Comparison of immediate colposcopy, repeat conventional cytology and hrHPV testing for the clinical management of ASC-US cytology in routine health services of Medellin, Colombia: The ASCUS-COL Trial.

In the context of opportunistic cervical cancer screening settings of low-and-middle-income countries, little is known about the benefits of high-risk human papillomavirus (hrHPV) testing on high-grade cervical abnormality detection among women with atypical squamous cells of undetermined significance (ASC-US) cytology in routine clinical practice. We compared the effectiveness of immediate colposcopy (IC), conventional cytology at 6 and 12 months (colposcopy if ≥ASC-US) (RC), and hrHPV testing (colposcopy if hrHPV-positive) (HPV) to detect cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) among women aged 20-69 years with ASC-US in routine care. Participants (n=2,661) were evenly randomized into three arms (n=882 IC, n=890 RC, n=889 HPV) to receive services by routine healthcare providers and invited to an exit visit 24 months after recruitment. Histopathology was blindly reviewed by a quality-control external panel (QC). The primary endpoint was the first QC-diagnosed CIN2+ or CIN3+ detected during three periods: enrolment (≤6 months for IC and HPV, ≤12 months for RC), follow-up (between enrolment and exit visit), and exit visit. The trial is completed. Colposcopy was done on 88%, 42%, and 52% of participants in IC, RC, and HPV. Overall, 212 CIN2+ and 52 CIN3+ cases were diagnosed. No differences were observed for CIN2+ detection (p=0.821). However, compared to IC, only HPV significantly reduced CIN3+ cases that providers were unable to detect during the 2-year routine follow-up (relative proportion 0.35, 95% CI 0.09-0.87). In this context, hrHPV testing was the most effective and efficient management strategy for women with ASC-US cytology.

Health-related quality of life of women after HPV testing as triage strategy for an abnormal Pap smear: a nested randomized pragmatic trial in a middle-income country.

BACKGROUND: Information obtained in studies on the impact of human papilloma virus (HPV) testing on health-related quality of life is contradictory. OBJECTIVE: To assess the impact on health-related quality of life of the HPV test, colposcopy, and cytology as triage strategies after a cytology with atypical squamous cells of undetermined significance (ASCUS) in Medellín, Colombia. METHODS: We carried out a nested analysis on the randomized pragmatic trial (ASCUS-COL). Women with ASCUS were assigned randomly to one of the 3 arms (Pap smear, colposcopy, HPV). Participants completed a questionnaire at baseline, two weeks after receiving the results of the triage tests and one year after the second questionnaire. We used the SF-36 to assess health-related quality of life. RESULTS: The sum score of the physical health component (PHC) and mental health component (MHC) increased significantly over time for the whole sample and there were no statistically significant differences between arms of PHC = survey 1: mean 52.4 (SD 8.21) vs. survey 3: mean 54.4 (SD 8.16) p < 0.0001 and of MHC = survey 1: mean 44.9 (SD 11.72) vs. survey 3: mean 48.1 (SD 11.20) p < 0.0001. A lower MHC occurred in women with lesser schooling, belonging to the public health care regimen, higher number of live births, and separated. A lower PHC was associated with the cytology arm, higher age, lesser schooling, and belonging to the subsidized regime. The risk of having depression went from 42% in the first survey to 26% in the third. CONCLUSION: The triage strategies affected health-related quality of life in the same manner. ClinicalTrials.gov Identifier: NCT02067468.

Time trends of human papillomavirus types in invasive cervical cancer, from 1940 to 2007.

Contribution over time of human papillomavirus (HPV) types in human cancers has been poorly documented. Such data is fundamental to measure current HPV vaccines impact in the years to come. We estimated the HPV type-specific distribution in a large international series of invasive cervical cancer (ICC) over 70 years prior to vaccination. Paraffin embedded ICC cases diagnosed between 1940 and 2007 were retrieved from eleven countries in Central-South America, Asia and Europe. Included countries reported to have low-medium cervical cancer screening uptake. Information on age at and year of diagnosis was collected from medical records. After histological confirmation, HPV DNA detection was performed by SPF-10/DEIA/LiPA25 (version1). Logistic regression models were used for estimating the adjusted relative contributions (RC) of HPV16 and of HPV18 over time. Among 4,771 HPV DNA positive ICC cases, HPV16 and HPV18 were the two most common HPVs in all the decades with no statistically significant variations of their adjusted-RC from 1940-59 to 2000-07 (HPV16-from 61.5 to 62.1%, and HPV18-from 6.9 to 7.2%). As well, the RC of other HPV types did not varied over time. In the stratified analysis by histology, HPV16 adjusted-RC significantly increased across decades in adenocarcinomas. Regarding age, cases associated to either HPV16, 18 or 45 were younger than those with other HPV types in all the evaluated decades. The observed stability on the HPV type distribution predicts a high and stable impact of HPV vaccination in reducing the cervical cancer burden in future vaccinated generations.

