) were also analyzed using IHC to determine correlations with angiogenesis in GC. RESULTS: ADAMTS5 expression was downregulated in gastric cancer tissues. Low expression of ADAMTS5 was associated with gender, histological type, degree of differentiation, M stage, TNM stage and vascular invasion, and was also an independent indicator of a poor prognosis for patients with GC. ADAMTS5 overexpression markedly inhibited GC cell migration and invasion and enhanced cell adhesion to the extracellular matrix (ECM), whereas knockdown of ADAMTS5 exerted the opposite effects. Furthermore, the ADAMTS5 expression status was negatively correlated with ETS1 expression and MVD. CONCLUSION: ADAMTS5 is downregulated in GC and suppresses tumor metastasis and angiogenesis by inhibiting ETS1-mediated changes in MVD and potentially acts as a novel prognostic marker and a potential therapeutic target in human GC.

The novel long noncoding RNA u50535 promotes colorectal cancer growth and metastasis by regulating CCL20.

Long noncoding RNAs (lncRNAs) have been emerging as master regulators of tumor growth and metastasis, but the functions and underlying mechanisms of lncRNAs in colorectal cancer (CRC) still need to be clarified. Here, we found a novel lncRNA u50535, which was greatly overexpressed in CRC tissues and was associated with poor prognosis in CRC patients. Function studies showed that u50535 was an oncogene in CRC both in vitro and in vivo. In mechanism, through RNA sequencing and rescue assay, we found that u50535 activates CCL20 signaling to promote cell proliferation and migration in CRC. Taken together, these findings suggest that u50535 can promote CRC growth and metastasis and may serve as a potential biomarker in CRC.

Screening for colorectal cancer in Tianhe, Guangzhou: results of combining fecal immunochemical tests and risk factors for selecting patients requiring colonoscopy.

OBJECTIVE: To explore the performance of a protocol combining fecal immunochemical test (FIT) and a high-risk factor questionnaire (HRFQ) for selecting patients requiring colonoscopy as part of a population-based colorectal cancer (CRC) screening program in China. METHODS: From 2015 to 2016, we conducted a CRC screening program for all residents aged 45 years or older in Tianhe District, Guangzhou City, China. Participants underwent an FIT and received an HRFQ as part of primary screening. Those with positive FIT and/or HRFQ results were considered to be at high risk and were recommended to undergo colonoscopy. RESULTS: A total of 10 074 subjects were recruited and enrolled in the screening program. In the enrolled population, 17.5% had positive FIT results and 19.4% had positive HRFQ results. Of those recommended to undergo diagnostic colonoscopy, 773 did so. The screening method's overall positive predictive value (PPV) was 4.9% for non-adenomatous polyps, 11.4% for low-risk adenomas (LRAs), 15.9% for high-risk adenomas (HRAs) and 1.6% for CRC. The PPVs of positive FIT results for non-adenomatous polyps, LRAs, HRAs and CRC were 5.2%, 15.9%, 22.5% and 2.5%, respectively. The PPVs of positive HRFQ results for non-adenomatous polyps, LRA, HRA and CRC were 4.1%, 10.2%, 14.3% and 1.4%, respectively. The PPVs associated with combined positive FIT and HRFQ results for non-adenomatous polyps, LRAs, HRAs and CRC were 4.5%, 16.4%, 23.7% and 2.8%, respectively. CONCLUSION: Our results suggest that this two-step CRC screening strategy, involving a combination of FIT and HRFQ followed by colonoscopy, is useful to identify early-stage CRC. The high detection rates and PPVs for CRC and adenomas encourage this strategy's use in ongoing screening programs.