骨转移瘤系统性分子靶向治疗靶点与药理学制剂研究

骨转移瘤骨骼微环境中，肿瘤细胞分泌多种细胞因子促进溶骨活性，而溶骨后释放的储存于骨内的生长因子又促进肿瘤细胞生长与侵袭，从而形成骨质破坏“恶性循环”。虽然骨骼微环境可造成骨质破坏的“恶性循环”，但也为骨转移瘤治疗提供了许多潜在性靶点。骨转移瘤分子靶点以核因子?κB受体活化因子（receptor activator of nuclear factor?κB, RANK）-核因子?κB受体活化因子配体（RANK ligand, RANKL）-骨保护素（osteoprotegerin, OPG）系统研究得为广泛与深入。骨转移瘤细胞可以促进骨基质细胞表达RANKL并抑制OPG的表达，RANKL与OPG比例失调是诱发骨质破坏的重要因素。溶骨产生的转移生长因子β在介导“恶性循环”中的作用越来越突出，转移生长因子β可以促进肿瘤细胞发生上皮-间质转变、血管生成以及免疫抑制。Src家族激酶、内皮素A受体、基质金属蛋白酶以及组蛋白酶K等均为骨转移瘤治疗的潜在性靶点。以狄诺塞麦为代表的靶向药理学制剂的本质均为阻断骨转移瘤骨质破坏“恶性循环”。骨转移瘤靶向制剂除了可以抑制骨转移瘤细胞骨质破坏外，部分还可以产生直接抗原发肿瘤效应，它们在延迟骨相关事件发生、延长患者生存期以及终提高患者生存质量方面发挥着重要作用。骨转移瘤患者已经可以从系统性分子靶向治疗中受益，进一步研发系统性靶向制剂对改善患者治疗选择、增强疗效具有重要意义。

Objective:To investigate the the correlation between lymphatic vascular invasion (LVI) and prognosis in T3/T4 gastric cancer after D2 resection, and establish an optimal classification of staging system. Methods: From Jan 2000 to Sep 2010, a total of 1, 283 T3/T4 gastric cancer patients undergoing D2 resection were enrolled. Univariate and multivariate analysis were used to investigate the prognostic value of gastric cancer patients. Homogeneity, discriminatory ability, and monotonicity of gradients of hypothetical N stage and UICC N stage were compared using linear trendχ2, likelihood ratioχ2 statistics, and Akaike information criterion (AIC) calculations.Results:Multivariate analysis identified LVI was an independent prognostic factor. The 3.5-year overall survival were worse in patients with LVI than those without LVI (P<0.001). LVI was corporated into N3b stage performed the optimum prognostic stratification, together with better homogeneity, discriminatory ability and monotonicity of gradients. Conclusion:LVI is an independent prognostic factor for T3/T4 gastric cancer atfer D2 resection, and may be considered to be incorporated into the UICC N3b stage.

Objective:This study examined the prognosis of the “node-negative with eLNs≤15” designation and the additional value of incorporating it into the pN1 designation in the seventh edition N classification.Methods: From Jan 2000 to Sep 2010, a total of 1,258 gastric cancer patients undergoing radical gastric resection were enrolled. We incorporated node-negative patients with eLNs≤15 into pN1 and compared this designation with the 7th edition UICC N stage for 3.5- year overall survival by univariate and multivariate analysis. Homogeneity, discriminatory ability, and monotonicity of gradients in hypothetical N stage and UICC N stage were compared using linear trendχ2, likelihood ratioχ2 statistics, and Akaike information criterion (AIC) calculations.Results:Node-negative patients with eLNs≤15 had worse survival compared with those with eLNs >15. The hypothetical N stage had higher linear trend and likelihood ratioχ2 scores and smaller AIC values compared with those for the 7th edition N stage, which represented the optimum prognostic stratification.Conclusion:Node-negative patients with eLNs≤15 can be considered to be incorporated into the pN1 stage in the 7th edition of th e TNM classiifcation.

Objective:Investigate the feasibility and effcacy of neoadjuvant chemoradiotherapy for locally advanced gastric cancer.Methods: Intensity-modulated radiotherapy (IMRT), with 50/45 Gy in 25 fractions. The concurrent chemotherapy regimens included oral TS-1 plus oxaliplatin 40 mg/m2 intravenously weekly (10 patients) or TS-1 alone (120 mg/day, 25 patients). Surgical resection was performed within 6~8 weeks atfer the last day of radiotherapy. Results:No grade 4 toxicity recorded. hTe incidence of grade 3 toxicity is 11.4%: thrombocytopenia (5.7%), neutropenia (2.9%) and radiation esophagitis (2.9%). Pathological complete response 8.6% (3/35).Surgery-related complications consisted of anastomotic leakage in 2 patients (7.1%), infection in 3 (10.7%) and hemorrhage in 2 (7.1%). No postoperative mortality was recorded. hTe 1-year and 2-year overall survival (OS) rates were 88.3% and 59.6%respectively.Conclusion:In this study, neoadjuvant chemoradiotherapy showed an acceptable toxicity and promising efficacy in patients with locally advanced gastric cancer.

