Development and Validation of a Radiomics Nomogram for Liver Metastases Originating from Gastric and Colorectal Cancer.

The origin of metastatic liver tumours (arising from gastric or colorectal sources) is closely linked to treatment choices and survival prospects. However, in some instances, the primary lesion remains elusive even after an exhaustive diagnostic investigation. Consequently, we have devised and validated a radiomics nomogram for ascertaining the primary origin of liver metastases stemming from gastric cancer (GCLMs) and colorectal cancer (CCLMs). This retrospective study encompassed patients diagnosed with either GCLMs or CCLMs, comprising a total of 277 GCLM cases and 278 CCLM cases. Radiomic characteristics were derived from venous phase computed tomography (CT) scans, and a radiomics signature (RS) was computed. Multivariable regression analysis demonstrated that gender (OR = 3.457; 95% CI: 2.102-5.684; p < 0.001), haemoglobin levels (OR = 0.976; 95% CI: 0.967-0.986; p < 0.001), carcinoembryonic antigen (CEA) levels (OR = 0.500; 95% CI: 0.307-0.814; p = 0.005), and RS (OR = 2.147; 95% CI: 1.127-4.091; p = 0.020) exhibited independent associations with GCLMs as compared to CCLMs. The nomogram, combining RS with clinical variables, demonstrated strong discriminatory power in both the training (AUC = 0.71) and validation (AUC = 0.78) cohorts. The calibration curve, decision curve analysis, and clinical impact curves revealed the clinical utility of this nomogram and substantiated its enhanced diagnostic performance.

A nomogram based on CT texture features to predict the response of patients with advanced pancreatic cancer treated with chemotherapy.

OBJECTIVE: This study aimed to evaluate the predictive value of computed tomography (CT) texture features in the treatment response of patients with advanced pancreatic cancer (APC) receiving palliative chemotherapy. METHODS: This study enrolled 84 patients with APC treated with first-line chemotherapy and conducted texture analysis on primary pancreatic tumors. 59 patients and 25 were randomly assigned to the training and validation cohorts at a ratio of 7:3. The treatment response to chemotherapy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST1.1). The patients were divided into progressive and non-progressive groups. The least absolute shrinkage selection operator (LASSO) was applied for feature selection in the training cohort and a radiomics signature (RS) was calculated. A nomogram was developed based on a multivariate logistic regression model incorporating the RS and carbohydrate antigen 19-9 (CA19-9), and was internally validated using the C-index and calibration plot. We performed the decision curve analysis (DCA) and clinical impact curve analysis to reflect the clinical utility of the nomogram. The nomogram was further externally confirmed in the validation cohort. RESULTS: The multivariate logistic regression analysis indicated that the RS and CA19-9 were independent predictors (P < 0.05), and a trend was found for chemotherapy between progressive and non-progressive groups. The nomogram incorporating RS, CA19-9 and chemotherapy showed favorable discriminative ability in the training (C-index = 0.802) and validation (C-index = 0.920) cohorts. The nomogram demonstrated favorable clinical utility. CONCLUSION: The RS of significant texture features was significantly associated with the early treatment effect of patients with APC treated with chemotherapy. Based on the RS, CA19-9 and chemotherapy, the nomogram provided a promising way to predict chemotherapeutic effects for APC patients.

Association of the CD4+/CD8+ ratio with response to PD-1 inhibitor-based combination therapy and dermatological toxicities in patients with advanced gastric and esophageal cancer.