Immunosuppression in cervical cancer with special reference to arginase activity.

INTRODUCTION: Cervical cancer is characterized by an immunosuppressive microenvironment and a Th2-type cytokine profile. Expression of arginase (ASE), the enzyme that converts L-arginine into L-ornithine and urea, is stimulated by Th2-type cytokines. OBJECTIVE: To assess the association of ASE activity and L-Arg metabolism products with cervical cancer. METHODS: Sera of 87 and 41 women with histologically confirmed by colposcopy-directed biopsy SCC and CIN3 respectively and 79 with normal cytology or Low-Grade Squamous Intraepithelial Lesion (LSIL), were evaluated. Cytokines were measured using Milliplex Human cytokine/chemokine kit. Arginase (ASE) activity was determined using an enzymatic assay. Levels of L-arginine, L-ornithine, putrescine and spermine were determined by HPLC. RESULTS: Significantly higher levels of ASE activity were observed in women with CIN3 (age-adjusted OR: 24.3; 95%CI: 3.82-155) and SCC (AOR: 9.8; 95%CI: 2.34-40.8). As expected, possibly due to high levels of ASE activity, higher levels of l-Arg were negatively associated with CIN3 (AOR: 0.03; 95%CI: 0.004-0.19) and SSC (AOR: 0.06; 95%CI: 0.02-0.24). Consistent with the role of ASE in the conversion of L-arginine to L-ornithine and polyamine production therefrom, women with cervical cancer had higher levels of spermine and putrescine. A correlation analysis revealed a significant albeit weak relationship between high levels of IL-10 and high levels of ASE (Pearson r=0.32, p-value=0.003) in women with cervical cancer. CONCLUSION: This study indicates that ASE activity and L-Arg degradation mechanisms of immunosuppression are present in cervical cancer. The results foster research in the design of possible strategies to inhibit ASE activity for therapy of cervical cancer.

Systematic under-ascertainment of anaplastic large cell lymphoma cases in cancer registries: report from a comprehensive cancer center.

INTRODUCTION: Breast implant-associated anaplastic large cell lymphoma (ALCL) has been rapidly rising in the US and around the world, leading to a mandated "black-box" label on all silicone- and saline-filled implants by the Food and Drug Administration (FDA). Because regulatory decisions in the US and around the world have been influenced primarily by risk estimates derived from cancer registries, it is important to determine their validity in identifying cases of ALCL. METHOD: We reviewed all cases of ALCL submitted to the New York State Cancer Registry from a large comprehensive cancer center in New York City from 2007 to 2019. To determine the possibility of misdiagnosis or under-diagnosis of ALCL cases reported to cancer registries, we accessed the sensitivity and specificity of the ICD-O-3 codes 9714 (ALCL) and 9702 (Mature T-cell lymphoma, not otherwise specified [T-NOS]) to identify pathologically-proven ALCL. RESULTS: We reviewed 2286,164 pathology reports from 47,466 unique patients with primary cancers. Twenty-eight cases of histologically-proven ALCL were identified. The sensitivity and specificity of the ICD-O-3 code 9714 (ALCL) were 82% and 100%, respectively. The sensitivity of the combined codes 9714/9702 (ALCL/T-NOS) was 96% and the specificity was 44%. CONCLUSION: Previous epidemiological studies that influenced regulatory decisions by the FDA may have systematically underestimated the risk of ALCL by at least 20%. We encourage updated global risk estimates of breast ALCL using methods that ensure adequate case ascertainment.

Clinical characteristics and HPV type in recurrent respiratory papillomatosis in Colombia.

OBJECTIVE: Describe factors associated with aggressive forms of recurrent respiratory papillomatosis (RRP). MATERIALS AND METHODS: One hundred eighty-nine RRP cases diagnosed between 1985 and 2009 were identified in pathological records. HPV was detected by the SPF-10 method with broad spectrum primers, (version 1). RESULTS: 113 patients had only one surgery (less aggressive) and 76, two or more interventions (more aggressive). The likelihood of aggressive lesions decreased with increasing age at diagnosis and HPV-11 was associated with no significant increase in the risk of aggressiveness. CONCLUSIONS: The age at diagnosis was the main determinant of RRP aggressiveness.

miRNAs signature as potential biomarkers for cervical precancerous lesions in human papillomavirus positive women.

