Prognostic value of the nutritional risk index in patients with newly diagnosed multiple myeloma.

The nutritional risk index (NRI), which is based on weight and albumin levels, is closely associated with the prognosis of many cancers. However, its prognostic value has not been investigated in patients with newly diagnosed multiple myeloma (NDMM). We aimed to assess the association between the NRI and survival outcomes in patients with NDMM. We retrospectively collected and analyzed clinical and laboratory data from patients with NDMM between 2005 and 2019 at our center. Patients were stratified into the high NRI (> 89) and low NRI (≤ 89) groups for prognostic analysis. The NRI and other variables were also explored to evaluate their prognostic value for overall survival (OS). A total of 638 patients diagnosed with NDMM were retrospectively included. Patients in the high NRI group had a significantly better median OS than those in the low NRI group (64 months vs 43 months, p < 0.001). In the multivariate analysis, a high NRI was shown to be an independent prognostic factor for OS (hazard ratio, 0.758; 95% confidence interval, 0.587-0.977; p = 0.033). Age, performance status, transplant status, and lactate dehydrogenase level were also independent prognostic factors for OS. In conclusion, our study demonstrates that the NRI is a simple and useful predictor of survival outcomes in patients with NDMM.

Circulating PD-L1 is associated with T cell infiltration and predicts prognosis in patients with CRLM following hepatic resection.

BACKGROUND: Exosomal PD-L1 (exoPD-L1) could induce immunosuppression functionally, thus impairing patients' survival in melanoma, NSCLC, and gastric cancer. However, no evidence demonstrates the feasibility of circulating exoPD-L1 and soluble PD-L1 (sPD-L1) as biomarkers for prognosis and early recurrence in colorectal liver metastasis (CRLM) patients following hepatectomy or their association with T cell infiltration at liver metastases. METHODS: In cohort 1, exoPD-L1 and sPD-L1 were preoperatively tested using ELISA. CD3, CD8, granzyme B (GB) and PD1 expressed at liver metastases were evaluated using immunohistochemistry. In cohort 2, exoPD-L1 and sPD-L1 were detected at baseline, before hepatectomy, after hepatectomy, and after disease progression. RESULTS: In cohort 1, higher preoperative exoPD-L1 or sPD-L1 significantly impaired RFS (exoPD-L1, P = 0.0043; sPD-L1, P = 0.0041) and OS (exoPD-L1, P = 0.0034; sPD-L1, P = 0.0061). Furthermore, preoperative exoPD-L1 was negatively correlated with CD3 + T-lymphocytes infiltrated at tumor center (CT), and GB and PD1 were expressed at tumor invasive margin (IM). Preoperative sPD-L1 was negatively correlated with CD3 + and CD8 + T-lymphocytes' infiltration at IM and CT, GB and PD1 expression at IM. In cohort 2, exoPD-L1 and sPD-L1 levels decreased following hepatectomy but increased when tumor progressed. Moreover, higher postoperative exoPD-L1 and sPD-L1 or a small reduction in exoPD-L1 and sPD-L1 levels after hepatectomy suggested higher early recurrence rate. CONCLUSIONS: Both preoperative exoPD-L1 and sPD-L1 had promising prognostic values and were associated with T cell infiltration at liver metastases in CRLM patients following hepatectomy. Dynamically tracking exoPD-L1 and sPD-L1 levels could monitor disease status and detect early recurrence.

Phosphoserine phosphatase as a prognostic biomarker in patients with gastric cancer and its potential association with immune cells.

BACKGROUND: Because of dismal prognosis in gastric cancer, identifying relevant prognostic factors is necessary. Phosphoserine phosphatase (PSPH) exhibits different expression patterns in many cancers and has been reported to affect the prognosis of patients with cancer. In this study, we examined the prognostic role of metabolic gene PSPH in gastric cancer based on the TCGA dataset and our hospital-based cohort cases. METHODS: We collected and analysed RNA-seq data of Pan-cancer and gastric cancer in the TCGA dataset and PSPH expression data obtained from immunohistochemical analysis of 243 patients with gastric cancer from Sun Yat-sen University cancer center. Further, Kaplan-Meier survival analysis and Cox analysis were used to assess the effect of PSPH on prognosis. The ESTIMATE and Cibersort algorithms were used to elucidate the relationship between PSPH and the abundance of immune cells using the TCGA dataset. RESULTS: We observed that PSPH expression displayed considerably high in gastric cancer and it was significantly associated with inferior prognosis (P = 0.043). Surprisingly, there was a significant relationship between lower immune scores and high expression of PSPH (P < 0.05). Furthermore, patients with a low amount of immune cells exhibited poor prognosis (P = 0.046). The expression of PSPH significantly increased in activated memory CD4 T cells, resting NK cells and M0 macrophages (P = 0.037, < 0.001, and 0.005, respectively). CONCLUSIONS: This study highlighted that PSPH influences the prognosis of patients with gastric cancer, and this is associated with the infiltration of tumour immune cells, indicating that PSPH may be a new immune-related target for treating gastric cancer.

