RESUMO
Despite being highly preventable, cervical cancer is the fourth most common cancer and cause of cancer death in women globally. In low-income countries, cervical cancer is often the leading cause of cancer-related morbidity and mortality. Women living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome are at a particularly high risk of cervical cancer because of an impaired immune response to human papillomavirus, the obligate cause of virtually all cervical cancers. Globally, approximately 1 in 20 cervical cancers is attributable to HIV; in sub-Saharan Africa, approximately 1 in 5 cervical cancers is due to HIV. Here, the authors provide a critical appraisal of the evidence to date on the impact of HIV disease on cervical cancer risk, describe key methodologic issues, and frame the key outstanding research questions, especially as they apply to ongoing global efforts for prevention and control of cervical cancer. Expanded efforts to integrate HIV care with cervical cancer prevention and control, and vice versa, could assist the global effort to eliminate cervical cancer as a public health problem.
Assuntos
Infecções por HIV/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/prevenção & controle , Detecção Precoce de Câncer , Feminino , Humanos , Hospedeiro Imunocomprometido , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Lesões Pré-Cancerosas/terapia , Prevenção Primária , Prevenção SecundáriaRESUMO
BACKGROUND: The incidence of anal cancer is substantially higher among persons living with the human immunodeficiency virus (HIV) than in the general population. Similar to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer; however, data from prospective studies of treatment for anal HSIL to prevent anal cancer are lacking. METHODS: We conducted a phase 3 trial at 25 U.S. sites. Persons living with HIV who were 35 years of age or older and who had biopsy-proven anal HSIL were randomly assigned, in a 1:1 ratio, to receive either HSIL treatment or active monitoring without treatment. Treatment included office-based ablative procedures, ablation or excision under anesthesia, or the administration of topical fluorouracil or imiquimod. The primary outcome was progression to anal cancer in a time-to-event analysis. Participants in the treatment group were treated until HSIL was completely resolved. All the participants underwent high-resolution anoscopy at least every 6 months; biopsy was also performed for suspected ongoing HSIL in the treatment group, annually in the active-monitoring group, or any time there was concern for cancer. RESULTS: Of 4459 participants who underwent randomization, 4446 (99.7%) were included in the analysis of the time to progression to cancer. With a median follow-up of 25.8 months, 9 cases were diagnosed in the treatment group (173 per 100,000 person-years; 95% confidence interval [CI], 90 to 332) and 21 cases in the active-monitoring group (402 per 100,000 person-years; 95% CI, 262 to 616). The rate of progression to anal cancer was lower in the treatment group than in the active-monitoring group by 57% (95% CI, 6 to 80; P = 0.03 by log-rank test). CONCLUSIONS: Among participants with biopsy-proven anal HSIL, the risk of anal cancer was significantly lower with treatment for anal HSIL than with active monitoring. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02135419.).
Assuntos
Neoplasias do Ânus , Infecções por HIV , Lesões Pré-Cancerosas , Lesões Intraepiteliais Escamosas , Conduta Expectante , Adulto , Neoplasias do Ânus/etiologia , Neoplasias do Ânus/patologia , Neoplasias do Ânus/prevenção & controle , Neoplasias do Ânus/terapia , Biópsia , Feminino , Infecções por HIV/complicações , Homossexualidade Masculina , Humanos , Masculino , Infecções por Papillomavirus/complicações , Lesões Pré-Cancerosas/etiologia , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/terapia , Estudos Prospectivos , Lesões Intraepiteliais Escamosas/etiologia , Lesões Intraepiteliais Escamosas/patologia , Lesões Intraepiteliais Escamosas/terapiaRESUMO
BACKGROUND: Detection and treatment of anal histologic high-grade squamous intraepithelial lesions (hHSIL) prevents anal cancer. However, anal hHSIL incidence among women with human immunodeficiency virus (HIV, WHIV) remains unknown. Performance of anal high-risk human papillomavirus ([hr]HPV), anal cytology (anal-cyt), and both for hHSIL detection longitudinally over 2 years also remains undetermined. METHODS: We determined 2-year incidence and cumulative risk estimates (2-y-CR) of anal hHSIL among WHIV using prevalence and incidence (per 100 person-years [py]) observations stratified by baseline hrHPV and/or anal-cyt results. RESULTS: In total, 229 WHIV with complete baseline data were included in the analysis; 114 women without prevalent anal hHSIL were followed with 2 annual evaluations. Median age was 51, 63% were Black, and 23% were Hispanic. Anal hrHPV or abnormal anal-cyt was associated with an increased risk of incident anal hHSIL at 2 years (18.9/100py [95% confidence interval {CI} 11.4-31.3] and 13.4/100py [95% CI 8.0-22.7], respectively) compared with no detection of anal HPV or negative cytology (2.8/100py [95% CI 1.1-7.4] and 4.2 [95% CI, 1.8-10.2]) The presence of anal hrHPV with abnormal cytology was associated with 2-y-CR of anal hHSIL of 65.6% (95% CI 55.4%-75%); negative hrHPV with negative cytology was associated with 2-y-CR of anal hHSIL of 9.2% (95% CI 7.0-16.0). CONCLUSIONS: Detection of anal hrHPV or abnormal anal cytology are comparable predictors for 2-y-CR of anal hHSIL. The absence of anal hrHPV combined with negative cytology was predictive of a lower (but measurable) risk of developing anal hHSIL. These findings provide important data to inform anal cancer screening guidelines for WHIV.
