Yuan Xiang Guan

Activated mammalian target of rapamycin is a potential therapeutic target in gastric cancer

BackgroundThe mammalian target of rapamycin (mTOR) plays a key role in cellular growth and homeostasis. The purpose of our present study is to investigate the expression of activated mTOR (p-mTOR) in gastric cancer patients, their prognostic significance and the inhibition effect of RAD001 on tumor growth and to determine whether targeted inhibition of mTOR could be a potential therapeutic strategy for gastric cancer.MethodsThe expression of p-mTOR was detected in specimens of 181 gastric cancers who underwent radical resection (R0) by immunohistochemistry. The correlation of p-mTOR expression to clinicopathologic features and survival of gastric cancer was studied. We also determined the inhibition effect of RAD001 on tumor growth using BGC823 and AGS human gastric cancer cell lines.ResultsImmunostaining for p-mTOR was positive in 93 of 181 (51.4%) gastric cancers, closely correlated with lymph node status and pTNM stage. Patients with p-mTOR positive showed significantly shorter disease-free survival (DFS) and overall survival (OS) rates than those with p-mTOR-negative tumors in univariable analyses, and there was a trend toward a correlation between p-mTOR expression and survival in multivariable analyses. RAD001 markedly inhibited dose-dependently proliferation of human gastric carcinoma cells by down-regulating expression of p70s6k, p-p70s6k, C-myc, CyclinD1 and Bcl-2, up-regulating expression of P53.ConclusionsIn gastric cancer, p-mTOR is a potential therapeutic target and RAD001 was a promising treatment agent with inducing cell cycle arrest and apoptosis by down-regulating expression of C-myc, CyclinD1 and Bcl-2, up-regulating expression of P53.

Identification of anaplastic lymphoma kinase break points and oncogenic mutation profiles in acral/mucosal melanomas.

Acral and mucosal melanomas, the two most common subtypes of melanoma in China, exhibit different genetic alterations and biologic behavior compared with other subtypes of melanomas. The purpose of this study was to identify the genetic alterations in patients with acral or mucosal melanomas in southern China. Fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) analysis, polymerase chain reaction (PCR), and quantitative real‐time reverse transcriptase PCR (qRT‐PCR) were used to assess the anaplastic lymphoma kinase (ALK) break points. Furthermore, a mass spectrometry–based genotyping platform was used to analyze 30 acral melanomas and 28 mucosal melanomas to profile 238 known somatic mutations in 19 oncogenes. ALK break points were identified in four acral cases (6.9%). Eight (13.8%) cases harbored BRAF mutations, six (10.3%) had NRAS mutations, four (6.9%) had KIT mutations, two (3.5%) had EGFR mutations, two (3.5%) had KRAS mutations, two (3.5%) had MET mutations, one (1.7%) had an HRAS mutation, and one (1.7%) had a PIK3CA mutation. Two cases exhibited co‐occurring mutations, and one case with a BRAF mutation had a translocation in ALK. This study represents a comprehensive and concurrent analysis of the major recurrent oncogenic mutations involved in melanoma cases from southern China. These data have implications for both clinical trial designs and therapeutic strategies.

Comparison of endoscopic ultrasonography and multislice spiral computed tomography for the preoperative staging of gastric cancer - results of a single institution study of 610 Chinese patients.

Background This study compared the performance of endoscopic ultrasonography (EUS) and multislice spiral computed tomography (MSCT) in the preoperative staging of gastric cancer. Methodology/Principal Findings A total of 610 patients participated in this study, all of whom had undergone surgical resection, had confirmed gastric cancer and were evaluated with EUS and MSCT. Tumor staging was evaluated using the Tumor-Node-Metastasis (TNM) staging and Japanese classification. The results from the imaging modalities were compared with the postoperative histopathological outcomes. The overall accuracies of EUS and MSCT for the T staging category were 76.7% and 78.2% (P=0.537), respectively. Stratified analysis revealed that the accuracy of EUS for T1 and T2 staging was significantly higher than that of MSCT (P<0.001 for both) and that the accuracy of MSCT in T3 and T4 staging was significantly higher than that of EUS (P<0.001 and 0.037, respectively). The overall accuracy of MSCT was 67.2% when using the 13th edition Japanese classification, and this percentage was significantly higher than the accuracy of EUS (49.3%) and MSCT (44.6%) when using the 6th edition UICC classification (P<0.001 for both values). Conclusions/Significance Our results demonstrated that the overall accuracies of EUS and MSCT for preoperative staging were not significantly different. We suggest that a combination of EUS and MSCT is required for preoperative evaluation of TNM staging.