The Immunoscore system predicts prognosis after liver metastasectomy in colorectal cancer liver metastases.

BACKGROUND: The Immunoscore was initially established to evaluate the prognosis of stage I/II/III colorectal cancer patients. However, the feasibility of the Immunoscore for the prognosis of colorectal cancer liver metastases (CRCLM) has not been reported. METHODS: Liver metastases in 249 CRCLM patients were retrospectively analyzed. The Immunoscore was assessed according to the counts and densities of CD3+ and CD8+ T cells in the central- and peritumoral areas by immunohistochemistry. The prognostic role of the Immunoscore for relapse-free survival (RFS) and overall survival (OS) was analyzed with Kaplan-Meier curves and Cox multivariate models, and confirmed via an internal validation. Receiver operating characteristic (ROC) curves were plotted to compare the prognostic values of the Immunoscore and the clinical risk score (CRS) system. RESULTS: CRCLM patients with high Immunoscores (> 2) had significantly longer RFS [median RFS (95% confidence interval; 95% CI) 21.4 (7.8-35.1) vs. 8.7 (6.8-10.5) months, P < 0.001] and OS [median OS (95% CI): not reached vs. 28.7 (23.2-34.2) months, P < 0.001] than those with low Immunoscores (≤ 2). After stratification by CRS, the Immunoscore retained a statistically significant prognostic value for OS. The areas under the ROC curves (AUROCs) of the Immunoscore and the CRS system for RFS were 0.711 [95% CI 0.642-0.781] and 0.675[95% CI 0.601-0.749] (P = 0.492), whereas the AUROC of the Immunoscore system for OS was larger than that of the CRS system [0.759 (95% CI 0.699-0.818) vs. 0.660 (95% CI 0.592-0.727); P = 0.029]. CONCLUSIONS: The Immunoscore of liver metastases can be applied to predict the prognosis of CRCLM patients following liver resection.

Decreased expression of BRCA1-associated protein 1 predicts unfavorable survival in gastric adenocarcinoma.

BRCA1-associated protein 1 (BAP1) has been reported as a novel tumor suppressor, while in gastric adenocarcinoma, the function of this protein was still await to be uncovered. Based on a large group of patients with gastric adenocarcinoma, our study aimed to have a further understanding about the correlation of BAP1 expression and patients' clinical outcomes. We performed quantitative PCR and Western blot to examine BAP1 expression in 38 cases of gastric adenocarcinoma samples and adjacent non-cancerous tissues. Immunochemistry was used to evaluate BAP1 expression in a large cohort of 474 paraffin-embedded specimens. The clinical and prognostic significance of BAP1 expression was statistically analyzed. Postoperative survival between groups was using Kaplan-Meier analysis. BAP1 was overexpressed in paracancerous normal mucosa compared with gastric cancer. Decreased BAP1 expression was associated with higher histologic grade (P = 0.044), tumor infiltration (P < 0.001), metastasis status (P = 0.023), and TNM stage (P < 0.001). Patients with low expression of BAP1 had shorter overall survival compared with those with high expression (P < 0.001). Patients' survival in stage N0 could be stratified by the expression of BAP1. Multivariate analysis showed that in gastric adenocarcinoma, BAP1 expressing level was an independent prognostic factor (RR = 0.575, P < 0.001). Decreased expression of BAP1 suggests pessimistic prognosis for gastric adenocarcinoma patients. Further studies are warranted.

Clinicopathologic characteristics and therapeutic responses of Chinese patients with non-small cell lung cancer who harbor an anaplastic lymphoma kinase rearrangement.