The host immune system affects the treatment response to immune checkpoint inhibitors and can be reflected by circulating immune cells. This study aimed to evaluate whether circulating T cell subtypes are correlated with clinical response and dermatological toxicities in patients with advanced gastric and esophageal cancer receiving PD-1 inhibitor-based combination therapy (n = 203). In the training cohort, Eastern Cooperative Oncology Group performance status (ECOG PS), PD-L1 expression, antibiotic use, and CD4+/CD8+ ratio were identified as independent prognostic factors in these patients, using a Cox regression model. A nomogram to predict the overall survival (OS) and survival probabilities was constructed using these factors. The nomogram showed good discrimination ability (C-index, 0.767) and was externally confirmed in the validation and test cohorts. Kaplan-Meier analysis showed that median OS in patients with a CD4+/CD8+ ratio ≥1.10 was 6.2 months, which was significantly shorter than that in patients with a CD4+/CD8+ ratio <1.10 (P < 0.001). Patients with a CD4+/CD8+ ratio <1.10 had a superior objective response (43.8% vs. 23.1%) and disease control (72.9% vs. 59.0%) rate, relative to those with ratio ≥ 1.10. In addition, PD-L1 expression, corticosteroid use, and CD4+/CD8+ ratio can independently predict dermatological toxicities. In conclusion, baseline CD4+/CD8+ ratio is a potential prognostic factor for patients with advanced gastric and esophageal cancer treated with PD-1 inhibitor-based combination therapy, and can independently predict dermatological toxicities. In addition, a nomogram incorporating CD4+/CD8+ ratio, ECOG PS, PD-L1 expression, and antibiotic use can predict OS with considerable accuracy.

Development and validation of a radiomics nomogram to discriminate advanced pancreatic cancer with liver metastases or other metastatic patterns.

BACKGROUND: Patients with advanced pancreatic cancer (APC) and liver metastases have much poorer prognoses than patients with other metastatic patterns. OBJECTIVE: This study aimed to develop and validate a radiomics model to discriminate patients with pancreatic cancer and liver metastases from those with other metastatic patterns. METHODS: We evaluated 77 patients who had APC and performed texture analysis on the region of interest. 58 patients and 19 patients were allocated randomly into the training and validation cohorts with almost the same proportion of liver metastases. An independentsamples t-test was used for feature selection in the training cohort. Random forest classifier was used to construct models based on these features and a radiomics signature (RS) was derived. A nomogram was constructed based on RS and CA19-9, and was validated with calibration plot and decision curve. The prognostic value of RS was evaluated by Kaplan-Meier methods. RESULTS: The constructed nomogram demonstrated good discrimination in the training (AUC = 0.93) and validation (AUC = 0.81) cohorts. In both cohorts, patients with RS > 0.61 had much poorer overall survival than patients with RS < 0.61. CONCLUSIONS: This study presents a radiomics nomogram incorporating RS and CA19-9 to discriminate patients who have APC with liver metastases from patients with other metastatic patterns.

USP39 promotes tumorigenesis by stabilizing and deubiquitinating SP1 protein in hepatocellular carcinoma.

Deubiquitinating enzyme (DUB) can hydrolyze ubiquitin molecules from the protein bound with ubiquitin, and reversely regulate protein degradation. The ubiquitin-specific proteases (USP) family are cysteine proteases, which owns the largest members and diverse structure among the currently known DUB. The important roles of ubiquitin-specific peptidase39 (USP39) in cancer have been widely investigated. However, little is known about the putative de-ubiquitination function of USP39 in hepatocellular carcinoma (HCC) and the mechanisms of USP39 regulating tumor growth. Here, we used bioinformatics methods to reveal that USP39 expression is significantly upregulated in several cancer database. High expression of USP39 is correlated with poor prognosis of HCC patients. Then, we identify the specificity protein 1 (SP1), as a novel subtract of the USP39. We observe that USP39 stabilizes SP1 protein and prolongs its half-life by promoting its deubiquitylation pathway. In addition, our results show USP39 promotes cell proliferation by SP1-depenet manner in vivo and vitro. Knocking-down of USP39 promotes the cell apoptosis and arrest of the cell cycle, whereas SP1 forcefully reversed these effects. Taken together, our results suggest that USP39 participates the deubiquitylation of SP1 protein, providing new pathway for understand the upstream signaling for oncogene SP1.

The value of miR-510 in the prognosis and development of colon cancer.

PURPOSE: Colon cancer is one of the malignant tumors that threatens human health. miR-510 was demonstrated to play roles in the progression of various cancers; its dysregulation was speculated to be associated with the development of colon cancer. METHODS: One hundred and thirteen colon cancer patients participated in this research. With the help of RT-qPCR, the expression of miR-510 in collected tissues and cultured cells was analyzed. The association between miR-510 expression level and clinical features and prognosis of patients was evaluated. Moreover, the effects of miR-510 on cell proliferation, migration, and invasion of colon cancer were assessed by CCK8 and Transwell assay. RESULTS: miR-510 significantly upregulated in colon cancer tissues and cell lines relative to the adjacent normal tissues and colonic cells. The expression of miR-510 was significantly associated with the TNM stage and poor prognosis of patients, indicating miR-510 was involved in the disease progression and clinical prognosis of colon cancer. Additionally, the upregulation of miR-510 significantly promoted cell proliferation, migration, and invasion of colon cancer, while its knockdown significantly inhibited these cellular processes. SRCIN 1 was the direct target of miR-510 during its promoted effect on the development of colon cancer. CONCLUSION: The upregulation of miR-510 acts as an independent prognostic indicator and a tumor promoter by targeting SRCIN 1 in colon cancer, which provides novel therapeutic strategies for colon cancer.

