Human papillomavirus DNA and antibodies to human papillomaviruses 16 E2, L2, and E7 peptides as predictors of survival in patients with squamous cell cervical cancer.

PURPOSE: To assess whether human papillomavirus (HPV) DNA detection in cervical cancer specimens, or antibodies to selected HPV 16 peptides are predictors of tumor recurrence and long-term survival in patients with squamous cell invasive cervical cancer. SUBJECTS AND METHODS: Four hundred seventy-one cases included in two population-based case-control studies underwent follow-up evaluation. The survival and cause of death were ascertained for 410 cases (87%), with a median follow-up time of 4.6 years after diagnosis. HPV DNA was assessed using an L1 polymerase chain reaction (PCR)-based system and Southern hybridization (SH) on scraped cytologic specimens or biopsies. HPV 16 antibodies to E2, L2, and E7 peptides were detected with enzyme-linked immunosorbent assay (ELISA). RESULTS: Clinical stage was the only independent prognostic factor for recurrence or survival. Although seropositivity to HPV 16 E7/3 peptide predicted a twofold excess risk of mortality (adjusted hazards ratio [HRa] = 2.0; 95% confidence interval [CI], 1.2 to 3.3), the association was restricted to stage I (HRa = 6.6; 95% CI, 1.2 to 37.6) and II (HRa = 5.9; 95% CI, 2.1 to 16.5) patients. The presence of HPV DNA (HRa = 0.9; 95% CI, 0.5 to 1.5), different estimates of the HPV viral load and the HPV type identified were not predictors of tumor recurrence or survival. CONCLUSION: The presence of antibodies to HPV 16 E7 proteins is of prognostic value in early-stage cervical cancer. Our results provide strong evidence that detection and typing of HPV DNA in cervical cells or tissues is not a prognostic factor for recurrence or survival.

Serological response to HPV16 in CIN-III and cervical cancer patients. Case-control studies in Spain and Colombia.

This study evaluates the association of antibodies against HPV-16-derived peptides with cervical cancer and estimates the sensitivity and specificity of the serological assays in relation to HPV DNA detection in cervical cells by PCR. Study subjects were derived from 4 case-control studies carried out in Spain and Colombia. Sera from 544 cases of CIN III and invasive cancer and of 543 age-matched controls were tested for antibodies to 5 peptides derived from E2, E7 (3 partially overlapping frames of HPV 16 denoted E7/ 1, E7/2, E7/3) and L2 open reading frames of HPV 16. HPV DNA was detected using a L1-PCR based method. Among cancer controls, antibody response to E2 and E7/1, E7/2, E7/3 was higher in Colombia (22.5%,7.2%,11.7%,12.6% respectively) than in Spain (17.1 %, 4.7%, 5.9%, 5.9%). E7 antibodies were related to stage, particularly in CIN III vs. invasive stages and less markedly within invasive stages. Detection of antibodies to the E7/1 was associated to CIN III (OR = 1.8). The risk of invasive cervical cancer was increased among those with antibodies to E2 (OR = 2.2), to E7/1 (OR = 4.2), to E7/2 (OR = 4.3), and to E7/3 (OR = 2.5). Presence of antibodies to all the 3 E7 peptides increased the risk of CIN III (OR = 5.6) and that of invasive cancer (OR = 17.5). High levels of antibodies to E7/1 or E7/2 or E7/3 increased the risk of invasive cervical cancer (OR for high levels of antibodies vs. negatives to E7/1 OR = 22.6; E7/2 OR = 7.5, E7/3 OR = 3.4). In the present analysis, antibodies to L2 were not associated with either CIN III or cervical cancer. Serological markers of HPV 16 detected less than half of the HPV-16-DNA-positive cases. It is concluded that antibodies to E2 and particularly E7 antigens are strongly associated with cervical cancer. Antibodies to E7 seem to be a moderate marker of tumor burden.

Presence of antibodies to seven human papillomavirus type 16-derived peptides in cervical cancer patients and healthy controls.

Sera from 133 cervical cancer patients and 154 healthy women (controls) from Spain and Colombia were tested in IgG-specific ELISAs for the presence of antibodies against seven peptides derived from five open-reading frames of human papillomavirus (HPV) type 16. Three of the peptides corresponded to overlapping regions of the N-terminal half of E7 protein; the other peptides corresponded to selected regions of E2, E4, L1, and L2 proteins. The prevalence of antibodies against E2 and E7 peptides was significantly different between patients and controls. The most marked differences were for E7 peptides. HPV DNA polymerase chain reaction diagnoses of cervical scrapes were available; these were correlated with serologic findings. In HPV-16 DNA-positive patients, E7 antibodies were more broadly and more strongly reactive than in other patient groups.

[Correlation of clinical and virologic diagnosis of cervical infection with human papillomaviruses]. / Korelace klinické a virologické diagnostiky infekce cervixu lidskými papilomaviry.

The presented investigation is concerned with contemporary diagnostic possibilities of HPV Infection of the Cervix. The authors present the results of virological examinations of 228 female patients in the Centre for Oncological Prevention. The examination was made by hybridization techniques, using probes specific for HPV 6, 11, 16 and 18 and by serological methods where IgG antibodies were assessed against synthetic peptides, corresponding to several HPV epitopes, as antigens. 156 women (68.4%) were virologically positive, 72 (31.6%) were negative. Subsequently the authors investigated the diagnostic accuracy of HPV changes of the cervix by clinical methods, i.e. colposcopy and cytology, as compared with virological methods. On colposcopic examination uncertain--i.e. insignificant--results were recorded in 24.6%, on cytological examination in 19.7%. In patients where these methods gave unequivocal results (either + or-) a correct forecast of the presence of HPV during colposcopic examination was recorded in 71.1%, in cytological examinations in 66.9%. At least one of the clinical methods assessing papilloma virus infection was prognostically correct in 90.4%. From the investigation ensures that prebioptic methods provide the clinician with relatively reliable information on the presence of HPV infection and enable him to select a therapeutic and dispensarization procedure adequate to the finding. However, they cannot replace virological examination among other reasons also because they cannot assess the HPV type.

Effects of antibiotics on the developing immune system.

A combination of penicillin and cloxacillin (Ampiclox, Beecham Research Laboratories) is indicated for prophylaxis and treatment of bacterial infections in premature babies or neonates. We studied the functional development of the immune system in the offspring of female ICR mice administered Ampiclox on days 13-16 of pregnancy in clinically relevant doses. Immune functions were assayed after immunization with sheep red blood cells in the 5th and 10th postnatal week. Changes of hemagglutinin antibodies, delayed-type hypersensitivity and proliferative responses of spleen lymphocytes and thymocytes were observed. Ampiclox influenced humoral immunity also when administered directly to rat young on postnatal days 9-11 or 14-16. Although the clinical relevance of our experimental data remains to be established an increased sensitivity of the developing immune system to immunomodulatory effects should be considered also in the context of antimicrobial therapy. (Fig. 6, Ref. 27.)