Poor Tumor Differentiation Research Articles

Tumor budding in gastric adenocarcinoma; reflections on tumor microenvironment and programmed death ligand 1 (PD-L1) expression

Introduction: The significance of tumor budding and programmed death ligand 1 (PD-L1) has not been established in gastric adenocarcinoma (GAC). Objectives: This study evaluated tumor budding and PD-L1 expression with regard to tumor microenvironment, clinicopathologic parameters, and overall survival in GAC. Patients and Methods: Totally, 102 GAC cases were assessed immunohistochemically. The associations of tumor budding and PD-L1 with clinicopathologic features, tumor-infiltrating lymphocytes (TILs), tumor stroma percentage (TSP), and overall survival were analyzed. Results: High tumor budding (42.2% of cases) was correlated with distal tumor location, large tumor size, Helicobacter pylori infection, poor differentiation (P = 0.0008, 0.033, 0.011, and 0.005, respectively), lymphovascular invasion, high tumor and nodal stages, and TSP (all P < 0.0001). Tumor budding was highest in the low TILs/high TSP group. PD-L1 expression (43.1% of cases) was correlated with proximal location (p = 0.00021), poor differentiation (P = 0.036), N stage (P = 0.049), high TILs (P < 0.0001), and low tumor budding (P = 0.002). PD-L1 expression was highest in the low tumor budding / high TILs category (P < 0.0001). Cox regression showed that high tumor budding (hazard ratio [HR]: 15.282, P = 0.024, 95% confidence interval [CI]: 1.441–162.069) and positive PD-L1 (HR: 7.502, P = 0.015, 95% CI: 1.469–38.31) were independent prognostic factors for overall survival. Conclusion: Tumor budding is correlated with poor prognostic parameters, whereas PD-L1 expression is inversely correlated with tumor budding. Both are independent predictors of short overall survival. Anti-PD-L1 immunotherapy could be effective in GAC with nodal metastasis, especially cases with high TILs and low tumor budding.

Risk Factors of Early Liver Metastasis for Pancreatic Ductal Adenocarcinoma after Radical Resection.

Background Liver metastasis arises in many postoperative patients with PDAC, occurring in the early stage appears to lead to a very poor prognosis. Objective We aimed to analyze the risk factors for early liver metastasis after radical resection for patients with pancreatic ductal adenocarcinoma (PDAC) and to indicate the poor prognosis of early liver metastasis. Methods Patients who underwent pancreatectomy for PDAC at the Ningbo Medical Centre Lihuili Hospital between January 2015 and June 2021 were included. The exclusion criteria were death within 30 days after the operation, complications with other malignancies, and a positive final resection margin (R1). Liver metastasis and its occurrence time were recorded, and risk factors for early (≤6 months) liver metastasis were analyzed by logistic regression models. The prognosis of patients with early liver metastasis and different recurrence patterns was analyzed by Kaplan–Meier curves and the log-rank test. Results From the identified cohort of 184 patients, 172 patients were included for further analysis. 55 patients developed early liver metastasis within 6 months after the operation. Univariate analysis showed that CA125 ≥ 30 IU/ml, tumor size ≥ 4 cm, poor tumor differentiation, and portal vein/superior mesenteric vein (PV/SMV) reconstruction were risk factors, and multivariate analysis showed that poor tumor differentiation and PV/SMV reconstruction were independent risk factors for early liver metastasis. The prognosis of liver metastasis was the worst among the different recurrence patterns. Early liver metastasis indicates a poor prognosis in patients with PDAC. Conclusions Poor differentiation and PV/SMV reconstruction are independent risk factors for early liver metastasis in patients with PDAC, and early liver metastasis indicates a poor prognosis.

