Incidence trends and survival analysis of appendiceal tumors in the United States: Primarily changes in appendiceal neuroendocrine tumors.

BACKGROUND: Appendiceal tumors are considered to be a relatively rare tumor of the gastrointestinal tract and the prognosis is unclear. This study comprehensively investigated trends in the epidemiology and survival of appendiceal tumors in the United States over the past approximately 20 years. METHODS: Patients with pathologically confirmed appendiceal tumors from 2000 to 2017 were selected from the Surveillance, Epidemiology and End Results (SEER) database. Age-adjusted incidence rates were calculated by SEER*Stat 8.4.0. The Kaplan-Meier method was used to analyze survival and prognostic factors were investigated by a multivariate Cox proportional risk model. RESULTS: Ultimately, 13,546 patients with appendiceal tumors between 2000 and 2017 were included. The annual incidence of colonic adenocarcinoma and mucinous adenocarcinoma remained relatively stable. Interestingly, the annual incidence of appendiceal neuroendocrine tumors (aNETs) increased significantly, from 0.03 to 0.90 per 100,000 person-years, with the most dramatic increase in the number of patients with localized disease. Patients with aNETs showed a significant improvement in survival between 2009-2017, compared to the period 2000-2008. Moreover, this improvement in survival over time was seen at all stages (localized, regional, distant) of aNETs. However, this improved survival over time was not seen in colonic and mucinous adenocarcinoma. CONCLUSIONS: The incidence of appendiceal neoplasms has increased significantly over the past nearly two decades, which is mainly due to the increased incidence and significant migration to earlier stages in aNETs. We must note that despite the increased incidence of aNETs, survival rates have improved at different disease stages.

KDM5 family of demethylases promotes CD44-mediated chemoresistance in pancreatic adenocarcinomas.

A growing body of evidence suggests that the histone demethylase-lysine demethylase 5 (KDM5) family is associated with drug resistance in cancer cells. However, it is still not clear whether KDM5 family members promote chemotherapy resistance in pancreatic ductal adenocarcinomas (PDAC). Comprehensive bioinformatics analysis was performed to investigate the prognostic value, and functional mechanisms of KDM5 family members in PDAC. The effects of KDM5 family members on drug resistance in PDAC cells and the relationship with CD44, as a stem cell marker, were explored by gene knockout and overexpression strategies. Finally, our findings were validated by functional experiments such as cell viability, colony formation and invasion assays. We found that the expression of KDM5A/C was significantly higher in gemcitabine-resistant cells than in sensitive cells, consistent with the analysis of the GSCALite database. The knockdown of KDM5A/C in PDAC cells resulted in diminished drug resistance, less cell colonies and reduced invasiveness, while KDM5A/C overexpression showed the opposite effect. Of note, the expression of KDM5A/C changed accordingly with the knockdown of CD44. In addition, members of the KDM5 family function in a variety of oncogenic pathways, including PI3K/AKT and Epithelial-Mesenchymal Transition. In conclusion, KDM5 family members play an important role in drug resistance and may serve as new biomarkers or potential therapeutic targets in PDAC patients.

The new 'coN' staging system combining lymph node metastasis and tumour deposit provides a more accurate prognosis for TNM stage III colon cancer.

