A new clinical model for predicting lymph node metastasis in T1 colorectal cancer.

PURPOSE: Lymph node metastasis (LNM) is a crucial factor that determines the prognosis of T1 colorectal cancer (CRC) patients. We aimed to develop a practical prediction model for LNM in T1 CRC. METHODS: We conducted a retrospective analysis of data from 825 patients with T1 CRC who underwent radical resection at a single center in China. All enrolled patients were randomly divided into a training set and a validation set at a ratio of 7:3 using R software. Risk factors for LNM were identified through multivariate logistic regression analyses. Subsequently, a prediction model was developed using the selected variables. RESULTS: The lymph node metastasis (LNM) rate was 10.1% in the training cohort and 9.3% in the validation cohort. In the training set, risk factors for LNM in T1 CRC were identified, including depressed endoscopic gross appearance, sex, submucosal invasion combined with tumor grade (DSI-TG), lymphovascular invasion (LVI), and tumor budding. LVI emerged as the most potent predictor for LNM. The prediction model based on these factors exhibited good discrimination ability in the validation sets (AUC: 79.3%). Compared to current guidelines, the model could potentially reduce over-surgery by 48.9%. Interestingly, we observed that sex had a differential impact on LNM between early-onset and late-onset CRC patients. CONCLUSIONS: We developed a clinical prediction model for LNM in T1 CRC using five factors that are easily accessible in clinical practice. The model has better predictive performance and practicality than the current guidelines and can assist clinicians in making treatment decisions for T1 CRC patients.

Potential Molecular Markers Related to Lymph Node Metastasis and Stalk Resection Margins in Pedunculated T1 Colorectal Cancers Using Digital Spatial Profiling: A Pilot Study with a Small Case Series.

There is a debate regarding the prediction of lymph node metastasis (LNM) in pedunculated T1 colorectal cancer (CRC). In this study with four cases of pedunculated T1 CRCs, we aimed to investigate gene expression variations based on the distance from the Haggitt line (HL) and identify potential molecular risk factors for LNM. By leveraging the Cancer Transcriptome Atlas and digital spatial profiling technology, we meticulously analyzed discrete regions, including the head, HL, proximal stalk region (300-1000 µm from HL), and distal stalk region (1500-2000 µm from HL) to identify spatially sequential molecular changes. Our findings showed significant overall gene expression variations among the head, proximal stalk, and distal stalk regions of pedunculated T1 CRCs compared to the control adenoma. Compared to LNM-negative T1 CRCs, LNM-positive T1 CRC showed that the expression of genes involved in immune-related pathways such as B2M, HLA-B, and HLA-E were significantly downregulated in the distal stalk region compared to the proximal stalk region. In summary, our results may tentatively suggest considering endoscopic resection of the stalk with a minimum 2000 µm margin from the HL, taking into account the gene expression alterations related to immune-related pathways. However, we acknowledge the limitations of this pilot study, notably the small case series, which may restrict the depth of interpretation. Further validation is imperative to substantiate these findings.

Deep Submucosal Invasion Is Not an Independent Risk Factor for Lymph Node Metastasis in T1 Colorectal Cancer: A Meta-Analysis.

BACKGROUND & AIMS: Deep submucosal invasion (DSI) is considered a key risk factor for lymph node metastasis (LNM) and important criterion to recommend surgery in T1 colorectal cancer. However, metastatic risk for DSI is shown to be low in the absence of other histologic risk factors. This meta-analysis determines the independent risk of DSI for LNM. METHODS: Suitable studies were included to establish LNM risk for DSI in univariable analysis. To assess DSI as independent risk factor, studies were eligible if risk factors (eg, DSI, poor differentiation, lymphovascular invasion, and high-grade tumor budding) were simultaneously included in multivariable analysis or LNM rate of DSI was described in absence of poor differentiation, lymphovascular invasion, and high-grade tumor budding. Odds ratios (OR) and 95% CIs were calculated. RESULTS: Sixty-seven studies (21,238 patients) were included. Overall LNM rate was 11.2% and significantly higher for DSI-positive cancers (OR, 2.58; 95% CI, 2.10-3.18). Eight studies (3621 patients) were included in multivariable meta-analysis and did not weigh DSI as a significant predictor for LNM (OR, 1.73; 95% CI, 0.96-3.12). As opposed to a significant association between LNM and poor differentiation (OR, 2.14; 95% CI, 1.39-3.28), high-grade tumor budding (OR, 2.83; 95% CI, 2.06-3.88), and lymphovascular invasion (OR, 3.16; 95% CI, 1.88-5.33). Eight studies (1146 patients) analyzed DSI as solitary risk factor; absolute risk of LNM was 2.6% and pooled incidence rate was 2.83 (95% CI, 1.66-4.78). CONCLUSIONS: DSI is not a strong independent predictor for LNM and should be reconsidered as a sole indicator for oncologic surgery. The expanding armamentarium for local excision as first-line treatment prompts serious consideration in amenable cases to tailor T1 colorectal cancer management.