Survival analysis of patients with early and standard onset colorectal cancer: A single center study.

e15512 Background: While more aggressive clinical/pathological features have been consistently described in between patients with early-onset (EO) and standard-onset (SO) colorectal cancer (CRC), survival data have been conflicting. While some studies report better survival rates for EO-CRC; others found that outcomes among groups are not different. In a prior study, using the Surveillance, Epidemiology and End Results (SEER), we reported that cancer-related survival did not differ between EO-CRC and SO-CRC; however, a main limitation was the lack of molecular status and treatment details among groups. This study aims to compare the survival of EO-CRC and SO-CRC patients at Montefiore Medical Center. Methods: Retrospective cohort among 690 patients diagnosed with metastatic colorectal cancer (CRC) at Montefiore Medical Center between 2010 and 2018. Patients were identified using the software Clinical Looking Glass and charts were reviewed manually to gather information about demographics (race/ethnicity defined as Non-Hispanic White [NHW], Non-Hispanic Black [NHB] and Hispanic [H], gender, comorbidity index, calculated using the Charlson comorbidity score), clinicopathological features (grade, tumor sidedness, K-ras mutation) and treatment-related characteristics (metastatectomy, lines of chemotherapy and use of biologics). EO-CRC was defined as CRC diagnosis before age 50 and SO-CRC as CRC diagnosed at 50 years or older. Overall survival was compared between EO-CRC and SO-CRC using Kaplan Meier and Cox regression analyses. Stata v15.1 was used for statistical analysis. Results: Of 690 patients with CRC, 139 (20.1%) had EO-CRC and 551 (79.9%) had SO-CRC. Participants with EO-CRC had a higher frequency of poorly-differentiated tumors (35.5% vs. 23.8%, p = 0.02), a lower comorbidity index (6 vs. 7, p < 0.001). and a higher use of biologics (70.5% vs. 60.8%, p = 0.03) compared to SO-CRC. K-ras mutation was available for 377 (54.5%) of cases and did not differ among groups (45.9% vs. 45.9%, p = 0.99). In a model adjusted for race/ethnicity, gender, comorbidity index, sidedness, use of biologics and metastatectomy, there was no difference in mortality among groups (HR:0.9, 95%CI: 0.58 – 1.43, p = 0.68). This result remained unchanged in a model restricted to patients with available K-ras-status (n = 75), adjusted for all these variables. Conclusions: Despite more aggressive clinical/pathological features in patients with EO-CRC, survival does not differ compared to SO-CRC.

Contrast-enhanced CT radiomics for prediction of recurrence-free survival in gallbladder carcinoma after surgical resection.

Gallbladder carcinoma (GBC) is the most common and aggressive biliary tract malignancy with high postoperative recurrence rates. This single-center study aimed to develop and validate a radiomics signature to estimate GBC recurrence-free survival (RFS). This study retrospectively included 204 consecutive patients with pathologically diagnosed GBC and were randomly divided into development (n = 142) and validation (n = 62) cohorts (7:3). The radiomics features of tumor were extracted from preoperative contrast-enhanced CT imaging for each patient. In the development cohort, the least absolute shrinkage and selection operator (LASSO) Cox regression was employed to develop a radiomics signature for RFS prediction. The patients were stratified into high-score or low-score groups according to their median value of radiomics score. A nomogram was established using multivariable Cox regression by incorporating significant pathological predictors and radiomics signatures. The radiomics signature based on 12 features could discriminate high-risk patients with poor RFS. Multivariate Cox analysis revealed that pT3/4 stage (hazard ratio, [HR] = 2.691), pN2 stage (HR = 3.60), poor differentiation grade (HR = 2.651), and high radiomics score (HR = 1.482) were independent risk variables associated with worse RFS and were incorporated to construct a nomogram. The nomogram displayed good prediction performance in estimating RFS with AUC values of 0.895, 0.935, and 0.907 at 1, 3, and 5 years, respectively. The radiomics signature and combined nomogram may assist in predicting RFS in GBC patients. • A radiomics signature extracted from preoperative contrast-enhanced CT can be a useful tool to preoperatively predict RFS of GBC. • T3/T4 stage, N2, poor tumor differentiation, and high radiomics score were positively associated with postoperative recurrence.

Metastatic conjunctival squamous cell carcinoma: a study of 5 patients.

