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1.
Lancet Oncol ; 22(4): 538-547, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33794207

RESUMEN

BACKGROUND: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. METHODS: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920. FINDINGS: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae. INTERPRETATION: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. FUNDING: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.


Asunto(s)
Braquiterapia/métodos , Imagen por Resonancia Magnética/métodos , Radioterapia Guiada por Imagen/métodos , Neoplasias del Cuello Uterino/radioterapia , Adulto , Anciano , Quimioradioterapia/métodos , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Calidad de Vida , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología
2.
Lancet Oncol ; 22(4): 548-557, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33794208

RESUMEN

BACKGROUND: Most uterine cervical high-risk human papillomavirus (HPV) infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies (GWASs) report associations between the HLA region and cervical cancer. Adopting a genome-wide approach, we aimed to compare genetic variation in women with invasive cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 with that in healthy controls. METHODS: We did a GWAS in a cohort of unrelated European individuals using data from UK Biobank, a population-based cohort including 273 377 women aged 40-69 years at recruitment between March 13, 2006, and Oct 1, 2010. We used an additive univariate logistic regression model to analyse genetic variants associated with invasive cervical cancer or CIN3. We sought replication of candidate associations in FinnGen, a large independent dataset of 128 123 individuals. We also did a two-sample mendelian randomisation approach to explore the role of risk factors in the genetic risk of cervical cancer. FINDINGS: We included 4769 CIN3 and invasive cervical cancer case samples and 145 545 control samples in the GWAS. Of 9 600 464 assayed and imputed single-nucleotide polymorphisms (SNPs), six independent variants were associated with CIN3 and invasive cervical cancer. These included novel loci rs10175462 (PAX8; odds ratio [OR] 0·87, 95% CI 0·84-0·91; p=1·07 × 10-9) and rs27069 (CLPTM1L; 0·88, 0·84-0·92; p=2·51 × 10-9), and previously reported signals at rs9272050 (HLA-DQA1; 1·27, 1·21-1·32; p=2·51 × 10-28), rs6938453 (MICA; 0·79, 0·75-0·83; p=1·97 × 10-17), rs55986091 (HLA-DQB1; 0·66, 0·60-0·72; p=6·42 × 10-28), and rs9266183 (HLA-B; 0·73, 0·64-0·83; p=1·53 × 10-6). Three SNPs were replicated in the independent Finnish dataset of 1648 invasive cervical cancer cases: PAX8 (rs10175462; p=0·015), CLPTM1L (rs27069; p=2·54 × 10-7), and HLA-DQA1 (rs9272050; p=7·90 × 10-8). Mendelian randomisation further supported the complementary role of smoking (OR 2·46, 95% CI 1·64-3·69), older age at first pregnancy (0·80, 0·68-0·95), and number of sexual partners (1·95, 1·44-2·63) in the risk of developing cervical cancer. INTERPRETATION: Our results provide new evidence for the genetic susceptibility to cervical cancer, specifically the PAX8, CLPTM1L, and HLA genes, suggesting disruption in apoptotic and immune function pathways. Future studies integrating host and viral, genetic, and epigenetic variation, could further elucidate complex host-viral interactions. FUNDING: NIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme.


Asunto(s)
Neoplasia Intraepitelial Cervical/genética , Proteínas de la Membrana/genética , Proteínas de Neoplasias/genética , Factor de Transcripción PAX8/genética , Neoplasias del Cuello Uterino/genética , Adulto , Anciano , Neoplasia Intraepitelial Cervical/patología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Antígenos HLA/genética , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Neoplasias del Cuello Uterino/patología
4.
BMC Infect Dis ; 21(1): 378, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33888090