Role of CT texture features for predicting outcome of pancreatic cancer patients with liver metastases.

Objective: The purpose of this study was to evaluate the prognostic value of computed tomography (CT) texture features of pancreatic cancer with liver metastases. Methods: We included 39 patients with metastatic pancreatic cancer (MPC) with liver metastases and performed texture analysis on primary tumors and metastases. The correlations between texture parameters were assessed using Pearson's correlation. Univariate Cox proportional hazards model was used to assess the correlations between clinicopathological characteristics, texture features and overall survival (OS). The univariate Cox regression model revealed four texture features potentially correlated with OS (P<0.1). A radiomics score (RS) was determined using a sequential combination of four texture features with potential prognostic value that were weighted according to their ß-coefficients. Furthermore, all variables with P<0.1 were included in the multivariate analysis. A nomogram,which was developed to predict OS according to independent prognostic factors, was internally validated using the C-index and calibration plots. Kaplan-Meier analysis and the log-rank test were performed to stratify OS according to the RS and nomogram total points (NTP). Results: Few significant correlations were found between texture features of primary tumors and those of liver metastases. However, texture features within primary tumors or liver metastases were significantly associated. Multivariate analysis showed that Eastern Cooperative Oncology Group performance status (ECOG PS), chemotherapy, Carbohydrate antigen 19-9 (CA19-9), and the RS were independent prognostic factors (P<0.05). The nomogram incorporating these factors showed good discriminative ability (C-index = 0.754). RS and NTP stratified patients into two potential risk groups (P<0.01). Conclusion: The RS derived from significant texture features of primary tumors and metastases shows promise as a prognostic biomarker of OS of patients with MPC. A nomogram based on the RS and other independent prognostic clinicopathological factors accurately predicts OS.

Clinical significance of site-specific metastases in pancreatic cancer: a study based on both clinical trial and real-world data.

Background: There is limited consensus on whether metastatic patterns are correlated with prognosis and treatment efficacy in pancreatic cancer. A better understanding of clinical implication of the metastatic patterns is pivotal for therapeutic decision-making and drug development. Methods: This study included 977 patients with metastatic pancreatic cancer (MPC) in three cohorts. The training cohort included 273 patients from clinical trial NCT00574275 and 367 patients from clinical trial NCT01124786. As the validation cohort, 337 patients from Changzhou No.2 People's Hospital and Shanghai General Hospital were enrolled. The correlations between different patterns of metastases and clinicopathological characteristics were investigated with the Pearson Chi-Square test. Kaplan-Meier analysis and log-rank test were applied to analyze the survival outcomes among groups with different metastatic patterns. The prognostic value of the number of metastatic sites and other variables was evaluated using the Cox regression model. Results: MPC patients aged ≥65 years had a higher rate of lung metastasis and those with liver metastasis were prone to have a high level of carbohydrate antigen 19-9 (CA19-9). Additionally, patients with isolated lung metastasis had much better overall survival (OS) than those with isolated liver or peritoneum metastasis. Cox regression analyses showed that the number of metastatic sites was an independent prognostic factor for OS in patients with MPC. Furthermore, for patients with one-site or two-site metastasis, there was a significant difference in OS among patients receiving no chemotherapy, monotherapy and combination therapy. However, for patients with more than two metastatic sites, receiving combination therapy or monotherapy showed limited superiority in OS over receiving no chemotherapy. Conclusion: MPC patients with isolated lung metastasis had better OS than those with isolated liver or peritoneum metastasis. Moreover, the number of metastatic sites showed prognostic and predictive value in patients with MPC.

The role of phosphoprotein phosphatases catalytic subunit genes in pancreatic cancer.