To describe the risk factors, clinical features, management, and outcomes in patients with metastatic conjunctival squamous cell carcinoma (mcSCC). Retrospective comparative study. Of the 1192 cases with ocular surface squamous neoplasia during the study period, 654 (55%) patients were biopsied and 223 (19%) had invasive squamous cell carcinoma (cSCC). Of these 223 patients with cSCC, locoregional metastasis developed in 4 (2%) and distant metastasis in 1 (0.4%) patient. Mean age at diagnosis of OSSN was 48years (median, 40years; range 35-74years). Tumors belonged to T2 (n = 2; 40%) and T4a (n = 3; 60%) at presentation. Primary treatment modalities included topical and subconjunctival interferon α 2B immunotherapy (n = 2; 40%), extended enucleation (n = 1; 20%) and orbital exenteration (n = 2; 40%). Metastases were noted after a mean period of 22months of onset of primary tumor (median, 18months; range 2-46months). Death from metastatic disease occurred in all patients over a mean follow-up period of 21months (median, 11months; range 1-46months). Bivariate regression analysis revealed smoking (p = 0.037, Odds Ratio (OR) = 0.13), tumor thickness ≥ 5mm (p = 0.015, OR = 17.78), orbital invasion (p = 0.018, OR = 1.00), and poor histopathological differentiation (p = 0.031, OR = 10.44) to be significant risk factors for mcSCC. Metastatic disease in cSCC is rare and risk factors for metastasis include smoking, thicker tumors, orbital tumor extension, and poor tumor differentiation. mcSCC is associated with high mortality.

Risk factors for cervical lymph node metastasis of head and neck squamous cell carcinoma: A retrospective population–based study

IntroductionHead and neck squamous cell carcinoma (HNSCC) is characterized by high frequency of early cervical lymph node metastases (LNMs), resulting in poor survival of patients. However, cervical LNMs are difficult to detect, which makes the decision–making of which patients should undergo neck dissection surgery challenging for surgeons. This study aimed to analyze the clinicopathological risk factors associated with cervical LNM and determine the indications for neck dissection in HNSCC patients. MethodsThe medical records of patients diagnosed with HNSCC who were treated at our hospital between January 2010 and June 2020 were retrospectively reviewed. A database of their clinicopathological data, including sex, age at diagnosis, primary tumor regions, tumor size, and grade, was constructed. The associations of these clinicopathological features with cervical LNM were analyzed using univariate and multivariate logistic regression analyses. The TCGA database were used to externally validate the risk factors. ResultsOverall, 531 patients with HNSCC were included; 38.6% had confirmed pathological cervical LNM. Univariate and multivariate analyses identified that tumor size and grade were independent risk factors associated with LNM (odds ratio = 1.338, 95% CI: 1.015–1.767, p < 0.05; odds ratio = 1.936, 95% CI: 1.46–2.587, p < 0.0001, respectively). The significant positive associations of tumor size and grade with LNM were externally validated in the TCGA datasets. ConclusionsHNSCC patients with large tumor size or poor tumor differentiation degree were at high risk of lymph node metastasis and were recommended to undergo neck dissection.

Management of adrenocorticotropic hormone-secreting neuroendocrine tumors and the role of bilateral adrenalectomy in ectopic Cushing syndrome

BackgroundNeuroendocrine tumors can cause ectopic Cushing syndrome, and most patients have metastatic disease at diagnosis. We identified risk factors for outcome, evaluated ectopic Cushing syndrome management, and explored the role of bilateral adrenalectomy in this population. MethodsThis was a retrospective study including patients with diagnosis of ectopic Cushing Syndrome secondary to neuroendocrine tumors with adrenocorticotropic hormone secretion treated at our quaternary referral center over a 40-year period (1980–2020). ResultsSeventy-six patients were included. Mean age at diagnosis was 46.3 ± 15.8 years. Most patients (N = 61, 80%) had metastases at ectopic Cushing syndrome diagnosis. Average follow-up was 2.9 ± 3.7 years (range, 4 months–17.2 years). Patients with neuroendocrine tumors before ectopic Cushing syndrome had more frequent metastatic disease and resistant ectopic Cushing syndrome. Patients with de novo hyperglycemia, poor neuroendocrine tumor differentiation, and metastatic disease had worse survival. Of those with nonmetastatic disease, 8 (53%) had ectopic Cushing syndrome resolution after neuroendocrine tumor resection, 3 (20%) were medically controlled, and 4 (27%) underwent bilateral adrenalectomy. In patients with metastatic neuroendocrine tumors, hypercortisolism was initially medically managed in 92%, 3% underwent immediate bilateral adrenalectomy, 2% had control after primary neuroendocrine tumor debulking, and 2% were lost to follow-up. Medical treatment resulted in hormonal control in 7 (13%) patients. Of the 49 patients with metastatic disease and medically resistant ectopic Cushing syndrome, 23 ultimately had bilateral adrenalectomy with ectopic Cushing syndrome cure in all. ConclusionPatients with neuroendocrine tumors before ectopic Cushing syndrome development were more likely metastatic and had worse survival. De novo hyperglycemia and poor neuroendocrine tumor differentiation were predictive of worse prognosis. Medical control of hypercortisolism is difficult to achieve in patients with neuroendocrine tumors–ectopic Cushing syndrome. Well-selected patients may benefit from bilateral adrenalectomy early in the treatment algorithm, and multidisciplinary management is essential in this complex disease.