RESUMEN

BACKGROUND: Sexually transmitted infections (STIs) such as Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and Syphilis have continued a significant public health problem, especially in areas with substandard infection prevention and control programs. It is known that STIs are largely associated with the increased occurrence of cervical cancer. To date, little is known about the burden of STIs among cervical cancer suspected women in Ethiopia. OBJECTIVES: To assess the seroprevalence of STIs and associated risk factors among cervical cancer suspected women with special emphasis on HIV, HBV, HCV, and Syphilis. METHODS: A hospital-based cross-sectional study was conducted among cervical cancer suspected women at the University of Gondar Comprehensive Specialized Hospital from February to April 2017. A pre-tested and structured questionnaire was used to collect data on patients' characteristics. The patient's serum or plasma samples were tested for HIV, HBV, HCV, and syphilis using enzyme-linked immunosorbent assay. In all aspects, the standard operational procedure was strictly followed. Data were analyzed using SPSS version 20 software and presented using tables. Statistical associations were measured using bivariate and multivariable logistic regression. A p-value of below 0.05 was considered statistically significant. RESULT: A total of 403 cervical cancer suspected women with the mean age of 42.54 (SD + 11. 24) years were enrolled in the study. The overall prevalence of STIs was 16.6% (67/403) and the prevalence of HIV, HBV, HCV, and syphilis was 36/403 (8.9%), 10/403 (2.5%), 4/403 (1%), and 29/403 (7.2%) respectively. History of multiple sexual partners (Adjusted OR = 3.02, 95%CI 1.57-5.79, P = 0.001), alcohol addiction (Adjusted OR = 2.2, 95%CI 1.07-4.5, P = 0.031), history of STI (Adjusted OR = 3.38; 95% CI: 1.76-6.47, P = 0.00) and not use of condom (Adjusted OR = 4.99; 95% CI: 1.5-16.16, P = 0.007) were significantly associated with STIs. CONCLUSION: The prevalence of STIs was generally higher among cervical cancer suspected patients. Health education is encouraged to promote awareness about the prevention of STIs.


Asunto(s)
Enfermedades de Transmisión Sexual/diagnóstico , Neoplasias del Cuello Uterino/patología , Adulto , Alcoholismo/complicaciones , Estudios Transversales , Etiopía/epidemiología , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Hepatitis B/diagnóstico , Hepatitis C/diagnóstico , Hepatitis C/epidemiología , Hospitales Especializados , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Prevalencia , Factores de Riesgo , Parejas Sexuales , Enfermedades de Transmisión Sexual/complicaciones , Enfermedades de Transmisión Sexual/epidemiología , Encuestas y Cuestionarios , Sífilis/diagnóstico , Sífilis/epidemiología
5.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652577

RESUMEN

Gene therapy research has advanced to clinical trials, but it is hampered by unstable nucleic acids packaged inside carriers and there is a lack of specificity towards targeted sites in the body. This study aims to address gene therapy limitations by encapsidating a plasmid synthesizing a short hairpin RNA (shRNA) that targets the anti-apoptotic Bcl-2 gene using truncated hepatitis B core antigen (tHBcAg) virus-like particle (VLP). A shRNA sequence targeting anti-apoptotic Bcl-2 was synthesized and cloned into the pSilencer 2.0-U6 vector. The recombinant plasmid, namely PshRNA, was encapsidated inside tHBcAg VLP and conjugated with folic acid (FA) to produce FA-tHBcAg-PshRNA VLP. Electron microscopy revealed that the FA-tHBcAg-PshRNA VLP has an icosahedral structure that is similar to the unmodified tHBcAg VLP. Delivery of FA-tHBcAg-PshRNA VLP into HeLa cells overexpressing the folate receptor significantly downregulated the expression of anti-apoptotic Bcl-2 at 48 and 72 h post-transfection. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay demonstrated that the cells' viability was significantly reduced from 89.46% at 24 h to 64.52% and 60.63%, respectively, at 48 and 72 h post-transfection. As a conclusion, tHBcAg VLP can be used as a carrier for a receptor-mediated targeted delivery of a therapeutic plasmid encoding shRNA for gene silencing in cancer cells.


