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.     

ELAM-1在鼻咽癌裸鼠移植瘤中的表达及其与转移的关系

目的 建立裸鼠鼻咽癌转移模型并探讨 E-选择素（ELAM-1）与鼻咽癌转移的相关性。方法 将鼻咽癌5-8F细胞悬液注射于裸鼠左后肢爪垫，观察裸鼠状态、成瘤情况并测量裸鼠体重及移植瘤长短径；采用连续病理切片苏木精-伊红染色观察移植瘤及转移情况，将16只人鼻咽癌荷瘤裸鼠分为转移组和非转移组；采用免疫组织化学法检测两组移植瘤组织中ELAM-1的表达。 结果 16只裸鼠均成瘤，成瘤率为100.0%，其中10只裸鼠出现转移瘤，转移率为62.5%。建模前，两组裸鼠体重差异无统计学意义［（13.83±0.56）g vs （14.62±0.30） g，t=1.026，P=0.071］。建模后4~7周，裸鼠瘤体体积呈指数增长，且转移组移植瘤增长速度较非转移组快，非转移组裸鼠瘤体体积小于转移组［（198.91 ± 163.29） mm³ vs （268.76 ±174.31） mm³，t=4.376，P=0.005］。ELAM-1在鼻咽癌裸鼠移植瘤、淋巴结转移灶及远处转移灶中的表达均为阳性，主要表达于细胞膜。转移组移植瘤光密度值高于非转移组（0.4497±0.0705 vs 0.0435±0.0082，t=4.388，P＝0.001）。结论 本研究成功构建稳定性好、转移率高的鼻咽癌裸鼠移植瘤转移模型，且ELAM-1在裸鼠移植瘤中高表达，可促进鼻咽癌裸鼠移植瘤生长和转移。     

A clinical study of nasopharyngeal masses

Out of 36511 patients attending the ENT OHD of R. G,. Aur Medical Callege & Hospital. Kolkata, in one year 0.08% patients were found tuning naspharyngeal mass. 30 cases of nasopharyngeal mass were studied. The peak incidence of nasopharyngeal mass was in the age group between II to 20 years (40%). The incidence in males (73%) was more than females(27%). The maximum ineldence was found among students (74%). Commonest ntuopharyngeal nuns teas antrochoanal polyp (30%). Next commlon masses were adenoids (23%)Juvenile angwfibroma(20%) and nasophartngeal carcinoma (13%). Nasal obstruction was the main presenting symptom(83%) followed by epistaxis (40%).     

腮腺显像对鼻咽癌放疗后腮腺功能的评价

目的利用腮腺显像研究鼻咽癌放疗后腮腺的摄取与排泄功能.方法48例鼻咽癌患者中,对38例肿瘤和肿大淋巴结行加速调强放疗（SMART）,其亚临床灶和预防照射区接受常规照射;余10例行常规放疗.放疗前后均行腮腺显像,计算腮腺的放射性摄取指数（UI）及酸性刺激后排泌指数（EI）,对腮腺功能损伤情况进行分析;同时记录患者口干程度并分级.结果鼻咽癌SMART组放疗后腮腺UI和EI分别下降21.9%和37.3%,中重度口干者12例;而常规放疗组腮腺功能明显下降,UI和EI分别下降56.1%和96.1%,中重度口干者9例,两者比较差异均有显著性（P＜0.05）.结论腮腺显像可灵敏地监测鼻咽癌放疗后腮腺功能.     

鼻咽癌CT灌注成像及其生物学相关性研究

目的研究鼻咽癌CT灌注值与肿瘤微血管密度（MVD）、肿瘤分期的关系，探讨多层螺旋CT灌注成像对鼻咽癌的临床应用价值。方法49例鼻咽部CT灌注检查中，鼻咽癌组30例，鼻咽癌放疗后组14例，正常鼻咽部5例，测量鼻咽癌和鼻咽黏膜位置的血流量（BF）、最大强化指数（PEI）、峰值到达时间（TTP）及血容量（BV）作为灌注指标，其中16例鼻咽癌活检组织行免疫组织化学CD34单抗染色后，Weidner方法计数MVD。各组灌注值比较行方差分析，CT灌注值、肿瘤分期与MVD之间行Spearman等级相关分析。结果49例中1例鼻咽癌灌注检查失败。鼻咽癌组（29例）肿瘤CT灌注值BF为（48．6±16．9）ml·100g^-1·min^-1，PEI为（32．3±7．9）HU，TTP为（17．5±4．9）s，BV为（12．8±4．4）ml·100g^-1；正常对照组（5例）BF、PEI、TTP、BV值分别为（15．9±5．9）ml·100g^-1·min^-1、（12.6±1．3）HU、（22．6±6．9）s、（3．5±0．5）ml·100g^-1；鼻咽癌放疗后组（14例）BF、PEI、TTP、BV值分别为（25．2±7．0）ml·100g^-1·min^-1、（19．8±5．9）HU、（22．6±4．3）s、（6．1±2．4）ml·100g^-1，三组各灌注值差异有统计学意义（P值均〈0．01）；相关分析显示，鼻咽癌组（29例）中TNM分期（其中Ⅰ期3例，Ⅱ期9例，Ⅲ期10例，Ⅳ期7例）与PEI和BV存在相关性（r值分别为0．48和0．50），与BF和TTP无明显相关性（r值分别为0．23和0．22）；16例鼻咽癌MVD为（30．8±12．6）个／高倍镜视野，与其BF（51．4±17．0）ml·100g^-1·min^-1、PEI（33．2±9．6）HU和TTP（16．3±4．1）8存在相关性（r值分别为0．85、0．60和0．78），与BV（13．2±5．6）ml·100g^-1弱相关（r=0．48）。结论鼻咽癌有着特征的CT灌注表现，多层螺旋CT灌注成像的灌注值可以反映鼻咽癌微血管密度特征，PEI和BV值与鼻咽癌的TNM分期存在一定的相关性。     

