Human papillomavirus testing 2007–2012: Co‐testing and triage utilization and impact on subsequent clinical management

In the United States, high‐risk human papillomavirus (HPV) testing is recommended for women with atypical squamous cells of unknown significance (ASC‐US) cytology, and co‐testing with cytology and HPV is a recommended option for screening women aged ≥30 years. No population‐based data are available to examine utilization of HPV testing in the United States. Using the New Mexico HPV Pap Registry data resource, we describe population trends (2007–2012) in utilization and positivity rates for HPV testing as a routine co‐testing screening procedure and for triage of ASC‐US and other cytologic outcomes. For women aged 30–65 years co‐testing increased from 5.2% in 2007 to 19.1% in 2012 (p < 0.001). Overall 82% of women with ASC‐US cytology who did not receive co‐testing also had an HPV test. HPV positivity was age and cytology result dependent but did not show time trends. For women with negative cytology, 64% received an additional screening test within 3 years if no co‐test was done or if it was positive, but this was reduced to 47% with a negative co‐test. Reflex HPV testing for ASC‐US cytology is well established and occurs in most women. Evidence for reflex testing is also observed following other abnormal cytology outcomes. Co‐testing in women aged 30–65 years has more than tripled from 2007 to 2012, but was still only used in 19.1% of women aged 30–65 years attending for screening in 2012. Women receiving co‐testing had longer repeat screening intervals, but rescreening within 3 years is still very common even with co‐testing.     

Effectiveness of a two‐stage strategy with HPV testing followed by visual inspection with acetic acid for cervical cancer screening in a low‐income setting

The World Health Organization recently advocated a two‐stage strategy with human papillomavirus (HPV) testing followed by visual inspection of the cervix with acetic acid (VIA) as a suitable option for cervical cancer screening. However, its accuracy has never been directly assessed in the context of primary screening. To evaluate effectiveness of HPV testing on self‐obtained specimens (self‐HPV) followed by VIA (sequential testing) in a low‐income setting, we recruited 540 women aged between 30 and 65 years in two Cameroonian periurban areas. Eligible women were counseled about cervical cancer and how to perform self‐sampling. HPV positive and a random sample of HPV‐negative women were called back for VIA and biopsy. Disease was defined by interpretation of cervical intraepithelial neoplasia Grade 2 or worse (CIN2+). Performances of VIA, self‐HPV and sequential testing were determined after adjustment for verification bias. HPV prevalence was 27.0%. VIA positivity was 12.9% and disease prevalence was 5%. Sensitivity and specificity of VIA for CIN2+ were 36.4% [95% confidence interval (CI): 15.2–64.6%] and 90.4% (95% CI: 85.4–93.7%), respectively. Sensitivity of self‐HPV [100.0% (95% CI: 79.6–100.0%)] was 66% higher than that of sequential testing [33.3% (95% CI: 15.2–58.3%)]. Meanwhile, specificity of self‐HPV [74.5% (95% CI: 70.6–78.1%)] was 22% lower than that of sequential testing [96.7% (95% CI: 94.8–97.9%)]. A two‐stage screening strategy with self‐HPV followed by VIA improves specificity of cervical cancer screening, but at the cost of an important loss of sensitivity. Ways to improve VIA performance or other tools are needed to increase positive predictive value of HPV testing.     

A high and increasing HPV prevalence in tonsillar cancers in Eastern Denmark, 2000–2010: The largest registry‐based study to date

The aim was to explore whether the incidence of tonsillar squamous cell carcinomas (TSCCs) increased in Eastern Denmark, 2000–2010, and whether human papillomavirus (HPV) could explain the increase, and to assess the association of HPV prevalence with gender, age, and origin (i.e., the certainty of tonsillar tumor origin). We applied HPV DNA PCR and p16 immunohistochemistry to all TSCCs registered in the Danish Head and Neck Cancer Group (DAHANCA) and in the Danish Pathology Data Bank (n = 632). Pathologists reviewed and subdivided the tumors into two groups: specified and nonspecified TSCCs. Approximately 10% of HPV‐positive tumors was genotyped by amplicon next‐generation sequencing. The overall crude incidence of TSCCs increased significantly (2.7% per year) and was explained by an increasing incidence of HPV‐positive TSCCs (4.9% per year). The overall HPV prevalence was 58%, with HPV16 being the predominant HPV type. In multivariate analysis, the HPV prevalence was associated with age (<55 vs. >60 years) (OR, 1.72; 95% CI 1.13–2.63) and origin (nonspecified vs. specified TSCCs) (OR, 0.15; 95% CI 0.11–0.22). The association of HPV prevalence with origin increased over time in specified TSCCs (OR per year, 1.10; 95% CI 1.01–1.19), whereas no change over time was observed among nonspecified TSCCs (OR per year, 0.99; 95% CI 0.90–1.08). In conclusion, the observed increase in the number of HPV‐positive TSCCs can explain the increasing number of TSCCs in Eastern Denmark, 2000–2010. HPV prevalence was associated with younger age (<55 years) and a high certainty of tonsillar tumor origin.     