Objective:Lymphadenectomy has been increasingly regarded as standard surgical procedure for advanced gastric cancer (GC), while necessity No.14v lymph node dissection for lower GC is still controversial.Methods: A total of 311 GC patients receiving D1+ (D1+7, 8a, 9) or D2 plus No.14v lymph node dissection in our center were enrolled. Patients were categorized into two groups based on No.14v lymph node status: positive group (PG) and negative group (NG).Results:Fifty patients (16.1%) had No.14v lymph node metastasis. Metastasis to No.4d, No.6 lymph node and distant metastasis were independent variables affecting No.14v lymph node metastasis. Patients with positive No.14v lymph node had a significant lower overall survival (OS) rate than those without (3-year OS, 34.0% vs. 67.0%,P<0.001).Conclusion:GC patients with positive No.4d and No.6 lymph node often metastasis to No.14v lymph node. Status of No.14v lymph node was an independent prognostic factor for GC staged TNM III. Patients with positive No.14v lymph node usually have a poor prognosis, while such patients without distant metastasis may beneift from a curative surgery.

Objective:hTe aim of this study was to investigate the expression of PHLPP1 in gastric cancer (GC), its potential influence on the prognosis of GC patients.Methods: In the present study, we examined the immunohistochemical expression of PHLPP1 on tissue microarrays (TMAs) containing 135 gastric adenocarcinoma tissues and 135 matched adjacent non-tumor tissues. Survival analysis according to PHLPP1 expression was calculated.Results:The majority of the adjacent non-tumor tissues showed positive-expression levels of PHLPP1 was 87.4% (118/135). In contrast, the positive rate of PHLPP1 in primary gastric cancer tissues was only 55.6% (75/135), significantly lower than that in adjacent non-tumor tissues (P<0.001). The Kaplan-Meier analysis showed that the overall survival (OS) rates of patients with negative PHLPP1 was significantly lower than that of patients with positive PHLPP1 (P=0.008). Multivariate survival analysis results showed that PHLPP1 was an independent predictor of the survival of patients with GC. Conclusion:This study indicates that aberrant expression of PHLPP1 was observed in GC and loss of PHLPP1 might identify patients with poor prognostic outcomes.

Objective:D2 lymphadenectomy has been increasingly regarded as standard surgical procedure for advanced gastric cancer (GC), while necessity No.14v lymph node dissection for distal GC is still controversial. Methods: A total of 920 distal GC patients receiving at least D1+ (D1+7, 8a, 9) or D2 lymph node dissection in our center were enrolled in this study, of whom, 243 patients also had the No.14v lymph node dissected. Other 677 patients without No.14v lymph node dissection were used for comparison.Results:Forty-five (18.5%) patients had No.14v lymph node metastasis. There was no significant difference in overall survival (OS) rate between patients with and without No.14v lymph node dissection. Following stratiifed analysis, in TNM stages I, II, IIIa and IV, No.14v lymph node dissection did not affect OS. In multivariate analysis, No.14v lymph node dissection was found to be an independent prognostic factor in patients with TNM stage IIIb/IIIc GC (HR =0.670, 95% CI, 0.506~0.886, P=0.005).Conclusion:Adding No.14v lymph node to D2 lymphadenectomy may be associated improved OS for middle and lower GC staged TNM IIIb/IIIc.

Objective:hTe aim of this study was to determine whether the EGFR statuscould significantly predict some benefit in overall survival and response to cetuximab in advanced GC xenografts.Methods: Two hundred xenografts derived from 20 GC patients were established. Then they were divided into cetuximab treated group and control group randomly.Results:Among the cetuximab treated group, 4 GC cases were identified responded to cetuximab.hTose cetuximab treated PDX models had longer OS than non-treated. High EGFR mRNA expression and immunohistochemistry score are more prone to response to cetuximab. EGFR amplification, mRNA and protein overexpression were associated with the OS in cetuximab treated PDX models. Moreover, in the PDX models derived from EGFR ampliifcation, mRNA or protein overexpression cases, the OS is signiifcantly different between the cetuximab treated and control group, while the OS in not statistically different in other cases.Conclusion:EGFR status predicts sensitivity to therapy and survival in GC treated with cetuximab, especially the mRNA and protein expression level.