Reduced DEFA5 Expression and STAT3 Activation Underlie the Submucosal Invasion of Early Gastric Cancers.

INTRODUCTION: Submucosal invasion is a core hallmark of early gastric cancer (EGC) with poor prognosis. However, the molecular mechanism of the progression from intramucosal gastric cancer (IMGC) to early submucosal-invasive gastric cancer (SMGC) is not fully understood. The objective of this study was to identify genes and pathways involved in the submucosal invasion in EGC using comprehensive gene expression analysis. METHODS: Gene expression profiling was performed for eight cases of IMGC and eight cases of early SMGC with submucosal invasion ≥500 µm. To validate the findings of gene expression analysis and to examine the gene expression pattern in tissues, immunohistochemical (IHC) staining was performed for 50 cases of IMGC and SMGC each. RESULTS: Gene expression analysis demonstrated that the expression levels of small intestine-specific genes were significantly decreased in SMGC. Among them, defensin alpha 5 (DEFA5) was the most downregulated gene in SMGC, which was further validated in SMGC tissues by IHC staining. Gene set enrichment analysis showed a strong association between SMGC, the JAK-STAT signaling pathway, and the upregulation of STAT3-activating cytokines. The expression of phosphorylated STAT3 was significant in the nucleus of tumor cells in SMGC tissues but not in areas expressing DEFA5. CONCLUSION: The results of this study strongly suggest that the downregulation of DEFA5 and the activation of STAT3 play a significant role in the submucosal invasion of EGC.

[Analysis of risk factors for depth of invasion and angiolymphatic invasion for circumferential superficial esophageal squamous cell carcinoma and precancerous lesion].

Objective: To analyze clinicopathological features of circumferential superficial esophageal squamous cell carcinoma and precancerous lesions and investigate the risk factors for deep submucosal invasion and angiolymphatic invasion retrospectively. Methods: A total of 116 cases of esophageal squamous epithelial high-grade intraepithelial neoplasia or squamous cell carcinoma diagnosed by gastroscopy, biopsy pathology and endoscopic resection pathology during November 2013 to October 2021 were collected, and their clinicopathological features were analyzed. The independent risk factors of deep submucosal invasion and angiolymphatic invasion were analyzed by logistic regression model. Results: The multivariate logistic regression analysis showed that drinking history (OR=3.090, 95% CI: 1.165-8.200; P<0.05), The AB type of intrapapillary capillary loop (IPCL) (OR=11.215, 95% CI: 3.955-31.797; P<0.05) were the independent risk factors for the depth of invasion. The smoking history (OR=5.824, 95% CI: 1.704-19.899; P<0.05), the presence of avascular area (AVA) (OR=3.393, 95% CI: 1.285-12.072; P<0.05) were the independent factors for the angiolymphatic invasion. Conclusions: The risk of deep submucosal infiltration is greater for circumferential superficial esophageal squamous cell carcinoma patients with drinking history and IPCL type B2-B3 observed by magnifying endoscopy, while the risk of angiolymphatic invasion should be vigilant for circumferential superficial esophageal squamous cell carcinoma patients with smoking history and the presence of AVA observed by magnifying endoscopy. Ultrasound endoscopy combined with narrowband imagingand magnification endoscopy can improve the accuracy of preoperative assessment of the depth of infiltration of superficial squamous cell carcinoma and precancerous lesions and angiolymphaticinvasion in the whole perimeter of the esophagus, and help endoscopists to reasonably grasp the indications for endoscopic treatment.

