A Phase I Dose Escalation Study of the Safety,Tolerability, and Pharmacokinetics of Ipilimumab in Chinese Patients with Select Advanced Solid Tumors

Lessons Learned

• The overall safety profiles of ipilimumab 3 mg/kg and 10 mg/kg administered every 3 weeks, were consistent between Chinese patients with solid tumors in the current study and patients from previous U.S. ipilimumab monotherapy studies. No new safety signals were identified.
• The mean systemic exposures to ipilimumab (assessed by first dose area under the curve during the dosing interval and maximum serum concentration) were numerically lower in the Chinese patient population than in U.S. patients for both 3 mg/kg and 10 mg/kg doses; however, the range of serum concentrations in the Chinese and U.S. populations overlapped (3 mg/kg and 10 mg/kg), suggesting that ipilimumab pharmacokinetics was ethnically insensitive in this study.

BackgroundThis phase I, open‐label study assessed ipilimumab safety, tolerability, pharmacokinetics (PK), immunogenicity, and antitumor activity in Chinese patients with unresectable, metastatic, recurrent malignant melanoma (MM) or nasopharyngeal carcinoma (NPC).MethodsOf 39 patients enrolled, 25 received ipilimumab (11 patients received 3 mg/kg, and 14 patients received 10 mg/kg). Reasons for not receiving treatment were withdrawal of consent (3 patients), no longer meeting the criteria (10 patients), and one recorded as “other.” During the induction phase, patients received ipilimumab (3 mg/kg, i.v.), on day 1 of a 3‐week cycle, to a maximum of four doses or progressive disease (PD). During the maintenance phase at week 24, patients received ipilimumab (3 mg/kg, i.v.) on day 1 of a 12‐week cycle, to a maximum of 3 years or PD. Considering the co‐primary safety and PK endpoints, the successive dosing required nine patients with two or fewer dose‐limiting toxicities during the 42‐day observation period to proceed with a new cohort of nine patients at 10 mg/kg.ResultsIpilimumab safety and PK profiles were similar in Chinese and predominantly White populations. Ipilimumab was well tolerated. Most adverse events (AEs) were grades 1–2 and experienced by 11 patients treated with 3 mg/kg and 14 patients treated with 10 mg/kg. There were no new safety concerns. Incidence of anti‐ipilimumab antibodies was low (1 of 10 in the 3 mg/kg patients and 2 of 13 in the 10 mg/kg patients) and without safety implications. In the 3 mg/kg group, 8 of 11 patients had PD. In the 10 mg/kg group (all NPC, 0 MM patients), 11 of 14 patients had PD. Three patients had stable disease (one at 3 mg/kg and two at 10 mg/kg).ConclusionIpilimumab was well tolerated in Chinese patients, showing similar safety and PK to previous studies in predominantly White populations.     

Study of skin neoplasms in a university hospital: integration of anatomopathological records and its interface with the literature

BackgroundSkin cancer is a highly prevalent condition with a multifactorial etiology resulting from genetic alterations, environmental and lifestyle factors. In Brazil, among all malignant tumors, skin cancers have the highest incidences.ObjectiveTo retrospectively evaluate the incidence, prevalence and profile of basal cell carcinoma, squamous cell carcinoma and cutaneous melanoma in Campos dos Goytacazes and region.Methods:In total, 2,207 histopathological reports of a local reference hospital were analyzed between January 2013 and December 2015, of which 306 corresponded to the neoplasms studied.Results:Of the 306 reports evaluated, 232 basal cell carcinomas (75.9%), 55 squamous cell carcinomas (18%) and 19 cutaneous melanomas (6.5%) were identified. The face was the most involved anatomical site (58.8%) and women (51%) were the most affected gender. The temporal analysis revealed a decrease in the overall incidence of 3.4% from 2013 to 2014 and 5.4% from 2014 to 2015. There was a 10.1% increase in basal cell carcinomas and 38% in melanomas in this period; however, there was a decrease in the number of squamous cell carcinomas of 14.8% during the studied years.Study limitations:Some samples of cutaneous fragments had no identification of the anatomical site of origin.Conclusion:Research that generates statistical data on cutaneous tumors produces epidemiological tools useful in the identification of risk groups and allows the adoption of more targeted and efficient future prevention measures.     

Sentinel lymph node localization and staging with a low-dose of superparamagnetic iron oxide (SPIO) enhanced MRI and magnetometer in patients with cutaneous melanoma of the extremity - The MAGMEN feasibility study