Biomarkers to identify women at risk of cervical cancer among those with high-risk HPV infection (hrHPV+) are needed. Deregulated expression of microRNAs (miRNAs) contributes to hrHPV-induced cervical carcinogenesis. We aimed at identifying miRNAs with the capacity to distinguish high (CIN2+) and low (≤ CIN1) grade cervical lesions. We sequenced miRNA libraries from Formalin-Fixed Paraffin-Embedded (FFPE) tissues from women with CIN2+ (n = 10) and age-matched women with ≤ CIN1 (n = 10), randomly and retrospectively selected from a trial that followed women for 24 months after a hrHPV+ test at the screening visit. Five miRNAs differentially expressed were validated by RT-qPCR in an independent set of FFPE tissues with a reviewed diagnosis of CIN2+ (n = 105) and ≤ CIN1 (n = 105). The Ingenuity Pathway Analysis (IPA) was conducted to identify mRNAs inversely correlated with the top 25 differentially expressed miRNAs. Inverse correlations with 401 unique mRNA targets were identified for fourteen of the top 25 differentially expressed miRNAs. Eleven of these miRNAs targeted 26 proteins of pathways deregulated by HPV E6 and E7 oncoproteins and two of them, miR-143-5p and miR-29a-3p, predicted CIN2+ and CIN3+ in the independent validation by RT-qPCR of FFPE tissues from hrHPV-positive women.

Age-specific seroprevalence of human papillomavirus 16, 18, 31, and 58 in women of a rural town of Colombia.

OBJECTIVE: The study's objective was to estimate human papillomavirus (HPV) genotype-specific seroprevalence to determine population HPV exposure and inform vaccine policy. METHODS: This study is a cross-sectional prevalence survey of 878 women of Pueblorrico, a rural town of Colombia. A standardized questionnaire was used to obtain information on demographic characteristics, sexual and reproductive history, and smoking habits. Seropositivity to HPV-16, -18, -31, and -58 was determined by virus-like particles in an enzyme-linked immunosorbent assay. RESULTS: Overall seropositivity to any HPV genotype was 27.9%. The combined seroprevalence of women 15 to 19 and 20 to 24 years old was 35.4% (95% confidence interval [CI], 25.9-46.2) and 36.0% (95% CI, 27.7-45.3), respectively. Seroprevalence for HPV-16 was 17% (95% CI, 14.6-19.6); for HPV-18, 9.8% (95% CI, 8.0-11.9); for HPV-31, 11.4% (95% CI, 9.5-13.7); and for HPV 58, 12.5% (95% CI, 10.5-14.9). Higher HPV seropositivity was associated with the lifetime number of occasional sexual partners (odds ratio, 3.05; 95% CI, 1.26-7.37) and having more than 2 regular sexual partners (odds ratio, 3.00; 95% CI, 1.21-7.45) in women younger than 44 and older than 45 years old, respectively. Use of oral contraceptives and tobacco/cigarettes was significantly associated with reduced HPV seropositivity in women older than 45 but not in women younger than 44 years old. CONCLUSIONS: Human papillomavirus seropositivity is associated with measures of sexual behavior, particularly a greater lifetime number of sexual partners. Hormonal and tobacco/cigarette use may be factors influencing the HPV seropositivity in women older than 45 years old.

Higher micronutrient intake is associated with human papillomavirus-positive head and neck cancer: a case-only analysis.

No studies have investigated dietary differences between head and neck squamous cell carcinoma (HNSCC) patients with human papillomavirus (HPV)-positive tumors and patients with HPV-negative tumors. This study was designed to investigate the relationship between diet and HPV status in HNSCC patients. Cases of HNSCC were recruited from 2 clinical centers participating in the University of Michigan Head and Neck Specialized Program of Research Excellence (SPORE). HPV tissue genotyping was performed, and epidemiological and dietary data collected. Multivariable logistic regression tested whether pretreatment consumption of 12 selected micronutrients was significantly associated with HPV-positive status in 143 patients newly diagnosed with cancer of the oral cavity or pharynx. After controlling for age, sex, body mass index, tumor site, cancer stage, problem drinking, smoking, and energy intake, significant and positive associations were observed between vitamin A, vitamin E, iron, ß-carotene, and folate intake and HPV-positive status (P(trend) < 0.05), suggesting that diet may be a factor in the improved prognosis documented in those with HPV-positive HNSCC. Dietary differences by HPV status should be considered in prognostic studies to better understand the influence of diet on HNSCC survival.

[Trends and social indicators of both mortality breast cancer and cervical cancer in Antioquia, Colombia, 2000-2007]. / Tendencias e indicadores sociales de la mortalidad por cáncer de mama y cuello uterino: Antioquia, Colombia, 2000-2007.

OBJECTIVE: To estimate the mortality age-standardized rates (ASR) for breast and cervical cancer from 2000-2007 and explore social indicators that explain the variability of rates in Antioquia. MATERIAL AND METHODS: The ASR was estimated by the direct method and linear regression was used to relate social indicators with rates by subregion. RESULTS: Breast and cervical cancer mortality ASRs in Antioquia were 11.3 and 9.1 per 100 000 woman-years respectively. In Medellin, the breast cancer mortality ASR was 12.5, 1.8 times the rate of cervical cancer. A decrease of cervical cancer ASR between 2000 and 2007 was observed in Medellin (p-value=0.03) but not in the rest of Antioquia. Cervical cancer mortality ASR was related to the percentage of poverty (p-value=0.0003). CONCLUSIONS: Mortality due to these neoplasms has remained constant in Antioquia. The wide variation in mortality from cervical cancer between regions seems to be associated with poverty.