Assuntos
Neoplasias do Ânus , Infecções por HIV , Infecções por Papillomavirus , Lesões Intraepiteliais Escamosas , Humanos , Feminino , Pessoa de Meia-Idade , HIV , Incidência , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Neoplasias do Ânus/diagnóstico , Lesões Intraepiteliais Escamosas/epidemiologia , Papillomaviridae/genéticaRESUMO
BACKGROUND: Although immunotherapy has emerged as a therapeutic strategy for many cancers, there are limited studies establishing the safety and efficacy in people living with HIV (PLWH) and cancer. METHODS: PLWH and solid tumors or Kaposi sarcoma (KS) receiving antiretroviral therapy and a suppressed HIV viral load received nivolumab at 3 mg/kg every 2 weeks, in two dose deescalation cohorts stratified by CD4 count (stratum 1: CD4 count > 200/µL and stratum 2: CD4 count 100-199/µL). An expansion cohort of 24 participants with a CD4 count > 200/µL was then enrolled. RESULTS: A total of 36 PLWH received nivolumab, including 15 with KS and 21 with a variety of other solid tumors. None of the first 12 participants had dose-limiting toxicity in both CD4 strata, and five patients (14%) overall had grade 3 or higher immune related adverse events. Objective partial response occurred in nine PLWH and cancer (25%), including in six of 15 with KS (40%; 95% CI, 16.3-64.7). The median duration of response was 9.0 months overall and 12.5 months in KS. Responses were observed regardless of PDL1 expression. There were no significant changes in CD4 count or HIV viral load. CONCLUSIONS: Nivolumab has a safety profile in PLWH similar to HIV-negative subjects with cancer, and also efficacy in KS. Plasma HIV remained suppressed and CD4 counts remained stable during treatment and antiretroviral therapy, indicating no adverse impact on immune function. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02408861.
Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Sarcoma de Kaposi , Humanos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Nivolumabe/efeitos adversos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Sarcoma de Kaposi/tratamento farmacológico , Contagem de Linfócito CD4 , Carga ViralRESUMO
ABSTRACT: This Research Letter summarizes all updates to the 2019 Guidelines through September 2023, including: endorsement of the 2021 Opportunistic Infections guidelines for HIV+ or immunosuppressed patients; clarification of use of human papillomavirus testing alone for patients undergoing observation for cervical intraepithelial neoplasia 2; revision of unsatisfactory cytology management; clarification that 2012 guidelines should be followed for patients aged 25 years and older screened with cytology only; management of patients for whom colposcopy was recommended but not completed; clarification that after treatment for cervical intraepithelial neoplasia 2+, 3 negative human papillomavirus tests or cotests at 6, 18, and 30 months are recommended before the patient can return to a 3-year testing interval; and clarification of postcolposcopy management of minimally abnormal results.