The Mutation Profiles of Common Oncogenes Involved in Melanoma in Southern China

tion, inflammation, and injury (Ouyang, 2010). Increasing IL-22R expression in keratinocytes by IFN-a may be one of the defense systems of injured skin. Damage causes infiltration of pDCs, which are activated by self-nucleic acid derived from damaged keratinocytes or other cells via Toll-like receptors 7 and 9, producing IFN-a/b (Gregorio et al., 2010). Although the detailed mechanisms remain unclear, IFN-a/b produced by pDCs influences IL-17and IL-22producing T cells by activation of myeloid dendritic cells (Gregorio et al., 2010). IL-22 signals via IL-22R inhibit keratinocyte terminal differentiation, causing thickening of the epidermis (Sa et al., 2007). IL-22 also induces production of heparin-binding epidermal growth factor-like growth factor from keratinocytes and may mediate the proliferation of the epidermis (Sa et al., 2007; Tohyama et al., 2009). Moreover, IL-22 induces expression of several genes in keratinocytes, such as human b-defensin 2 and S100 family genes, that are antimicrobial proteins (Wolk et al., 2006; Ouyang, 2010). Although these cellular responses will usually become downregulated after the repair of injury, the responses may trigger the development of lesions in psoriasis. Further studies will be necessary to clarify this mechanism.

PD-L1 expression is associated with FOXP3+ regulatory T-Cell infiltration of soft tissue sarcoma and poor patient prognosis

Background: Programmed death ligand-1(PD-L1) functions as a negative mediator of immune response through different pathways in anti-tumor immunity. Recent studies have reported that PD-L1 plays a pivotal role in the function of regulatory T-cells (Tregs). Although increases in FOXP3+ Tregs infiltration and PD-L1 expression have been revealed in several cancers, their correlation with soft tissue sarcoma remains unknown. Methods: We included 163 cases of soft tissue sarcoma who were diagnosed and underwent extensive and radical resection at the Sun Yat-sen University Cancer Center, Guangzhou, China, from 2000-2010. PD-L1 and FOXP3 expression was evaluated by immunohistochemistry. Correlation between their expressions and associations with clinicopathological features were studied. Results: Among 163 STS samples, 19 (11.7%) exhibited PD-L1 positivity, and 41 (25.2%) cases expressed high FOXP3+ Treg infiltration. Significant correlation between PD-L1 expression and FOXP3+Treg infiltration in STS was identified (r=0.450, p<0.001). In univariate analysis, PD-L1 expression was significantly associated with high tumor grade and the age of patients, while the presence of FOXP3+ in tumor infiltrating Tregs was significantly associated with the age of patients, high tumor stage, higher tumor grade and tumor depth. Multivariate analysis revealed PD-L1 and FOXP3 as independent prognostic indicators significantly associated with OS and DFS. Conclusions: Our study revealed that PD-L1 and FOXP3+Tregs may work synergistically in promoting immune evasion of the tumors in soft tissue sarcoma. A combined strategy to block PD-L1/PD-1 with simultaneous depletion of Tregs may show promise in enhancing the therapeutic efficacy of these patients.

