Progression to and spontaneous regression of high-grade anal squamous intraepithelial lesions in HIV-infected and uninfected men

Tong, Winnie; Jin, Fengyi; McHugh, Leo; Maher, Tara; Sinclair, Brett; Grulich, Andrew E.; Hillman, Richard J.; Carr, Andrew

doi:10.1097/qad.0b013e3283633111

Cited by 99 publications

(79 citation statements)

References 26 publications

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“…S1). These findings are consistent with medical observations that very few lesions ever progress to cancer (26,27). Like our model, these studies also find that most lesions regress to undetectable size.…”

Section: Significancesupporting

confidence: 90%

“…Our model predicts a similarly wide distribution of total SNMs due to the stochastic period that cancers linger at the critical population size N* while accumulating mutations. To compare these data with various models we normalized the total number of mutations by their median (27) because several evolutionary parameters and sequencing decisions can alter these distributions by a multiplicative factor (SI Appendix). Our model agrees with the data when the effect size of drivers is large (s d ≈ 0.4).…”

Section: Significancementioning

confidence: 99%

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Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

McFarland

Mirny

Korolev

2014

Proc. Natl. Acad. Sci. U.S.A.

151

187

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Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations-a natural consequence of cancer's elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor's load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies.

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Section: Significancesupporting

confidence: 90%

Section: Significancementioning

confidence: 99%

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

McFarland

Mirny

Korolev

2014

Proc. Natl. Acad. Sci. U.S.A.

151

187

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“…The natural history parameters for disease progression and regression were based on a cost-effectiveness analysis by Czoski-Murray et al [12], who derived these estimates from two large prospective cohort studies [13, 14]. Data from Tong et al [15] were used to estimate HGAIN regression. The progression rates of HPV to LGAIN and HPV to HGAIN are unknown.…”

Section: Methodsmentioning

confidence: 99%

Clinical effectiveness and cost-effectiveness of quadrivalent human papillomavirus vaccination in HIV-negative men who have sex with men to prevent recurrent high-grade anal intraepithelial neoplasia

Deshmukh¹,

Chiao²,

Das³

et al. 2014

Vaccine

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We examined the long-term clinical and economic benefits of quadrivalent human papillomavirus (qHPV) vaccine as a secondary/adjunct prevention strategy in the prevention of recurrent high-grade intraepithelial neoplasia (HGAIN) in HIV-negative men who have sex with men (MSM) and are 27 years or older. We constructed a Markov model to evaluate the clinical effectiveness and cost-effectiveness of two strategies: (1) no qHPV vaccine after treatment for HGAIN versus (2) qHPV vaccine after treatment for HGAIN. Model parameters, including natural history of anal cancer, vaccine efficacy measured in terms of hazard ratio (HR) (risk of recurrent HGAIN), HGAIN treatment efficacy, utilities, and costs, were obtained from the literature. The outcomes were measured in terms of lifetime risk of anal cancer, lifetime cost, quality-adjusted life years, and incremental cost-effectiveness ratios (ICERs). Sensitivity analysis was conducted on all model parameters. We found that vaccinating HIV-negative MSM reduced the lifetime risk of anal cancer by 60.77% at an ICER of US$87,240 (95% CI, $22,301–$144,187) per quality-adjusted life-year. The results were highly sensitive to vaccine efficacy, transition of HGAIN to anal cancer, cost of treatment for HGAIN, vaccine degree of protection over time, and the vaccine duration of protection and less sensitive to HPV clearance, cost of qHPV, and the transitions from normal to low-grade anal intraepithelial neoplasia (LGAIN) and normal to HGAIN. With an HR of 0.3, the ICER was well below a $50,000 willingness-to-pay threshold; with an HR of 0.5, the ICER was still below a threshold of $100,000. The most critical disease-related factor influencing the cost-effectiveness was the progression of HGAIN to anal cancer. At an annual transition probability below 0.001, the ICER was below $50,000. Vaccinating HIV-negative MSM treated for HGAIN decreases the lifetime risk of anal cancer and is likely to be a cost-effective intervention.

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“…8 It had previously been generally accepted that most biopsy proven HSIL ( b HSIL) would persist and eventually progress to cancer if not treated; however, recent research has shown that some b HSIL may regress without treatment. 13 In HIV-infected individuals with HSIL ACyt, there is an estimated five year progression rate to invasive anal cancer of 1.7%. 14 …”

Section: Introductionmentioning

confidence: 99%

Anal Cancer Screening in Men Who Have Sex With Men in the Multicenter AIDS Cohort Study

D’Souza

Wentz

Wiley

et al. 2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Objective To evaluate the prevalence of anal cytology (ACyt) abnormalities among HIV-infected and HIV-uninfected men who have sex with men (MSM) Design Multicenter cohort study of 723 HIV-infected and 788 HIV-uninfected MSM with ACyt, with a second ACyt collected two years later. Referral for high-resolution anoscopy (HRA) was suggested for abnormal ACyt. Methods ACyt samples were collected using a polyester swab and liquid cytology media, and read in a central laboratory. Results Prevalence of any abnormal ACyt was 25% in HIV-uninfected MSM, and increased to 38%, 41%, and 47% among HIV-infected MSM with current CD4+ T-cell counts ≥500, 350–499, and <350 cells/mm3 (p<0.001), respectively. Anal HPV16 DNA was also more common in HIV-infected than HIV uninfected MSM (25% vs 16%, p<0.001). Abnormal baseline ACyt together with prevalent HPV16 DNA detection was present in only 7% of HIV-uninfected MSM compared to 18% of HIV-infected MSM with current CD4<350, p<0.001). Among HIV-infected men, 56% of the men with low grade squamous intraepithelial lesions ASC-US/LSIL and 81% of men with atypical squamous cells cannot exclude high grade (ASC-H/)/high grade SIL (HSIL) had lower grade ACyt findings 18–30 months later (“regressed”). However, 19% of untreated HIV-infected men with ASC-H/HSIL cytology maintained that same grade of cytology at their second test approximately two years later, and 15% with ASC-US/LSIL “progressed” to ASC-H/HSIL. Abnormal ACyt had high sensitivity (96%) but low specificity (17%) for biopsy proven HSIL. Conclusions Prevalence of abnormal ACyt remains elevated in HIV-infected men during the current ART era.

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Progression to and spontaneous regression of high-grade anal squamous intraepithelial lesions in HIV-infected and uninfected men

Abstract: High-grade ASILs frequently spontaneously regress. Longer-term, prospective studies are required to determine whether these regressions are sustained.

Cited by 99 publications

References 26 publications

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

Clinical effectiveness and cost-effectiveness of quadrivalent human papillomavirus vaccination in HIV-negative men who have sex with men to prevent recurrent high-grade anal intraepithelial neoplasia

Anal Cancer Screening in Men Who Have Sex With Men in the Multicenter AIDS Cohort Study

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