Assuntos
Infecções por Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Feminino , Gravidez , Humanos , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/terapia , Consenso , Gestão de Riscos , Colposcopia , Esfregaço Vaginal , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , PapillomaviridaeRESUMO
PURPOSE: Belize has among the highest cervical cancer incidence and mortality rates of Latin American and Caribbean countries. This study evaluates the perspectives of key stakeholders for cervical cancer screening in Belize and identifies the barriers and facilitators for providing equitable access to prevention services. METHODS: Semi-structured interviews discussing cervical cancer screening were conducted with key stakeholders across the six districts of Belize in 2018. Interviews were transcribed, coded, and analyzed thematically; themes were organized by levels of the social-ecological model. RESULTS: We conducted 47 interviews with health care providers (45%), administrators (17%), government officials (25%), and other stakeholders (13%). Majority (78%) of interviews were from the public sector. Perceived barriers to cervical cancer screening were identified across multiple levels: (1) Individual Patient: potential delays in Pap smear results and fear of a cancer diagnosis; (2) Provider: competing clinician responsibilities; (3) Organizational: insufficient space and training; (4) Community: reduced accessibility in rural areas; and (5) Policy: equipment and staffing budget limitations. The main facilitators we identified included the following: (1) at the Community level: resource-sharing between public and private sectors and dedicated rural outreach personnel; (2) at the Policy level: free public screening services and the establishment of population-based screening. CONCLUSION: Despite free, publicly available cervical cancer screening in Belize, complex barriers affect access and completion of management when abnormal screening tests are identified. Provider workload, education outreach, and additional funding for training and facilities are potential areas for strengthening this program and increasing detection and management for cervical cancer control.
Assuntos
Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/prevenção & controle , Neoplasias do Colo do Útero/epidemiologia , Detecção Precoce de Câncer , Belize , Pesquisa Qualitativa , Acessibilidade aos Serviços de Saúde , Programas de Rastreamento/métodosRESUMO
PURPOSE: To determine whether treatment of anal high-grade squamous intraepithelial lesions (HSIL), vs active monitoring, is effective in reducing incidence of anal cancer in persons living with HIV, the US National Cancer Institute funded the Phase III ANal Cancer/HSIL Outcomes Research (ANCHOR) clinical trial. As no established patient-reported outcomes (PRO) tool exists for persons with anal HSIL, we sought to estimate the construct validity and responsiveness of the ANCHOR Health-Related Symptom Index (A-HRSI). METHODS: The construct validity phase enrolled ANCHOR participants who were within two weeks of randomization to complete A-HRSI and legacy PRO questionnaires at a single time point. The responsiveness phase enrolled a separate cohort of ANCHOR participants who were not yet randomized to complete A-HRSI at three time points: prior to randomization (T1), 14-70 (T2), and 71-112 (T3) days following randomization. RESULTS: Confirmatory factor analysis techniques established a three-factor model (i.e., physical symptoms, impact on physical functioning, impact on psychological functioning), with moderate evidence of convergent validity and strong evidence of discriminant validity in the construct validity phase (n = 303). We observed a significant moderate effect for changes in A-HRSI impact on physical functioning (standardized response mean = 0.52) and psychological symptoms (standardized response mean = 0.60) from T2 (n = 86) to T3 (n = 92), providing evidence of responsiveness. CONCLUSION: A-HRSI is a brief PRO index that captures health-related symptoms and impacts related to anal HSIL. This instrument may have broad applicability in other contexts assessing individuals with anal HSIL, which may ultimately help improve clinical care and assist providers and patients with medical decision-making.
Assuntos
Neoplasias do Ânus , Infecções por HIV , Lesões Intraepiteliais Escamosas , Humanos , Qualidade de Vida/psicologia , Lesões Intraepiteliais Escamosas/diagnóstico , Lesões Intraepiteliais Escamosas/patologia , Canal Anal , Inquéritos e Questionários , Neoplasias do Ânus/patologia , Infecções por HIV/patologiaRESUMO
Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch family genes and proteins and to investigate the therapeutic effect of γ-secretase inhibitors (GSIs), indirect inhibitors of Notch signaling, in uLMS. We determined expression of Notch genes and proteins in benign uterine smooth muscle tissue, fibroids, and uLMS samples by immunostaining and in two uLMS cell lines, SK-UT-1B (uterine primary) and SK-LMS-1 (vulvar metastasis) by RT-PCR, Western blot and immunostaining. We exposed our cell lines to GSIs, DAPT and MK-0752, and measured expression of HES1, a downstream effector of Notch. Notch proteins were differentially expressed in uLMS. Expression of NOTCH3 and NOTCH4 was higher in uLMS samples than in benign uterine smooth muscle and fibroids. Expression of NOTCH4 was higher in SK-LMS-1 compared to SK-UT-1B. Exposure of SK-UT-1B and SK-LMS-1 to DAPT and MK-0752 decreased expression of HES1 and decreased uLMS cell viability in a dose- and time-dependent manner that was unique to each GSI. Our findings suggest that GSIs are potential therapeutics for uLMS, albeit with limited efficacy.