Lymph node metastasis in T1 colorectal cancer with the only high-risk histology of submucosal invasion depth ≥ 1000 µm.

PURPOSE: The number of patients undergoing additional surgery after endoscopic resection (ER) for T1 colorectal cancer (CRC) is increasing. Regarding high-risk histology of lymph node metastasis (LNM) in T1 CRC, a submucosal invasion depth ≥ 1000 µm (T1b) alone may be related to a low incidence of LNM. This study was conducted to clarify the incidence of LNM and to identify factors associated with LNM in T1 CRC with high-risk histology characterized only by T1b. METHODS: We retrospectively investigated patients with pathological T1b CRC who underwent colorectal resection between 2010 and 2020. Patients were divided into two groups with high-risk histology: those in whom the only high-risk feature was T1b (low-risk T1b group, n = 263), and those with T1b as well as lymphovascular invasion, tumor budding, or poorly differentiated or mucinous adenocarcinoma (high-risk T1b group, n = 289). The incidences of LNM and recurrence were compared. Multivariate analysis was performed to identify factors associated with LNM in the low-risk T1b group. RESULTS: The incidences of LNM were 3.8% and 21.6% in the Low- and High-risk T1b groups, respectively (p < 0.01), while the 5-year recurrence rates in the two groups were 0.6% and 3.4%, respectively (p = 0.10). Multivariate analysis revealed that only a predominant histological type of moderately differentiated adenocarcinoma (p = 0.04) was independently associated with LNM in the low-risk T1b group. CONCLUSION: When considering the omission of additional surgery after ER in cases of T1 CRC whose only high-risk histological feature is T1b, attention should be paid to the predominant histological type.

Artificial intelligence predicts lymph node metastasis or risk of lymph node metastasis in T1 colorectal cancer.

BACKGROUND: The treatment strategies for colorectal cancer (CRC) must ensure a radical cure of cancer and prevent over/under treatment. Biopsy specimens used for the definitive diagnosis of T1 CRC were analyzed using artificial intelligence (AI) to construct a risk index for lymph node metastasis. METHODS: A total of 146 T1 CRC cases were analyzed. The specimens for analysis were mainly biopsy specimens, and in the absence of biopsy specimens, the mucosal layer of the surgical specimens was analyzed. The pathology slides for each case were digitally imaged, and the morphological features of cancer cell nuclei were extracted from the tissue images. First, statistical methods were used to analyze how well these features could predict lymph node metastasis risk. A lymph node metastasis risk model using AI was created based on these morphological features, and accuracy in test cases was verified. RESULTS: Each developed model could predict lymph node metastasis risk with a > 90% accuracy in each region of interest of the training cases. Lymph node metastasis risk was predicted with 81.8-86.3% accuracy for randomly validated cases, using a learning model with biopsy data. Moreover, no case with lymph node metastasis or lymph node risk was judged to have no risk using the same model. CONCLUSIONS: AI models suggest an association between biopsy specimens and lymph node metastases in T1 CRC and may contribute to increased accuracy of preoperative diagnosis.

Activated macrophages promote invasion by early colorectal cancer via an interleukin 1ß-serum amyloid A1 axis.

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA-sequencing (RNA-seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues and detected significant upregulation of serum amyloid A1 (SAA1) in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Coculture experiments using CRC cell lines and THP-1 cells suggested that interleukin 1ß (IL-1ß) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL-1ß. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1-like/M2-like macrophages at SAA1-positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of matrix metalloproteinase-9 in macrophages. Our data suggest that tumor-associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1 and that SAA1 may be a predictive biomarker and a useful therapeutic target.

The risk of lymph node metastasis in T1 colorectal cancer: new parameters to assess the degree of submucosal invasion.