INTRODUCTION: The rearrangement of the anaplastic lymphoma kinase (ALK) gene accounts for approximately 1%-6% of lung adenocarcinoma cases and defines a molecular subgroup of tumors characterized by clinical sensitivity to ALK inhibitors such as crizotinib. This study aimed to identify the relationship between ALK rearrangement and the clinicopathologic characteristics of non-small cell lung cancer (NSCLC) and to analyze the therapeutic responses of crizotinib and conventional chemotherapy to ALK rearrangement in NSCLC patients. METHODS: A total of 487 lung cancer patients who underwent testing for ALK rearrangement in our department were included in this study. ALK rearrangement was examined by using fluorescence in situ hybridization (FISH) assay. RESULTS: Among the 487 patients, 44 (9.0%) were diagnosed with ALK rearrangement by using FISH assay. In 123 patients with adenocarcinoma who were non-smokers and of a young age (≤ 58 years old), the frequency of ALK rearrangement was 20.3% (25/123). Short overall survival (OS) was associated with non-adenocarcinoma tumor type (P = 0.006), poorly differentiated tumors (P = 0.001), advanced-stage tumors (P < 0.001), smoking history (P = 0.008), and wild-type epidermal growth factor receptor (EGFR) (P = 0.008). Moreover, patients with poorly differentiated and advanced-stage tumors had a shorter time to cancer progression compared with those with well differentiated (P = 0.023) and early-stage tumors (P = 0.001), respectively. CONCLUSIONS: ALK-rearranged NSCLC tends to occur in younger individuals who are either non-smokers or light smokers with adenocarcinoma. Patients with ALK rearrangement might benefit from ALK inhibitor therapy.

Inflammatory response signature score model for predicting immunotherapy response and pan-cancer prognosis.

Background: Inflammatory responses influence the outcome of immunotherapy and tumorigenesis by modulating host immunity. However, systematic inflammatory response assessment models for predicting cancer immunotherapy (CIT) responses and survival across human cancers remain unexplored. Here, we investigated an inflammatory response score model to predict CIT responses and patient survival in a pan-cancer analysis. Methods: We retrieved 12 CIT response gene expression datasets from the Gene Expression Omnibus database (GSE78220, GSE19423, GSE100797, GSE126044, GSE35640, GSE67501, GSE115821 and GSE168204), Tumor Immune Dysfunction and Exclusion database (PRJEB23709, PRJEB25780 and phs000452.v2.p1), European Genome-phenome Archive database (EGAD00001005738), and IMvigor210 cohort. The tumor samples from six cancers types: metastatic urothelial cancer, metastatic melanoma, gastric cancer, primary bladder cancer, renal cell carcinoma, and non-small cell lung cancer.We further established a binary classification model to predict CIT responses using the least absolute shrinkage and selection operator (LASSO) computational algorithm. Findings: The model had high predictive accuracy in both the training and validation cohorts. During sub-group analysis, area under the curve (AUC) values of 0.82, 0.80, 0.71, 0.7, 0.67, and 0.64 were obtained for the non-small cell lung cancer, gastric cancer, metastatic urothelial cancer, primary bladder cancer, metastatic melanoma, and renal cell carcinoma cohorts, respectively. CIT response rates were higher in the high-scoring training cohort subjects (51%) than the low-scoring subjects (27%). The five-year survival rates in the high- and low score groups of the training cohorts were 62% and 21%, respectively, while those of the validation cohorts were 54% and 22%, respectively (P < 0·001 in all cases). Inflammatory response signature score derived from on-treatment tumor specimens are highly predictive of response to CIT in patients with metastatic melanoma. A significant correlation was observed between the inflammatory response scores and tumor purity. Regardless of the tumor purity, patients in the low score group had a significantly poorer prognosis than those in the high score group. Immune cell infiltration analysis indicated that in the high score cohort, tumor-infiltrating lymphocytes were significantly enriched, particularly effector and natural killer cells. Inflammatory response scores were positively correlated with immune checkpoint genes, suggesting that immune checkpoint inhibitors may have benefited patients with high scores. Analysis of signature scores across different cancer types from The Cancer Genome Atlas revealed that the prognostic performance of inflammatory response scores for survival in patients who have not undergone immunotherapy can be affected by tumor purity. Interleukin 21 (IL21) had the highest weight in the inflammatory response model, suggesting its vital role in the prediction mode. Since the number of metastatic melanoma patients (n = 429) was relatively large among CIT cohorts, we further performed a co-culture experiment using a melanoma cell line and CD8 + T cell populations generated from peripheral blood monocytes. The results showed that IL21 therapy combined with anti-PD1 (programmed cell death 1) antibodies (trepril monoclonal antibodies) significantly enhanced the cytotoxic activity of CD8 + T cells against the melanoma cell line. Conclusion: In this study, we developed an inflammatory response gene signature model that predicts patient survival and immunotherapy response in multiple malignancies. We further found that the predictive performance in the non-small cell lung cancer and gastric cancer group had the highest value among the six different malignancy subgroups. When compared with existing signatures, the inflammatory response gene signature scores for on-treatment samples were more robust predictors of the response to CIT in metastatic melanoma.