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

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. 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. 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). 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.

Patient and pathological predictors of management strategy for malignant polyps following polypectomy: a systematic review and meta-analysis

PurposeMalignant polyps present a treatment dilemma for clinicians and patients. This meta-analysis sought to identify the factors that predicted the management strategy for patients diagnosed with a malignant polyp.MethodsA literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Cochrane Collaboration prognostic studies guidelines. Reports from 1985 onwards were included, data on patient and pathological factors were extracted and random effects meta-analysis models were used.ResultsFifteen studies were included. Seven studies evaluated lymphovascular invasion (LVI). The odds of surgery were significantly higher in malignant polyps with LVI (OR 2.20, 95% CI 1.36–3.55). Ten studies revealed the odds of surgery were significantly higher with positive polypectomy margins (OR 8.09, 95% CI 4.88–13.40). Tumour differentiation was compared in eight studies. There were significantly lower odds of surgery in malignant polyps with well/moderate differentiation compared with poor differentiation (OR 0.31, 95% CI 0.21–0.46). There were non-significant trends favouring surgical resection in younger patients, males and Haggitt 4/Kikuchi Sm3 lesions. There was considerable heterogeneity in the meta-analyses for the variables age, gender, polyp morphology and Haggitt/Kikuchi level (I2 > 75%).ConclusionThis meta-analysis has demonstrated that LVI, positive polypectomy resection margins, and poor tumour differentiation significantly predict malignant polypectomy patients who underwent subsequent surgery. Age and gender were important factors predicting management, but not consistently across studies, whilst polyp morphology and Haggitt/Kikuchi levels did not significantly predict the management strategy. Further research may assist in understanding the management preferences.

Recurrence After Resection of Pancreatic Cancer: Can Radiomics Predict Patients at Greatest Risk of Liver Metastasis?

Liver metastasis (LM) after pancreatic ductal adenocarcinoma (PDAC) resection is common but difficult to predict and has grave prognosis. We combined preoperative clinicopathological variables and quantitative analysis of computed tomography (CT) imaging to predict early LM. We retrospectively evaluated patients with PDAC submitted to resection between 2005 and 2014 and identified clinicopathological variables associated with early LM. We performed liver radiomic analysis on preoperative contrast-enhanced CT scans and developed a logistic regression classifier to predict early LM (< 6 months). In 688 resected PDAC patients, there were 516 recurrences (75%). The cumulative incidence of LM at 5 years was 41%, and patients who developed LM first (n = 194) had the lowest 1-year overall survival (OS) (34%), compared with 322 patients who developed extrahepatic recurrence first (61%). Independent predictors of time to LM included poor tumor differentiation (hazard ratio (HR) = 2.30; P < 0.001), large tumor size (HR = 1.17 per 2-cm increase; P = 0.048), lymphovascular invasion (HR = 1.50; P = 0.015), and liver Fibrosis-4 score (HR = 0.89 per 1-unit increase; P = 0.029) on multivariate analysis. A model using radiomic variables that reflect hepatic parenchymal heterogeneity identified patients at risk for early LM with an area under the receiver operating characteristic curve (AUC) of 0.71; the performance of the model was improved by incorporating preoperative clinicopathological variables (tumor size and differentiation status; AUC = 0.74, negative predictive value (NPV) = 0.86). We confirm the adverse survival impact of early LM after resection of PDAC. We further show that a model using radiomic data from preoperative imaging combined with tumor-related variables has great potential for identifying patients at high risk for LM and may help guide treatment selection.