Compelling evidence suggests that phosphoprotein phosphatases (PPPs) are involved in a large spectrum of physiological and pathological processes, but little is known about their roles in pancreatic cancer. We investigated the expression level, prognostic value, and potential function of PPPs with data from Oncomine, GEPIA, THPA, and TCGA databases and an independent cohort of patients with pancreatic cancer. Among all the PPP catalytic subunits (PPPcs), the transcription levels of PPP1CA, PPP1CB, PPP3CA, PPP3CB, and PPP4C were higher in pancreatic cancer than in normal pancreas (P<0.01, fold change > 2). Kaplan-Meier analysis showed that high transcription levels of PPP1CA, PPP1CB, PPP2CA, PPP2CB, PPP3CA, and PPP4C correlated with poorer survival. In contrast, patients with high levels of PPP3CB, PPP3CC, PPP5C, PPP6C, and PPEF2 had much better prognoses. Data from THPA and patients with pancreatic cancer enrolled in our hospital also confirmed the prognostic value of PPP1CA, PPP1CB, PPP2CA, PPP2CB, PPP3CA, PPP3CB, and PPP6C at the protein level. In addition, the Pearson Chi-square test showed that PPP3CB level was significantly correlated with T and N stages. GO and KEGG analyses showed that the genes and pathways related to the pathogenesis and progression of pancreatic cancer were greatly affected by alterations in PPPcs. Results of the present study suggest that PPP1CA, PPP1CB, PPP2CA, PPP2CB, and PPP3CA have deleterious effects but PPP3CB, PPP5C, and PPP6C have beneficial effects on pancreatic cancer.

Lactate-Modulated Immunosuppression of Myeloid-Derived Suppressor Cells Contributes to the Radioresistance of Pancreatic Cancer.

The mechanisms responsible for radioresistance in pancreatic cancer have yet to be elucidated, and the suppressive tumor immune microenvironment must be considered. We investigated whether the radiotherapy-augmented Warburg effect helped myeloid cells acquire an immunosuppressive phenotype, resulting in limited treatment efficacy of pancreatic ductal adenocarcinoma (PDAC). Radiotherapy enhanced the tumor-promoting activity of myeloid-derived suppressor cells (MDSC) in pancreatic cancer. Sustained increase in lactate secretion, resulting from the radiation-augmented Warburg effect, was responsible for the enhanced immunosuppressive phenotype of MDSCs after radiotherapy. Hypoxia-inducible factor-1α (HIF-1α) was essential for tumor cell metabolism and lactate-regulated activation of MDSCs via the G protein-coupled receptor 81 (GPR81)/mTOR/HIF-1α/STAT3 pathway. Blocking lactate production in tumor cells or deleting Hif-1α in MDSCs reverted antitumor T-cell responses and effectively inhibited tumor progression after radiotherapy in pancreatic cancer. Our investigation highlighted the importance of radiation-induced lactate in regulating the inhibitory immune microenvironment of PDAC. Targeting lactate derived from tumor cells and the HIF-1α signaling in MDSCs may hold distinct promise for clinical therapies to alleviate radioresistance in PDAC.

A Systematic Inflammation-based Model in Advanced Pancreatic Ductal Adenocarcinoma.

Emerging evidence revealed the critical role of systematic inflammation in pancreatic ductal adenocarcinoma (PDAC). In the present study, we reviewed the records of 279 patients with advanced PDAC. Among them, 147 cases were used as the training cohort and another 132 as the validation cohort. In the training cohort, distant metastasis, carbohydrate antigen 19-9 (CA19-9), Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR) were independent prognostic factors in Cox regression. A nomogram based on these factors was generated to predict median survival time and survival probabilities at 6, 12, and 18 months. The nomogram showed a better discriminatory ability than the American Joint Committee on Cancer (AJCC) TNM staging (C-index: 0.727 vs. 0.610). In the validation cohort, a nomogram composed of the same variables also showed a high discriminatory ability (C-index: 0.784). In the low-risk group with a nomogram total point (NTP) value of more than 175, patients receiving combination therapy showed better prognosis than those receiving monotherapy (P=0.015). In conclusion, the nomogram based on inflammatory biomarkers can serve as useful prognostic tool for advanced PDAC. In addition, patients with high NTP can greater benefit from combination chemotherapy than monotherapy.