No survival benefit from postoperative adjuvant chemotherapy after D2 radical resection for the patients with stage II gastric cancer

Objective: To evaluate the effect of 2 regimens of postoperative combination chemotherapies on the prognosis of early stage gastric cancer patients. Methods: A total of 268 patients with stage II gastric cancer underwent D2 resection in our Cancer Center between January 1990 and December 2006 were recruited. Among them, 34 patients received the FAM regimen (5-fluorouracil [5-FU] 600 mg/m2 intravenous [IV] drip on days 1, 8, 29, and 36; doxorubicin 30 mg/m2 IV bolus injection on days 1 and 29; and mitomycin-C 10 mg/m2 IV bolus injection on day 1; repeated every 8 weeks) and 81 patients received the FOLFOX regimen (oxaliplatin 100 mg/m2 IV drip on days 1 and 15; leucovorin 400 mg/m2 IV drip on days 1 and 15; 5-FU 400 mg/m2 IV bolus injection; 5-FU 2.4/3.0 mg/m2 continuous IV infusion for 48 hours on day 1, 2, 15, and 16; repeated every 4 weeks for at least 4 cycles). Patients were followed-up until December 2008. The Kaplan-Meier method was used to compare survival rates between treatment groups. Results: The 1-, 3-, 5-, and 10-year survival rates for the patients who received postoperative chemotherapy versus the patients who underwent surgery only were 98%, 84%, 58%, 18% versus 96%, 78%, 59%, 22%, respectively (P > 0.05). Furthermore, the survival rates for patients who received the FAM and FOLFOX regimens were not significantly different (P > 0.05). Conclusions: Postoperative adjuvant chemotherapy did not produce survival benefits for the patients with stage II gastric cancer. Randomized controlled clinical trials are demanded to confirm the finding from this study.

The absence of the ERBB4 hotspot mutations in melanomas in patients from southern China

V-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4) has been reported to be somatically mutated in 19% of melanoma cases. To investigate the prevalence of ERBB4 mutations in melanoma patients from southern China, we analyzed 117 formalin-fixed, paraffin-embedded melanoma samples archived in the Sun Yat-sen University Cancer Center. A matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) platform was used to screen for mutations. No ERBB4 hotspot mutations were detected. Our results indicate that ERBB4 mutations may play a limited role in melanomas in China; therefore, targeting the ERBB4 mutation in melanoma patients from southern China may not be a promising strategy.

Prognostic value of the C-reactive protein/Albumin Ratio (CAR) in patients with operable soft tissue sarcoma

Background The preoperative C-reactive protein/Albumin ratio (CAR) is valuable for predicting the prognosis of patients with various types of cancers. The aim of the present study is to investigate the prognostic value of the preoperative CAR and compare it with other systemic inflammatory response markers in patients with soft tissue sarcoma (STS). Methods This retrospective study included 206 patients with STS. The optimal cutoff value of the CAR was determined by receiver operating characteristic (ROC) analysis. The impact of the CAR and other clinicopathological features on overall survival (OS) and disease-free survival (DFS) was evaluated using univariate and multivariate Cox regression analyses. Kaplan-Meier survival analyses were used to compare groups classified by the CAR. Additionally, the area under the receiver operating characteristic curve (AUC) was used to compare the predictive ability of the CAR, high-sensitivity modified Glasgow prognostic score (Hs-mGPS), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR). Results The optimal cut-off value of the CAR was 0.1035 according to the ROC analysis. An increased CAR (≥0.1035) was significantly associated with older age, larger tumor size, deep tumor location, higher tumor grade and more advanced American Joint Committee on Cancer (AJCC) stage (all P<0.05). Patients with an elevated CAR (≥0.1035) exhibited a shorter median survival time and lower 5-year OS rate than those with a CAR<0.1035 (68.2 vs 115.8 months, P = 0.000; 44.6% vs 80.9%, P = 0.000, respectively). The results of a multivariate analysis indicated that the CAR (Hazard ratio (HR) 2.47, 95% confidence interval (CI) 1.47-4.14, P = 0.001) was an independent prognostic factor for OS along with tumor grade (P<0.05). Additionally, the CAR exhibited a greater AUC value (0.662) than the NLR and PLR, but the value was equal to the Hs-mGPS. Conclusions The preoperative CAR is an independent prognostic factor predicting prognosis in STS and exhibits superior prognostic ability compared to the established inflammation-based prognostic indices.