OBJECTIVE: Despite controversy over its origin and definition, the significance of tumour deposit (TD) has been underestimated in the tumour node metastasis (TNM) staging system for colon cancer, especially in stage III patients. We aimed to further confirm the prognostic value of TD in stage III colon cancer and to establish a more accurate 'coN' staging system combining TD and lymph node metastasis (LNM). METHODS: Information on stage III colon cancer patients with a definite TD status was retrospectively collected from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2017. The effect of TD on prognosis was estimated using Cox regression analysis. Maximally selected rank statistics were used to select the optimal cut-off value of TD counts. The predictive power of conventional N staging and the new coN staging was evaluated and compared by Akaike's information criterion (AIC), Harrell's concordance index (C-index) and time-dependent receiver operating characteristic (ROC) curves. Clinicopathological data of stage III colon cancer patients in the Xiangya database from 2014 to 2018 were collected to validate the coN staging system. RESULTS: A total of 39,185 patients with stage III colon cancer were included in our study: 38,446 in the SEER cohort and 739 in the Xiangya cohort. The incidence of TD in stage III colon cancer was approximately 30% (26% in SEER and 30% in the Xiangya database). TD was significantly associated with poorer overall survival (OS) (HR = 1.37, 95% CI 1.31-1.44, p < 0.001 in SEER). The optimal cut-off value of TD counts was 4, and the patients were classified into the TD0 (count = 0), TD1 (count = 1-3) and TD2 (count ≥ 4) groups accordingly. The estimated 5-year OS was significantly different among the three groups (69.4%, 95% CI 68.8%-70.0% in TD0; 60.5%, 95% CI 58.9%-62.2% in TD1 and 42.6%, 95% CI 39.2%-46.4% in TD2, respectively, p < 0.001). The coN system integrating LNM and TD was established, and patients with stage III colon cancer were reclassified into five subgroups (coN1a, coN1b, coN2a, coN2b and coN2c). Compared with conventional N staging, the coN staging Cox model had a smaller AIC (197097.581 vs. 197358.006) and a larger C-index (0.611 vs. 0.601). The AUCs of coN staging at 3, 5 and 7 years were also greater than those of conventional N staging (0.6305, 0.6326, 0.6314 vs. 0.6186, 0.6197, 0.6160). Concomitant with the SEER cohort results, the coN staging Cox model of the Xiangya cohort also had a smaller AIC (2883.856 vs. 2906.741) and a larger C-index (0.669 vs. 0.633). Greater AUCs at 3, 5 and 7 years for coN staging were also observed in the Xiangya cohort (0.6983, 0.6774, 0.6502 vs. 0.6512, 0.6368, 0.6199). CONCLUSIONS: Not only the presence but also the number of TDs is associated with poor prognosis in stage III colon cancer. A combined N staging system integrating LNM and TD provides more accurate prognostic prediction than the latest AJCC N staging in stage III colon cancer.

Cytoskeletal and Cytoskeleton-Associated Proteins: Key Regulators of Cancer Stem Cell Properties.

Cancer stem cells (CSCs) are a subpopulation of cancer cells possessing stemness characteristics that are closely associated with tumor proliferation, recurrence and resistance to therapy. Recent studies have shown that different cytoskeletal components and remodeling processes have a profound impact on the behavior of CSCs. In this review, we outline the different cytoskeletal components regulating the properties of CSCs and discuss current and ongoing therapeutic strategies targeting the cytoskeleton. Given the many challenges currently faced in targeted cancer therapy, a deeper comprehension of the molecular events involved in the interaction of the cytoskeleton and CSCs will help us identify more effective therapeutic strategies to eliminate CSCs and ultimately improve patient survival.

Prognostic factors and individualized nomograms predicting overall survival in stage IV rectal cancer patients with different metastatic status: a SEER-based study.

Background: The prognosis of rectal cancer patients with different metastatic status was significantly different. Our aim was to identify prognostic factors for metastatic rectal cancer (mRC) patients with different metastatic status and to construct specific nomograms to predict overall survival (OS). Methods: This study retrospectively analyzed mRC patients from 2010 to 2016 in the Surveillance, Epidemiology, and End Results Program database. All patients were ultimately divided into four groups: synchronous liver metastasis, synchronous lung metastasis, synchronous other organs metastasis and synchronous multiple metastases. Univariate and multivariate cox analyses were performed to screen out independent factors for each group. Individualized nomograms were constructed in different metastatic modes. The concordance index (C-index), decision curve analysis (DCA), time-dependent receiver operating characteristic (ROC) curve and calibration curve were performed to verify these nomograms. Results: Finally, 10,407 mRC patients were included in this study. Age, tumor grade, surgery of primary tumor, and chemotherapy were identified as common independent prognostic factors for each subgroup (all P<0.05). Other independent prognostic factors specific to each group included radiotherapy and marital status in the liver metastasis group, race, N stage, and the presence or absence of site-specific metastases in the multiple metastases group (all P<0.05). Higher T staging suggested worse OS in the group with liver, lung, and multiple site metastases. Individualized nomograms predicting 1-, 2-, and 3-year OS for each group were constructed by combining all independently significant risk factors in each group. The area under the curve (AUC) values and C-indexes of these nomograms created by each subgroup were greater than 0.7. All calibration curves and DCA curves showed that these nomograms had good clinical application significance. Conclusions: Individualized prognostic nomograms were constructed for mRC patients with different metastatic status based on different prognostic factors. These nomograms presented satisfactory predictive effects, which helps to provide survival assessment and individualized treatment decision-making for mRC patients with different metastatic status.