The clinical implication of CD45RA+ naïve T cells and CD45RO+ memory T cells in advanced pancreatic cancer: a proxy for tumor biology and outcome prediction.

Naïve and memory T cells play a pivotal role in solid tumor pathogenesis but their role in pancreatic cancer progression remains elusive. Thus, we aimed to investigate their clinical potential in advanced pancreatic cancer (APC). Flow cytometry was performed to evaluate the level of baseline peripheral naïve and memory T cells from 137 APC patients before receiving first-line chemotherapy. Interrelationships between naïve, memory T cells and clinicopathological variables were evaluated using Pearson's correlation. The prognostic impact of naïve and memory T cells were assessed by Kaplan-Meier analysis and Cox regression. The correlation between naïve/memory T cells and tumor progression was investigated by Student's t test. CD4+ naïve/memory ratio showed close correlations with hemoglobin, red blood cell (RBC), absolute neutrophil count (ANC) and platelet while CD8+ naïve/memory ratio was correlated with hemoglobin, RBC and CEA. Higher baseline lever of CD4+ CD45RO+ /CD4+ was correlated with better overall survival (OS) (P = 0.036). Patients with CD4+ naïve/memory ratio ≥0.36 had a poorer OS than those with CD4+ naïve/memory ratio <0.36 (P = 0.021). In addition, CD4+ naïve/memory ratio showed independent prognostic impact (HR 1.427, 95% CI 1.033-1.973, P = 0.031). Furthermore, poorer clinical response was correlated with higher level of CD8+ naïve/memory ratio after the third cycle of chemotherapy (P = 0.01). Besides, patients with a lower level of CD8+ naïve/memory ratio had longer progression-free survival (PFS) (P = 0.028). We propose CD4+ naïve/memory ratio as a novel prognostic biomarker for APC. In addition, CD8+ naïve/memory ratio can be a candidate marker for predicting PFS and the change of its level may reflect the progression of APC.

Interaction of H. pylori with toll-like receptor 2-196 to -174 ins/del polymorphism is associated with gastric cancer susceptibility in southern China.

BACKGROUND: Genetic polymorphisms of Toll-like receptors play important roles in gastric carcinogenesis. The aim of this study was to determine the role of TLR2-196 to -174 ins/del polymorphism in gastric cancer susceptibility and prognosis. METHODS: This study included 520 people from southern China. Samples were genotyped by the allele-specific polymerase chain reaction, among which 10% were randomly selected for sequencing. The serological method was used to determine Helicobacter pylori. RESULTS: The TLR2 genotype was not associated with the risk of H. pylori infection. The del/del genotype exhibited significantly higher gastric cancer risk (adjusted OR 2.59, 95% CI 1.33‒5.07) than that of the ins/ins genotype. Further stratification analyses demonstrated that the del/del genotype was associated with a risk of intestinal gastric cancer (adjusted OR 2.62, 95% CI 1.34-5.14). In addition, the presence of the del/del genotype and the H. pylori infection conferred a synergistic effect (OR 3.04, 95% CI 1.33‒6.98) for the development of gastric cancer. The del/del genotype was not associated with a poor prognosis in gastric cancer patients. CONCLUSION: The del/del genotype is associated with an increased gastric cancer risk in the southern Chinese population. However, TLR2 polymorphism is neither associated with H. pylori infection, nor with a poor prognosis.

Prediction of overall survival for metastatic pancreatic cancer: Development and validation of a prognostic nomogram with data from open clinical trial and real-world study.

It is necessary to develop prognostic tools of metastatic pancreatic cancer (MPC) for optimizing therapeutic strategies. Thus, we tried to develop and validate a prognostic nomogram of MPC. Data from 3 clinical trials (NCT00844649, NCT01124786, and NCT00574275) and 133 Chinese MPC patients were used for analysis. The former 2 trials were taken as the training cohort while NCT00574275 was used as the validation cohort. In addition, 133 MPC patients treated in China were taken as the testing cohort. Cox regression model was used to investigate prognostic factors in the training cohort. With these factors, we established a nomogram and verified it by Harrell's concordance index (C-index) and calibration plots. Furthermore, the nomogram was externally validated in the validation cohort and testing cohort. In the training cohort (n = 445), performance status, liver metastasis, Carbohydrate antigen 19-9 (CA19-9) log-value, absolute neutrophil count (ANC), and albumin were independent prognostic factors for overall survival (OS). A nomogram was established with these factors to predict OS and survival probabilities. The nomogram showed an acceptable discrimination ability (C-index: .683) and good calibration, and was further externally validated in the validation cohort (n = 273, C-index: .699) and testing cohort (n = 133, C-index: .653).The nomogram total points (NTP) had the potential to stratify patients into 3-risk groups with median OS of 11.7, 7.0 and 3.7 months (P < .001), respectively. In conclusion, the prognostic nomogram with NTP can predict OS for patients with MPC with considerable accuracy.