Asunto(s)
Silenciador del Gen , Técnicas de Transferencia de Gen , Virus de la Hepatitis B , Plásmidos , Proteínas Proto-Oncogénicas c-bcl-2 , ARN Interferente Pequeño , Neoplasias del Cuello Uterino , Femenino , Células HeLa , Humanos , Plásmidos/genética , Plásmidos/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/genética , ARN Interferente Pequeño/biosíntesis , ARN Interferente Pequeño/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología
6.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670397

RESUMEN

Even though cervical cancer is partly preventable, it still poses a great public health problem throughout the world. Current therapies have vastly improved the clinical outcomes of cervical cancer patients, but progress in new systemic treatment modalities has been slow in the last years. Especially for patients with advanced disease this is discouraging, as their prognosis remains very poor. The pathogen-induced nature, the considerable mutational load, the involvement of genes regulating the immune response, and the high grade of immune infiltration, suggest that immunotherapy might be a promising strategy to treat cervical cancer. In this literature review, we focus on the use of PD-1 blocking therapy in cervical cancer, pembrolizumab in particular, as it is the only approved immunotherapy for this disease. We discuss why it has great clinical potential, how it opens doors for personalized treatment in cervical cancer, and which trials are aiming to expand its clinical use.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoterapia , Proteínas de Neoplasias/antagonistas & inhibidores , Recurrencia Local de Neoplasia/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias del Cuello Uterino/terapia , Femenino , Humanos , Metástasis de la Neoplasia , Proteínas de Neoplasias/inmunología , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patología
7.
Carbohydr Polym ; 260: 117793, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33712141

RESUMEN

The present study demonstrates the extrusion printing of highly viscous and thixotropic hydroxyethylcellulose-based bioinks blended with various concentrations of sodium alginate (SA) and embedded with HeLa cells. The cell viability is shown to be inversely proportional to the relative SA content and can be as high as 81.5 % following one day of incubation. Furthermore, the biocompatibility of the hydrogel matrix supports cell proliferation resulting in an order of magnitude larger number of cells after a 7-day incubation. The cell viability is negatively affected mostly by the extrusion printing itself with some cell death occurring during their embedding in the hydrogels. After embedding the HeLa cells in the blends containing 1 and 2.5 % SA, the cell viability is not significantly affected by the residence time of up to 90 min before the bioink extrusion. The printed constructs can be utilized as a cervical tumor model.


Asunto(s)
Bioimpresión , Celulosa/análogos & derivados , Alginatos/química , Supervivencia Celular/efectos de los fármacos , Celulosa/química , Femenino , Células HeLa , Humanos , Hidrogeles/química , Hidrogeles/farmacología , Tinta , Paclitaxel/química , Paclitaxel/farmacología , Reología , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología
8.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33669021

RESUMEN

The expression of p16 is a good surrogate of human papillomavirus (HPV) infection in HPV-associated cancers. The significance of p16 expression, HPV genotype and genera in the outcome of patients with HPV-associated cervical cancer (CC) is unclear. Our aim is to ascertain the prognostic significance of these factors. Data from 348 patients (median age: 47.5 years old) with CC, diagnosed in two referral centers, were retrospectively collected. Advanced disease (FIGO2018 IB2-IV) was present in 68% of patients. A single HPV genotype was identified in 82.8% of patients. The most common HPVs were HPV16 (69%) and HPV18 (14%). HPV genera reflected this distribution. HPV16 tumors presented at an earlier stage. P16 was negative in 18 cases (5.2%), 83.3% of which were squamous cell carcinomas. These cases occurred in older patients who tended to have advanced disease. In the univariate analysis, HPV16 (HR: 0.58; p = 0.0198), α-9 genera (HR: 0.37; p = 0.0106) and p16 overexpression (HR: 0.54; p = 0.032) were associated with better survival. HPV16 (HR: 0.63; p = 0.0174) and α-9 genera (HR: 0.57; p = 0.0286) were associated with less relapse. In the multivariate analysis, only the International Federation of Gynecology and Obstetrics (FIGO) stage retained an independent prognostic value. HPV16, α-9 genera and p16 overexpression were associated with better survival, although not as independent prognostic factors. Patients with p16-negative HPV-associated CC were older, presented with advanced disease and had worse prognosis.