BackgroundIn patients with melanoma, sentinel lymph node (SLN) status is pivotal for treatment decisions. Current routine for SLN detection combines Technetium^99m (Tc⁹⁹) lymphoscintigraphy and blue dye (BD). The primary aim of this study was to examine the feasibility of using a low dose of superparamagnetic iron oxide (SPIO) injected intracutaneously to detect and identify the SLN, and the secondary aim was to investigate if a low dose of SPIO would enable a preoperative MRI-evaluation of SLN status.MethodsPatients with melanoma of the extremities were eligible. Before surgery, a baseline MRI of the nodal basin was followed by an injection of a low dose (0.02–0.5 mL) of SPIO and then a second MRI (SPIO-MRI). Tc⁹⁹ and BD was used in parallel and all nodes with a superparamagnetic and/or radioactive signal were harvested and analyzed.ResultsFifteen patients were included and the SLNB procedure was successful in all patients (27 SLNs removed). All superparamagnetic SLNs were visualized by MRI corresponding to the same nodes on scintigraphy. Micrometastatic deposits were identified in four SLNs taken from three patients, and SPIO-MRI correctly predicted two of the metastases. There was an association between MRI artefacts in the lymph node and the dose SPIO given.DiscussionIt is feasible to detect SLN in patients with melanoma using a low dose of SPIO injected intracutaneously compared with the standard dual technique. A low dose of SPIO reduces the lymph node MRI artefacts, opening up for a non-invasive assessment of SLN status in patients with cancer.     

外源性p53对不同LET辐射诱导人黑色素瘤细胞系A375死亡途径的影响

目的 观察外源性P53蛋白对不同传能线密度(LET)射线辐照诱导肿瘤细胞凋亡和坏死的影响,并探讨其可能的机制。方法 人黑色素瘤细胞系A375(wild-type p53)经携带人野生型p53基因的腺病毒载体(AdCMV-p53)感染后分别给予X射线和碳离子束照射,采用克隆形成法测定细胞辐射敏感性,Hoechst 33258和吖啶橙-溴化乙锭双染荧光显微镜下观察细胞凋亡和坏死。结果1高LET辐照时,A375细胞和转导人野生型p53基因的A375细胞(A375/p53)的辐射敏感性没有明显差异;2虽然辐射诱导细胞凋亡比例的增加依赖于LET升高,但是无论高LET或低LET,外源性P53蛋白均可有效诱导细胞凋亡。3高LET辐照时,A375细胞的坏死细胞明显高于A375/p53细胞。结论 尽管高LET辐射对A375和A375/p53细胞的存活无明显影响,但是对细胞凋亡的诱导却部分依赖于P53蛋白的功能,P53蛋白可能在调节细胞死亡类型中发挥重要作用。这对临床应用高LET辐射联合p53基因治疗恶性黑色素瘤有一定参考意义。     

直肠肛管恶性黑色素瘤的临床特征分析

目的了解原发性直肠肛管恶性黑色素瘤的临床特点。方法回顾性分析9例原发性直肠肛管恶性黑色素瘤的临床资料,并复习文献。结果直肠肛管恶性黑色素瘤以女性多见,平均发病年龄56岁,病程5.8个月;首发症状以血便为最常见,其次为肛门肿物突出。94.7%的直肠肛管恶性黑色素瘤在距离肛缘5.0cm范围内;肿瘤最大径(3.3±2.1)cm;其中54.5%可活动;有19.1%的肿瘤表面光滑;6.6%的肿瘤质地软;14.0%同期发现转移,肝转移最常见,腹股沟淋巴结转移其次;的病例出现误诊,超过者被误诊为良性疾病;手术治疗中以Miles术为主,经肛门局部切除术其次。结论直肠肛管恶性黑色素瘤极易误诊。手术治疗为主。     

膜表达热休克蛋白70真核表达载体的构建及其对肿瘤细胞的转染

目的构建普遍适合性的膜表达热休克蛋白70(HSP70)的真核表达载体,修饰并建立HSP 70表达并结合在细胞膜表面的肿瘤细胞.方法RT-PCR法从人胚肾中获取HSP 70的cDNA,扩增成带酶切位点的目的基因.选择载体pDisplay,将目的基因插入载体多克隆酶位点中.DNA测序证实后,以脂质体转染的方法,将载体转染到黑色素瘤细胞.用G418抗性筛选获得阳性克隆.结果酶切电泳和DNA测序证实载体构建正确;目的基因的上游带信号肽序列,下游带跨膜序列.RT-PCR产物电泳、Westem Blotting、激光共聚焦显微镜和流式细胞术证实大量HSP 70表达并结合在转染的黑色素瘤细胞膜表面.结论成功地构建了膜表达HSP 70的真核表达载体;转染到黑色素瘤细胞后,细胞膜表面表达丰富的HSP70.转染细胞可以进一步制备新型瘤苗.     

In vivo anti-melanoma activities of the Melan-A/MART-1101–115 T CD4+ cell peptide

Malignant melanoma causes significant health problems. The identification of tumour-associated antigens has led to novel approaches to increase T cell mediated anti-tumour immune response. Melan-A/MART-1 has been use as target antigen for several T cell based immunotherapeutic treatments. More recently, the critical role of CD4+ T cells in inducing and maintaining anti-tumour immunity has been increasingly recognized. In order to optimize tumour immunotherapy, greater efforts have been concentrated on the identification of tumour antigens presented by MHC class II molecules to CD4+ T cells. In a publication, Tiwari et al. (2004) [1] have identified by a computational approach the 15-mer amino-acid sequence 101–115 (PPAYEKLSAEQSPPP) of the Melan-A/MART-1 as a good target for a vigorous and safe immunotherapy. Therefore, we have investigated the in vivo anti-tumour activity of this peptide in a murine melanoma model. For the prophylactic treatment, 20 μg or 50 μg peptide was subcutaneously injected in mice once a week during 3 weeks before tumour induction. Treatment with 50 μg peptide significantly affected tumour development. Thus, our preliminary data demonstrate potential in vivo prophylactic activity of the 101–115 peptide-based vaccine to control melanoma growth.     