上颌骨Le Fort I型截骨进路切除巨大鼻咽纤维血管瘤

目的:探讨上颌骨LeFortI型截骨进路切除累及翼腭凹、颞下凹巨大鼻咽纤维血管肿瘤的可行性。方法:采用矫正上颌骨先天或后天畸形的LeFortI型截骨术式进路,切除位于鼻咽部、筛窦等深在部位的纤维血管瘤。结果:该进路术野显露充分,取得了理想的治疗效果。结论:上颌骨LeFortI型截骨进路是切除鼻咽、颅底部纤维血管瘤的理想进路。     

鼻咽癌骨转移核素显像分析

目的：探讨鼻咽癌骨转移喷射有显像的特点及规律。方法：选择６１例鼻咽癌患者做全身骨核素显像。结果：６１例鼻咽癌患者中有３９例骨显像异常，结合临床及Ｘ线诊断为骨转移，骨转移的发生率为６３．９％，临床Ⅰ、Ⅱ、Ⅲ、Ⅳ期的发生率分别是０、４１．７％、５７．７％、８６．４％。３９例骨转移患者中３６例多发病灶（占９２．３％），３例为单发病灶（占７．７％）。骨转移的部位以脊柱为多见，其余依次为胸部、骨盆、肢体和颅     

鼻咽癌病因学的病例—对照研究

本文以病例—对照的方法探讨了在黑龙江省与鼻咽癌发生有关的危险因素。调查鼻咽癌病例及对照共127对。在单因素与条件Logistic回归分析中均表明幼儿期食咸鱼(OR=5.5, χ²=4.92, P<0.05)及长期生活在烧煤的环境中(OR=1.894, χ²=4.655, P<0.05)可能与鼻咽癌的发生有关。此外,条件Logistic回归分析还发现,鼻窦炎病史也可能与鼻咽癌的发生有联系(B=1.385, exp(B)=3,995, P<0.1)。在对病例及对照的一级亲属患恶性肿瘤情况的调查中发现,鼻咽癌病例组有肿瘤家族史者多于对照组,其差异有统计学意义(χ²=10.32, P<0.01)。     

PsD007对四株NPC细胞放射敏感性的影响

采用ＭＴＴ方法观察癌光啉结合＾６０Ｃｏγ射线放射对四株人鼻咽癌细胞体外放射增敏作用，结果表明在一定的ＰｓＤ００７浓度范围内，随ＰｓＤ００７浓度的升高，放射对细胞的杀灭作用明显增强，当浓度分别为１．２５，６．２５，１２．５，２５和５０μｇ／ｍｌ时，对四株细胞杀灭增加倍数分别为１．０１－１．０６，１．１５－１．２９，１．２８－１．５９，１．７９－３．１８，２．８６－５．５５；放射量效存活曲线按多靶单击     

A suggested clinical score to predict the severity of adenoid obstruction in children

Chronic nasal obstruction in children is a very common disorder. Obstructing adenoid is usually the first to blame. Though the clinical assessment is essential, it is often considered unreliable or insufficient. We conducted a prospective clinical study to validate a clinical score predicting the severity of adenoid obstruction in symptomatic children. The clinical score (CS) included mouth breathing, snoring, restless sleep, frequent waking-up at night and obstructive breathing during sleep. Each item received a score of 0 or 1. The palatal airway was evaluated on a lateral nasopharyngeal x-ray. The degree of obstruction was assessed intra-operatively by a laryngeal mirror using a 3-grade scale. The volume of each adenoid specimen was measured. Eighty-six patients were enrolled, 51 boys and 35 girls, aged 13–181 months (mean 52, median 45). The CS correlated very well with the intra-operative findings (p < 0.01) and with the degree of palatal airway obstruction (p < 0.05) but not with the volume of the adenoid removed (p > 0.05). The CS was higher in children younger than 3 years (CS > 3 in 85.7% vs. 29.2%), having more frequent obstructive breathing during sleep (71.43% vs. 21.54%). A CS of three or higher, predicted severe obstruction in 96.5% of patients, as detected intra-operatively. The suggested CS is simple to use and is highly reliable in identifying children in need for adenoidectomy, in the context of normal anterior rhinoscopy and tonsils less than grade three.This work was presented at the podium of the XVIII IFOS in Rome, Italy on June 26, 2005.