A tumor-associated endothelial signature score model in immunotherapy and prognosis across pan-cancers.

Background: The tumor-associated endothelial cell (TAE) component plays a vital role in tumor immunity. However, systematic tumor-associated endothelial-related gene assessment models for predicting cancer immunotherapy (CIT) responses and survival across human cancers have not been explored. Herein, we investigated a TAE gene risk model to predict CIT responses and patient survival in a pan-cancer analysis. Methods: We analyzed publicly available datasets of tumor samples with gene expression and clinical information, including gastric cancer, metastatic urothelial cancer, metastatic melanoma, non-small cell lung cancer, primary bladder cancer, and renal cell carcinoma. We further established a binary classification model to predict CIT responses using the least absolute shrinkage and selection operator (LASSO) computational algorithm. Results: The model demonstrated a high predictive accuracy in both training and validation cohorts. The response rate of the high score group to immunotherapy in the training cohort was significantly higher than that of the low score group, with CIT response rates of 51% and 27%, respectively. The survival analysis showed that the prognosis of the high score group was significantly better than that of the low score group (all p < 0·001). Tumor-associated endothelial gene signature scores positively correlated with immune checkpoint genes, suggesting that immune checkpoint inhibitors may benefit patients in the high score group. The analysis of TAE scores across 33 human cancers revealed that the TAE model could reflect immune cell infiltration and predict the survival of cancer patients. Conclusion: The TAE signature model could represent a CIT response prediction model with a prognostic value in multiple cancer types.

Primary lymphoma of the uterine cervix: a clinicopathologic study of 13 cases with review of additional 54 cases in the literature.

Primary lymphoma of the uterine cervix (LUCX) is extremely rare, and its diagnosis is challenging. However, its clinicopathological features have not been well characterized. Thirteen primary LUCX patients were retrospectively studied, and 54 patients from the literature were reviewed. Primary LUCX was identified in 0.22% (13/6000) of patients with uterine cervical malignancies in our institution. The patients' median age was 51 years (range: 22-85 years). All patients had a bulk of neoplasms in the uterine cervix. The median tumour diameter was 6 cm (range: 1.5-10 cm). Approximately 78.0% (39/50) of the patients initially presented with irregular vaginal bleeding or discharge. Moreover, 86.7% (39/45) had Ann Arbor stage I or II. Diffuse large B-cell lymphoma, not otherwise specified, was the most common type, accounting for 85.0% (57/67) of primary LUCX cases. Follicular lymphoma (7.5%, 5/67), extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (4.5%, 3/67), mantle cell lymphoma (MCL), blastoid variant (1.5%, 1/67), and peripheral T-cell lymphoma (1.5%, 1/67) were occasionally observed. Three patients (7.1%, 3/42) with DLBCL, NOS died from the disease during the follow-up period. Their 5-year overall survival (OS) rate was 93.5%. The patient with MCL, blastoid variant in our present cohort died of the disease 33 months after diagnosis. Primary LUCX is an extremely rare condition. The clinical symptoms are non-specific. DLBCL, NOS is the most common histologic type, showing a favourable outcome with accurate diagnosis and timely and optimal treatment.

Comprehensive analysis reveals potential therapeutic targets and an integrated risk stratification model for solitary fibrous tumors.