Expression of glucose transporter 1 (SLC2A1) - Clinicopathological associations and survival in an Indian cohort of colorectal cancer patients.

Glucose transporter 1 (GLUT1) facilitates the uptake of glucose in malignant cells. We investigated GLUT1 transcript expression in colorectal cancer (CRC) tumors and explored its relationship to clinicopathological features, diabetes condition, and patient survival. The expression of GLUT1 was determined using fluorescent probe-based quantitative real-time polymerase chain reaction assay of tumor tissue and corresponding normal mucosa from 180 archived formalin-fixed, paraffin-embedded tissue blocks of ninety upfront surgically resected colorectal adenocarcinoma cases. Clinical information was collected from the hospital medical records and statistical analyses were performed. Compared to normal mucosa tissue, the GLUT1 expression was significantly elevated in CRC tumor tissue (0.024 ± 0.056 vs. 0.004 ± 0.005; P < 0.0001). The expression was significantly more in poorly differentiated tumors than well/moderately differentiated tumors (P = 0.024) and in patients with liver metastasis (P = 0.013). The high GLUT1 expression correlated with advanced tumor stage (P = 0.003), liver metastasis (P = 0.003), poor tumor differentiation (P = 0.02), and death (P = 0.001). In univariate Cox regression analysis for survival, high GLUT1 expression, presence of any comorbidity, diabetic condition, advanced or metastatic stage, and liver metastasis were significant risk factors for death. CRC patients with high GLUT1 expression showed worse survival outcomes than those with low GLUT1 expression (P = 0.001). Furthermore, the high GLUT1/diabetes (+) patients had an inferior survival outcome than the patients with low GLUT1/diabetes (+) condition. GLUT1 is significantly upregulated in colorectal adenocarcinoma. The expression correlated with poor tumor histology, higher stage, hepatic metastases, and adverse survival in the study cohort.

HSPB11 is a Prognostic Biomarker Associated with Immune Infiltrates in Hepatocellular Carcinoma.

PurposeHeat shock proteins (HSPs) play important roles in oncogenesis and malignant progression. HSPB11 is highly expressed in many malignant tumors, but research on its role in hepatocellular carcinoma (HCC) is insufficient.Patients and MethodsA comprehensive analysis of HSPB11 in HCC was performed based on data of patients with HCC and those from online public databases.ResultsHSPB11 was overexpressed in HCC, with a high discrimination ability between tumor and normal tissues (area under the curve =0.923). HSPB11 overexpression correlated with advanced tumor stage, poorer tumor differentiation, and worse prognosis and was an independent risk factor for HCC prognosis. The nomogram and calibration models composed of HSPB11, T stage, and M stage had good abilities to predict the 1-, 3-, and 5-year survival rates of patients. HSPB11 was determined to be involved in multiple oncogenic processes, including cell cycle checkpoints, the G2M checkpoint, E2F targets, Rho GTPases, and KRAS signaling. HSPB11 expression was related to immune cell infiltration, especially that of Th2 cells and dendritic cells.ConclusionHSPB11 is involved in oncogenesis and immune regulation in HCC and is a potential prognostic biomarker and therapeutic target.

Impact of ≥ 0.1-mm free resection margins on local intramural residual cancer after local excision of T1 colorectal cancer.