Asunto(s)
Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Papillomaviridae/genética , Infecciones por Papillomavirus/virología , Neoplasias del Cuello Uterino/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/virología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Estudios de Cohortes , Femenino , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Centros de Atención Terciaria , Regulación hacia Arriba , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Adulto Joven
9.
BMC Cancer ; 21(1): 243, 2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33685404

RESUMEN

BACKGROUND: It is very important to accurately delineate the CTV on the patient's three-dimensional CT image in the radiotherapy process. Limited to the scarcity of clinical samples and the difficulty of automatic delineation, the research of automatic delineation of cervical cancer CTV based on CT images for new patients is slow. This study aimed to assess the value of Dense-Fully Connected Convolution Network (Dense V-Net) in predicting Clinical Target Volume (CTV) pre-delineation in cervical cancer patients for radiotherapy. METHODS: In this study, we used Dense V-Net, a dense and fully connected convolutional network with suitable feature learning in small samples to automatically pre-delineate the CTV of cervical cancer patients based on computed tomography (CT) images and then we assessed the outcome. The CT data of 133 patients with stage IB and IIA postoperative cervical cancer with a comparable delineation scope was enrolled in this study. One hundred and thirteen patients were randomly designated as the training set to adjust the model parameters. Twenty cases were used as the test set to assess the network performance. The 8 most representative parameters were also used to assess the pre-sketching accuracy from 3 aspects: sketching similarity, sketching offset, and sketching volume difference. RESULTS: The results presented that the DSC, DC/mm, HD/cm, MAD/mm, ∆V, SI, IncI and JD of CTV were 0.82 ± 0.03, 4.28 ± 2.35, 1.86 ± 0.48, 2.52 ± 0.40, 0.09 ± 0.05, 0.84 ± 0.04, 0.80 ± 0.05, and 0.30 ± 0.04, respectively, and the results were greater than those with a single network. CONCLUSIONS: Dense V-Net can correctly predict CTV pre-delineation of cervical cancer patients and can be applied in clinical practice after completing simple modifications.


Asunto(s)
Cuello del Útero/diagnóstico por imagen , Imagenología Tridimensional , Redes Neurales de la Computación , Planificación de la Radioterapia Asistida por Computador/métodos , Neoplasias del Cuello Uterino/terapia , Cuello del Útero/patología , Cuello del Útero/cirugía , Femenino , Humanos , Estadificación de Neoplasias , Radioterapia Ayuvante/métodos , Tomografía Computarizada por Rayos X , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología
10.
BMC Cancer ; 21(1): 281, 2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33726684

RESUMEN

BACKGROUND: Cervical cancer is the fourth cancer worldwide. The Human Papilloma Virus is responsible for 99% of the cases but the distribution of its genotypes varies among populations. We aimed to identify HPV genotypes distribution in women with grade 2/3 cervical intraepithelial dysplasia or invasive cervical cancer in Guadeloupe, a French Caribbean territory with a population mainly of African descent. METHODS: We used paraffin-embedded tumors for viral DNA extraction from women diagnosed between 2014 and 2016 and identified by the population-based cancer registry. The HPV Genotyping was performed with the InnoLIPA HPV Genotyping Extra kit®. RESULTS: Overall, 213 samples out of the 321 eligible records were analyzed. The HPV status was positive for 94% of the cases. The five most common oncogenic HPV genotypes were HPV31 (47%), HPV33 (38%), HPV16 (32%), HPV44 (31%) and HPV26 (28%). HPV18 was found in only in 5% of the cases. Among the studied cases, 94% had multiple infections. More than 60% of single infections were HPV16-related, accounting for 35% of HPV16 infections. CONCLUSIONS: These results show a different distribution of oncogenic HPVs in Guadeloupe with "31 >  33 > 16" and a high frequency of multiple infections. Despite a lower coverage, the nine-valent vaccine is nevertheless adequate.


