DNA methylation markers have universal prognostic value for anal cancer risk in HIV-negative and HIV-positive individuals.
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ABSTRACT:
SUBMITTER: van der Zee RP
PROVIDER: S-EPMC8564631 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human papillomavirus (HPV)-induced anal intraepithelial neoplasia (AIN, graded 1-3) is highly prevalent in HIV-positive (HIV+) men who have sex with men (MSM), but only a minority of lesions progresses to cancer. Our study aimed to characterise comprehensively anal tissue samples from a cross-sectional series (n = 104) of HIV+ MSM and longitudinal series (n = 40) of AIN2/3 progressing to cancer using different biomarkers. The cross-sectional series consisted of 8 normal, 26 AIN1, 45 AIN2, 15 AIN3 and 10 anal squamous cell carcinoma. Tissue sections were immunohistochemically (IHC) stained for p16 (viral transformation marker), Ki-67 (cellular proliferation marker) and HPV-E4 (viral production marker). We evaluated the expression of IHC markers and compared it with DNA methylation, a marker for malignant transformation. E4 positivity decreased, whereas p16 and Ki-67 scores and methylation marker positivity increased (P values < .001) with increasing severity of anal lesions. Within AIN2, a heterogeneous biomarker pattern was observed concerning E4, p16 and methylation status, reflecting the biological heterogeneity of these lesions. In the longitudinal series, all AIN2/3 and carcinomas showed high p16 and Ki-67 expression, strong methylation positivity and occasional E4 positivity. We earlier showed that high methylation levels are associated with progression to cancer. The observed E4 expression in some AIN2/3 during the course of progression to cancer and absence of E4 in a considerable number of AIN1 lesions make the potential clinical significance of E4 expression difficult to interpret. Our data show that IHC biomarkers can help to characterise AIN; however, their prognostic value for cancer risk stratification, next to objective methylation analysis, appears to be limited.
| S-EPMC9292283 | biostudies-literature
Project description:BACKGROUND:The aim of the present study was to evaluate patient factors that affect the progression of anal dysplasia in human immunodeficiency virus (HIV)-positive individuals. METHODS:A retrospective cohort study of HIV-positive adults with human papilloma virus related anal lesions was performed from 2012 to 2017. All patients underwent surgical excision or biopsy and fulguration of lesions in the operating room without using high resolution anoscopy. Patients with initial presentation of squamous cell carcinoma were excluded. The study was designed to investigate progression between the first available histology and either the follow up histology or a negative examination. Patient files were reviewed and data was collected. A bivariate analysis of continuous and categorical variables was performed. RESULTS:One hundred and sixty-one patients met the inclusion criteria. Ninety-seven percent were male. Mean age was 41 years. Thirty-five percent were African American and 47% were Caucasian. After a median follow-up interval of 331 days (IQR 120-615 days) 14 (9%) of patients had progression of disease. Visible lesions on initial presentation, as opposed to lesions found in patients undergoing examination under anesthesia because of HSIL on anal pap smear, was associated with progression (p = 0.0.2). A lower initial CD4 count (p?=?0.01) and initial surgical pathology of anal condylomata (p?=?0.01) were also associated with progression. High-risk serotype was associated with no change or regression (p?=?0.01). CONCLUSIONS:In our large cohort of HIV-positive patients treated without high resolution anoscopy the rate of progression was low. Most notably, visible lesions at initial presentation and CD4 count when lower were associated with progression. Initial surgical pathology of anal condylomata was associated with progression, while high-risk serotypes correlated with regression or stability. Identification of risk factors has important implications concerning postoperative surveillance and counseling of HIV-positive patients with anal condylomata/ anal dysplasia.