Validation of Lymphocyte-to-Monocyte Ratio as a Prognostic Factor in Advanced Pancreatic Cancer: An East Asian Cohort Study of 2 Countries.

OBJECTIVES: Although the prognostic value of lymphocyte-to-monocyte ratio (LMR) has been recently demonstrated in solid tumors, little is known of its impact on advanced pancreatic cancer (APC). This study evaluates and validates the cutoff value of LMR for predicting palliative chemotherapy outcome using a transnational cohort of APC patients. METHODS: A total of 405 APC patients receiving first-line palliative chemotherapy were retrospectively reviewed. Of these, 153 patients were from Shanghai General Hospital (training set) and 252 patients were from Kyoto University Hospital (validation set). The optimal cutoff value of LMR was determined by a generating receiver operating characteristic curve for the training set. The association between LMR and survival was evaluated using log-rank tests, and a Cox regression model was used to validate the independent prognostic significance of LMR in APC patients. RESULTS: The optimal cutoff value of LMR was 2.8. Overall survival was significantly longer in patients with LMR of 2.8 or greater than those with LMR of less than 2.8 (P < 0.001). Cox regression analysis showed that LMR was an independent prognostic factor. The impact of LMR was widely observed in all subgroups except the performance status 2 subgroup. CONCLUSIONS: Lymphocyte-to-monocyte ratio may be considered as a promising prognostic marker for APC patients receiving palliative chemotherapy.

Pretreatment C-reactive protein to albumin ratio for predicting overall survival in advanced pancreatic cancer patients.

Although previous studies demonstrated that elevated C-reactive protein to albumin ratio (CAR) predicted poor prognosis in various solid tumors, little was known about the prognostic value of CAR in patients with advanced pancreatic cancer (APC). The aim of the present study was to assess CAR as one independent prognostic factor in predicting overall survival (OS) in APC patients who had received palliative chemotherapy. Data of 142 APC patients who received palliative chemotherapy between 2009 and 2014 were retrospectively documented. We classified the patients into two groups based on the optimal cutoff value of CAR identified by generating receiver operating characteristics (ROC) curve. The clinicopathological parameters were compared between two CAR groups. Pearson correlation test showed that the level of C-reactive protein (CRP) was inversely correlated with albumin (r = -0.387; P < 0.001). Kaplan-Meier analysis demonstrated overall survival (OS) was significantly longer in CAR < 0.156 group than CAR ≥ 0.156 group (11.2 vs 5.9 months, P < 0.001). CAR was an independent prognostic factor for OS in the Cox regression model (HR, 1.623; 95% CI, 1.093-2.410; P = 0.016). Furthermore, the discrimination ability of CAR (AUC = 0.648, P = 0.025) was slightly higher than that of other inflammation-based factors. Therefore, pretreatment CAR could be an independent prognostic biomarker for APC patients.

Simultaneous high expression of PLD1 and Sp1 predicts a poor prognosis for pancreatic ductal adenocarcinoma patients.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with few therapeutic options. Recently, insight into cancer biology suggested abnormal lipid metabolism to be a risk factor for human malignancies. As a key enzyme implicated in lipid metabolism, PLD1 was elevated in various human cancer associating with malignant phenotypes. However, little was known about its expression and function in PDAC. We showed that PLD1 was elevated in both the cell lines and clinical samples of PDAC, and it positively correlated with vascular invasion (p = 0.041) and responsible for a poor prognosis (p = 0.009). Meanwhile, we also found Sp1 to be elevated in the disease, correlating with vascular invasion (p = 0.007). Moreover, the correlation assay suggested that PLD1 positively correlated with Sp1 in the clinical sample (r = 0.390; p < 0.001) and the cell lines. Finally, we showed that co-high expression of both the factors confers the poorest prognosis for the patients, and that their simultaneous high expression might be an independent prognostic factor (p = 0.001; HR = 3.427; 95% CI 1.629-7.211).

