Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment

BackgroundHuman papillomavirus vaccines prevent human papillomavirus infection and cervical precancers. The impact of vaccinating women with a current infection or after treatment for an human papillomavirus-associated lesion is not fully understood.ObjectivesTo determine whether human papillomavirus-16/18 vaccination influences the outcome of infections present at vaccination and the rate of infection and disease after treatment of lesions.Study DesignWe included 1711 women (18−25 years) with carcinogenic human papillomavirus infection and 311 women of similar age who underwent treatment for cervical precancer and who participated in a community-based trial of the AS04-adjuvanted human papillomavirus-16/18 virus-like particle vaccine. Participants were randomized (human papillomavirus or hepatitis A vaccine) and offered 3 vaccinations over 6 months. Follow-up included annual visits (more frequently if clinically indicated), referral to colposcopy of high-grade and persistent low-grade lesions, treatment by loop electrosurgical excisional procedure when clinically indicated, and cytologic and virologic follow-up after treatment. Among women with human papillomavirus infection at the time of vaccination, we considered type-specific viral clearance, and development of cytologic (squamous intraepithelial lesions) and histologic (cervical intraepithelial neoplasia) lesions. Among treated women, we considered single-time and persistent human papillomavirus infection, squamous intraepithelial lesions, and cervical intraepithelial neoplasia 2 or greater. Outcomes associated with infections absent before treatment also were evaluated. Infection-level analyses were performed and vaccine efficacy estimated.ResultsMedian follow-up was 56.7 months (women with human papillomavirus infection) and 27.3 months (treated women). There was no evidence of vaccine efficacy to increase clearance of human papillomavirus infections or decrease incidence of cytologic/histologic abnormalities associated with human papillomavirus types present at enrollment. Vaccine efficacy for human papillomavirus 16/18 clearance and against human papillomavirus 16/18 progression from infection to cervical intraepithelial neoplasia 2 or greater were −5.4% (95% confidence interval −19,10) and 0.3% (95% confidence interval −69,41), respectively. Among treated women, 34.1% had oncogenic infection and 1.6% had cervical intraepithelial neoplasia 2 or greater detected after treatment, respectively, and of these 69.8% and 20.0% were the result of new infections. We observed no significant effect of vaccination on rates of infection/lesions after treatment. Vaccine efficacy estimates for human papillomavirus 16/18 associated persistent infection and cervical intraepithelial neoplasia 2 or greater after treatment were 34.7% (95% confidence interval −131, 82) and −211% (95% confidence interval −2901, 68), respectively. We observed evidence for a partial and nonsignificant protective effect of vaccination against new infections absent before treatment. For incident human papillomavirus 16/18, human papillomavirus 31/33/45, and oncogenic human papillomavirus infections post-treatment, vaccine efficacy estimates were 57.9% (95% confidence interval −43, 88), 72.9% (95% confidence interval 29, 90), and 36.7% (95% confidence interval 1.5, 59), respectively.ConclusionWe find no evidence for a vaccine effect on the fate of detectable human papillomavirus infections. We show that vaccination does not protect against infections/lesions after treatment. Evaluation of vaccine protection against new infections after treatment and resultant lesions warrants further consideration in future studies

The protective effect of vein cuffed anastomoses is not mechanical in origin

Purpose: Intimal hyperplasia (IH) is a proliferative process of vascular smooth muscle cells that occurs after an arterial injury, particularly at outflow anastomoses of prosthetic bypass grafts. IH causes stenosis that leads ultimately to graft flow reduction and thrombosis. We have demonstrated previously that vein cuff interposition between an expanded polytetrafluoroethylene (e-PTFE) graft and artery at distal anastomoses diminished IH formation in the arterial outflow as compared with noncuffed anastomoses. Improved long-term patency rates associated with the placement of an interposition vein cuff at the distal anastomosis of e-PTFE grafts to infrageniculate arteries have also been demonstrated clinically. This study examined the mechanical factors that may contribute to the protective effect of cuffed anastomoses. These factors include the expansibility of the vein cuff as compared with e-PTFE, as well as the angle of the cuffed anastomosis. Methods: Compatible animals were selected by use of platelet aggregation studies. Nine dogs, group A, received a 4 mm e-PTFE graft plus a 1 cm long interposition vein cuff at the distal anastomosis in the left carotid artery. The same procedure was done on the right side, and in addition the vein cuff was encircled by an e-PTFE jacket incorporated into the anastomosis to prevent the expansion of the vein cuff with arterial pulsation. To study the effect of distal anastomotic angle and geometry on the formation of IH, five dogs, group B, received a 4 mm e-PTFE graft in both sides. On the left, the distal anastomosis was performed between the graft and the artery at an acute angle as it is commonly done when a bypass graft is placed. On the right side a 1 cm long, 6 mm diameter e-PTFE segment was interposed between the artery and the graft at a perpendicular angle. This geometry mimicked the right angle of a vein cuff - to-artery anastomosis. After 10 weeks the grafts were harvested, and the thickness of IH was measured with an ocular micrometer under light microscopy. Results: In group A, one dog had bilateral graft thrombosis (12%), and these grafts were discarded. In the remaining eight dogs there was no statistically significant difference in the thickness of IH between the right (jacketed group) and the left side (nonjacketed/control group), showing that vein cuff expansibility did not play a role in protecting against the formation of IH. In group B, bilateral graft thrombosis occurred in four of five dogs (80%), suggesting that the perpendicular anastomotic angle was not protective. Conclusion: These results suggested that the protective effect of the vein cuff is not mechanical in origin. (J VASC SURG 1995;21:558-66.). © 1995 Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter

Renal insufficiency and use of revascularization among a national cohort of men with advanced lower extremity peripheral arterial disease.

Although peripheral arterial disease is prevalent in patients with renal insufficiency, little is known about how the disease is managed in this patient group. The management of advanced limb ischemia was examined in a large cohort of male veterans (n = 6227). Patients were classified according to whether they underwent lower extremity revascularization, amputation, or no procedure within the first 6 mo after their first diagnosis of critical limb ischemia, defined as ischemic rest pain, ulceration, or gangrene. The association of renal insufficiency with revascularization and the association of management strategy with mortality within 1 yr of cohort entry were measured. Within 6 mo of initial diagnosis of critical limb ischemia, 39% of patients underwent lower extremity revascularization, 27% underwent major amputation, and 34% did not undergo either procedure. Patients with an estimated GFR 30 to 59 (adjusted odds ratio [OR] 0.84; 95% confidence interval [CI] 0.72 to 0.96), 15 to 29 ml/min per 1.73 m2 (OR 0.47; 95% CI 0.35 to 0.65), 15 ml/min per 1.73 m2 not on dialysis (OR 0.32; 95% CI 0.16 to 0.62), and dialysis patients (OR 0.62; 95% CI 0.47 to 0.84) were less likely to undergo revascularization than those with an estimated GFR \u3e or = 60 ml/min per 1.73 m2. At all levels of renal function, mortality risk was lowest for patients who underwent revascularization. Patients with critical limb ischemia and concomitant renal insufficiency are less likely to be treated with revascularization. However, among patients with renal insufficiency, mortality is lowest for patients who receive a revascularization. Further studies are needed to determine the optimal care for this high-risk patient group

Symptomatology and Anatomic Patterns of Peripheral Vascular Disease: Differing Impact of Smoking and Diabetes

We retrospectively examined the impact of smoking and diabetes on the clinical presentation and arteriographic pattern of occlusion in 227 patients evaluated for symptomatic infrainguinal arterial disease. The age at which significant symptomatology developed did not differ for diabetics and nondiabetics. Diabetics had significantly more occlusion in the large arteries of the calf, however, particularly in the peroneal and posterior tibial arteries. Despite this, the extent of occlusive disease in the pedal arch was not influenced by diabetes. Diabetics also tended to present more frequently with gangrene or ulcer (\u3e 70%) when compared to nondiabetic smokers (41%, p \u3c .01). Smokers presented with symptomatic disease earlier than nonsmokers (p \u3c .0005). Intermittent claudication was strongly associated with smoking; among 33 patients with claudication, 32 were smokers. In contrast to the effect of diabetes, smokers appeared to have less extensive occlusive disease in the large arteries of the calf than nonsmokers. Nondiabetic nonsmokers constituted less than 10% of our study population and presented at a significantly older age. Nevertheless, despite the absence of either risk factor, this group also tended to present with gangrene or ulcer relatively frequently (71%). Although diabetes and smoking are both risk factors for atherosclerotic disease, we conclude that their impact on the angiographic pattern of occlusion and clinical presentation differs substantially. © 1989, Annals of Vascular Surgery, Inc.. All rights reserved

Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment.