| S-EPMC6582960 | biostudies-literature
Project description:BackgroundThe glucocorticoid receptor (NR3C1, GR) is frequently downregulated in breast tumors, and evidence suggests it acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer. We previously found that methylation of the GR promoter CpG island represses gene expression and occurs in ER+ breast tumors. In this study, the prognostic and predictive value of GR methylation was examined in ER+ patients from the CCTG MA.12 clinical trial of tamoxifen versus placebo in women with early breast cancer.MethodsWe developed a targeted multiplex bisulfite next-generation sequencing assay to detect methylation at multiple GR promoter regions in DNA from formalin-fixed paraffin-embedded (FFPE) samples. Following validation in a small cohort of breast tumors, ER+ FFPE tumor samples from MA.12 (n?=?208) were tested. Survival analyses evaluated the impact of GR promoter methylation on patient overall survival (OS) and disease-free survival (DFS).ResultsAn analysis of TCGA data found that GR methylation is prevalent in ER+ tumors and is associated with decreased gene expression and analysis of public microarray data (KM Plotter) linked decreased GR expression to a poor outcome. In MA.12, two GR promoter regions (U and C) each had prognostic value, but with opposite effects on the outcome. U methylation was associated with poor OS (HR?=?1.79, P?=?0.041) whereas C methylation was associated with better OS (HR?=?0.40, P?=?0.040) and DFS (HR?=?0.49, P?=?0.037). The classification of patients based on the methylation status of the two regions was prognostic for OS (P?=?0.006) and DFS (P?=?0.041) and revealed a group of patients (U methylated, C unmethylated) with very poor outcomes. Placebo-treated patients in this high-risk group had worse OS (HR?=?2.86, P?=?0.002) and DFS (HR?=?2.09, P?=?0.014) compared to the rest of the cohort.ConclusionRegion-specific GR promoter methylation was an independent prognostic marker for patient survival and identified a subset of patients with poor prognosis, particularly without tamoxifen treatment. These findings provide a foundation for future studies into GR methylation as a promising prognostic biomarker in ER+ breast cancer.
| S-EPMC6825343 | biostudies-literature
Project description:OBJECTIVE:To test whether HIV is associated with brain large artery vulnerable intima. DESIGN:Cross-sectional study of autopsied HIV-positive (HIV+) cases sex and age-matched to HIV-negative (HIV-) controls. METHODS:Brain large arteries from 302 autopsied cases (50% HIV+) were evaluated morphometrically for the presence of atherosclerosis, size of necrotic core, and fibrous cap thickness. Intima vulnerability was measured as intima elastolytic score [0-5, based on intimal metalloproteinases (MMP)-2, MMP-3, and MMP-9, and tissue inhibitor for MMP-1 and MMP-2 staining], intima inflammatory score (0-3, based on intimal presence of CD3 and CD68 cells and TNF-? staining), neoangiogenesis (factor VIII staining), and apoptosis (caspase 3 staining). Hierarchical generalized linear models were used to obtain the beta estimates and their 95% confidence intervals, adjusting for demographics and vascular risk factors. RESULTS:The prevalence of atherosclerosis did not differ by HIV status. Necrotic cores filled larger proportions of the intima in HIV+ individuals with CD4 cell count above 200?cells/?l at death compared to HIV- controls (adjusted B?=?11.6%, P?=?0.04). HIV+ individuals had greater elastolytic scores (adjusted B?=?0.34, P?=?0.02), especially those with less than 200 CD4 cells/?l at death (adjusted B?=?0.41, P?=?0.01). Intima inflammation, neoangiogenesis, and apoptosis were not different among HIV+ cases versus HIV- controls. CONCLUSION:Individuals with HIV and CD4 cell count at least 200?cells/?l at death had relatively larger necrotic cores, whereas those with HIV and CD4 cell count below 200?cells/?l at death had evidence of increased connective tissue remodeling in the intima. These findings suggest an increased potential for endothelial erosion, thrombosis, and plaque rupture that may relate to higher risk for vascular events.
| S-EPMC6136984 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) has a significant clinical relevance of being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. Increased aggressiveness of this tumor, as well as resistance to standard drug therapies, may be associated with the presence of stem cell populations within the tumor. Several stemness markers have been described for the various histological subtypes of breast cancer, such as CD44, CD24, CD133, ALDH1, and ABCG2. The role of these markers in breast cancer is not clear yet and above all there are conflicting opinions about their real prognostic value. To investigate the role of CSCs markers in TNBC cancerogenesis and tumor progression, we selected 160 TNBCs samples on which we detected protein expression of CD44, CD24, CD133, ALDH1, and ABCG2 by immunohistochemistry. Our results highlighted a real prognostic role only for CD44 in TNBCs. All other CSCs markers do not appear to be related to the survival of TNBC patients. In conclusion, despite the fact that the presence of the cancer stem cells in the tumor provides important information on its potential aggressiveness, today their detection by immunohistochemistry is not sufficient to confirm their role in carcinogenesis, because specific markers probably are not yet identified.
