A phase II trial with anti-Lewis-Y monoclonal antibody (hu3S193) for the treatment of platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma.

OBJECTIVES: The primary objective was to evaluate the clinical efficacy of hu3S193, a humanized monoclonal antibody against the Lewis-Y antigen, in patients with platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma. Secondary objectives were safety and pharmacokinetics. In addition, we sought to determine the potential interaction of clinical benefit and patient characteristics. METHODS: This two-stage, multicenter, single arm, phase II trial enrolled eligible patients to receive hu3S193 weekly at a dose of 20mg/m(2) intravenously for 8 weeks (1 cycle) to a maximum of 3 cycles. Efficacy was measured as clinical benefit rate (objective response or stable disease for at least 24 weeks). RESULTS: 26 of 31 patients were eligible for efficacy analysis. No complete/partial responses were observed. Six patients had stable disease for 24+weeks [clinical benefit rate 23% (95% CI=9.77%-46.71%)]. Median PFS was 8.4 weeks (95% CI=6.0 to 16.1). Median PFS differed between patients with no ascites and no visceral disease and patients with ascites and/or visceral disease [16.1 vs. 8.1 weeks (p=0.0058)]. The most commonly reported treatment-related adverse events were fatigue (19.3%) and nausea (16.2%). Allergic reactions occurred in 6 patients (5 with Grade 1/2; 1 with Grade 3). CONCLUSIONS: Hu3S193 lacked sufficient activity in the first stage of the study to open enrollment to the second stage. However, based on the longer PFS in patients with no ascites and no visceral disease, consolidation strategies in platinum sensitive disease are currently being tested.

Cox-2, EGFR, and ERBB-2 expression in cervical intraepithelial neoplasia and cervical cancer using an automated imaging system.

We hypothesized that the activation of cyclooxygenase (COX)-2, epidermal growth factor receptor (EGFR), and ErbB-2 signaling is required for cervical intraepithelial neoplasia (CIN) lesions to progress to cervical cancer. A retrospective analysis was performed in 179 patients with Stage I squamous cell carcinoma (SCC) and 233 patients with CIN (112 CIN I, 47 CIN II, and 74 CIN III). COX-2, EGFR, and ErbB-2 expression was analyzed by immunohistochemistry using the ACIS III automated imaging system. The mean expression of COX-2, EGFR, and ErbB-2 was compared between the various stages of CIN and SCC. COX-2 mean expression was predominantly cytoplasmic, increasing significantly from CIN I to CIN II, CIN III, and SCC (P<0.001). EGFR mean expression also rose significantly during tumor progression from CIN I to SCC (P=0.001). CIN I samples were negative for ErbB-2 expression. CIN II, CIN III, and SCC were considered positive for ErbB-2 expression in 2.2%, 14%, and 16.2% of cases, respectively. There was also a statistically significant correlation between increase of ErbB-2 positivity from CIN to SCC. We conclude that COX-2, EGFR, and ErbB-2 expression increase significantly during the progression of CIN to cancer.

Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine.

BACKGROUND: The duration of protection afforded by vaccines represents a critical test of their utility as public health interventions. Some vaccines induce long-term immunity, while others require booster doses. Vaccines that induce long-term protection are usually characterized by the generation of immune memory. Recent trials of a quadrivalent (types 6, 11, 16, 18) human papillomavirus (HPV) vaccine have demonstrated high efficacy through 5 years of follow-up. We evaluated the extent to which the vaccine is able to generate HPV type-specific immune memory. METHODS: A total of 552, 16-23-year-old women were enrolled in a double-blind, placebo-controlled study. At enrollment, subjects were randomized in a 1:1 ratio to receive three-dose regimens of quadrivalent HPV vaccine or placebo with 3 years' follow-up. A subset of 241 subjects (n=114 in the quadrivalent HPV vaccine group and n=127 in the placebo group) underwent 2 further years of follow-up. All extension subjects received quadrivalent HPV vaccine at month 60 to examine the extent of immune memory in response to the primary vaccination series. RESULTS: Serum anti-HPV levels declined post-vaccination, but reached a plateau at month 24 that remained stable through month 60. Administration of a challenge dose of vaccine induced a classic anamnestic response, with anti-HPV levels 1 week post-challenge reaching levels observed 1 month following the completion of the three-dose primary series. At 1 month post-challenge, anti-HPV responses were higher than those observed 1-month post-dose 3. DISCUSSION: A three-dose regimen of quadrivalent HPV vaccine induces high efficacy and stable anti-HPV levels for at least 5 years. Vaccination also induces robust immune memory. These findings suggest that the efficacy of this vaccine will be long lasting.

Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18.

Human papillomavirus (HPV) infection causes cervical cancer and genital warts. Young women (1106) were randomized to receive one of three formulations of a quadrivalent HPV (Types 6/11/16/18) L1 virus-like particle (VLP) vaccine or one of two placebo formulations. The goal was to assess vaccine safety and immunogenicity in baseline HPV 6/11/16 or 18-naïve and previously infected subjects. All three formulations were highly immunogenic. At Month 2 (postdose 1), among women with vaccine-type antibodies at baseline, vaccine-induced anti-HPV responses were approximately 12- to 26-fold higher than those observed in baseline-naïve women, suggesting an anamnestic response. Following an initial, similar sized decline, anti-HPV responses plateaued and remained stable through end-of-study (3.0 years). No vaccine-related serious adverse experiences were reported.

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial.

BACKGROUND: A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). METHODS: 277 young women (mean age 20.2 years [SD 1.7]) were randomly assigned to quadrivalent HPV (20 microg type 6, 40 microg type 11, 40 microg type 16, and 20 microg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20.0 years [1.7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. FINDINGS: Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0.0001) in those assigned vaccine compared with those assigned placebo. INTERPRETATION: A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.

Estudos das técnicas para pesquisa do linfonodo sentinela no câncer de mama / Study of the techniques for the sentinel limph node in breast cancer

A linfadenectomia axilar no carcinoma de mama é válida, somente se houver comprometimento linfonodal. Os métodos para se predizer o "status" linfonodal eram, na maioria dos casos, invasivos. A pesquisa do linfonodo sentinela tem apresentado alto valor preditivo negativo (VPN). Conhecer sua resprodutividade e limitaçöes é importante para sua aplicabilidade. O objetivo: estudo de várias técnicas para a pesquisa do linfonodo sentinela (LS). Metodologia: foram estudados 81 casos de carcinoma de mama com axila clinicamente negativa, e em 36 casos foi usada a técnica com corante, em 6 casos a técnica "probe" e em 39 a asscociaçäo das duas técnicas. Realizou-se linfadenectomia axilar (LA) em todos os casos, menos em 2. Resultados: "o LS foi encontrado em 74 casos e destes 35 apresentaram-se com metástase axiliares. Houve 2 casos de falso-negativo. Dos 36 casos estudados pelo método com corante, encontrou-se o LS em 32, dos quais 21 apresentavam metástase axiliares; houve um caso falso-negativo. Dos 6 casos com método do "probe", encontrou-se o LS em todos, havia dois com comprometimento axiliar e näo houve falso-negativo. Dos 39 casos estudados com associaçäo dos 2 métodos, encontrou-se o LS em 36. Em 34 destes, näo houve caso falso-negativo. Nos outros 2 casos, houve discordância dos 2 métodos; destes, um era falso-negativo (estes 2 casos emcontravam-se nos primeiros 6 com o uso do "probe"). Conclusäo: o VPN do LS é muito alto nas diversas técnicas e será usado como método para se evitar a LA em determinados casos