High expression of GRK3 is associated with favorable prognosis in pancreatic ductal adenocarcinoma

Background

It was found that G-protein-coupled receptor kinase 3 (GRK3) played key biological roles in some cancers. However, its associations with clinicopathologic features and prognosis in pancreatic ductal adenocarcinoma (PDAC) remain unknown.

Vascular proliferation is associated with survival in pancreatic ductal adenocarcinoma

In pancreatic ductal adenocarcinoma (PDAC), the benefit of current chemotherapy and radiation therapy is very limited, even in radically resected patients. New treatment strategies, for example based on the inhibition of the tumour's blood supply, need to be explored. We have investigated angiogenesis markers and their associations with relapse and survival in 52 histologically confirmed cases of PDAC. Angiogenesis in the primary tumour was evaluated by microvessel density (MVD), vascular proliferation index (VPI) and the presence of glomeruloid microvascular proliferations (GMP). These features were analysed in the context of clinicopathological variables, KRAS mutation status, relapse location and survival. MVD (median 134 microvessels/mm², range 88–177) and VPI (median 3.2%, range 1.6–4.9) were associated with larger tumour size and lymph node metastasis. MVD was also related to the occurrence of liver metastases. Both variables were associated with survival in univariate and multivariate analyses. GMPs were present in 32 (62%) of the cases. Patients who exhibited MVD and VPI values above median, and GMP positivity, had a median survival of only 4.2 months after surgery. In conclusion, the angiogenesis markers MVD and VPI have a significant impact on survival. By also including GMP, a subgroup of PDAC patients with particularly short survival could be identified.     

High microvessel density in pancreatic ductal adenocarcinoma is associated with high grade

The objectives of this work are to study angiogenesis in pancreatic ductal adenocarcinoma using computerized morphometric and image analysis and to compare the microvascular density in intratumoral and peritumoral areas and normal pancreatic tissue. Microvascular density was analyzed in 60 cases of pancreatic ductal adenocarcinoma and 30 samples of normal pancreatic tissue using an avidin–biotin immunoperoxidase technique with an anti-CD31 antibody. Microvascular density (MVD) was analyzed through digital microimaging and computerized analysis. The blood vessel density in the tumor was significantly higher than in peritumoral areas and in normal pancreatic tissue. Well differentiated pancreatic ductal adenocarcinomas contained higher MVD than poorly differentiated carcinomas. In pancreatic adenocarcinoma, MVD is higher than in peritumoral tissue or normal pancreatic tissue.     

Low expression of nucleus accumbens‐associated protein 1 predicts poor prognosis for patients with pancreatic ductal adenocarcinoma

Nucleus accumbens‐associated protein 1 (NAC1) is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. High expression of NAC1 is considered to have adverse effects on prognosis through negative regulation of growth arrest and DNA‐damage–inducible 45‐γ interacting protein 1 (GADD45GIP1) in ovarian and cervical carcinomas. In the present study, the expression of NAC1 in pancreatic ductal adenocarcinoma (PDA) was measured using immunohistochemistry and computer‐assisted image analysis in order to investigate its correlation with various clinicopathological parameters and prognosis. Patients with low‐NAC1 PDA had worse overall survival (P = 0.0010) and a shorter disease‐free survival (P = 0.0036) than patients with high‐NAC1 PDA. This was a clinical effect opposite to that reported in ovarian and cervical carcinomas. Furthermore, knockdown of NAC1 in pancreatic carcinoma cell lines did not increase expression of the GADD45GIP1 protein. These results indicate that the gene(s) regulated by NAC1 vary depending on the types of carcinoma or originating tissue, and that low expression of NAC1 predicts poor prognosis for patients with PDA.     

Circulating IL-35 in pancreatic ductal adenocarcinoma patients

IL-35 is a novel inhibitory cytokine that is mainly produced by regulatory T-cells (Tregs) and is required for Treg-mediated immunosuppression. However, the plasma levels of IL-35 in patients with pancreatic ductal adenocarcinoma (PDAC) have never been investigated. In this study, we found that plasma IL-35 levels more significantly increased in PDAC patients than in normal controls (134.53 ± 92.45 pg/mL vs. 14.26 ± 6.56 pg/mL). IL-35 mRNA levels were positively correlated with plasma IL-35 levels (EBI3, R = 0.925, p < 0.01; p35, R = 0.916, p < 0.01). Furthermore, IL-35 expression levels were associated with lymph node metastasis (p = 0.001) and late tumor stage (p = 0.002). For the resected patients, high IL-35 expression levels were associated with large tumor size (p < 0.01), higher TNM classification T staging (p < 0.05), and late tumor stage (p < 0.05). In conclusion, circulating IL-35 in PDAC patients significantly increased, suggesting that regulating the expression of IL-35 may provide a new possible target for the treatment of PDAC patients, especially for the resectable ones.     