Background and study aims A free resection margin (FRM) > 1 mm after local excision of a T1 colorectal cancer (CRC) is known to be associated with a low risk of local intramural residual cancer (LIRC). The risk is unclear, however, for FRMs between 0.1 to 1 mm. This study evaluated the risk of LIRC after local excision of T1 CRC with FRMs between 0.1 and 1 mm in the absence of lymphovascular invasion (LVI), poor differentiation and high-grade tumor budding (Bd2–3). Patients and methods Data from all consecutive patients with local excision of T1 CRC between 2014 and 2017 were collected from 11 hospitals. Patients with a FRM ≥ 0.1 mm without LVI and poor differentiation were included. The main outcome was risk of LIRC (composite of residual cancer in the local excision scar in adjuvant resection specimens or local recurrence during follow-up). Tumor budding was also assessed for cases with a FRM between 0.1 and 1mm. Results A total of 171 patients with a FRM between 0.1 and 1 mm and 351 patients with a FRM > 1 mm were included. LIRC occurred in five patients (2.9 %; 95 % confidence interval [CI] 1.0–6.7 %) and two patients (0.6 %; 95 % CI 0.1–2.1 %), respectively. Assessment of tumor budding showed Bd2–3 in 80 % of cases with LIRC and in 16 % of control cases. Accordingly, in patients with a FRM between 0.1 and 1 mm without Bd2–3, LIRC was detected in one patient (0.8%; 95 % CI 0.1–4.4 %). Conclusions In this study, risks of LIRC were comparable for FRMs between 0.1 and 1 mm and > 1 mm in the absence of other histological risk factors.

Combination of IL-34 and AFP improves the diagnostic value during the development of HBV related hepatocellular carcinoma

IL-34 involves in host immunity regulated carcinogenesis. Alpha-fetoprotein (AFP) is related to the development of HCC. We explored if combination of IL-34 and APF could improve the diagnostic value in HBV related hepatocellular carcinoma (HBV-HCC). Serum was obtained from HBV patients or healthy control. Liver tissue was obtained from liver biopsy in CHB, HBV related cirrhosis patients or curative resection in HBV-HCC patients. Serum IL-34 and MCSF, or intrahepatic IL-34, MCSF and CD68+ tumor associate macrophages (TAMs) were determined using ELISA or immunohistochemistry. Serum IL-34 was 1.7, 1.3 or 2.3-fold higher in HBV-HCC than that of CHB, HBV related cirrhosis or healthy control, which was inhibited following trans-hepatic arterial chemoembolization (TACE) in HBV-HCC patients. Intra-hepatic IL-34 was higher in HBV-HCC than that of the other three groups. Intra-hepatic IL-34 was associated with high HBV-DNA, HBeAg−, poor differentiation and small tumor size of HBV-HCC patients. Intra-hepatic TAMs in HBV-HCC were increased 1.7 or 1.3-fold, compared to that from CHB or HBV-cirrhosis patients. Intra-hepatic TAMs were associated with high HBV-DNA, high tumor differentiation, small tumor size, abnormal AFP and more tumor number. AFP plus serum IL-34, showed the highest AUC (0.837) with sensitivity (0.632) and highest specificity (0.931), suggesting that AFP plus IL-34 enhances the reliability for prediction of the development of HBV-HCC among CHB patients. Circulating and intra-hepatic IL-34 was upregulated gradually in HBV disease progression from CHB, cirrhosis and HCC. IL-34 may be used as a diagnostic biomarker and potential therapeutic target for the management of HBV-HCC.

Male-specific long non-coding RNA testis-specific transcript, Y-linked 15 promotes gastric cancer cell growth by regulating Wnt family member 1/β-catenin signaling by sponging microRNA let-7a-5p

ABSTRACT The present study is aimed to investigate the regulatory effects and related mechanism of long non-coding RNA testis-specific transcript, Y-linked 15 (TTTY15) in gastric carcinoma (GC) cell proliferation, migration, invasion, apoptosis and epithelial–mesenchymal transition (EMT). TTTY15 expression in GC tissue samples and cells was detected by quantitative real-time PCR (qRT-PCR), and the correlation between TTTY15 expression and GC clinicopathological indicators was analyzed. Cell counting kit-8 (CCK-8), BrdU, flow cytometry and Transwell assays were performed for detecting GC cell proliferation, migration, invasion and apoptosis. Western blot was performed for detecting the expressions of EMT-associated proteins (N-cadherin and E-cadherin), Wnt family member 1 (Wnt1) protein and β-catenin protein. Bioinformatics analysis was conducted to predict, and RNA immunoprecipitation (RIP) assay and dual-luciferase reporter gene assay were performed to verify the targeted relationships of microRNA let-7a-5p (let-7a-5p) with TTTY15 and Wnt1 mRNA 3'UTR. It was found that TTTY15 expression was significantly up-regulated in GC tissues and cells, and was associated with advanced TNM stage and poor tumor differentiation. TTTY15 overexpression promoted GC cell proliferation, migration and invasion, the expressions of N-cadherin, Wnt1 and β-catenin protein, and inhibited the apoptosis and E-cadherin expression, while knocking down TTTY15 had the opposite effects. TTTY15 directly targeted let-7a-5p and negatively regulated its expression. Wnt1 was the target gene of let-7a-5p, and TTTY15 could indirectly and positively regulate Wnt1 expression. In conclusion, TTTY15 promotes GC progression, by regulating the let-7a-5p/Wnt1 axis to activate the Wnt/β-catenin pathway.