Solitary fibrous tumors (SFTs) are rare mesenchymal tumors with unpredictable evolution and with a recurrence or metastasis rate of 10-40%. Current medical treatments for relapsed SFTs remain ineffective. Here, we identify potential therapeutic targets and risk factors, including IDH1 p.R132S, high PD-L1 expression, and predominant macrophage infiltration, suggesting the potential benefits of combinational immune therapy and targeted therapy for SFTs. An integrated risk model incorporating mitotic count, density of Ki-67+ cells and CD163+ cells, MTOR mutation is developed, applying a discovery cohort of 101 primary non-CNS patients with negative tumor margins (NTM) and validated in three independent cohorts of 210 SFTs with the same criteria, and in 36 primary CNS SFTs with NTM. Compared with the existing models, our model shows significantly improved efficacy in identifying high-risk primary non-CNS and CNS SFTs with NTM for tumor progression.Our findings hold promise for advancing therapeutic strategies and refining risk prediction in SFTs.

Overexpression of the secretory small GTPase Rab27B in human breast cancer correlates closely with lymph node metastasis and predicts poor prognosis.

BACKGROUND: The secretory small GTPase Rab27b was recently identified as an oncogene in breast cancer (BC) in vivo and in vitro studies. This research was designed to further explore the clinical and prognostic significance of Rab27B in BC patients. METHODS: The mRNA/protein expression level of Rab27B was examined by performing Real-time PCR, western blot, and immunohistochemistry (IHC) assays in 12 paired BC tissues and matched adjacent noncancerous tissues (NAT). Then we carried out IHC assay in a large cohort of 221 invasive BC tissues, 22 normal breast tissues, 40 fibroadenoma (FA), 30 ductual carcinoma in situ (DCIS) and 40 metastatic lymph nodes (LNs). The receiver operating characteristic curve method was applied to obtain the optimal cutoff value for high Rab27B expression. Epithelial-mesenchymal transition (EMT) marker expression levels were detected in relation to Rab27B expression. RESULTS: We observed that the increased expression of Rab27B was dependent upon the magnitude of cancer progression (P < 0.001). The elevated expression of Rab27B was closely correlated with lymph node metastasis, advanced clinical stage, ascending pathology classification, and positive ER status. Furthermore, patients with high expression of Rab27B had inferior survival outcomes. Multivariate Cox regression analysis proved that Rab27B was a significantly independent risk factor for patients' survival (P < 0.001). Furthermore, a significant positive relationship was observed between Rab27B expression and elevated mesenchymal EMT markers. CONCLUSION: Our findings suggest that overexpression of Rab27B in BC coincides with lymph node metastasis and acquisition of a poor prognostic phenotype.

Grocott Methenamine Silver Staining Is the Optimal Approach to Histological Diagnosis of Pulmonary Cryptococcosis.

Background: Histological staining methods for Cryptococcus identification vary in accuracy. This study aimed to investigate the clinical value of Grocott methenamine silver (GMS), periodic acid-Schiff (PAS), and Alcian blue (AB) staining in the diagnosis of pulmonary cryptococcosis (PC). Methods: From April 2004 to June 2021, the clinical and pathological data of 152 patients with PC were collected from the Department of Pathology, Sun Yat-sen University Cancer Center. The sensitivity and identifiability of GMS, PAS, and AB staining for histological diagnosis were systematically evaluated using statistical methods combined with the microscopic characteristics of PC cases. Results: Statistical analysis showed that the detection rates of GMS, PAS, and AB staining were 100.0% (152/152), 94.7% (144/152), and 81.6% (124/152), respectively. McNemar's test showed that the sensitivity of GMS was significantly higher than those of PAS (P = 0.008) and AB stains (P < 0.001). Both PAS and AB stains had obvious non-specific staining, which interfered with the detection of Cryptococcus, and increased diagnostic difficulties. In contrast, in GMS staining, Cryptococcus spores were prominent with a clean background and were clearly observed at low or medium power magnification, with the identifiability significantly better than those of PAS or AB staining. Conclusion: GMS staining had sensitivity up to 100%, and identifiability that was better than those of PAS and AB staining. GMS is the best method for histological diagnosis of PC.

A single nucleotide polymorphism in the matrix metalloproteinase 2 promoter is closely associated with high risk of nasopharyngeal carcinoma in Cantonese from southern China.