Sp1 and COX2 expression is positively correlated with a poor prognosis in pancreatic ductal adenocarcinoma.

Previous studies showed that celecoxib, a cyclooxygenase-2 (COX2) inhibitor, can inhibit angiogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC) via the suppression of specificity protein 1 (Sp1). In this study, we investigated the prognostic value of Sp1 and COX2 in 88 PDAC patients. Our study showed there was a positive correlation between Sp1 and COX2 expression (P=0.001) by using the Spearman's rank test. Pearson Chi-square test revealed that Sp1 and COX2 expression were positively associated with lymph node metastasis (P<0.05, both). In addition, the Kaplan-Meier analysis showed that patients with Sp1- or COX2-positive expression exhibited poorer overall survival (OS) than those with Sp1- or COX2-negative expression (P<0.05, all). Most importantly, Sp1- and COX2-negative patients had the best OS (P=0.01). In multivariate analysis, Sp1 expression (P=0.03), COX2 expression (P=0.04), and nuclear grade (P=0.009) were found to be independent predictors for OS. Moreover, we confirmed that Sp1 could upregulate the expression of COX2 in PDAC cell lines by western blot analysis, and both are of important prognostic value in PDAC.

The M2 phenotype of tumor-associated macrophages in the stroma confers a poor prognosis in pancreatic cancer.

Macrophages play a critical role in the initiation and progression of various solid tumors. However, their prognostic significance in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. This study investigated the distribution patterns of macrophages in PDAC and possible association with the overall survival (OS). We found significant differences in macrophage density (identified by CD68 and CD163 immunopositivity; p < 0.001 for both) between primary cancer and paired adjacent normal tissues. Most macrophages in cancerous pancreatic tissues were located in the stroma rather than the islets (p = 0.032 and p < 0.001). We also demonstrated that a high total macrophage density (characterized by CD68 immunopositivity) correlated with an absence of jaundice before surgery (p = 0.03) and that a high density of M2 macrophages (characterized by CD163 immunopositivity) in the stroma strongly correlated with the tumors located in the tail and body of the pancreas (p = 0.04). In addition, OS was shorter in patients with high-density M2 macrophage infiltration than in those with low-density M2 macrophage infiltration (p = 0.012). Moreover, multivariate analysis revealed that dense M2 macrophage infiltration into the stroma was an independent prognostic factor for PDAC patients (p = 0.02).

The Joint Effects of Lifestyle Factors and Comorbidities on the Risk of Colorectal Cancer: A Large Chinese Retrospective Case-Control Study.

BACKGROUND: Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality. In previous epidemiologic studies, the respective correlation between lifestyle factors and comorbidity and CRC has been extensively studied. However, little is known about their joint effects on CRC. METHODS: We conducted a retrospective case-control study of 1,144 diagnosed CRC patients and 60,549 community controls. A structured questionnaire was administered to the participants about their socio-demographic factors, anthropometric measures, comorbidity history and lifestyle factors. Logistic regression model was used to calculate the odds ratio (ORs) and 95% confidence intervals (95%CIs) for each factor. According to the results from logistic regression model, we further developed healthy lifestyle index (HLI) and comorbidity history index (CHI) to investigate their independent and joint effects on CRC risk. RESULTS: Four lifestyle factors (including physical activities, sleep, red meat and vegetable consumption) and four types of comorbidity (including diabetes, hyperlipidemia, history of inflammatory bowel disease and polyps) were found to be independently associated with the risk of CRC in multivariant logistic regression model. Intriguingly, their combined pattern- HLI and CHI demonstrated significant correlation with CRC risk independently (ORHLI: 3.91, 95%CI: 3.13-4.88; ORCHI: 2.49, 95%CI: 2.11-2.93) and jointly (OR: 10.33, 95%CI: 6.59-16.18). CONCLUSIONS: There are synergistic effects of lifestyle factors and comorbidity on the risk of colorectal cancer in the Chinese population.