BACKGROUND: Human papillomavirus vaccines prevent human papillomavirus infection and cervical precancers. The impact of vaccinating women with a current infection or after treatment for an human papillomavirus-associated lesion is not fully understood. OBJECTIVES: To determine whether human papillomavirus-16/18 vaccination influences the outcome of infections present at vaccination and the rate of infection and disease after treatment of lesions. STUDY DESIGN: We included 1711 women (18-25 years) with carcinogenic human papillomavirus infection and 311 women of similar age who underwent treatment for cervical precancer and who participated in a community-based trial of the AS04-adjuvanted human papillomavirus-16/18 virus-like particle vaccine. Participants were randomized (human papillomavirus or hepatitis A vaccine) and offered 3 vaccinations over 6 months. Follow-up included annual visits (more frequently if clinically indicated), referral to colposcopy of high-grade and persistent low-grade lesions, treatment by loop electrosurgical excisional procedure when clinically indicated, and cytologic and virologic follow-up after treatment. Among women with human papillomavirus infection at the time of vaccination, we considered type-specific viral clearance, and development of cytologic (squamous intraepithelial lesions) and histologic (cervical intraepithelial neoplasia) lesions. Among treated women, we considered single-time and persistent human papillomavirus infection, squamous intraepithelial lesions, and cervical intraepithelial neoplasia 2 or greater. Outcomes associated with infections absent before treatment also were evaluated. Infection-level analyses were performed and vaccine efficacy estimated. RESULTS: Median follow-up was 56.7 months (women with human papillomavirus infection) and 27.3 months (treated women). There was no evidence of vaccine efficacy to increase clearance of human papillomavirus infections or decrease incidence of cytologic/histologic abnormalities associated with human papillomavirus types present at enrollment. Vaccine efficacy for human papillomavirus 16/18 clearance and against human papillomavirus 16/18 progression from infection to cervical intraepithelial neoplasia 2 or greater were -5.4% (95% confidence interval -19,10) and 0.3% (95% confidence interval -69,41), respectively. Among treated women, 34.1% had oncogenic infection and 1.6% had cervical intraepithelial neoplasia 2 or greater detected after treatment, respectively, and of these 69.8% and 20.0% were the result of new infections. We observed no significant effect of vaccination on rates of infection/lesions after treatment. Vaccine efficacy estimates for human papillomavirus 16/18 associated persistent infection and cervical intraepithelial neoplasia 2 or greater after treatment were 34.7% (95% confidence interval -131, 82) and -211% (95% confidence interval -2901, 68), respectively. We observed evidence for a partial and nonsignificant protective effect of vaccination against new infections absent before treatment. For incident human papillomavirus 16/18, human papillomavirus 31/33/45, and oncogenic human papillomavirus infections post-treatment, vaccine efficacy estimates were 57.9% (95% confidence interval -43, 88), 72.9% (95% confidence interval 29, 90), and 36.7% (95% confidence interval 1.5, 59), respectively. CONCLUSION: We find no evidence for a vaccine effect on the fate of detectable human papillomavirus infections. We show that vaccination does not protect against infections/lesions after treatment. Evaluation of vaccine protection against new infections after treatment and resultant lesions warrants further consideration in future studies

Construction and validation of tissue microarrays of ductal carcinoma in situ and terminal duct lobular units associated with invasive breast carcinoma

Construction of tissue microarrays (TMAs) to efficiently characterize large sets of noninvasive epithelial lesions in the breast by immunohistochemistry is an appealing investigative approach, but presents technical challenges. We report methodologic studies performed to optimize methods for building TMAs from noninvasive breast tissues collected in a large case-control study of breast cancer. Using a manual arraying technique with 2.0-mm diameter needles, we constructed TMAs from specimens obtained from 32 women with breast cancer containing the following targets: (1) 28 terminal duct lobular units (TDLUs); (2) 28 ductal carcinomas in situ, and (3) 23 invasive carcinomas. Using careful target selection, we achieved representation of ∼80% of noninvasive targets with sustained preservation through section 30 of the TMAs. Immunohistochemical staining of TDLU targets demonstrated positive staining for estrogen receptor (ER) in 30.8% of tubules and for progesterone receptor (PR) in 50.0%. To establish an efficient method to evaluate staining results in TDLUs, we created a categorical scoring system to approximate the percentage of tubules containing positive stained cells (\u3c10%, 10% to 50%, ≥50%), and compared the results with those obtained by tubule counting. Comparison between the two methods demonstrated exact agreement for 70.8% of ER and 79.2% of PR stains without two-category discrepancies. ER/PR expression levels in multiple (up to 4) noninvasive targets of the same tissue type (TDLU or DCIS) from a single block showed good correlation. These data suggest that it is feasible to produce TMAs of noninvasive breast structures, albeit with careful selection of targets, and that immunostains of such cores may permit efficient immunohistochemical characterization of peritumoral tissues. Additional exploration of this approach is needed. Copyright © 2006 by Lippincott Williams & Wilkins