Assuntos
Leiomioma , Leiomiossarcoma , Neoplasias Pélvicas , Neoplasias Uterinas , Feminino , Inibidores e Moduladores de Secretases gama , Humanos , Leiomiossarcoma/tratamento farmacológico , Leiomiossarcoma/genética , Leiomiossarcoma/metabolismo , Inibidores da Agregação Plaquetária/uso terapêutico , Receptores Notch , Transdução de Sinais , Neoplasias Uterinas/patologiaRESUMO
BACKGROUND: Antibodies to programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) may perturb human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) by reversing HIV latency and/or boosting HIV-specific immunity, leading to clearance of infected cells. We tested this hypothesis in a clinical trial of anti-PD-1 alone or in combination with anti-CTLA-4 in people living with HIV (PLWH) and cancer. METHODS: This was a substudy of the AIDS Malignancy Consortium 095 Study. ART-suppressed PLWH with advanced malignancies were assigned to nivolumab (anti-PD-1) with or without ipilimumab (anti-CTLA-4). In samples obtained preinfusion and 1 and 7 days after the first and fourth doses of immune checkpoint blockade (ICB), we quantified cell-associated unspliced (CA-US) HIV RNA and HIV DNA. Plasma HIV RNA was quantified during the first treatment cycle. Quantitative viral outgrowth assay (QVOA) to estimate the frequency of replication-competent HIV was performed before and after ICB for participants with samples available. RESULTS: Of 40 participants, 33 received nivolumab and 7 nivolumab plus ipilimumab. Whereas CA-US HIV RNA did not change with nivolumab monotherapy, we detected a median 1.44-fold increase (interquartile range, 1.16-1.89) after the first dose of nivolumab and ipilimumab combination therapy (P = .031). There was no decrease in the frequency of cells containing replication-competent HIV, but in the 2 individuals on combination ICB for whom we had longitudinal QVOA, we detected decreases of 97% and 64% compared to baseline. CONCLUSIONS: Anti-PD-1 alone showed no effect on HIV latency or the latent HIV reservoir, but the combination of anti-PD-1 and anti-CTL-4 induced a modest increase in CA-US HIV RNA and may potentially eliminate cells containing replication-competent HIV. CLINICAL TRIALS REGISTRATION: NCT02408861.
Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , HIV-1 , Neoplasias , Antígeno CTLA-4 , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Receptor de Morte Celular Programada 1 , Latência ViralRESUMO
BACKGROUND: Primary human papillomavirus (HPV) screening (PHS) utilizes oncogenic human papillomavirus (oncHPV) testing as the initial cervical cancer screening method and typically, if positive, additional reflex-triage (eg, HPV16/18-genotyping, Pap testing). While US guidelines support PHS usage in the general population, PHS has been little studied in women living with HIV (WLWH). METHODS: We enrolled n = 865 WLWH (323 from the Women's Interagency HIV Study [WIHS] and 542 from WIHS-affiliated colposcopy clinics). All participants underwent Pap and oncHPV testing, including HPV16/18-genotyping. WIHS WLWH who tested oncHPV[+] or had cytologic atypical squamous cells of undetermined significance or worse (ASC-US+) underwent colposcopy, as did a random 21% of WLWH who were oncHPV[-]/Pap[-] (controls). Most participants additionally underwent p16/Ki-67 immunocytochemistry. RESULTS: Mean age was 46 years, median CD4 was 592 cells/µL, 95% used antiretroviral therapy. Seventy WLWH had histologically-determined cervical intraepithelial neoplasia grade 2 or greater (CIN-2+), of which 33 were defined as precancer (ie, [i] CIN-3+ or [ii] CIN-2 if concurrent with cytologic high grade squamous intraepithelial lesions [HSILs]). PHS had 87% sensitivity (Se) for precancer, 9% positive predictive value (PPV), and a 35% colposcopy referral rate (Colpo). "PHS with reflex HPV16/18-genotyping and Pap testing" had 84% Se, 16% PPV, 30% Colpo. PHS with only HPV16/18-genotyping had 24% Colpo. "Concurrent oncHPV and Pap Testing" (Co-Testing) had 91% Se, 12% PPV, 40% Colpo. p16/Ki-67 immunochemistry had the highest PPV, 20%, but 13% specimen inadequacy. CONCLUSIONS: PHS with reflex HPV16/18-genotyping had fewer unnecessary colposcopies and (if confirmed) could be a potential alternative to Co-Testing in WLWH.