| S-EPMC4609334 | biostudies-literature
Project description:BACKGROUND:Men who have sex with men (MSM) are at increased risk for anal cancer. In cervical cancer screening, patterns of repeated cytology results are used to identify low- and high-risk women, but little is known about these patterns for anal cytology among MSM. METHODS:We analyzed Multicenter AIDS Cohort Study (MACS) data for MSM who were offered anal cytology testing annually (HIV-positive) or every 2 years (HIV-negative) for 4 years. RESULTS:Following an initial negative (normal) cytology, the frequency of a second negative cytology was lower among HIV-positive MSM with CD4???500 (74%) or CD4?<?500 (68%) than HIV-negative MSM (83%) (p?<?0.001). After an initial abnormal cytology, the frequency of a second abnormal cytology was highest among HIV-positive MSM with CD4?<?500 (70%) compared to CD4???500 (53%) or HIV-negative MSM (46%) (p?=?0.003). Among HIV-positive MSM with at least three results, 37% had 3 consecutive negative results; 3 consecutive abnormal results were more frequent among CD4?<?500 (22%) than CD4???500 (10%) (p?=?0.008). CONCLUSIONS:More than one-third of HIV-positive MSM have consistently negative anal cytology over three years. Following abnormal anal cytology, a repeated cytology is commonly negative in HIV-negative or immunocompetent HIV-positive men, while persistent cytological abnormality is more likely among HIV-positive men with CD4?<?500.
| S-EPMC5909063 | biostudies-literature
Project description:BackgroundAnal squamous cell carcinoma (ASCC) is uncommon, yet seen more frequently in the setting of the human immunodeficiency virus (HIV). Chemoradiotherapy is the definitive modality of treatment for patients with ASCC; this study examines factors impacting clinical outcomes in a large cohort of HIV-positive and HIV-negative patients.MethodsA retrospective review was conducted of patients treated for nonmetastatic ASCC at a single institution between 2005 and 2018. Freedom from local recurrence (FFLR), freedom from distant metastasis, and overall survival (OS) were calculated using the Kaplan-Meier method, and univariate and multivariate analysis were performed using the Cox proportional hazards model.ResultsDuring the study period, 111 patients initiated definitive treatment for ASCC. Median age of the entire cohort was 56.7 years (interquartile range, 51.5-63.5), with 52 patients (46.8%) being HIV-positive. At median follow-up of 28.0 months, the 2- and 5-year FFLR were 78.2% (95% confidence interval [CI], 70.4-87.0) and 74.6% (95% CI, 65.8-84.5), respectively. Multivariate analysis revealed time from diagnosis to treatment initiation (median, 8 weeks; hazard ratio, 1.06; 95% CI, 1.03-1.10) to be significantly associated with worse FFLR and OS. HIV-positive patients had a trend toward worse FFLR (log-ranked p = .06). For HIV-positive patients with post-treatment CD4 less than 150 cells per mm3 , there was significantly worse OS (log-ranked p = .015).ConclusionA trend toward worse FFLR was seen in HIV-positive patients, despite similar baseline disease characteristics as HIV-negative patients. Worse FFLR and OS was significantly associated with increased time from diagnosis to treatment initiation. Poorer OS was seen in HIV-positive patients with a post-treatment CD4 count less than 150 cells per mm3 .Implications for practiceHuman immunodeficiency virus (HIV)-positive patients with anal squamous cell carcinoma can represent a difficult clinical scenario. Definitive radiation with concurrent chemotherapy is highly effective but can result in significant toxicity and a decrease in CD4 count that could predispose to HIV-related complications. As HIV-positive patients have largely been excluded from prospective clinical trials, this study seeks to provide greater understanding of their outcomes with radiation therapy, potential predictors of worse local control and overall survival, and those most at risk after completion of treatment.
| S-EPMC7485368 | biostudies-literature
Project description:BACKGROUND:Although it has been purported that HIV-positive individuals may experience a greater degree of intoxication than HIV-negative individuals following acute alcohol consumption, no research to date has empirically tested this supposition. The present investigation entailed a randomized controlled experiment to identify whether the administration of a weight-specified dose of alcohol would lead to differential blood alcohol concentrations (BACs) among HIV-positive versus HIV-negative men. METHODS:In a specialized barroom laboratory, 143 men (n = 76 HIV-positive and n = 67 HIV-negative; mean age = 42.9) consumed beverages based on a formulation of 0.7 g alcohol/kg body weight over a 15-minute time frame. BAC was assessed via breathalyzer at 2 set time points (10 and 13 minutes postconsumption) and then periodically until detoxification (BAC < 0.040%). Primary outcomes included (i) area under the curve (AUC), calculated based on all of one's BAC readings, (ii) "BAC-EXP," defined as one's BAC reading 13 minutes postconsumption, and (iii) BAC-PEAK, defined as one's highest recorded BAC reading. RESULTS:Contrary to predictions, AUC (t(141) = 2.23, p = 0.027), BAC-EXP (t(141) = 2.68, p = 0.008), and BAC-PEAK (t(141) = 2.29, p = 0.023) were significantly lower among HIV-positive versus HIV-negative participants. These effects were sustained in multivariable models controlling for age, race, and AUDIT-based hazardous drinking classification. Among the HIV-positive sample, outcomes did not significantly differ based on HIV viral load detectability, antiretroviral therapy (ART) status, or ART adherence. CONCLUSIONS:The administration of a controlled, weight-specified dose of alcohol led to lower BACs among HIV-positive versus HIV-negative participants. These differences might derive from decreased body fat percentage and delayed gastric emptying associated with HIV seropositivity; however, additional research is necessary to verify these mechanisms. Unique alcohol dosing formulas based on HIV serostatus may be required in future alcohol administration experiments involving HIV-positive samples.