Matrix metalloproteinase 2 (MMP2) has been shown to play an important role in several steps of cancer development. The -1306C/T polymorphism of the MMP2 gene displays a strikingly lower promoter activity than the T allele, and the CC genotype in the MMP2 promoter has been reported to associate with the development of several cancers. To assess the contribution of the MMP2 -1306C/T polymorphism to the risk of nasopharyngeal carcinoma (NPC), we conducted a case-control study and analyzed MMP2 genotypes in 370 patients with NPC and 390 frequency-matched controls using real-time PCR-based TaqMan allele analysis. We found that subjects with the CC genotype had an increased risk (OR = 1.55, 95% CI = 1.05-2.27) of developing NPC compared to those with the CT or TT genotypes. Furthermore, we found that the risk of NPC was markedly increased in subjects who were smokers (OR = 15.04, 95% CI = 6.65-33.99), heavy smokers who smoked ≥ 20 pack-years (OR = 18.66, 95% CI = 7.67-45.38), or young (<60 years) at diagnosis (OR = 1.52, 95% CI = 1.01-2.29). Our results provide molecular epidemiological evidence that the MMP2 -1306C/T promoter polymorphism is associated with NPC risk, and this association is especially noteworthy in heavy smokers.

Polymorphisms of death pathway genes FAS and FASL and risk of nasopharyngeal carcinoma.

The FAS receptor/ligand system is a key regulator of apoptotic cell death and corruption of this signaling pathway has been shown to participate in carcinogenesis. Functional polymorphisms in the FAS (FAS -1377G/A) and FASL (FASL -844T/C) genes alter their transcriptional activity. Therefore, we examined the association between these polymorphisms and the risk of developing nasopharyngeal carcinoma (NPC). FAS -1377G/A and FASL -844T/C genotypes were determined by PCR-based RFLP analysis in 582 patients with NPC and 613 frequency-matched controls. We observed a significantly increased risk of NPC associated with the FAS -1377AA genotype [odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.21-2.35] compared with the FAS -1377 GG genotype. In addition, elevated NPC risk was also found among subjects carrying both FAS -1377AA and FASL -844CC genotypes compared with both FAS -1377GG and FASL -844CT or -844TT, the OR was 2.39 (95% CI = 1.50-3.79). After stratification by smoking status, heavy smokers (≥15 pack-years) carrying FAS -1377AA genotype had an increased risk of NPC compared with FAS -1377GG genotype (OR = 3.48, 95% CI = 1.66-7.30). Furthermore, we observed a statistically significant interaction between the two polymorphisms and heavy smoking status (OR = 5.92, 95% CI = 1.91-18.3). Our study provides the first evidence that functional FAS -1377 G/A and FASL -844 T/C polymorphisms are associated with the risk of NPC, and this association is especially noteworthy in tobacco smokers.

Polymorphisms of methylenetetrahydrofolate reductase are associated with a high risk of nasopharyngeal carcinoma in a smoking population from Southern China.

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in converting folate to a compound which serves as a methyl donor for DNA methylation, an epigenetic modification known to be dysregulated in carcinogenesis. This case-control study assessed the contribution of MTHFR polymorphisms to the risk of nasopharyngeal carcinoma (NPC). MTHFR genotypes C677T and A1298C in 529 NPC patients and 577 frequency-matched controls were determined by PCR-based restriction fragment length polymorphism. We found a 1.57-fold increased risk of NPC in subjects with the MTHFR 1298AC genotype compared to subjects with the MTHFR 1298AA genotype. In addition, an elevated NPC risk was also found in subjects with both the MTHFR 677CT and 1298AC genotypes [odds ratio (OR) = 2.15, 95% confidence interval (CI) = 1.37-3.39] compared to subjects with the 677CC/1298AA genotypes. Furthermore, we observed an additive interaction between MTHFR polymorphisms and smoking status on the increased risk of NPC. The OR was 6.72 (95% CI = 1.85-24.48) among heavy smokers (pack-years ≥15) carrying 677TT compared with nonsmokers carrying the 677CC genotype. The OR was 7.23 (95% CI = 4.22-12.38) or 12.75 (95% CI = 2.74-59.3) among subjects carrying the 1298AC or 1298CC genotype in heavy smokers (pack-years ≥15) compared with 1298AA in nonsmokers. Our results provide the first molecular epidemiological evidence that MTHFR polymorphisms associate with the risk of NPC and this association is especially noteworthy in heavy smokers.

MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis.