Prognosis of clear cell renal cell carcinoma patients stratified by age: A research relied on SEER database.

Objective: Clear cell renal cell carcinoma may affect patients of any age. To date, there are only a limited number of large data studies on renal clear cell carcinoma in different age groups. This study assessed CCRCC risk factors in different age groups using the Surveillance Epidemiology and End Results (SEER) database. Methods: We selected 58372 cases from the SEER database. These patients were divided into seven different age groups. Cox regression models were used to find independent risk factors for the survival of CCRCC patients. Based on independent risk factors, a nomogram was drawn with R software. Kaplan-Meier method for survival analysis and X-tile software were used to find the optimal age group for diagnosis. Results: Univariate analysis revealed that patients' age, sex, race, marital status, grade, TNM (tumor, node, metastasis) stage, surgery, WHO/ISUP grade were correlated with survival (P<0.01). Age was an independent risk factor for survival in patients with CCRCC according to multivariate Cox regression analysis (p<0.01). All-cause mortality and tumor-specific mortality increased according to the increasing age of the patients. The optimal cut-off values for age were defined as 58 and 76 years and 51 and 76 years, respectively, according to overall survival (OS) and cause-specific survival (CSS). Conclusion: There is a negative correlation between age and survival of CCRCC patients. The difference in prognosis of patients in different age groups has important implications for clinical treatment. Therefore, the diagnosis and treatment plan should be based on more detailed age grouping, which is more beneficial to improving the prognosis and survival of patients.

The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is rich in dense fibrotic stroma that are composed of extracellular matrix (ECM) proteins. A disruption of the balance between ECM synthesis and secretion and the altered expression of matrix remodeling enzymes lead to abnormal ECM dynamics in PDAC. This pathological ECM promotes cancer growth, survival, invasion, and alters the behavior of fibroblasts and immune cells leading to metastasis formation and chemotherapy resistance, which contribute to the high lethality of PDAC. Additionally, recent evidence highlights that ECM, as a major structural component of the tumor microenvironment, is a highly dynamic structure in which ECM proteins establish a physical and biochemical niche for cancer stem cells (CSCs). CSCs are characterized by self-renewal, tumor initiation, and resistance to chemotherapeutics. In this review, we will discuss the effects of the ECM on tumor biological behavior and its molecular impact on the fundamental signaling pathways in PDAC. We will also provide an overview of how the different ECM components are able to modulate CSCs properties and finally discuss the current and ongoing therapeutic strategies targeting the ECM. Given the many challenges facing current targeted therapies for PDAC, a better understanding of molecular events involving the interplay of ECM and CSC will be key in identifying more effective therapeutic strategies to eliminate CSCs and ultimately to improve survival in patients that are suffering from this deadly disease.

Survival effects of primary and metastatic surgical treatment in metastatic small intestinal tumors: A propensity score-matching study.

OBJECTIVE: To analyze the effects of primary tumor resection and metastatic lesion resection on the survival of metastatic small intestinal tumors. METHODS: The research subjects were patients with metastatic small bowel tumors identified from 2004 to 2016 in the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching and Kaplan-Meier analyses were performed to analyze the effect of surgery on the prognosis. RESULTS: A total of 4,034 patients from the SEER database were analyzed. Both before and after the propensity score-matching analysis, the prognosis of patients who underwent primary tumor surgery and metastatic surgery was better than that of patients who did not undergo surgery; all were patients with metastatic small bowel adenocarcinoma (mSIA) or metastatic small intestinal neuroendocrine tumors (mSI-NETs) (all p < .005). Patients with mSIA and adequate lymph node dissection had a longer prognosis than mSIA patients with inadequate lymph node dissection, but this survival benefit was not present in mSI-NET patients. It made no difference in the prognosis of mSIA and mSI-NETs whether localized surgery or intestine-ectomy was performed. Patients with mSIA who underwent primary and metastatic excision plus chemotherapy had the best overall survival and cancer-specific survival rates, whereas mSI-NET patients who underwent primary and metastatic excision had the best overall survival and cancer-specific survival rates (all p < .001). CONCLUSION: In these carefully selected patients, primary tumor resection and/or metastatic lesion resection significantly improved the survival rates for patients with mSIA and mSI-NETs. The mSIA patients with resectable primary tumors seemed to require a sufficient number of lymph node dissections more than the patients with well-differentiated mSI-NETs.