Assuntos
Alphapapillomavirus , Infecções por HIV , Infecções por Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Detecção Precoce de Câncer , Feminino , HIV , Infecções por HIV/diagnóstico , Papillomavirus Humano 16/genética , Papillomavirus Humano 18 , Humanos , Programas de Rastreamento , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Gravidez , Neoplasias do Colo do Útero/diagnóstico , Esfregaço VaginalRESUMO
ABSTRACT: The American Cancer Society (ACS) released updated cervical cancer screening guidelines in 2020 that endorse a shift in practice to primary human papillomavirus (HPV) screening in people with a cervix, beginning at ages of 25-65 years. When access to US Food and Drug Administration-approved primary HPV testing is not available, the ACS offers cotesting or cytology as acceptable alternative strategies but suggests that these testing modalities may be excluded from future iterations of the guidelines. The ASCCP recognizes the benefits and risks of primary HPV cervical cancer screening while acknowledging the barriers to widespread adoption, including implementation issues, the impact of limited HPV vaccination in the United States, and inclusion of populations who may not be well represented on primary HPV screening trials, such as underrepresented minorities. The ASCCP endorses the 2018 US Preventive Services Task Force Recommendation Statement and supports the ACS cervical cancer screening guidelines. Most importantly, the ASCCP endorses any cervical cancer screening for secondary prevention of cervical cancer and recommends interventions that improve screening for those who are underscreened or unscreened.
Assuntos
Guias como Assunto , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Idoso , American Cancer Society , Feminino , Humanos , Pessoa de Meia-Idade , Papillomaviridae , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus , Estados Unidos , Neoplasias do Colo do Útero/virologia , Esfregaço VaginalRESUMO
Cervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV-negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR-E6-E7-E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B-cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flanking BCL11B DNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70-BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novel BCL11B variants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV-associated tumorigenesis.
Assuntos
Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Neoplasias do Colo do Útero/genética , Sequência de Bases , Carcinogênese/genética , Carcinogênese/metabolismo , DNA Viral/análise , Feminino , Genômica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pessoa de Meia-Idade , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/metabolismoRESUMO
BACKGROUND: Women living with human immunodeficiency virus (WLHIV) have disproportionately high rates of squamous cell carcinoma of the anus compared with the general population of women. Anal high-grade squamous intraepithelial lesions (HSILs) precede anal cancer, and accurate studies of HSIL prevalence among WLHIV in the United States are lacking. METHODS: The AIDS Malignancy Consortium 084 study was a multicenter national trial to evaluate the prevalence of and risk factors for anal HSIL in a US cohort. Eligible participants were WLHIV aged ≥18 years with no history of anal HSIL. Study participants had an examination including collection of cervical/vaginal and anal specimens, followed by high-resolution anoscopy with biopsy. RESULTS: We enrolled 256 women with evaluable anal pathology. The mean age was 49.4 years, 64% women were non-Hispanic black, 67% were former or current smokers, and 56% reported ever having anal sex with a man. The median CD4 T-cell count was 664 cells/µL. The prevalence of anal histologic HSIL (hHSIL) was 27% (95% confidence interval [CI], 22%-33%). There was a strong concordance (240/254) between local and consensus pathologists for hHSIL vs less than hHSIL (κ = 0.86 [95% CI, .79-.93]). Current CD4 count of ≤200 cells/µL was the strongest predictor of consensus anal hHSIL diagnosis (adjusted odds ratio [aOR], 10.34 [95% CI, 3.47-30.87]). History of anoreceptive intercourse was also associated with hHSIL (aOR, 2.44 [95% CI, 1.22-4.76]). CONCLUSIONS: The prevalence of anal hHSIL in WLHIV in the United States was 27% in this study where all participants received high-resolution anoscopy and biopsy.