Asunto(s)
Neoplasia Intraepitelial Cervical/virología , Coinfección/epidemiología , Infecciones por Papillomavirus/epidemiología , Vacunas contra Papillomavirus/administración & dosificación , Neoplasias del Cuello Uterino/virología , Adulto , Neoplasia Intraepitelial Cervical/epidemiología , Neoplasia Intraepitelial Cervical/patología , Neoplasia Intraepitelial Cervical/prevención & control , Cuello del Útero/patología , Cuello del Útero/virología , Coinfección/diagnóstico , Coinfección/prevención & control , Coinfección/virología , ADN Viral/aislamiento & purificación , Femenino , Guadalupe/epidemiología , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/aislamiento & purificación , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/aislamiento & purificación , Humanos , Incidencia , Persona de Mediana Edad , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/virología , Estudios Retrospectivos , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/prevención & control
11.
BMC Cancer ; 21(1): 289, 2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33736612

RESUMEN

BACKGROUND: Cervical cancer is a gynecologic cancer type that develops in the cervix, accounting for 8% mortality of all female cancer patients. Infection with specific human papillomavirus (HPV) types is considered the most severe risk factor for cervical cancer. In the context of our socioeconomic conditions, an increasing burden of this disease and high mortality rate prevail in Bangladesh. Although several researches related to the epidemiology, HPV vaccination, and treatment modalities were conducted, researches on the mutation profiles of marker genes in cervical cancer in Bangladesh remain unexplored. METHODS: In this study, five different genomic regions within the top three most frequently mutated genes (EGFR, KRAS and PIK3CA) in COSMIC database with a key role in the development of cervical cancers were selected to study the mutation frequency in Bangladeshi patients. In silico analysis was done in two steps: nucleotide sequence analysis and its corresponding amino acid analysis. RESULTS: DNA from 46 cervical cancer tissue samples were extracted and amplified by PCR, using 1 set of primers designed for EGFR and 2 sets of primers designed for two different regions of both PIK3CA and KRAS gene. In total, 39 mutations were found in 26 patient samples. Eleven different mutations (23.91%), twenty-four different mutations (52.17%) and four mutations (8.7%) were found in amplified EGFR, PIK3CA and KRAS gene fragments, respectively; among which 1 (EGFR) was common in seven patient samples and 2 (PIKCA) were found in more than 1 patient. Our study shows that except for KRAS, the frequency of observed mutations in our patients is higher than those reported earlier in other parts of the world. Most of the exonic mutations were found only in the PIK3CA and EGFR genes. CONCLUSIONS: The study can be used as a basis to build a mutation database for cervical cancer in Bangladesh with the possibility of targetable oncogenic mutations. Further explorations are needed to establish future diagnostics, personalized medicine decisions, and other pharmaceutical applications for specific cancer subtypes.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias del Cuello Uterino/genética , Adulto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Bangladesh , Biomarcadores de Tumor/antagonistas & inhibidores , Cuello del Útero/patología , Cuello del Útero/cirugía , Quimioterapia Adyuvante/métodos , Fosfatidilinositol 3-Quinasa Clase I/genética , Toma de Decisiones Clínicas , Simulación por Computador , Análisis Mutacional de ADN , Técnicas de Apoyo para la Decisión , Receptores ErbB/genética , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapia
12.
Gynecol Oncol ; 161(2): 414-421, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33771396

RESUMEN

OBJECTIVE: The current coronavirus pandemic caused a significant decrease in cancer-related encounters resulting in a delay in treatment of cancer patients. The objective of this study was to examine the survival effect of delay in starting concurrent chemo-radiotherapy (CCRT) in women with locally-advanced cervical cancer. METHODS: This is a retrospective observational study querying the National Cancer Database from 2004 to 2016. Women with stage IB2-IVA squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix who received definitive CCRT with known wait-time for CCRT initiation after cancer diagnosis were eligible (N=13,617). Cox proportional hazard regression model with restricted cubic spline transformation was fitted to assess the association between CCRT wait-time and all-cause mortality in multivariable analysis. RESULTS: The median wait-time to start CCRT was 6 (IQR 4-8) weeks. In a multivariable analysis, older age, non-Hispanic black and Hispanic ethnicity, recent year of diagnosis, Medicaid and uninsured status, medical comorbidities, and absence of nodal metastasis were associated with longer CCRT wait-time (P<.05). Women with aggressive tumor factors (poorer differentiation, large tumor size, nodal metastasis, and higher cancer stage) were more likely to have a short CCRT wait-time (P<.05). After controlling for the measured covariates, CCRT wait-time of 6.1-9.8 weeks was not associated with increased risk of all-cause mortality compared to a wait-time of 6 weeks. Similar association was observed when the cohort was stratified by histology, cancer stage, tumor size, or brachytherapy use. CONCLUSION: An implication of this study for the current coronavirus pandemic is that in the absence of aggressive tumor factors, a short period of wait-time to start definitive CCRT may not be associated with increased risk of mortality in women with locally-advanced cervical cancer.