| S-EPMC6120761 | biostudies-literature
Project description:BackgroundHigh dietary salt and a lack of reduced blood pressure (BP) at night (non-dipping) are risk factors for the development of hypertension which may result in end-organ damage and death. The effect of high dietary salt on BP in black people of sub-Saharan Africa living with HIV is not well established. The goal of this study was to explore the associations between salt sensitivity and nocturnal blood pressure dipping according to HIV and hypertension status in a cohort of adult Zambian population.MethodsWe conducted an interventional study among 43 HIV-positive and 42 HIV-negative adults matched for age and sex. Study participants were instructed to consume a low (4?g) dietary salt intake for a week followed by high (9?g) dietary salt intake for a week. Salt resistance and salt sensitivity were defined by a mean arterial pressure difference of ?5?mmHg and???8?mmHg, respectively, between the last day of low and high dietary salt intervention. Nocturnal dipping was defined as a 10-15% decrease in night-time blood pressure measured with an ambulatory blood pressure monitor.ResultsThe median age was 40?years for both the HIV-positive and the HIV-negative group with 1:1 male to female ratio. HIV positive individuals with hypertension exhibited a higher BP sensitivity to salt (95%) and non-dipping BP (86%) prevalence compared with the HIV negative hypertensive (71 and 67%), HIV positive (10 and 24%) and HIV-negative normotensive (29 and 52%) groups, respectively (p <?0.05). Salt sensitivity was associated with non-dipping BP and hypertension in both the HIV-positive and HIV-negative groups even after adjustment in multivariate logistic regression (<?0.001).ConclusionsThe results of the present study suggest that high dietary salt intake raises blood pressure and worsens nocturnal BP dipping to a greater extent in hypertensive than normotensive individuals and that hypertensive individuals have higher dietary salt intake than their normotensive counterparts. Regarding HIV status, BP of HIV-positive hypertensive patients may be more sensitive to salt intake and demonstrate more non-dipping pattern compared to HIV-negative hypertensive group. However, further studies with a larger sample size are required to validate this.
| S-EPMC7809779 | biostudies-literature
Project description:Anal cancer used to be a rare cancer traditionally associated with elderly women. There are approximately 5260 cases per year in the U.S. (1). The onslaught of the Human Immunodeficiency Virus (HIV) virus has led to a change in anal cancer demographics. Anal cancer is on the rise in the U.S and the number of anal cases documented has quadrupled in the past 20 yrs correlating with the rise of the HIV epidemic. The incidence of anal cancer is 40 to 80 fold higher in the HIV positive (HIV+) population when compared to the general population (2). With the advent of highly active antiretroviral therapy (HAART), HIV+ patients are living longer as less are progressing to AIDS. As a consequence non AIDS defining cancers such as anal cancer are on the rise. Factors implicated in the etiology of anal cancer in HIV+ patients include (Human papillomavirus) HPV virus status, sexual habits, and a history of smoking. HPV 16 and receptive anal intercourse (RAI) increase the risk of anal cancer by 33% over the general population. In the general population, the rate of anal cancer is approximately 0.9 cases per 100,000. In patients with a history of RAI, the rate approaches 35 cases per 100,000 which is equivalent to the prevalence of cervical cancer (3). Smokers are eight times more likely to develop anal cancer. There has been much discussion about tailoring treatment decisions in HIV+ patients with anal cancer. This review focuses on squamous cell carcinomas of the anal canal which comprise 80 to 90% of all anal cancers diagnosed and highlight key issues in the management of HIV+ anal cancer patients including recent clinical trials.
| S-EPMC3397564 | biostudies-other