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Chuanliang Cui,
Lili Mao,
Zhihong Chi,
Lu Si, Xinan Sheng,
Yan Kong,
Siming Li,
Bin Lian,
Kangsheng Gu,
Min Tao,
Xin Song,
Tongyu Lin,
Xiubao Ren,
Shukui Qin,
Jun Guo
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ABSTRACT: Endostatin is a potent endogenous angiogenic inhibitor with implicated antitumor activity. However, efficacy of recombinant human endostatin (rhES) in clinical trials is controversial, and application of rhES in treatment of metastatic melanoma awaits further investigations. This phase II trial evaluated the efficacy and safety of a soluble and stable rhES (Endostar) plus dacarbazine in patients with metastatic melanomas that contains no mutations in c-kit and BRAF genes. A total of 110 patients received placebo plus dacarbazine (250 mg/m(2), n = 54) or Endostar (7.5 mg/m(2)) plus dacarbazine (250 mg/m(2), n = 56). The primary end points were progression-free survival (PFS) and overall survival (OS). Median PFS in the Endostar plus dacarbazine arm was 4.5 months versus 1.5 months in the placebo plus dacarbazine arm (hazard ratio (HR) = 0.578; P = 0.013). There were statistically significant improvements in OS (median, 12.0 months versus 8.0 months; HR, 0.522; P = 0.005) in favor of the Endostar plus dacarbazine arm. The regimen was generally well tolerated and had a manageable toxicity profile. Our trial suggests that Endostar plus dacarbazine is well tolerated in patients with metastatic melanoma harboring no genetic mutations popular for targeted therapy and yields a significant improvement in PFS and OS.Molecular Therapy (2013); doi:10.1038/mt.2013.79.
Molecular Therapy 05/2013; · 6.87 Impact Factor
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Lu Si,
Xiaowei Xu,
Yan Kong,
Keith T Flaherty,
Zhihong Chi,
Chuanliang Cui, Xinan Sheng,
Siming Li,
Jie Dai,
Weiwei Yu,
Jun Guo
Journal of Clinical Oncology 12/2011; 30(4):e37-40. · 18.37 Impact Factor
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ABSTRACT: Mutations of NRAS and BRAF have been described in Caucasian melanomas. However, the status and the clinical significance of BRAF and NRAS mutations in the Asian population have not been investigated on a large scale.
Melanoma samples (n=432) were analysed for mutations in exons 11 and 15 of the BRAF gene, and exons 1 and 2 of the NRAS gene in genomic DNA by polymerase chain reaction (PCR) amplification and Sanger sequencing. Mutations of BRAF and NRAS genes were correlated to clinicopathologic features and prognosis of the patients.
The incidence of somatic mutations within the BRAF and NRAS genes was 25.5% (110/432) and 7.2% (31/432), respectively. Among the 110 patients with BRAF mutations, 98 patients (89.1%) had V600E mutations. Melanomas without chronic sun-induced damage (Non-CSD) were more likely (P<0.01) to show BRAF mutations while NRAS mutation frequency was unbiased between melanoma subtypes. Patients with genetic mutations in BRAF (P<0.01) or NRAS (P=0.04) gene are more likely to have ulceration as compared to patients without BRAF or NRAS mutations, respectively. Both BRAF (P=0.003) and NRAS mutations (P=0.031) are inversely correlated to overall survival.
BRAF mutation is frequent while mutations in NRAS gene are rare. The most prevalent BRAF mutation type is V600E. Patients with mutations in BRAF or NRAS gene are frequently present with ulceration, and mutation in BRAF or NRAS gene is indicator for poor prognosis. Our study may warrant a clinical trial of kinase inhibitors targeting BRAF V600E in Chinese and Asian melanoma patients.
European journal of cancer (Oxford, England: 1990) 07/2011; 48(1):94-100. · 4.12 Impact Factor
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ABSTRACT: High-dose Interferon-α-2b (HD-IFN) is an adjuvant treatment for melanoma. However, clinical trials for HD-IFN have not been reported in acral melanoma (AM), the predominant subtype of cutaneous melanoma in Asian population.
Patients with resected high-risk (stage IIb-IIIc) AM were randomly assigned to a regimen of 4-week (arm A: 15 × 10(6)U/m(2)d1-5/w × 4w) or 1-year adjuvant HD-IFN (arm B: 15 × 10(6)U/m(2)d1-5/w × 4w+9 × 10(6)Utiw × 48w), respectively. The endpoints were relapse-free survival (RFS), overall survival (OS) and toxicities.