Asunto(s)
Adenocarcinoma/terapia , Carcinoma Adenoescamoso/terapia , Carcinoma de Células Escamosas/terapia , Tiempo de Tratamiento , Neoplasias del Cuello Uterino/terapia , Adenocarcinoma/secundario , Adulto , Afroamericanos/estadística & datos numéricos , Factores de Edad , Anciano , Anciano de 80 o más Años , Carcinoma Adenoescamoso/secundario , Carcinoma de Células Escamosas/secundario , Quimioradioterapia , Femenino , Hispanoamericanos/estadística & datos numéricos , Humanos , Metástasis Linfática , Medicaid/estadística & datos numéricos , Pacientes no Asegurados/estadística & datos numéricos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Factores Raciales , Estudios Retrospectivos , Tasa de Supervivencia , Carga Tumoral , Estados Unidos , Neoplasias del Cuello Uterino/patología
14.
Anaesthesia ; 76 Suppl 4: 46-55, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33682092

RESUMEN

A number of benign and malignant gynaecological conditions can cause infertility. Advancements in assisted reproductive technologies have facilitated the rapidly evolving subspecialty of fertility preservation. Regardless of clinical indication, women now have the reproductive autonomy to make fully informed decisions regarding their future fertility. In particular, there has been an increasing interest and demand among patients and healthcare professionals for fertility-sparing surgery. Gynaecologists find themselves continually adapting surgical techniques and introducing novel procedures to facilitate this rapidly emerging field and anaesthetists need to manage the consequent physiological demands intra-operatively. Not only is it important to understand the surgical procedures now undertaken, but also the intra-operative management in an ever evolving field. This article reviews the methods of fertility-sparing surgery and also describes important anaesthetic challenges including peri-operative care for women undergoing complex fertility-sparing surgeries such as uterus transplantation.


Asunto(s)
Anestésicos/administración & dosificación , Útero/cirugía , Endometriosis/patología , Endometriosis/cirugía , Femenino , Preservación de la Fertilidad , Humanos , Leiomioma/patología , Leiomioma/cirugía , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/cirugía , Útero/trasplante
15.
Ceska Gynekol ; 86(1): 17-21, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33752404

RESUMEN

OBJECTIVE: The aim of this study was to compare the serum levels of TFF3, AIF-1, S100-A11 and DKK1 in surgically staged patients with cervical cancer, and in healthy female controls. METHODS: In total 85 consecutive patients dia-gnosed at the Department of Obstetrics and Gynecology, University Hospital in Olomouc with cervical cancer undergoing radical hysterectomy or fertility sparing surgery with pelvic lymphadenectomy were included. Ninety patients who underwent elective total hysterectomy for nonmalignant disorder represented a control group. In all patients, preoperative serum samples were taken and separated; the sera were all stored at -80 °C until analysis for TFF3, AIF-1, S100-A11 and DKK1. RESULTS: According to the final histopathological examination, 32 (40.5%) out of 79 cervical cancer patients with microscopically examined lymph nodes were lymph node-positive. S100-A11 (P < 0.0001) and AIF-1 levels (P < 0.0001) were higher in cervical cancer patients than in controls. Furthermore, the serum levels of S100-A11 (P > 0.04) and AIF-1 (P > 0.01) were significantly higher in lymph node-positive patients as compared to lymph node-negative patients. The levels of TFF3 and DKK1 were higher (P < 0.0001) in controls than in cervical cancer patients and were not different in groups with or without nodal involvement. CONCLUSION: S100-A11 and AIF-1 represent potential bio-markers in patients with cervical cancer. Moreover, the levels of S100-A11 and AIF-1 increase in patients with lymph node  involvement.