PURPOSE: In T1 colorectal cancer, the depth is the main factor assessing the degree of submucosal invasion (DSI) to predict the risk of lymph node metastasis (LNM). The width (WSI) and the area of submucosal invasion (ASI) have been suggested as additional parameters to assess the risk of LNM. A review of the literature was undertaken on the correlation between WSI and ASI parameters and the incidence of LNM. METHODS: A Medline, PubMed, and Cochrane Library search was performed to retrieve all studies reporting correlation between WSI/ASI and risk of LNM in T1 colorectal cancer. RESULTS: Eight studies including 1727 patients were identified. All considered the degree of WSI and its influence on LNM: seven assessed different width cut-off of submucosal invasion, and one study the mean width of submucosal invasion in patients having or not involved lymph nodes. The WSI was significantly a prognostic factor for LNM (p < 0.05) in four studies. Both 2 and 3 mm seem to be the most discriminatory cut-off values of submucosal width invasion in defining the risk difference of LNM above and below the cut-off (2 mm, OR = infinite; 3 mm, OR = 6.9). Patients having a cut-off ≤ 5 mm of WSI showed a low risk (5.6%) of LNM rendering radical surgery unnecessary. Four studies assessed the risk of LNM according to the involved submucosal area (width × depth). In two of these, the ASI was a significant prognostic factor for LNM (p < 0.05). CONCLUSION: The WSI and ASI seem to be reliable prognostic factors for LNM in T1 colorectal cancer. There is no agreement on ideal cut-off value.

Endoscopic features of submucosal invasive non-ampullary duodenal carcinomas.

BACKGROUND AND AIM: It is imperative to distinguish superficial non-ampullary duodenal carcinomas (NADCs) between intramucosal and submucosal invasive carcinoma for treatment selection. The aim of this study was to evaluate the clinicopathological differences of intramucosal and submucosal carcinoma. METHODS: This was a retrospective, single-center study comprising 134 patients with 137 superficial NADCs during May 2005 and March 2018. Clinicopathological characteristics and treatment outcomes data were used to perform a comparative analysis of endoscopic findings, preoperative diagnoses of depth of cancer, and treatment outcomes of histologically diagnosed intramucosal and submucosal carcinoma. RESULTS: Of the 137 NADCs, 125 (91%) were intramucosal, and 12 (9%) were submucosal. The proportion of submucosal carcinoma was significantly higher on the oral side of the papilla than on the anal side (16% vs 1%, P = 0.002). Submucosal tumor-like appearance was more frequent in submucosal than in intramucosal carcinoma (58% vs 13%, P = 0.001). There was no significant difference in tumor diameter between the groups, but 33% of submucosal carcinomas were ≤ 10 mm. Correct preoperative diagnosis of depth was achieved in 33% of submucosal carcinoma. Submucosal carcinoma was frequently underestimated when tumor diameters were ≤ 10 mm. Conversely, intramucosal carcinoma was frequently overestimated when the tumor was ≥ 30 mm and had thickness or giant nodules. Lymph node metastasis was found in one submucosal carcinoma patient. CONCLUSIONS: The possibility of submucosal invasion should be considered when NADCs are located on the oral side of the papilla or have submucosal tumor-like appearance even if tumor diameters are ≤ 10 mm.

Low Frequency of Lymph Node Metastases in Patients in the United States With Early-stage Gastric Cancers That Fulfill Japanese Endoscopic Resection Criteria.

BACKGROUND & AIMS: In the West, early gastric cancer is increasingly managed with endoscopic resection (ER). This is, however, based on the assumption that the low prevalence and risk of lymph node metastases observed in Asian patients is applicable to patients in the United States. We sought to evaluate the frequency of and factors associated with metastasis of early gastric cancers to lymph nodes, and whether the Japanese ER criteria are applicable to patients in the US. METHODS: We performed a retrospective study of 176 patients (mean age 68.5 years; 59.1% male; 58.5% white) who underwent surgical resection with lymph node dissection of T1 and Tis gastric adenocarcinomas, staged by pathologists, at 7 tertiary care centers in the US from January 1, 1999, through December 31, 2016. The frequency of lymph node metastases and associated risk factors were determined. RESULTS: The mean size of gastric adenocarcinomas was 23.0 ± 16.6 mm-most were located in the lower-third of the stomach (67.0%), invading the submucosa (55.1%), and moderately differentiated (31.3%). Lymphovascular invasion was observed in 18.2% of lesions. Overall, 20.5% of patients had lymph node metastases. Submucosal invasion (odds ratio, 3.9; 95% CI, 1.4-10.7) and lymphovascular invasion (odds ratio, 4.6; 95% CI, 1.8-12.0) were independently associated with increased risk of metastasis to lymph nodes. The frequency of lymph node metastases among patients fulfilling standard and expanded Japanese criteria for ER were 0 and 7.5%, respectively. CONCLUSIONS: The frequency of lymph node metastases among patients with early gastric cancer in a US population is higher than that of published Asian series. However, early gastric cancer lesions that meet the Japanese standard criteria for ER are associated with negligible risk of metastasis to lymph nodes, so ER can be recommended for definitive therapy. Expanded criteria cancers appear to have a higher risk of metastasis to lymph nodes, so ER may be considered for select cases.