HLA、HPV感染与宫颈癌相关性研究进展

人类白细胞抗原(human leucocyte antigen,HLA)是人类主要组织相容性抗原系统.90年代以来,先后发现多种HLA等位基因和单体型与人乳头瘤病毒(human papillomavirus,HPV)感染、子宫颈上皮内瘤样病变(cervical intraepithelial neoplasia,CIN)和宫颈癌相关联.本文就近年来HLA与HPV、CIN和宫颈癌的研究进展作一综述.     

The effects of d-cycloserine and MK-801 on the performance of rats in two spatial learning and memory tasks

The present study was undertaken to investigate the effects of modulation of the (NMDA) receptor on learning and memory. Thus, the performance of rats treated with d-cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor complex, and MK-801, a noncompetitive NMDA receptor antagonist, either alone or concurrently were assessed in radial arm maze and water maze tasks. Administration of MK-801 (0.1 mg/kg, i.p.) impaired acquisition in the water maze (increased escape latency and distance) and working memory in the radial arm maze (increased re-entries) in rats. Moreover, in the radial arm maze, MK-801 disrupted locomotion (increased latencies and decreased arm entries per minute) and impaired the acquisition of reference memory (increased number of errors) performance of rats. d-Cycloserine (0.03, 0.3, 1.0, 3.0, 10 mg/kg, i.p.) had no effects on acquisition or memory performance of control or MK-801-treated rats in either of these tasks. However, d-cycloserine (0.03, 0.3, 3.0 mg/kg) reversed the MK-801-induced disruption in locomotion. Furthermore, 3.0 mg/kg d-cycloserine increased behavioral activity and also decreased the time needed to complete the task in control animals. To conclude, our results suggest that the consequences of NMDA receptor modulation on learning and memory processes and sensorimotor functions may be functionally different or have distinct anatomical locations.     

Risk factors for the progression or persistence of untreated mild dysplasia of the uterine cervix

To identify the factors that may predict the progression or persistence of untreated mild dysplasia of the uterine cervix, we performed a retrospective review of 118 patients with histologically verified mild dysplasia who underwent colposcopic biopsies between January 1999 and December 2003. Regression to normal occurred in 70.3%, progression to moderate dysplasia or worse occurred in 11.0%, and persistence of mild dysplasia occurred in 18.7%. In regression/progression analysis, progression of untreated mild dysplasia was 34.5% (10/29) in patients with high viral loads (> or =100 relative light units/positive control [RLU/PC]) and 4.5% (3/67) in those with low viral loads (1 to <100 RLU/PC) and negative human papillomavirus (HPV) tests (P < 0.001). Women with high viral loads had a 13-fold greater chance of progression of untreated mild dysplasia than those with low viral loads and negative HPV tests (CI: 2.494-95.297; P = 0.0022). Those associated with both positive smear and positive HPV test (12/45 = 26.7%) were at a greater risk of progression of untreated mild dysplasia as compared with those with positive smear and negative HPV (0/17 = 0.0%) or those with negative smear and positive HPV test (1/18 = 5.6%). Those with high viral loads and both with positive smear and positive HPV test should be followed closely because of their increased risk of progression of untreated mild dysplasia.     