Asunto(s)
Neoplasias del Cuello Uterino , Femenino , Humanos , Histerectomía , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Metástasis Linfática , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/cirugía
16.
Am J Clin Oncol ; 44(4): 162-168, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33606367

RESUMEN

OBJECTIVE: Invasive pattern of endocervical adenocarcinomas (EACs) is known to influence lymph node metastasis and cancer recurrence. In this study we describe the prognostic significance of necrotic tumor debris (NTD) and tumor nuclear grade on recurrence risk stratification of early-stage cervical adenocarcinoma. METHODS: Patients who underwent surgery from 2007 to 2018 for International Federation of Gynecology and Obstetrics (FIGO) stage IA1-IB2 EAC, for whom pathology was available for review were included in this study. Clinico-pathologic variables and clinical recurrence risk stratification (low, intermediate, or high risk) were correlated to intraluminal NTD and tumor nuclear grade (N3). RESULTS: Among 50 patients meeting inclusion criteria, all were managed surgically and clinically risk stratified as low (n=33), intermediate (n=13), and high risk (n=4). Twenty-three patients (46%) were NTD-N3 negative and 27 (54%) were NTD-N3 positive. NTD-N3 was significantly associated with higher stage, tumor grade, larger tumor size, positive lymphovascular space invasion, and recurrence of disease (P=0.025). Patients with stage IB1 EAC who were stratified as intermediate or high-risk for recurrence were positive for NTD-N3. Lack of NTD-N3 had 100% negative predictive value for disease recurrence. CONCLUSIONS: NTD-N3, a novel pathologic finding, may be used to further stratify overall recurrence risk, and may play a role in individualization of patient care in early-stage EAC.


Asunto(s)
Adenocarcinoma/patología , Neoplasias del Cuello Uterino/patología , Adulto , Anciano , Núcleo Celular/ultraestructura , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Necrosis , Clasificación del Tumor , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Proyectos Piloto , Reproducibilidad de los Resultados , Factores de Riesgo
17.
Arch Gynecol Obstet ; 303(3): 777-785, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33544202

RESUMEN

OBJECTIVE: To determine the accuracy of uterine corpus invasion (UCI) diagnosis in patients with cervical cancer and identity risk factors for UCI and depth of invasion. METHODS: Clinical data of patients with cervical cancer who underwent hysterectomy between 2004 and 2016 were retrospectively reviewed. UCI was assessed on uterine pathology. Independent risk factors for UCI and depth of invasion were identified using binary and ordinal logistic regression models, respectively. RESULTS: A total of 2,212 patients with cervical cancer from 11 medical institutions in China were included in this study. Of these, 497 patients had cervical cancer and UCI, and 1,715 patients had cervical cancer and no UCI, according to the original pathology reports. Retrospective review of the original pathology reports revealed a missed diagnosis of UCI in 54 (10.5%) patients and a misdiagnosis in 36 (2.1%) patients. Therefore, 515 patients with cervical cancer and UCI (160 patients with endometrial invasion, 176 patients with myometrial invasion < 50%, and 179 patients with myometrial invasion ≥ 50%), and 1697 patients with cervical cancer without UCI were included in the analysis. Older age, advanced stage, tumor size, adenocarcinoma, parametrial involvement, resection margin involvement, and lymph node metastasis were independent risk factors for UCI. These risk factors, except resection margin involvement, were independently associated with depth of UCI. CONCLUSIONS: UCI may be missed or misdiagnosed in patients with cervical cancer on postoperative pathological examination. Older age, advanced stage, tumor size, adenocarcinoma, parametrial involvement, resection margin involvement, and lymph node metastasis were independent risk factors for UCI and depth of UCI, with the exception of resection margin involvement.