Endoscopic Prediction of Tumor Invasion Depth in Early Gastric Signet Ring Cell Carcinoma.

INTRODUCTION: Signet ring cell carcinoma (SRC) is a poorly differentiated cancer of the stomach. Recent studies imply that early gastric SRC can be well managed by endoscopic resection. Unfortunately, unlike differentiated cancers, the endoscopic features of early gastric SRC have not been well studied. This study evaluated the endoscopic features of early gastric SRC, as well as the risk factors for submucosal (SM) invasion. METHOD: The medical records of patients from 7 tertiary hospitals (Daejeon and Chungcheong province) were reviewed to examine endoscopic findings and clinical data. These patients underwent surgery or endoscopic resection between January 2011 and December 2016 and were divided into 2 groups (derivation group and validation group) in order to develop and validate an endoscopic scoring system for SM invasion. RESULTS: In total, 331 patients (129 in the derivation group and 202 in the validation group) were enrolled in this study. In the derivation group, the risk factors for SM invasion, namely, fold convergence, nodular mucosal change, and deep depression, were identified by logistic regression analysis (ORs 3.4, 5.9, and 6.0, p < 0.05). A depth-prediction score was created by assigning 1 point for fold convergence and 2 points for other factors. When validation lesions of 0.5 point or more were diagnosed as SM invasion, the sensitivity and specificity were 76.8-78.6% and 61.6-74.7% respectively. CONCLUSION: Fold convergence, nodular mucosal change, and deep depression are risk factors for SM invasion in early gastric SRC. Our depth-prediction scoring system may be useful for differentiating SM cancers.

Potential of Helicobacter pylori-uninfected signet ring cell carcinoma to invade the submucosal layer.

BACKGROUND AND AIM: The typical histology of Helicobacter pylori-uninfected gastric cancer is signet ring cell carcinoma (SRCC) localized in the mucosal layer, but the potential of these SRCCs to invade the submucosal layer is unclear. This study aimed to investigate the clinicopathological characteristics of SRCC in H. pylori-uninfected patient and its prevalence in diffuse-type gastric cancer (DGC) within Japan. METHODS: We enrolled consecutive pure DGC patients diagnosed with the disease either localized in the mucosal layer or with submucosal invasion. H. pylori infection was investigated, and the patients were divided into three groups according to histological types: pure SRCC, SRCC with poorly differentiated adenocarcinoma (PDA), and pure PDA. RESULTS: Of the 345 pure DGC patients, 132 (38%), 127 (37%), and 86 (25%) had pure SRCC, SRCC with PDA, and pure PDA histologies, respectively. The prevalence of H. pylori infection and the SM ratio were significantly lower in the pure SRCC group than other groups (P < 0.01). Twenty-two (6.4%) patients, including two with submucosal invasion, were negative for H. pylori and had mucosal SRCC component in the cancer lesions. Of the 259 SRCC cases (pure SRCC or SRCC + PDA), H. pylori-uninfected cases had different clinicopathological characteristics compared with H. pylori-positive cases. Particularly, the ratio of patients with submucosal invasive SRCC was significantly lower in the H. pylori-uninfected gastric cancer group than in those with H. pylori infection. CONCLUSION: Helicobacter pylori-uninfected gastric cancer is not rare among pure DGC patients in Japan. SRCC in patients without H. pylori infection is less likely to be invasive.

The Role of an Undifferentiated Component in Submucosal Invasion and Submucosal Invasion Depth After Endoscopic Submucosal Dissection for Early Gastric Cancer.