To investigate the global expression profile of miRNAs in primary breast cancer (BC) and normal adjacent tumor tissues (NATs) and its potential relevance to clinicopathological characteristics and patient survival, the genome-wide expression profiling of miRNAs in BC was investigated using a microarray containing 435 mature human miRNA oligonucleotide probes. Nine miRNAs of hsa-miR-21, hsa-miR-365, hsa-miR-181b, hsa-let-7f, hsa-miR-155, hsa-miR-29b, hsa-miR-181d, hsa-miR-98, and hsa-miR-29c were observed to be up-regulated greater than twofold in BC compared with NAT, whereas seven miRNAs of hsa-miR-497, hsa-miR-31, hsa-miR-355, hsa-miR-320, rno-mir-140, hsa-miR-127 and hsa-miR-30a-3p were observed to be down-regulated greater than twofold. The most significantly up-regulated miRNAs, hsa-mir-21 (miR-21), was quantitatively analyzed by TaqMan real-time PCR in 113 BC tumors. Interestingly, among the 113 BC cases, high level expression of miR-21 was significantly correlated with advanced clinical stage (P = 0.006, Fisher's exact text), lymph node metastasis (P = 0.007, Fisher's exact text), and shortened survival of the patients (hazard ratio [HR]=5.476, P < 0.001). Multivariate Cox regression analysis revealed this prognostic impact (HR=4.133, P = 0.001) to be independent of disease stage (HR=2.226, P = 0.013) and histological grade (HR=3.681, P = 0.033). This study could identify the differentiated miRNAs expression profile in BC and reveal that miR-21 overexpression was correlated with specific breast cancer biopathologic features, such as advanced tumor stage, lymph node metastasis, and poor survival of the patients, indicating that miR-21 may serve as a molecular prognostic marker for BC and disease progression.

Cavin3 Suppresses Breast Cancer Metastasis via Inhibiting AKT Pathway.

OBJECTIVE: Cavin3 is a putative tumor suppressor protein. However, its molecular action on tumor regulation is largely unknown. The aim of the current study is to explore the implication of cavin3 alteration, its clinical significance, and any potential molecular mechanisms in the regulation of breast cancer (BC). METHODS: TCGA (The Cancer Genome Atlas) and GTEx (Genotype-Tissue Expression) data bases, and 17 freshly paired BC and adjacent normal tissues were analyzed for mRNA levels of Cavin3. Furthermore, cavin3 protein expression from 407 primary BC samples were assessed by immunohistochemistry (IHC) and measured by H-score. The clinical significance of cavin3 expression was explored by Kaplan-Meier analysis and the Cox regression method. In vitro biological assays were performed to elucidate the function and underlying mechanisms of cavin 3 in BC cell lines. RESULTS: Cavin3 mRNA was dramatically down-regulated in BC compared with the negative control. The median H-score of cavin3 protein by IHC was 50 (range 0-270). There were 232 (57%) and 175 (43%) cases scored as low (H-score≤50) and high (H-score >50) levels of cavin3, respectively. Low cavin3 was correlated with a higher T and N stage, and worse distant metastasis-free survival (DMFS) and overall survival (OS). Multivariate survival analysis revealed low cavin3 was an independent fact for worse DMFS. In BC cells, an overexpression of cavin3 could inhibit cell migration and invasion, and significantly decreased the level of p-Akt. Knockout of cavin3, meanwhile, promoted cell invasion ability and increased the level of p-AKT. CONCLUSION: Cavin3 expression is significantly lower in BC and is correlated with distant metastasis and worse survival. Cavin3 functions as a metastasis suppressor via inhibiting the AKT pathway, suggesting cavin3 as a potential prognostic biomarker and a target for BC treatment.

Upregulation of caveolin-1 and CD147 expression in nasopharyngeal carcinoma enhanced tumor cell migration and correlated with poor prognosis of the patients.

Expression of caveolin-1 (Cav-1) and extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) and their prognostic significance were analyzed in archive NPC samples. Cav-1 and CD147 were overexpressed in 49.48% (96/194) and 59.39% (117/197) of NPC, respectively. Both Cav-1 and CD147 expression levels correlated significantly with metastasis (p = 0.025 and 0.017, respectively) and a lower 5-year survival rate (p = 0.02 and 0.0009, respectively). In addition, Cav-1 expression levels correlated significantly with local recurrence (p = 0.038). Multivariate Cox regression analysis indicated that combination of high Cav-1 and CD147 expression was a significant, independent prognosis predictor in patients with NPC (HR = 2.135; p = 0.006). Functional studies revealed that overexpression of Cav-1 promoted secretion of MMP-3 and MMP-11 (active) proteins, as well as an increase in the migratory ability of CNE1 and CNE2 cells, while siRNA-mediated silencing of Cav-1 or CD147 led to reduced levels of MMP-3 and MMP-11(active) secretion, and reduced migration capacity of CNE1 and CNE2 cells. We observed a positive correlation between Cav-1 and CD147 expression in NPC (rho = 0.330, p = 0.000), CD147 protein levels were upregulated in Cav-1 overexpressing CNE1 and CNE2 cells, whereas siRNA-mediated silencing of Cav-1 led to the downregulation of CD147 expression. Our results indicate that Cav-1 and CD147 overexpression predict poor NPC prognosis and enhanced tumor cell migration, which is associated with MMP-3 and MMP-11 (active) secretion.