Serologic response to human papillomavirus 16 among Australian women with high-grade cervical intraepithelial neoplasia

This study evaluated the detection of human papillomavirus (HPV) 16 antibody in HPV 16-associated cervical intraepithelial neoplasia (CIN) in Australian women. Seroreactivity to HPV 16 L1 virus-like particles was assessed in patients with CIN 2 (n= 169) and CIN 3 (n= 229) lesions previously tested for the presence of HPV DNA. Seropositivity was significantly commoner in women with HPV 16 DNA-positive lesions (98/184) than in women with no HPV DNA in the lesion (15/47) or with HPV of types other than 16 in the lesion (43/167) (P= 0.0004). In addition, seropositivity was observed in 33% (55/169) of women with CIN 2 and 46% (106/229) of women with CIN 3, in keeping with the lower fraction of CIN 2 (57/169) than CIN 3 (127/229) biopsies positive for HPV 16 DNA. HPV 16 seropositivity is most common in women with HPV 16-associated CIN, but many patients with HPV-associated CIN 3 are seronegative, and HPV 16 seropositivity is common in women with CIN associated with other HPV types. Overall, HPV 16 serology is a poor predictor of presence of HPV 16-associated CIN 3 in patient population studied.     

Factors predicting intermediate endpoints of cervical cancer and exposure to human papillomavirus (HPV) infections in young women screened as potential targets for prophylactic HPV vaccination in south of Brazil

OBJECTIVE: To explore the predictors of intermediate endpoints of cervical cancer in 500 women living in Porto Alegre. STUDY DESIGN: Five hundred randomly selected women (mean age 20.3 years, range 15-25) were screened using PCR detecting 25 HPV types (HPV6, 11, 16, 18, 31, 33, 34, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 66, 68, 70, and 74). Women were interviewed and serum samples were analysed for antibodies to HPV16 and HPV18 VLPs. Regression models were constructed to analyse predictive factors for (a) HPV PCR status, (b) HPV16-seropositivity, (c) HPV18-seropositivity, and (d) SIL in the PAP smear, used as intermediate endpoints of cervical cancer. RESULTS: Specific HPV types were identified in 137 (27.4%) of the 157 (31.4%) PCR-positive women. PAP test result was the most powerful independent predictor of HPV status in PCR (p = 0.0001), followed by the sexual activity started (p = 0.001) (adjusted OR 34.075, 95% CI: 4.650-249.715). PAP test SIL was independently predicted only by the HPV PCR status (p = 0.0001) (OR 7.561, 95% CI: 2.787-20.514). HPV16 and HPV18 serostatus were the most significant predictors of each other (p=0.0001), and the life-time number of sexual partners was more significant (p=0.001) predictor of HPV16 than HPV18 serostatus (p = 0.049). CONCLUSION: These data are useful in evaluating the exposure status of the women to the risk factors of cervical cancer in south of Brazil.     

高危型人乳头瘤病毒检测在宫颈癌筛查中的应用价值

目的探讨将HR-HPV检测作为宫颈癌筛查手段的意义和价值。方法2004-12-2005-04对301医院妇产科门诊就诊的1231例患者,进行HPVDNA的杂交捕获法二代(HPV-HCⅡ)和液基细胞学(Thinprepcytol-ogytest,TCT)的检测,作为宫颈癌及其癌前病变的初筛。131例因细胞学异常,或细胞学正常而HPV检测阳性,或细胞学正常HPV阴性、而临床高度怀疑病变的患者行阴道镜下多点活检,结合病理结果进行分析。结果(1)1231例样本中,经TCT检测正常者1077例(87·43%),ASCUS32例(2·60%),ASCUS-H34例(2·76),LSIL73例(5·93%),HSIL15例(1·22%)。131例阴道镜下多点组织活检,病理证实炎症68例(51·91%),CINⅠ20例(15·27%),CINⅡ18例(13·74%),CINⅢ16例(12·21%),浸润癌4例(4·35%),湿疣5例(3·82%)。(2)HPV总感染率34%,HPV阳性者418例,年龄平均(36·93±10·8)岁,HPV阴性者813例,年龄平均(39·68±11·8)岁,HPV阳性组的年龄明显小于HPV阴性组,P<0·01。各病理组HPV感染率分别为:炎症58·82%,CINⅠ80%,CINⅡ72·22%,CINⅢ100%,浸润癌100%,湿疣60%。(3)阴道镜下多点活检结果:TCT和HPV均(-)者,无高度病变的发生;TCT(-)和HPV( )者中,≥CINⅡ的检出率11·1%(1/9),TCT异常和HPV阳性同时存在的病例中,≥CINⅡ的检出率最高40·5%(32/79);仅TCT异常而HPV(-)者13·2%(5/38),且5例均为CINⅡ,无原位癌和浸润癌的发生。结论持续的HR-HPV感染与宫颈病变的演进有关;HR-HPV检测是有价值的辅助诊断技术,与细胞学联合检测,为最佳宫颈癌筛查方案。