BACKGROUND/AIMS: The role of an undifferentiated component in submucosal invasion and submucosal invasion depth (SID) for lymph node metastasis (LNM) of early gastric cancer (EGC) with deep submucosal invasion (SID ≥500 µm from the muscularis mucosa) after endoscopic submucosal dissection (ESD) has not been fully understood. This study aimed to clarify the risk factors (RFs), including these factors, for LNM in such patients. METHODS: We enrolled 513 patients who underwent radical surgery after ESD for EGC with deep submucosal invasion. We evaluated RFs for LNM, including an undifferentiated component in submucosal invasion and the SID, which was subdivided into 500-999, 1,000-1,499, 1,500-1,999, and ≥2,000 µm. RESULTS: LNM was detected in 7.6% of patients. Multivariate analysis revealed that an undifferentiated component in submucosal invasion (OR 2.22), in addition to tumor size >30 mm (OR 2.51) and lymphatic invasion (OR 3.07), were the independent RFs for LNM. However, the SID was not significantly associated with LNM. CONCLUSION: An undifferentiated component in submucosal invasion was one of the RFs for LNM, in contrast to SID, in patients who underwent ESD for EGC with deep submucosal invasion. This insight would be helpful in managing such patients.

Endoscopic submucosal dissection for early gastric cancer on the lesser curvature in upper third of the stomach is a risk factor for postoperative delayed gastric emptying.

BACKGROUND: Advances in Endoscopic submucosal dissection (ESD) technology have established ESD for early gastric cancer as a safe and stable technique. However, ESD may induce delayed gastric emptying and the cause of food residue retention in the stomach after ESD is not clear. This study aimed to clarify risk factors for delayed gastric emptying with food retention after gastric ESD. METHODS: We retrospectively examined for food residue in the stomach 1 week after ESD was performed for early gastric carcinoma at Osaka Saiseikai Nakatsu Hospital from February 2008 to November 2016. RESULTS: Food residue was observed in 68 (6.1%) of 1114 patients who underwent gastric ESD. The percentage of lesions located on the lesser curvature of the upper third of the stomach was 45.6% (31/68) in the food residue group and 3.5% (37/1046) in the non-food residue group, which was significantly different (P < 0.01). Multivariate logistic regression analysis revealed that lesions on the lesser curvature of the upper third of the stomach (Odds ratio [OR] 23.31, 95% confidence interval [CI] 12.60-43.61, P < 0.01), post-ESD bleeding (OR 4.25, 95%CI 1.67-9.80, P < 0.01), submucosal invasion (OR 2.80, 95%CI 1.34-5.63, P < 0.01), and age over 80 years (OR 2.34, 95%CI 1.28-4.22, P < 0.01) were independent risk factors for food retention after gastric ESD. Of the 68 patients, 3 had food residue in the stomach on endoscopic examination for follow-up observation after the ESD ulcer had healed. CONCLUSIONS: Delayed gastric emptying with food retention after gastric ESD was associated with lesions located in the lesser curvature of the upper stomach, submucosal invasion of the lesion, age older than 80 years, and post-ESD bleeding, though it was temporary in most cases.

Downregulation of microRNA-100/microRNA-125b is associated with lymph node metastasis in early colorectal cancer with submucosal invasion.

A majority of early colorectal cancers (CRCs) with submucosal invasion undergo surgical operation, despite a very low incidence of lymph node metastasis. Our study aimed to identify microRNAs (miRNAs) specifically responsible for lymph node metastasis in submucosal CRCs. MicroRNA microarray analysis revealed that miR-100 and miR-125b expression levels were significantly lower in CRC tissues with lymph node metastases than in those without metastases. These results were validated by quantitative real-time PCR in a larger set of clinical samples. The transfection of a miR-100 or miR-125b inhibitor into colon cancer HCT116 cells significantly increased cell invasion, migration, and MMP activity. Conversely, overexpression of miR-100 or miR-125b mimics significantly attenuated all these activities but did not affect cell growth. To identify target mRNAs, we undertook a gene expression array analysis of miR-100-silenced HCT116 cells as well as negative control cells. The Ingenuity Pathway Analysis, TargetScan software analyses, and subsequent verification of mRNA expression by real-time PCR identified mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 receptor (IGF1R) as direct, and Fas and X-linked inhibitor-of-apoptosis protein (XIAP) as indirect candidate targets for miR-100 involved in lymph node metastasis. Knockdown of each gene by siRNA significantly reduced the invasiveness of HCT116 cells. These data clearly show that downregulation of miR-100 and miR-125b is closely associated with lymph node metastasis in submucosal CRC through enhancement of invasion, motility, and MMP activity. In particular, miR-100 may promote metastasis by upregulating mTOR, IGF1R, Fas, and XIAP as targets. Thus, miR-100 and miR-125b may be novel biomarkers for lymph node metastasis of early CRCs with submucosal invasion.