A total of 158 patients were enrolled in this study and 147 patients were eligible for survival analysis. With a median follow-up of 36.1 months, median RFS for arm A and arm B were 17.9 months and 22.5 months, respectively (P=0.72). Stratified analysis showed that RFS curves of patients in stage IIIb-IIIc were statistically different between arm A and arm B (P=0.02). The median RFS of patients with more nodal metastases (n⩾3) was shorter (P=0.004) in arm A (3.3 months) than that in arm B (11.9 months). Grade 1/2 adverse effects were observed in both groups. However, patients in arm B showed higher incidence of reversible Grade 3/4 hepatotoxicity (P=0.03).
The induction dose of 15 × 10(6)U/m(2) and the maintenance dose of 9 × 10(6)U were tolerable, which may be the optional dose intensity for adjuvant IFN-α-2b therapy in Chinese high risk AM population. No statistical significance was detected in RFS between the 4-week and 1-year regimen while a 1-year regimen may show clinical benefits in patients with stage IIIb-IIIc AM or with ≥ 3 nodal metastases.
European journal of cancer (Oxford, England: 1990) 07/2011; 47(10):1498-503. · 4.12 Impact Factor
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Jun Guo,
Lu Si,
Yan Kong,
Keith T Flaherty,
Xiaowei Xu,
Yanyan Zhu,
Christopher L Corless,
Li Li,
Haifu Li, Xinan Sheng, [......],
Zhihong Chi,
Siming Li,
Mei Han,
Lili Mao,
Xuede Lin,
Nan Du,
Xiaoshi Zhang,
Junling Li,
Baocheng Wang,
Shukui Qin
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ABSTRACT: Melanomas harbor aberrations in the c-Kit gene. We tested the efficiency of the tyrosine kinase inhibitor imatinib in selected patients with metastatic melanoma harboring c-Kit mutations or amplifications.
Forty-three patients with metastatic melanoma harboring c-Kit aberrations were enrolled on this phase II trial. Each patient received a continuous dose of imatinib 400 mg/d unless intolerable toxicities or disease progression occurred. Fifteen patients who experienced progression of disease were allowed to escalate the dose to 800 mg/d.
Forty-three patients were eligible for evaluation, and the median follow-up time was 12.0 months. The median progression-free survival (PFS) was 3.5 months, and the 6-month PFS rate was 36.6%. Rate of total disease control was 53.5%: 10 patients (23.3%; 95% CI, 10.2% to 36.4%) and 13 patients (30.2%; 95% CI, 16.0% to 44.4%) achieved partial response (PR) and stable disease (SD), respectively. Eighteen patients (41.9%) demonstrated regression of tumor mass. Notably, nine of the 10 PRs were observed in patients with mutations in exons 11 or 13. The 1-year overall survival (OS) rate was 51.0%. The median PFS and OS times for patients who had PR or SD versus disease progression were 9.0 months versus 1.5 months (P < .001) and 15.0 months versus 9.0 months (P = .036), respectively. Imatinib 400 mg/d was well tolerated, and only one of the 15 patients who received dose escalation to 800 mg/d achieved SD.
Imatinib demonstrated significant activity in patients with metastatic melanoma harboring genetic c-Kit aberrations, with an overall response rate of 23.3%. Escalation to 800 mg/d could not restore disease control.
Journal of Clinical Oncology 06/2011; 29(21):2904-9. · 18.37 Impact Factor
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Yan Kong,
Lu Si,
Yanyan Zhu,
Xiaowei Xu,
Christopher L Corless,
Keith T Flaherty,
Li Li,
Haifu Li, Xinan Sheng,
Chuanliang Cui,
Zhihong Chi,
Siming Li,
Mei Han,
Lili Mao,
Aiping Lu,
Jun Guo
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ABSTRACT: KIT aberrations were described in acral and mucosal melanomas in largely Caucasian populations. Asian populations are more prone to develop acral and mucosal than cutaneous melanomas, and may harbor a high frequency of KIT aberrations.
Melanoma subtypes (n = 502) were analyzed histologically to determine melanoma subtype. Tissue samples were analyzed for mutations in exons 9, 11, 13, 17, and 18 of KIT gene in genomic DNA by PCR amplification and Sanger sequencing. The copy numbers of the KIT gene were analyzed by quantitative PCR, and protein expression levels of KIT (CD117) were determined by immunohistochemistry.
The most common melanoma subtypes were acral (38.4%) and mucosal (33.3%) melanomas in this population. The overall incidence of somatic mutations within the KIT gene was 10.8% (54/502), and all subtypes of melanoma contained KIT mutations. Increases in KIT gene copy numbers were correlated to CD117 overexpression. The genetic mutations of KIT were unrelated to the age, gender, stage, thickness, and ulceration of primary melanomas. Importantly, the overall survival of melanoma patients with KIT mutations (P = 0.001) or with KIT aberrations (mutation plus amplification, P = 0.0002) was significantly shorter than that of patients without such alterations.