Complex glandular pattern is an aggressive morphology that predicts poor prognosis of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant neoplasm with various morphologies. Recognition of histological patterns that can predict prognosis is important in pathological examination. Recently, the complex glandular pattern was defined as a morphology associating the poor prognosis in lung adenocarcinoma. We investigated the significance of the complex glandular pattern in PDAC by performing a retrospective analysis. Among 240 consecutive cases of conventional PDACs, 21 cases in which complex glandular pattern constituted >50 % of the total tumor volume (CG-PDACs) were identified. The prevalence of CG-PDAC was 8.8 % among all preoperative therapy-naïve and surgically resected conventional PDACs. Compared to the control PDACs (n = 95), the CG-PDACs were characterized by significantly higher prevalence of small- to medium-sized artery invasion (71.4 % vs. 14.7 %, p < 0.0001), intratumoral necrosis (59.1 % vs. 16.8 %, p < 0.0001), tumor budding (mean: 15.5 vs. 12.5 per 0.785 mm², p = 0.04), significantly higher Ki67 proliferative index (mean: 75.0 % vs. 54.7 %, p < 0.0001), and the HNF1α−/KRT81+ (quasi-mesenchymal) immunophenotype (42.9 % vs. 19.0 %, p = 0.004). In Kaplan-Meier analyses, the CG-PDAC patients achieved significantly worse disease-free survival (DFS) and overall survival (OS) compared to the control PDAC patients; the respective median DFS and OS were 6.3 and 17.7 months for CG-PDACs, and 22.6 and 52.8 months for control PDACs. A multivariate Cox regression analysis showed that predominance of complex glandular pattern was an independent prognostic factor (hazard ratio: 2.95; 95 % confidence interval: 1.46–5.98; p = 0.003). Our results provide new insights into the complex glandular pattern in conventional PDACs as a novel and potentially useful prognostic factor.     

Pathological complete response and prognosis after neoadjuvant chemotherapy in patients with HER2-low breast cancer

BackgroundThe development of novel human epidermal growth factor receptor 2 (HER2) antibody drug conjugates brings encouraging opportunities for the treatment of HER2-low breast cancer. In this study, we investigated the clinical factors and prognosis of HER2-low breast cancer after neoadjuvant chemotherapy (NAC).MethodsData from patients diagnosed with HER2-zero or HER2-low breast cancer at a single center between January 2017 and December 2021 who underwent NAC followed by surgery were retrospectively reviewed. HER2 status was detected by immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH), and classified as HER2-zero (IHC 0), HER2-low (IHC 1+ or IHC 2+ and FISH–), and HER2-positive (IHC 3+ or IHC 2+ and FISH+). Baseline characteristics were analyzed and compared between the HER2-low and HER2-zero groups. Survival outcomes were analyzed using the Kaplan–Meier method with the log-rank test and Cox proportional-hazards regression analysis.ResultsThe sample comprised 132 patients with HER2-zero [n = 62 (47.0 %)] and HER2-low [n = 70 (53.0 %)] breast cancer. Relative to the HER2-zero group, the HER2-low group contained larger proportions of patients with hormone receptor (HR) positivity (37.1 % vs. 75.7 %, P < 0.001) and low nuclear grades and Ki-67 indices (both P < 0.05). The pathological complete response (pCR) rate was significantly lower in the HER2-low group than in the HER2-zero group (20.0 % vs. 37.1 %, P = 0.03). At the final follow-up [median 20 (range 4–66) months], patients with HER2-low status had significantly favorable disease-free survival (DFS) and overall survival (OS) outcomes relative to those with HER2-zero status (87.1 % vs. 71.0 %, P = 0.02 and 94.3 % vs. 82.3 %, P = 0.02, respectively). HER2-low status and pCR were independent prognostic factors for DFS [hazard ratio (HR) = 0.31, 95 % confidence interval (CI) 0.13–0.75, P = 0.009 and HR = 0.08, 95 % CI 0.01–0.67, P = 0.02, respectively].ConclusionThis analysis revealed that HER2-low status is associated significantly with HR positivity and low nuclear grades, Ki-67 indices, and pCR rate. It is also associated with favorable DFS and OS outcomes after NAC. HER2-low status and pCR are independent prognostic factors for DFS.     

Chromosomal instability in pancreatic ductal cells from patients with chronic pancreatitis and pancreatic adenocarcinoma

Pancreatic adenocarcinoma is a disease with high mortality for which chronic pancreatitis confers a markedly increased risk. We hypothesize that chromosome instability and genomic damage occur in pre-neoplastic pancreatic ductal epithelium, and that this damage may be related to oxidative stress. We used dual-color fluorescence in situ hybridization with centromere probes and locus-specific arm probes for chromosome arms 11q, 17p, and 18q to identify genomic instability in cultures of normal-appearing human pancreatic ductal epithelium from normal organ donor controls compared to patients with chronic pancreatitis or pancreatic adenocarcinoma. To examine early pancreatic tumorigenesis, we studied only normal-appearing pancreatic ductal cells adjacent to pancreatitis or carcinoma. We found that, compared to the finding in normal controls, chromosomal abnormalities are present in normal-appearing human pancreatic ductal epithelia obtained from patients with chronic pancreatitis or pancreatic adenocarcinoma. Furthermore, these chromosomal abnormalities could be induced in cultured pancreatic ductal epithelium from normal organ donors by chronic exposure to dilute hydrogen peroxide, suggesting that oxidative stress may contribute to the development of chromosomal instability in the pancreas. These results elucidate a potential mechanism linking chronic pancreatitis to pancreatic cancer and suggest that chromosomal instability may be an early event in the pathogenesis of pancreatic cancer.     