Diagnostic performance of conventional endoscopy in the identification of submucosal invasion by early gastric cancer: the "non-extension sign" as a simple diagnostic marker.

BACKGROUND AND AIM: The ability to differentiate between mucosal (M) or microinvasive submucosal (SM1: depth of less than 500 µm) and invasive submucosal (SM2: depth of 500 µm or more) cancer is paramount when choosing the method of treatment for early gastric cancer (EGC). The "non-extension sign" relates to a localized increase in thickness and rigidity due to massive submucosal invasion by a cancer. The present study sought to assess the ability of conventional endoscopy (CE) to correctly identify SM2 cancer using only the non-extension sign. METHODS: This is a retrospective study based on a prospectively collected database. EGCs had been diagnosed according to invasion depth as M-SM1 or SM2. In terms of the endoscopic diagnostic criterion, lesions positive for the non-extension sign were classified as SM2 cancers, while those negative for the non-extension sign were classified as M-SM1 cancers. Histopathological findings were used as the gold standard. RESULTS: We examined a total of 863 lesions from 704 patients, comprising 104 true-positive, 733 true-negative, 9 false-positive, and 17 false-negative lesions. This yielded a sensitivity of 92.0 % (95 % confidence interval (CI), 87.0-97.0 %), a specificity of 97.7 % (95 % CI, 96.7-98.8 %), a positive predictive value of 85.9 % (95 % CI, 79.7-92.1 %), a negative predictive value of 98.8 % (95 % CI, 98.0-99.6 %), and a diagnostic accuracy of 96.9 % (95 % CI, 95.8-98.1 %). CONCLUSION: The non-extension sign may be useful for accurately determining the suitability of minimally invasive endoscopic treatment. Nevertheless, considering the limitations of retrospective analysis, a further prospective study is warranted to confirm the diagnostic reliability of the non-extension sign.

Is the assessment of submucosal invasion still useful in the management of early rectal cancer? A study of 91 consecutive patients.

AIM: The only studies on the prognosis of T1 tumours are old and investigate colic and rectal cancers. Very few studies use Kikuchi's classification (of dividing submucosa into three strata) to evaluate the depth of the submucosal invasion. This study aimed to assess the pathological risk factors for lymph node metastasis (LNM), and the pathological and oncological results of patients with early rectal cancer (ERC, pT1 tumour). METHOD: Between 2000 and 2014, 91 consecutive patients undergoing surgery [primary total mesorectal excision (TME) or local excision (LE) alone, or LE followed by TME] for ERC were included. RESULTS: Eighteen patients underwent LE, 22 underwent LE followed by TME and 51 underwent primary total TME. After TME (n = 73), 16 (23%) patients had LNM. The LNM rate was 15% for Sm1 tumours, 14% for Sm2 tumours and 30% for Sm3 tumours. In multivariate analysis, lymphovascular invasion (P = 0.027) and high tumour budding (P = 0.037) were the only independent factors predictive of LNM. The depth of submucosal invasion was not associated with an increased risk of LNM. After a mean follow up of 56 ± 46 months, 5-year overall survival, specific survival and disease-free survival were, respectively, 82%, 93% and 75%. No significant difference of survival was found according to the depth of submucosal invasion or to the surgical management. CONCLUSION: Histological features seem to be stronger risk factors for LNM than depth of submucosal invasion. Considering the LNM rate, TME should be discussed after LE in terms of one of these pathological criteria.

Can endoscopic papillectomy be curative for early ampullary adenocarcinoma of the ampulla of Vater?