Assuntos
Neoplasias do Ânus , Infecções por HIV , Infecções por Papillomavirus , Canal Anal , Neoplasias do Ânus/epidemiologia , Feminino , HIV , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Prevalência , Fatores de Risco , Lesões Intraepiteliais EscamosasRESUMO
We examined whether automated visual evaluation (AVE), a deep learning computer application for cervical cancer screening, can be used on cervix images taken by a contemporary smartphone camera. A large number of cervix images acquired by the commercial MobileODT EVA system were filtered for acceptable visual quality and then 7587 filtered images from 3221 women were annotated by a group of gynecologic oncologists (so the gold standard is an expert impression, not histopathology). We tested and analyzed on multiple random splits of the images using two deep learning, object detection networks. For all the receiver operating characteristics curves, the area under the curve values for the discrimination of the most likely precancer cases from least likely cases (most likely controls) were above 0.90. These results showed that AVE can classify cervix images with confidence scores that are strongly associated with expert evaluations of severity for the same images. The results on a small subset of images that have histopathologic diagnoses further supported the capability of AVE for predicting cervical precancer. We examined the associations of AVE severity score with gynecologic oncologist impression at all regions where we had a sufficient number of cases and controls, and the influence of a woman's age. The method was found generally resilient to regional variation in the appearance of the cervix. This work suggests that using AVE on smartphones could be a useful adjunct to health-worker visual assessment with acetic acid, a cervical cancer screening method commonly used in low- and middle-resource settings.
Assuntos
Colo do Útero/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Programas de Rastreamento/instrumentação , Smartphone/economia , Displasia do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/prevenção & controle , Biópsia , Colo do Útero/patologia , Conjuntos de Dados como Assunto , Aprendizado Profundo , Diagnóstico Diferencial , Feminino , Humanos , Programas de Rastreamento/economia , Programas de Rastreamento/métodos , Curva ROC , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/patologiaRESUMO
OBJECTIVE: For the 2019 ASCCP Risk-Based Management Consensus Guidelines, we conducted a systematic review of diagnostic assays for postcolposcopy and posttreatment management. MATERIALS AND METHODS: A literature search was conducted to identify articles reporting on tests/assays for cervical cancer screening, triage, postcolposcopy surveillance, and posttreatment surveillance published between 2012 and 2019 in PubMed and Embase. Titles and abstracts were evaluated by co-authors for inclusion. Included articles underwent full-text review, data abstraction, and quality assessment. Pooled absolute pretest and posttest risk estimates were calculated for studies evaluating management of patients after treatment. RESULTS: A total of 2,862 articles were identified through the search. Of 50 articles on postcolposcopy, 5 were included for data abstraction. Of 66 articles on posttreatment, 23 were included for data abstraction and were summarized in the meta-analysis. The pooled posttreatment risk of cervical intraepithelial neoplasia (CIN) 2+ in all studies was 4.8% (95% CI = 3.4%-6.8%), ranging from 0.4%-19.5% (τ = 0.57) in individual studies. Among individuals testing negative for human papillomavirus (HPV) posttreatment, the risk of CIN 2+ was 0.69% (95% CI = 0.3%-1.5%); among individuals testing positive for HPV posttreatment, the risk of CIN 2+ was 18.3% (95% CI = 12.1%-26.6%) in all studies. All risk estimates were substantially higher for liquid-based cytology. The HPV-cytology co-testing provided slightly better reassurance compared with HPV alone at the cost of much higher positivity. CONCLUSIONS: Despite a large number of published studies on postcolposcopy and posttreatment surveillance, only few met criteria for abstraction and were included in the meta-analysis. More high-quality studies are needed to evaluate assays and approaches that can improve management of patients with abnormal screening.
Assuntos
Papillomaviridae/isolamento & purificação , Medição de Risco/estatística & dados numéricos , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/epidemiologia , Colposcopia , Feminino , Humanos , Guias de Prática Clínica como Assunto , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Esfregaço VaginalRESUMO
OBJECTIVE: We adapted the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool for studies of cervical cancer screening and management and used the adapted tool to evaluate the quality of studies included in a systematic review supporting the 2019 Risk-Based Management Consensus Guidelines. METHODS: We evaluated the quality of all studies included in our systematic review for postcolposcopy (n = 5) and posttreatment (n = 23) surveillance using QUADAS-2 criteria. Subsequently, we adapted signaling questions to indications of cervical cancer screening and management. An iterative process was carried out to evaluate interrater agreement between 2 study authors (M.A.C. and N.W.). Discrepant ratings were discussed, and criteria were adapted accordingly. We also evaluated the influence of study quality on risk estimates and between study variation using stratified subgroup meta-analyses. RESULTS: Twelve signaling questions for bias assessment that were adapted to or newly developed for cervical cancer screening and management are described here. Interrater agreement on bias assessment increased from 70% to 83% during the adaptation process. Detailed assessment of bias and applicability showed that all studies on postcolposcopy management and 90% of studies on posttreatment management had high risk of bias in at least 1 domain. Most commonly, high risk of bias was observed for the patient selection domain, indicating the heterogeneity of study designs and clinical practice in reported studies. CONCLUSIONS: The adapted QUADAS-2 will have broad application for researchers, evidence evaluators, and journals who are interested in designing, conducting, evaluating, and publishing studies for cervical cancer screening and management.