Elevated expressions of survivin and VEGF protein are strong independent predictors of survival in advanced nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China. The China 1992 TNM staging system has been widely used for prognosis prediction of NPC patients in China. Although NPC patients can be classified according to their clinical stage in this system, their prognosis may vary significantly. METHOD: 280 cases of NPC with clinical follow-up data were collected and expressions of survivin and VEGF in tumor tissues were investigated by immunohistochemistry (IHC). Apoptosis index (AI) in 100 cases of NPC was detected by the TUNEL method. RESULTS: Expression of survivin and VEGF were significantly associated with TNM stage, T-stage and metastasis of NPC. The patients with survivin and VEGF over-expression presented lower 5-year survival rate, as compared to those of low-expression (42.32% vs. 70.54%, 40.1% vs. 67.8%, respectively, P < 0.05), especially in advanced stage patients (36.51% vs. 73.41%, 35.03% vs. 65.22%, respectively, P < 0.05). The 5-year survival rate in NPC patients with survivin and VEGF dual over-expression was significantly lower than that of patients with dual low-expression (18.22% vs. 73.54%, respectively; P = 0.0003). Multivariate analysis indicated that both survivin and VEGF over-expression in NPC tumor tissues were strong independent factors of poor prognosis in NPC patients. The mean AI in the 39 survivin low-expression cases was 144.7 +/- 39.9, which was significantly higher than that in 61 survivin over-expression cases (111.6 +/- 39.8) (T test, P < 0.05). CONCLUSION: Survivin and VEGF over-expression are independent prognostic factors for the patients with NPC. These results also suggest that tumor survivin and VEGF expressions are valuable prognostic markers for prognosis prediction in NPC patients.

AXL-GAS6 expression can predict for adverse prognosis in non-small cell lung cancer with brain metastases.

PURPOSE: Patients with non-small cell lung cancer (NSCLC) brain metastases (BM) have poor clinical outcomes. We sought to determine if AXL-GAS6 expression can be used as independent prognostic biomarkers for NSCLC BM. METHODS: We retrospectively studied the medical records of 98 patients diagnosed with advanced metastatic NSCLC from December 2000 to June 2014. Out of a total of 98 patients with NSCLC metastases, 66 patients were identified to have brain metastases. The expressions of AXL and GAS6 were assessed by standard immunohistochemistry and correlated with clinicopathological factors and overall survival (OS) outcomes. RESULTS: The expression of AXL was positively associated with GAS6 expression (P < 0.001), and tumor differentiation (P = 0.014) in advanced NSCLC with metastases. AXL expression displayed no association with gender, age, smoking history, pathology, T stage, N stage, CEA, and LDH. In univariate analysis, both AXL and GAS6 were found to predict worse OS outcomes (AXL: HR 1.77, 95% CI 1.13-2.79, P = 0.01; GAS6: HR 1.80, 95% CI 1.14-2.84, P = 0.01). In the brain metastasis subgroup, the expression of AXL was positively associated with GAS6 expression (P < 0.001). Both AXL and GAS6 were found to predict worse BM-OS outcomes in univariate analysis (AXL: HR 2.19, 95% CI 1.33-4.10, P = 0.005; GAS6: HR 2.04, 95% CI 1.01-3.71, P = 0.019). In multivariate analysis, high co-expression of AXL/GAS6 was found to be an independent unfavorable risk factor for the overall study population (HR 2.33, 95% CI 1.40-3.87, P = 0.0011) and also in BM (HR 2.76, 95% CI 1.45-5.25, P = 0.001), predicting worse survival outcome. CONCLUSIONS: AXL-GAS6 co-expression represents a potential independent prognostic biomarker for survival outcome in NSCLC BM patients.