BACKGROUND: The therapeutic role of endoscopic papillectomy (EP) for early ampullary cancer (AC) is still controversial. The aim of the present study was to evaluate the curative potential of EP for early AC and to identify predictors of lymph node metastases (LNMs). METHODS: We retrospectively reviewed 173 patients who were prospectively included in a database and who underwent EP between 1999 and 2013. Adenocarcinoma was present in 28 resected specimens. An additional surgery was proposed in cases of duodenal submucosal infiltration, duct ingrowth, R1 resection or lymphovascular invasion. Clinicopathological information and outcomes were collected, and predictors of LNMs were evaluated. RESULTS: Duodenal submucosal invasion was present in 16/28 cases and LNMs, in 9/28 cases. ACs of the biliopancreatic subtype were smaller (NS); 100 % had submucosal invasion, and 71 % had LNMs. Smaller tumour size, biliopancreatic subtype and submucosal invasion were significantly correlated with LNMs (p < 0.028, p < 0.028 and p < 0.014). Predictive factors of LNMs in the multivariate analysis were submucosal invasion and tumour size (OR 0.032, p < 0.023 and OR 0.711, p < 0.035). EP was curative in 100 % of cancers with R0 resection and no evidence of submucosal or lymphovascular invasion. CONCLUSION: EP may be curative for patients with AC limited to the duodenal mucosa or the sphincter of Oddi without lymphovascular invasion. Due to the presence of more invasive stages at diagnosis, EP may not be curative for ACs of the biliopancreatic subtype. The significance of tumour size is limited by other confounders, such as the histological subtype.

Early-stage adenocarcinoma of the esophagus with mid to deep submucosal invasion (pT1b sm2-3): the frequency of lymph-node metastasis depends on macroscopic and histological risk patterns.

The rate of lymph-node (LN) metastasis in early adenocarcinoma (EAC) of the esophagus with mid to deep submucosal invasion (pT1b sm2/3) has not yet been precisely defined. The aim of the this study was to evaluate the rate of LN metastasis in pT1b sm2/3 EAC depending on macroscopic and histological risk patterns to find out whether there may also be options for endoscopic therapy as in cancers limited to the mucosa and the upper third of the submucosa. A total of 1.718 pt with suspicion of EAC were referred for endoscopic treatment (ET) to the Dept. of Internal Medicine II at HSK Wiesbaden 1996-2010. In 230/1.718 pt, the suspicion (endoscopic ultrasound, EUS) or definitive diagnosis of pT1b EAC (ER/surgery) was made. Of these, 38 pt had sm2 lesions, and 69 sm3. Rate of LN metastasis was analyzed depending on risk patterns: histologically low-risk (hisLR): G1-2, L0, V0; histologically high-risk (hisHR): ≥1 criterion not fulfilled; macroscopically low-risk (macLR): gross tumor type I-II, tumor size ≤2 cm; macroscopically high-risk (macHR): ≥1 criterion not fulfilled; combined low-risk (combLR): hisLR+macLR; combined high-risk (combHR): at least 1 risk factor. LN rate was only evaluated in pt who had proven maximum invasion depth of sm2/sm3, and who in case of ET had a follow-up (FU) by EUS of at least 24 months. 23/38 pt with pT1b sm2 lesions and 39/69 pt with sm3 lesions fulfilled our inclusion criteria. In the pT1b sm2 group, rate of LN metastasis in the hisLR, hisHR, combLR, and combHR groups were 8.3% (1/12), 36.3% (4/11), 0% (0/5), and 27.8% (5/18). In the pT1b sm3 group, rate of LN metastasis in the hisLR, hisHR, combLR and combHR groups were 28.6% (2/7), 37.5% (12/32), 25% (1/4), and 37.1% (13/35). 30-day mortality of surgery was 1.7% (1/58 pt). In EAC with pT1b sm2/3 invasion, the frequency of LN metastasis depends on macroscopic and histological risk patterns. Surgery remains the standard treatment, because the rate of LN metastasis appears to be higher than the mortality risk of surgery. Whether a highly selected group of pT1b sm2 patients with a favourable risk pattern may be candidates for endoscopic therapy cannot be decided until the results of larger case volumes are available.