Clinical benefit in Phase-I trials of novel molecularly targeted agents: does dose matter?

Phase-I trials traditionally involve dose-escalation to determine the maximal tolerated dose (MTD). With conventional chemotherapy, efficacy is generally deemed to be dose-dependent, but the same may not be applicable to molecularly targeted agents (MTAs). We analysed consecutive patients included in Phase-I trials at the Royal Marsden Hospital from 5 January 2005 to 6 June 2006. We considered only trials of monotherapy MTAs in which the MTD was defined. Three patient cohorts (A, B, and C) were identified according to the dose received as a percentage of the final trial MTD (0–33%, 34–65%, >66%). Potential efficacy was assessed using the non-progression rate (NPR), that is, complete/partial response or stable disease for at least 3 months by RECIST. A total of 135 patients having progressive disease before enrolment were analysed from 15 eligible trials. Median age was 57 years (20–86); male : female ratio was 1.8 : 1. Cohort A, B, and C included 28 (21%), 22 (16%), and 85 (63%) patients; NPR at 3 and 6 months was 21% and 11% (A), 50% and 27% (B), 31% and 14% (C), respectively, P=0.9. Median duration of non-progression (17 weeks; 95% CI=13–22) was not correlated with the MTD level, P=0.9. Our analysis suggests that the potential for clinical benefit is not confined to patients treated at doses close to the MTD in Phase-I trials of MTAs.     

The diagnosis of an intramuscular metastasis aid from a finding on a computerized tomography scan

A case of an intramuscular metastasis is reported in which a computerized tomography scan aided in the diagnosis. The clinical features of intramuscular metastases and the importance of performing a thorough review of the soft tissue structures displayed on computerized tomography scans is discussed.     

马来酰亚胺苯甲氨酯聚乙二醇修饰膜蛋白掩盖AB和RhD抗原制备通用血型红细胞

聚乙二醇(PEG)上的活性基团结合在红细胞表面掩盖血型抗原是制备通用血型红细胞的途径之一,这些PEG链有很强的水合作用,能覆盖红细胞表面的大片区域,阻断血型抗原与抗体结合。甲基氧PEG-5000(mPEG-5000)是常用的红细胞修饰剂,主要修饰蛋白上的氨基基团。在氯化氰脲酸(CnCl)催化下,mPEG-5000与红细胞膜上氨基形成共价键连接,掩盖Rh抗原和A或B抗原。CnCl-PEG-5000浓度越高,血型抗原的覆盖效果越好。由于微环境下A和B血型抗原处无氨基基团或者氨基基团不能被CnCl-PEG-5000修饰,不能完全阻断抗-A、B与A和B血型抗原结合。本文报道…     

Pneumocystis carinii pneumonia manifested as a hilar mass and cavitary lesion: an atypical presentation in a patient receiving aerosolized pentamidine prophylaxis

A case of Pneumocystis carinii pneumonia (PCP) in a patient with AIDS was manifested radiographically as a hilar mass and cavitary lesion. The patient had been receiving aerosolized pentamidine as prophylaxis against PCP. Nonuniform deposition of aerosolized pentamidine was probably responsible for this atypical radiographic appearance of PCP.     

Evidence that the Lub blood group antigen is located on red cell membrane glycoproteins of 85 and 78 kd

A murine monoclonal antibody of specificity anti-Lub was produced. Immunoblotting of the electrophoretically separated components of membranes from Lu(b+) red cells with the monoclonal antibody identified two glycoproteins of relative molecular mass 85 and 78 kd, respectively. The expression of Lub antigenic activity on these glycoprotein components was shown to be dependent on the presence of one or more N-glycosidically linked oligosaccharides and on the presence of disulphide bonding.     

Gonorrhea

During a 10-year period from 1976 to 1985, N. gonorrhoeae demonstrated remarkable genetic resiliency in developing clinically important antimicrobial resistance through a variety of chromosomal mutations and by acquiring either entire plasmids or resistance determinants on plasmids from other species. Gonococcal resistance is widespread, and few communities will be spared all types. None of the newer diagnostic technologies has provided any performance or cost advantages over traditional Gram-stained smears and cultures. The two most important components of a control program are (1) the National Gonococcal Isolate Surveillance project and (2) treatment with ceftriaxone, 125 or 250 mg intramuscularly, which is active against all known types of resistance and will cure all forms of uncomplicated gonorrhea, including the more difficult-to-treat infections of the pharynx and anorectum. Fear of AIDS has had a powerful motivating effect on sexual behavior, and in the United States has been associated with an overall reduction in incidence of gonorrhea in homosexual men of over 95%. After peaking in 1985, incidence of gonorrhea in white heterosexual men and women has declined as well. A diagnosis of gonorrhea in 1990 implies recent high-risk behavior for acquiring HIV infection. The gonorrhea epidemic in the United States is rapidly contracting down around poor urban minorities; although this is not good, at least it tells us where to target our resources.     

Treatment of uncomplicated gonorrhea with rosoxacin.

In a randomized, double-blind, dose-ranging study, single oral doses of rosoxacin were used to treat 126 patients with uncomplicated genital or anorectal gonorrhea. Neisseria gonorrhoeae was eradicated from 5 (28%) of 18 men treated with 100 mg, compared with 101 (94%) of 108 men and women treated with 200 mg, 300 mg, or 400 mg (P less than 0.001). Susceptibility to rosoxacin was determined for 6 pretreatment gonococcal isolates from these patients and for 194 stored clinical isolates; 296 (98.7%) of these 300 isolates, including 10 strains of penicillinase-producing N. gonorrhaeae, required a minimal inhibitory concentration of less than or equal to 0.062 microgram/ml. Urethral or cervical infection with Chlamydia trachomatis coexisted with gonococcal infection in 14 (22%) of 63 patients and persisted in 7 of 10 patients treated with rosoxacin. Postgonococcal urethritis developed in 11 (34%) of 32 men who were monitored for 12 to 30 days. Sixty-four subjects (51%) developed transient dizziness, drowsiness, altered visual perceptions, or other symptoms suggestive of central nervous system dysfunction after treatment with rosoxacin, but these symptoms were not clearly dose related. Rosoxacin in doses of greater than or equal to 200 mg appears to be effective for single-dose treatment of uncomplicated gonorrhea, but further studies of its possible central nervous system toxicity are indicated.