In China, the prevalent melanomas are acral and mucosal melanomas. KIT mutations are detected in all melanoma subtypes. Our study suggests that increases in KIT gene copy numbers, but not KIT mutations, may be correlated to CD117 overexpression. For the first time, our study suggests that genetic KIT aberration is an adverse prognostic factor for melanoma.
Clinical Cancer Research 02/2011; 17(7):1684-91. · 7.74 Impact Factor
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ABSTRACT: Malignant melanoma is a rare disease in Asia, and knowledge on its characteristics and clinical outcome in Asian patients is limited. The purpose of this observational study was to determine the clinical presentation and outcome of patients with melanoma in China.
A database was prospectively established for the purpose of this analysis. The elements of the database included basic demographic data of patients and prognosticators previously reported in literature, as well as follow-up data including clinical outcome after treatment. Medical record of all patients with pathologically diagnosed malignant melanoma consulted in our center since 2006 were retrieved and reviewed. No patient was excluded in this study. Statistical analyses including survival and multivariate analyses of factors associated with survival were respectively performed by Kaplan-Meier method and Cox proportional hazard model.
A total of 522 consecutive and nonselected cases were evaluated. There were 218 cases (41.8%) of acral lentiginous melanoma (ALM), 118 (22.6%) of mucosal melanoma (MCM), 103 (19.7%) of nodular melanoma (NM), 33 (6.3%) of superficial spreading melanoma (SSM), and others were Lentigo maligna melanoma or unclassifiable disease. The proportion of patients with clinical stage I, II, III, and IV diseases were 6.1%, 55.9%, 25.1%, and 12.8%, respectively. Among the 357 cases of cutaneous melanoma, 234 patients (65.5%) had ulceration.The 5-year overall survival rate of all 522 patients was 41.6%, and the median survival time was 3.92 years (95% CI, 3.282 to 4.558). Five-year survival rates of patients with stage I, II, III, and IV diseases were 94.1%, 44.0%, 38.4% and 4.6% respectively (P < 0.001). Multivariate analysis revealed that clinical stage and the ulceration were two significant prognosticators for OS. In addition, extent of surgery and use of adjuvant therapy were significant prognosticators for DFS in patients with non-metastatic disease after definitive treatment. Pathological subtype was not a significant prognostic factor to predict wither OS or DFS.
Prognoses of patients with malignant melanoma diagnosed in China were suboptimal, and most patients were diagnosed with locally advanced disease (i.e., stage II or above). ALM and MCM are the two most commonly diagnosed pathological subtypes. Clinical staging and presence of ulceration was significantly associated with clinical outcome in terms of OS, while treatment strategy including extent of surgery and use of adjuvant therapy were significant predictors of DFS.
BMC Cancer 02/2011; 11:85. · 3.01 Impact Factor
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Jun Guo,
Jun Zhu, Xinan Sheng,
Xiaopei Wang,
Li Qu,
Yan Han,
Yuexiang Liu,
Hui Zhang,
Ling Huo,
Shuhui Zhang,
Baohe Lin,
Zhi Yang
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ABSTRACT: Dendritic cells (DC) are potent antigen-presenting cells that can present tumor antigens chaperoned by heat shock proteins (HSPs), while local hyperthermia (LHT) can increase the expression of HSPs. In this study, we determine if intratumoral injection of immature DC after LHT (LHT+IT-DC) induces systemic antitumor immunity in patients with advanced melanoma, and investigate the potential immunological mechanisms involved in the treatments. Patients were randomly assigned to intratumoral administration of autologous immature DC triweekly, with (LHT+IT-DC, arm A, n = 9) or without (IT-DC, arm B, n = 9) LHT. Our results showed that there were no grade 3/4 toxicities. The time to progress (TTP) of arm A was 5 months, significantly longer than that in arm B (2 months, p < 0.05). However, the overall survival time had no statistical difference (13 months vs. 6 months, p > 0.05) between the 2 groups. Our ELISPOT assay showed a significantly increased melanoma-specific IFN-gamma production in arm A, suggesting that LHT+IT-DC was more effective in the induction of cytotoxic T lymphocytes (CTL) than IT-DC alone. Furthermore, we detected an increased HSPs expression 4 hr after the first LHT, an enhanced Th1/Th2 chemokines production 24 hr after the first LHT+IT-DC treatment, a promoted migration of DC to afferent lymph nodes, and a decreased infiltration of regulatory T cells (CD4(+)CD25(+)) and an increased infiltration of active CTL (CD8(+)CD28(+)) 48 hr after the third DC injection in arm A patients. Therefore, LHT+IT-DC can induce effective specific antitumor immunity and facilitate a Th1-polarized immune response in patients with advanced melanoma.
International Journal of Cancer 07/2007; 120(11):2418-25. · 5.44 Impact Factor