Parafibromin Is Highly Expressed in Hepatocellular Carcinoma and Its Expression Correlates with Poor Prognosis

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Much progress has been made regarding the understanding of hepatocarcinogenesis, yet the long-term survival rate of HCC patients remains poor. Recent efforts have shown parafibromin has a pathologic role in many human cancers, but little is known about the effects of parafibromin in HCC. This study aimed to investigate the pattern of parafibromin expression and its clinicopathologic significance in human HCC. Immunohistochemical analysis of HCC and matched non-tumor liver tissues from 50 HCC patients showed that the nuclear expression of parafibromin was higher in HCC tissues (50/50 cases) than in non-tumor liver tissues (17/50 cases). Moreover, elevated parafibromin expression was found to be significantly correlated with the presence of microvascular invasion (p = 0.017), hepatitis virus infection-induced occurrence (p = 0.005), and poorer tumor differentiation (Edmondson–Steiner grade; p = 0.000). Kaplan–Meier analysis showed that HCC patients with elevated parafibromin expression had poorer recurrence-free (p = 0.014, log-rank test = 6.079) and overall survival (p = 0.036, log-rank test = 4.414). These findings indicate parafibromin may be related to the pathogenesis of HCC and a potential prognostic marker for HCC patients after hepatectomy.

Histogram analysis of 18F-FDG PET imaging SUVs may predict the histologic grade of oral squamous cell carcinoma

We tested the hypothesis that histogram analysis parameters of standardized uptake values (SUVs) obtained preoperatively using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) are significantly influenced by differences in metabolic capacity due to the histologic grade of oral squamous cell carcinoma (OSCC). The study included 62 patients who were clinically diagnosed with OSCC and received surgical treatment after an 18F-FDG PET examination. Histogram analysis was performed using all voxels contained in the tumor area of each patient with an SUV ≥2.5. The histogram parameters calculated were the mean and standard deviation of SUVs, maximum SUV, metabolic tumor volume, skewness, and kurtosis. Statistical analyses were performed using a Mann-Whitney U test to calculate the significance of differences in these parameters between groups with well- and moderately- or poorly-differentiated tumors. Statistical significance was assumed at P < .05. Only a comparison of kurtosis in the histogram showed a significant difference between the well- and moderately/poorly-differentiated tumors (P=.0294). The distribution of metabolic capacity in oral squamous cell carcinoma tissues revealed on an 18F-FDG PET examination may help identify the histologic grade. This finding may provide valuable information for determining the subsequent treatment plan and predicting disease prognosis.

Tumour grade and stage are associated with specific body composition phenotypes with visceral obesity predisposing the host to a less aggressive tumour in colorectal cancer