Assuntos
Pesquisa/normas , Neoplasias do Colo do Útero/diagnóstico , Colposcopia , Detecção Precoce de Câncer , Feminino , HumanosRESUMO
BACKGROUND: While prophylactic human papillomavirus (HPV) vaccination exists, women are still developing cervical intraepithelial neoplasia (CIN) grade 2 or 3 for which an immunotherapeutic, non-surgical, approach may be effective. The primary aim was to assess the efficacy of tipapkinogen sovacivec (TS) vaccine in achieving histologic resolution of CIN2/3 associated with high risk (HR) HPV types. METHODS: Women 18â¯years and older who had confirmed CIN2/3 were enrolled in a randomized, double blind, placebo-controlled phase II trial and assigned to drug in a 2:1 ratio (vaccine:placebo). The primary endpoint occurred at month 6 when the excisional therapy was performed; cytology and HR HPV typing were performed at months 3, 6 and every six months through month 30. The safety population included all patients who received at least one dose of study drug. RESULTS: Of the 129 women randomized to vaccine and 63 to placebo, complete resolution was significantly higher in the vaccine group than placebo for CIN 2/3 regardless of the 13 HR HPV types assayed (24% vs. 10%, pâ¯<â¯0.05); as well as for only CIN 3 also regardless of HR HPV type (21% vs. 0%, pâ¯<â¯0.01). Irrespective of baseline HPV infection, viral DNA clearance was higher in the vaccine group compared to placebo (pâ¯<â¯0.01). The vaccine was well tolerated with the most common adverse events being injection site reactions. CONCLUSIONS: The TS vaccine provides histologic clearance of CIN 2/3 irrespective of HR HPV type in one third of subjects and is generally safe through 30â¯months.
Assuntos
Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/uso terapêutico , Displasia do Colo do Útero/terapia , Neoplasias do Colo do Útero/terapia , Adolescente , Adulto , Método Duplo-Cego , Feminino , Seguimentos , Genótipo , Humanos , Reação no Local da Injeção/etiologia , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Vacinas contra Papillomavirus/efeitos adversos , Estudos Prospectivos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Adulto Jovem , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/virologiaRESUMO
PURPOSE: To determine the feasibility, safety, and tolerability of concomitant chemoradiotherapy administered at standard doses in HIV-infected women with locally-advanced cervical cancer (LACC) receiving antiretroviral therapy (ART). PATIENTS AND METHODS: Eligible participants had HIV infection and untreated, histologically-confirmed, invasive carcinoma of the uterine cervix, FIGO stages IB2, IIA (if tumor >4â¯cm), IIB, IIIA, IIIB, or IVA and met standard eligibility criteria. Subjects were prescribed 41.4-45â¯Gy external beam radiation therapy followed by high dose rate brachytherapy concomitant with up to six weekly doses of cisplatin 40â¯mg/m2 and were followed for 12â¯months. RESULTS: Sixty-four women were screened at two sites in sub-Saharan Africa, of whom 40 eligible participants were enrolled, for a screening ratio of 1.60. Of the 38 eligible participants who initiated study treatment, 31 (82%) completed treatment. By the 12-month follow-up visit, 7 women had died of disease and 29 of 31 (94%) returned for follow-up. One-year progression-free survival was 76.3% (95% CI, 59.4-86.9%), and did not significantly differ according to stage at entry (pâ¯=â¯0.581). Participant-reported adherence to ART was high; by 12â¯months, 93% of participants had an undetectable viral load. The most common grade 3 or 4 adverse event was decreased lymphocyte count that affected all treated participants. Non-hematologic serious adverse events were similar to those observed in women with LACC without HIV infection. CONCLUSIONS: The majority of HIV-infected women with LACC can complete concomitant chemoradiotherapy with the same cisplatin dose used in HIV-uninfected women with comparable tolerability and high ART adherence while on treatment.