The Survival Effect of Radiotherapy on Stage IIB/III Pancreatic Cancer Undergone Surgery in Different Age and Tumor Site Groups: A Propensity Scores Matching Analysis Based on SEER Database.

BACKGROUND: It remains controversial whether radiotherapy (RT) improves survival in patients with stage IIB/III PDAC. A growing number of studies have found that patients' age at diagnosis and tumor site not only affect prognosis, but also may lead to different treatment responses. Therefore, the purpose of this study was to verify whether the survival effect of radiotherapy in patients with stage IIB/III PDAC varies across age and tumor site groups. METHODS: The target population was selected from PDAC patients undergone surgery in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016. This study performed the Pearson's chi-square test, Cox regression analysis, Kaplan-Meier (K-M) method, and focused on propensity frequency matching analysis. RESULTS: Neither neoadjuvant radiotherapy (nRT) nor adjuvant radiotherapy (aRT) patient group had probably improved survival among early-onset patients. For middle-aged patients, nRT seemed to fail to extend overall survival (OS), while aRT might improve the OS. Plus, both nRT and aRT were associated with improved survival in elderly patients. The aRT might be related with survival benefits in patients with pancreatic head cancer, while nRT was not. And RT in patients with PDAC at other sites did not appear to provide a survival benefit. CONCLUSION: Carefully selected data from the SEER database suggested that age and tumor location may be the reference factors to guide the selection of RT for patients with stage IIB/III PDAC. These findings are likely to contribute to the development of personalized treatment for patients with stage IIB/III PDAC.

Extracellular Matrix Stiffness: New Areas Affecting Cell Metabolism.

In recent years, in-depth studies have shown that extracellular matrix stiffness plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Most of these processes entail metabolic reprogramming of cells. However, the exact mechanism through which extracellular matrix stiffness leads to metabolic reprogramming remains unclear. Insights regarding the relationship between extracellular matrix stiffness and metabolism could help unravel novel therapeutic targets and guide development of clinical approaches against a myriad of diseases. This review provides an overview of different pathways of extracellular matrix stiffness involved in regulating glucose, lipid and amino acid metabolism.

Development and validation of prognostic nomograms for early-onset locally advanced colon cancer.

BACKGROUND: The incidence of colorectal cancer in patients younger than 50 years has been increasing in recent years. OBJECTIVE: Develop and validate prognostic nomograms predicting overall survival (OS) and cancer-specific survival (CSS) for early-onset locally advanced colon cancer (EOLACC) based on the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: The entire cohort comprised 13,755 patients with EOLACC. The nomogram predicting OS for EOLACC displayed that T stage contributed the most to prognosis, followed by N stage, regional nodes examined (RNE) and surgery. The nomogram predicting CSS for EOLACC demonstrated similar results. Various methods identified the discriminating superiority of the nomograms. X-tile software was used to classify patients into high-risk, medium-risk, and low-risk according to the risk score of the nomograms. The risk stratification effectively avoided the survival paradox. CONCLUSIONS: We established and validated nomograms for predicting OS and CSS based on a national cohort of almost 13,000 EOLACC patients. The nomograms could effectively solve the issue of survival paradox of the AJCC staging system and be an excellent tool to integrate the clinical characteristics to guide the therapeutic choice for EOLACC patients. METHODS: Nomograms were constructed based on the SEER database and the Cox regression model.

Sequence-dependent base-stacking stabilities guide tRNA folding energy landscapes.

The folding of bacterial tRNAs with disparate sequences has been observed to proceed in distinct folding mechanisms despite their structural similarity. To explore the folding landscapes of tRNA, we performed ion concentration-dependent coarse-grained TIS model MD simulations of several E. coli tRNAs to compare their thermodynamic melting profiles to the classical absorbance spectra of Crothers and co-workers. To independently validate our findings, we also performed atomistic empirical force field MD simulations of tRNAs, and we compared the base-to-base distances from coarse-grained and atomistic MD simulations to empirical base-stacking free energies. We then projected the free energies to the secondary structural elements of tRNA, and we observe distinct, parallel folding mechanisms whose differences can be inferred on the basis of their sequence-dependent base-stacking stabilities. In some cases, a premature, nonproductive folding intermediate corresponding to the Ψ hairpin loop must backtrack to the unfolded state before proceeding to the folded state. This observation suggests a possible explanation for the fast and slow phases observed in tRNA folding kinetics.