Objective:The study is a prospective, open, randomized multicenter phase III clinical trial with two arms that aims to elucidate superiority of D2 plus No.14v lymph node dissection in comparison with standard D2 surgery in patients with curable distal gastric cancer staged cT4N+M0. hTe primary endpoint is overall survival secondary endpoint is disease-free survival. Each treatment arm includes 255 patients, providing an expected hazard ratio of 0.6.Methods:A prospective, open, randomized multicenter phase III clinical trial was designed to elucidate superiority of D2 plus No.14v lymph node dissection in improving overall survival with regard to standard D2 surgery in patients with curable distal gastric cancer staged cT4N+M0. hTe study is a multi-institutional prospective randomized controlled trial, with participating institutions including 20 specialized centers. Treatment methodsEnrolled patients are randomized to 14v- (arm A) or to 14v + (arm B).Results:End points the primary endpoint is overall survival secondary endpoint is disease-free survival.Conclusion:Results are unifnished.

Systemic chemotherapy is the basic palliative treatment for metastatic nasopharyngeal carcinoma (NPC); however, it is not known whether locoregional radiotherapy targeting the primary tumor and regional lymph nodes affects the survival of patients with metastatic NPC. Therefore, we aimed to retrospectively evaluate the benefits of locoregional radiotherapy. A total of 408 patients with metastatic NPC were included in this study. The mortality risks of the patients undergoing supportive treatment and those undergoing chemotherapy were compared with that of patients undergoing locoregional radiotherapy delivered alone or in combination with chemotherapy. Univariate and multivariate analyses were conducted. The contributions of independent factors were assessed after adjustment for covariates with significant prognostic associations (P<0.05). Both locoregional radiotherapy and systemic chemotherapy were identified as significant independent prognostic factors of overall survival (OS). The mortality risk was similar in the group undergoing locoregional radiotherapy alone and the group undergoing systemic chemotherapy alone [multi-adjusted hazard ratio (HR) = 0.9, P = 0.529]; this risk was 60% lower than that of the group undergoing supportive treatment (HR = 0.4, P = 0.004) and 130% higher than that of the group undergoing both systemic chemotherapy and locoregional radiotherapy (HR = 2.3, P < 0.001). In conclusion, locoregional radiotherapy, particularly when combined with systemic chemotherapy, is associated with improved survival of patients with metastatic NPC.

220例完全切除Ⅱ期非小细胞肺癌术后患者的生存分析

Background and Objective: Surgery is the main therapy for patients with stage-ll non-small cell lung cancer (NSCLC), but patients still have an unsatisfactory prognosis even though complete resection is usually possible. Adjuvant chemotherapy provides low rates of clinical benefit as well. We retrospectively analyzed prognostic factors of patients with completely resected stage-ll NSCLC to find patients with unfavorable factors for proper management. Methods: Clinical data of 220 patients with complete resections of stage-ll NSCLC at the Sun Yat-sen University Cancer Center between January 1998 and December 2004 were retrospectively analyzed. Cumulative survival was analyzed by the Kaplan-Meier method and compared by log rank test. Prognosis was analyzed by the Cox proportional hazards model. Results: The overall 3- and 5-year survival rates were 58.8% and 47.9%, respectively. The 3- and 5-year disease-free survival rates were 45.8% and 37.0%, respectively. Of the 220 patients, 86 (39.1%) had recurrence or metastasis. A univariate analysis demonstrated that age (> 55 years), blood type, the presence of symptoms, chest pain, tumor volume (> 20 cm3), total number of removed lymph nodes (≥10), number of involved N1 lymph nodes (≥3 ), total number of removed N2 lymph nodes (> 6), and the ratio of involved N1 lymph nodes (≥35%) were significant prognostic factors for 5-year survival. In the multivariate analysis, age (> 55 years), chest pain, tumor volume (> 20 cm3), total number of removed lymph nodes (≥10), and number of involved N1 lymph nodes (≥ 3) were independent prognostic factors for 5-year survival. Conclusions: For patients with completely resectable stage-ll NSCLC, having > 55 years, presenting chest pain, tumor volumes > 20 cm3, and ≥ 3 involved N1 lymph nodes were adverse prognostic factors, and ≥ 10 removed lymph nodes was a favorable one. Patients with poor prognoses might be treated by individual adjuvant therapy for better survival.