Assuntos
Cisplatino/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/virologia , Adulto , Antirretrovirais/uso terapêutico , Antineoplásicos/uso terapêutico , Quimiorradioterapia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Radiossensibilizantes/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/radioterapiaRESUMO
BACKGROUND: Anal cancer, caused by oncogenic types of human papillomavirus, is a growing problem in the United States. A key focus of anal cancer prevention has been screening for and treating precancerous high-grade squamous intraepithelial anal lesions (HSILs). OBJECTIVES: To develop a health-related symptom index for HSIL using qualitative techniques because anal HSIL and its treatment may have a negative impact on health-related quality of life (HRQOL), and no HRQOL measure specific to this condition and treatment currently exists. METHODS: Expert consultation was used to guide one-on-one concept elicitation interviews with participants to identify HRQOL aspects they attribute to their anal HSIL and its treatment. This resulted in a draft instrument, which was administered to an independent participant sample, where cognitive interview techniques assessed comprehension. RESULTS: Eighteen anal HSIL-related concepts were identified by the expert panel. Across the 41 concept elicitation interviews, 23 items representing physical symptoms, physical impacts, and psychological symptoms were identified to comprise the initial measure, which was then evaluated during three rounds of cognitive interviews (n = 45). Several questionnaire aspects were refined on the basis of participant input, with three additional items added per expert/participant recommendation. One item was removed because of poor comprehension, resulting in a 25-item measure. CONCLUSIONS: Using state-of-the-art qualitative methodology, we have established the content validity of this new instrument, the ANCHOR Anal HSIL Health-Related Symptom Index. Quantitative validation efforts are currently underway. The participant-driven process of developing this tool will facilitate a participant-centered evaluation of the impact on morbidity for treatment of anal HSIL or observation without treatment.
Assuntos
Neoplasias do Ânus/complicações , Psicometria/normas , Qualidade de Vida/psicologia , Lesões Intraepiteliais Escamosas Cervicais/psicologia , Adulto , Neoplasias do Ânus/psicologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria/instrumentação , Psicometria/métodos , Lesões Intraepiteliais Escamosas Cervicais/complicações , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: We prospectively evaluated patients with completely resected uterine serous carcinoma (USC) treated with radiation "sandwiched" between carboplatin/paclitaxel (C/T). The primary objective was to determine the safety profile, and the secondary outcome was to evaluate progression-free and overall survival. METHODS: Surgically staged patients with completely resected USC were enrolled to receive 3 cycles of paclitaxel 175 mg/m and carboplatin (area under the curve, 6-7.5) every 21 days, followed by radiotherapy and an additional 3 cycles of T/C at area under the curve of 5-6 (6 cycles + radiotherapy). Toxicity was graded according to National Cancer Institute Common Toxicity Criteria, version 4.03. Kaplan-Meier and log-rank tests were used to compare survival probabilities. RESULTS: One hundred forty patients were enrolled, of which 132 were evaluable, completed at least 3 cycles of chemotherapy and radiation. One hundred seven (81%) completed 6 cycles of chemotherapy and radiation. Patients with early-stage (I/II) disease have survival probabilities of 0.96 and 0.81 at 2 and 5 years. Patients with stage I USC and lymphovascular invasion have considerably worse overall survival, with 2.7 times' higher risk of death than those without lymphovascular invasion. Patients with late-stage (III/IV) disease had overall survival probabilities of 0.64 and 0.18 at 2 and 5 years, which is far higher survival than what has been reported in single-modality trials. Interestingly, and different than what is reported in other studies, there is no difference in survival in African Americans versus whites/other races who were evaluable. Of the 779 cycles administered, 22% and 14% of cycles were associated with grades 3 and 4 hematologic toxicities, respectively. Grades 3 and 4 nonhematologic toxicities occurred in 6.9% of cycles. CONCLUSIONS: The long-term follow-up in this study demonstrates that "sandwich" therapy is an efficacious, well-tolerated treatment approach with acceptable toxicities. Lymphovascular invasion (LVSI) is a significantly poor prognostic factor in stage I USC. Multimodal "sandwich" therapy should be considered in all USC patients who have undergone complete surgical resection and staging.