Abnormal expression of Nek2 in pancreatic ductal adenocarcinoma: a novel marker for prognosis

Nek2 is a serine/threonine kinase that has a critical role in mitosis during the cell division process. Despite its importance in centrosome regulation and spindle formation, no direct binders are reported between human pancreatic cancer and Nek2 protein. Our aim in studying Nek2 expression and survival in PDA patients is to determine whether Nek2 is a valuable prognostic factor in PDA tumorigenesis. We found that Nek2 mRNA was elevated in PDA tissues. A high level of expression of Nek2 was significantly correlated with histological differentiation (P=0.042), lymph node metastasis (P=0.003) and tumor stage (P=0.001). Patients with a high Nek2 expression had a significantly worse overall survival (OS) than those patients with low Nek2 expression (P=0.002). Univariate and multivariate analysis revealed that high expression of Nek2 could serve as an independent predictor of poor prognosis. These results indicate that Nek2 could be a promising prognostic molecular marker and an attractive therapeutic target for PDA.     

Decreased RGS6 expression is associated with poor prognosis in pancreatic cancer patients

Regulator of G-protein signaling 6 (RGS6), a member of a family of RGS proteins, has been reported to involve in multiple processes during tumor development. However, its role in pancreatic cancer has not been studied yet. In this study, we aimed to investigate the expression of RGS6 in pancreatic cancer and its role in predicting outcomes of patients with pancreatic cancer. We first measured the expression of RGS6 mRNA in 20 cases of tumor tissues and matched adjacent non-tumorous tissues by quantitative real-time PCR and examined RGS6 protein by immunohistochemistry in tissue microarrays containing 90 tumor and 90 paired adjacent non-tumor tissues. Decreased RGS6 mRNA detected in primary tumor, compared with their non-tumor counterparts. In addition, decreased RGS6 protein expression was associated with tumor differentiation (P = 0.027), pT classification (P = 0.034), smoking status (P = 0.041) and a poor survival (P = 0.007). Cox proportional hazards regression modeling analysis revealed that lymph node metastasis (P = 0.001; hazard ratio, 2.347, 95% CI, 1.387-3.972), tumor differentiation (P = 0.015; hazard ratio, 0.505, 95% CI, 0.291-0.876) and RGS6 expression (P = 0.048; hazard ratio, 0.567, 95% CI, 0.324-0.994) were three independent prognostic factors. Taken together, these date demonstrate that RGS6 decreases in tumor tissue and may serve as a novel biomarker for outcomes in pancreatic cancer patients and be a potential therapeutic target potential therapeutic target.     

Molecular characterisation of pancreatic ductal adenocarcinoma in patients under 40

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) rarely affects people under 40. OBJECTIVES: To determine whether the clinical, pathomorphological and genetic features of PDAC occurring in young patients (相似文献   

Good glycaemic control is associated with a better prognosis in breast cancer patients with type 2 diabetes mellitus

Although diabetes mellitus (DM) is one of the risk factors associated with increased breast cancer (BC) mortality, the effects of glycaemic control on the prognosis of BC have not been thoroughly evaluated. This retrospective study aimed to evaluate the relationship between glycaemic control and BC prognosis and to determine an optimal target of glycaemic control for BC patients with diabetes. We included 2812 stage 0–3 BC women, of whom 145 were diabetic and were 2667 non-diabetic. In those with diabetes, a mean haemoglobin A1C (HbA1C) <?7% (n?=?77) was defined as well-controlled diabetes, while a mean HbA1C >?9% (n?=?16) was defined as poorly controlled diabetes. All of the BC populations were followed from the date on which BC was diagnosed until 31 December 2015. Cox regression analysis was performed to estimate the adjusted hazards for all-cause mortality and BC-specific mortality. After controlling for the baseline and BC-related confounders, the adjusted hazard ratio (HR) for all-cause mortality and the HR for BC-specific mortality were 3.65 (95% confidence interval [95% CI] 1.13–11.82) and 8.37 (95% CI 1.90–36.91), respectively, for poorly controlled diabetic women and non-DM women. However, for the diabetic women with good glycaemic control, the HRs of all-cause mortality and BC-specific mortality were not significantly different (HR 0.91, 95% CI 0.42–1.01; HR 0.77, 95% CI 0.18–3.32, respectively) from those for both mortalities in non-DM patients. For moderate controlled diabetic women, the HRs for all-cause mortality and BC-specific mortality were 1.95 (95% CI 0.89–4.27) and 3.55 (95% CI 1.369–9.30), respectively. This pilot and retrospective cohort study reveals a relationship between glycaemic control and BC prognosis in diabetic women. In addition, well-controlled HbA1C, with maintained mean HbA1C values under 7%, may be associated with a better progression outcome of BC.