18F-FDG PET/CT在黑色素瘤中的应用价值

目的 探讨18F-脱氧葡萄糖(FDG)PET/CT显像在黑色素瘤诊断、临床分期及监测治疗后肿瘤复发与转移灶中的应用价值.方法 黑色素瘤患者61例,均进行18F-FDG PET/CT全身显像.所有PET、CT及PET/CT融合图像均通过融合软件进行帧对帧对比分析.肿瘤病灶根据病理学检查、多种影像学检查及临床随访结果诊断.结果 18F-FDG PET/CT显像对黑色素瘤病灶检出的灵敏度、特异性和准确性分别为90.9%(40/44)、88.2%(15/17)和90.2%(55/61).其中12例治疗前患者中,18F-FDG PET/CT显像诊断的灵敏度为83.3%(10/12).在黑色素瘤病灶局部切除、尚未进行其他治疗的9例患者中,5例残余病灶18F-FDG PET/CT显像检出3例;4例远处转移灶患者全被检出,提高了临床分期,改变了治疗方案.首先发现转移性黑色素瘤病灶并且手术切除后,寻找原发灶的7例患者中,18F-FDG PET/CT检出原发灶2例,4例其他转移灶全被检出.黑色素瘤患者根治术后监测肿瘤复发或转移患者33例,18F-FDG PET/CT显像灵敏度、特异性和准确性分别为100.0%(19/19)、85.7%(12/14)和93.9%(31/33).与同期临床其他影像学检查比较,18F-FDG PET/CT显像发现更多,33例患者中,16例(48.5%)病灶提高临床分期;7例(21.2%)排除可疑病灶,降低临床分期;10例(30.3%)检出病灶与临床一致.结论 18F-FDG PET/CT显像对于黑色素瘤的诊断,残余病灶、复发病灶及转移灶的检出,临床分期的明确具有重要价值.     

Lymphoscintigraphy as a predictor of lymphatic drainage from cutaneous melanoma

Background: If cutaneous lymphoscintigraphy (CL) is accurate in predicting the draining lymph node basins at risk from primary axial melanomas, then regional metastases should only occur in those lymph node basins identified by CL. Methods: This study is a retrospective review of patients undergoing CL for primary axial melanomas from June 1, 1985, until June 31, 1992. Data retrieved included age, gender, number of basins identified, location of basins identified, management of basins, recurrence in lymphatics, development of distant disease, and long-term follow-up. Results: A total of 181 patients underwent elective LND, and 48 patients (27%) had melanoma in the nodes within the dissected basin. Of these 181 patients, seven developed nodal metastases as their site of first recurrence. All seven recurrences were seen at sites dissected or at sites indicated by CL, which the primary surgeon elected not to treat initially. Of the 116 patients observed, 16 (14%) developed lymph node metastases as their first site of recurrence. Fifteen of these 16 patients had their site of lymph node metastases predicted by CL. In this study, CL predicted 98.6% of all lymph node metastases. Conclusions: The high overall reliability of CL as demonstrated by long-term follow-up indicates that the information obtained by CL can be reliably used to guide intervention. Initial evaluation of patients with high-risk cutaneous melanomas at sites with ambiguous lymphatic drainage must include CL in order to determine the draining lymph node basins and to plan therapy. Presented at the 47th Annual Cancer Symposium of The Society of Surgical Oncology, Houston, Texas, March 17–20, 1994.     

Lymphatic drainage from the skin of the back to retroperitoneal and paravertebral lymph nodes in melanoma patients

Background: Preoperative lymphoscintigraphy (LS) with^99mTc antimony sulphide colloid is now part of the routine management of patients with intermediate thickness melanoma at the Sydney Melanoma Unit. Over a 13-year period, 1375 patients have been examined using LS, and we have observed many unusual lymphatic drainage pathways, including direct drainage through the body wall to retroperitoneal and paravertebral lymph nodes from the skin of the back. The aim of this study was to determine the incidence of such drainage in the 542 patients who had primary melanoma sites on the posterior trunk. Methods: The lymphoscintigrams performed on these patients were examined for the presence of direct lymphatic drainage through the posterior body wall to sentinel nodes in the retroperitoneal and paravertebral regions. Results: Lymphatic drainage directly through the body wall to such lymph nodes occurred in 14 of these 542 patients. Conclusions: Preoperative knowledge of the presence of this lymph drainage pattern may influence surgical management, and follow-up investigations in these patients can be tailored to ensure that the relevant areas are examined with anatomic imaging or F18-FDG PET scans.