BackgroundSarcopenia, myosteatosis and visceral obesity (VO) are known to negatively impact on outcomes from colorectal cancer (CRC). Little is known about tumour factors associated with these body composition (BC) phenotypes. We aimed to identify whether histopathological tumour characteristics were associated with various BC phenotypes. MethodsA prospectively collected database of patients undergoing surgery for primary CRC at a tertiary referral unit in the United Kingdom was analysed. Sarcopenia, myosteatosis and VO were identified on preoperative CT. Binary logistic regression modelling was performed to determine significant associations between tumour stage, grade and BC phenotype. ResultsFinal analysis included 795 patients; median age 69, 56% male, 65% were sarcopenic, 72% myosteatotic, 52% VO and 20% had sarcopenic obesity (SO). VO patients were significantly less likely to have advanced T Stage (T3-4) OR0.62(95%CI 0.44–0.86, p = 0.005); nodal metastases OR0.60(95%CI 0.44–0.82, p = 0.001); vascular invasion OR0.63(95%CI 0.46–0.88, p = 0.006) and poor tumour differentiation OR0.49(95%CI 0.28–0.86, p = 0.012). Myosteatotic patients were more likely to have metastatic disease OR2.31(95%CI 1.15–4.63, p = 0.018) but less likely to have poorly differentiated tumours OR0.48(95%CI 0.27–0.86, p = 0.013). SO patients were significantly more likely to have poorly differentiated tumours OR2.01(95%CI 1.04–3.87, p = 0.037). ConclusionVO predisposes to earlier stage tumours with a less aggressive tumour phenotype. The SO group have adverse tumour characteristics which may be explained by differences in fat distribution. Myosteatosis relates to increased likelihood of distant metastasis that may be related to a systemic inflammatory response, despite the association with better differentiated tumours.

Clinicopathologic characteristics of early-onset colorectal cancer

The aim of this study was to analysis of the clinicopathological characteristics and prognosis of colorectal cancer (CRC) under the age of 50 years. Between January 2009 and December 2018, 1,126 primary CRC patients were included from National Health Insurance Service Ilsan Hospital. The patients were divided into group 1 (n=111, ≤50 years) and group 2 (n=1,015, >50 years). The clinicopathologic features and prognostic outcomes were compared. In addition, to analyze whether there were any differences of those characteristics in 3 groups, patients aged under 50 years were divided into their 20s, 30s, and 40s. Group 1 had a slightly higher distribution in the left colon and rectum, lower T stage I and higher T stage IV rate, and a significantly higher distribution in stage N2 than group 2 (30.6%:16.3%, P<0.001). Poor histological differentiation of tumors was significantly high in group 1 (P=0.003). The 5-year survival rate for those in their 30s (69.2%) and 40s (91.6%) was higher than those in their 20s who died immediately after surgery (P<0.001). The 5-year disease-free survival rate was also confirmed to be meaningful for each age group, with 0% in their 20s, 53.8% in their 30s, 79.2% in their 40s (P<0.001). Although the age was not an independent prognostic factor for overall survival in this study, the early onset group of CRCs is more advanced at the time of diagnosis and has a more aggressive histologic type.

Metastatic risk profile of microscopic lymphatic and venous invasion in papillary thyroid cancer.

The aim of this study was to define the suitability of microscopic lymphatic and venous invasion for prediction of lymph node and distant metastases in papillary thyroid cancer. Stratification by microscopic lymphatic and venous invasion, and multivariable analyses on lymph node and distant metastases including microscopic lymphatic and venous invasion as independent variables. Tertiary referral centre. 422 patients who had ≥5 lymph nodes removed at initial thyroidectomy. Lymph node and distant metastases. Patients with microscopic lymphatic invasion had larger primary tumours than patients without and more often revealed microscopic venous invasion, multifocal tumour growth and lymph node metastases. Patients with microscopic venous invasion exhibited larger primary tumours than patients without and more commonly had microscopic lymphatic invasion, poor tumour differentiation, lymph node metastases and distant metastases. Prediction of lymph node metastases by microscopic lymphatic invasion was better than prediction of distant metastases by microscopic venous invasion regarding sensitivity (61.0 vs. 33.3%) and positive predictive value (92.6 vs. 20.9%), comparable regarding specificity (89.6 and 93.4%), and worse regarding negative predictive value (51.9 vs. 95.3%) and accuracy (70.1 vs. 87.7%). On multivariable logistic regression analysis, microscopic lymphatic invasion was associated with lymph node metastasis (odds ratio [OR] 11.1) and multifocal tumour growth (OR 2.4), whereas primary tumour size (OR 5.8 for tumours >40mm relative to tumours ≤20mm) and multifocal tumour growth (OR 3.1) were associated with distant metastasis. Stricter histopathological criteria are warranted to enhance the utility of microscopic vascular invasion for prediction of distant metastases in papillary thyroid cancer.