Asunto(s)
Adenocarcinoma/patología , Histerectomía , Invasividad Neoplásica/patología , Neoplasias del Cuello Uterino/patología , Adenocarcinoma/epidemiología , Adenocarcinoma/cirugía , Adulto , Anciano , Estudios de Casos y Controles , China/epidemiología , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Factores de Riesgo , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/cirugía
18.
Arch Gynecol Obstet ; 303(4): 1049-1056, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33624123

RESUMEN

PURPOSE: This study was aimed to quantify genomic DNA breakages in the cervical epithelium cells of patients diagnosed with different grades of cervical lesions using a quick test based on chromatin dispersion after controlled protein depletion. The association between the progressive stages of cervical dysplasia and the levels of DNA damage, taking into account the presence of papillomavirus human (HPV) infection, was investigated. METHODS: A hospital-based unmatched case-control study was conducted during 2018 with a sample of 78 women grouped according to histological diagnosis as follows: 23 women with low grade-squamous intraepithelial lesion (LG-SIL), 34 women with high grade- squamous intraepithelial lesion (HG-SIL), and three women with cervical carcinoma (CC). In parallel, 15 women without cervical lesions were included as a Control cohort. DNA damage levels in cervical epithelial cells were assessed using the chromatin dispersion test (CDT) and controlled in parallel with DNA breakage detection coupled with florescent in situ hybridization (DBD‒FISH) using whole genomic DNA probes. RESULTS: CDT produces different morphotypes in the cervical epithelium that can be associated with the level of DNA breakage revealed with DBD‒FISH. A significant increase of DNA damage was correlated with the histological progression of the patients and human papillomavirus (HPV) infection. CONCLUSION: The CDT is a simple, accurate and inexpensive morphological bioassay to identify different levels DNA damage that can be associated with the level of abnormal cells present in the cervical epithelium in patients who commonly present HPV infection.


Asunto(s)
Neoplasia Intraepitelial Cervical/diagnóstico , Cromatina , Células Epiteliales/patología , Infecciones por Papillomavirus/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Adulto , Estudios de Casos y Controles , Neoplasia Intraepitelial Cervical/patología , Femenino , Humanos , Persona de Mediana Edad , Papillomaviridae , Infecciones por Papillomavirus/patología , Neoplasias del Cuello Uterino/patología , Adulto Joven
19.
Lancet Oncol ; 22(3): 361-369, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33556324

RESUMEN

BACKGROUND: Screening for breast cancer and cervical cancer in the newly independent states of the former Soviet Union is largely opportunistic, and countries in the region have among the highest cervical cancer incidence in the WHO European Region. We aimed to compare the stage-specific distributions and changes over time in breast cancer and cervical cancer incidence in the newly independent states of the former Soviet Union. METHODS: We collected breast cancer and cervical cancer incidence data from official statistics from Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Republic of Moldova, Russian Federation, Ukraine, and Uzbekistan for the years 2008-17 by tumour, node, metastasis (TNM) stage, and by age where population-based cancer registry data were available. We used log-linear regression to quantify the changes over time in age-standardised rates. FINDINGS: During the period 2013-17, more than 50% of breast cancer cases across the analysed countries, and more than 75% of breast cancer cases in Belarus, Kazakhstan, and Ukraine, were registered at stages I-II. The proportion of stage I breast cancer cases was highest in the screening age group (50-69 years) compared with other ages in Moldova and the Russian registries, but was highest in those aged 15-49 years in Georgia and Ukraine. Breast cancer stage-specific incidence rates increased over time, most prominently for stage I cancers. For cervical cancer, the proportions of cancers diagnosed at a late stage (stages III and IV) were high, particularly in Moldova and Armenia (>50%). The proportion of stage I cervical cancer cases decreased with age in all countries, whereas the proportions of late stage cancers increased with age. Stage-specific incidence rates of cervical cancer generally increased over the period 2008-17. INTERPRETATION: Our results suggest modest progress in early detection of breast cancer in the newly independent states of the former Soviet Union. The high proportions of early-stage disease in the absence of mammography screening (eg, in Belarus) provide a benchmark for what is achievable with rapid diagnosis. For cervical cancer, there is a need to tackle the high burden and unfavourable stage-specific changes over time in the region. A radical shift in national policies away from opportunistic screening toward organised, population-based, quality-assured human papillomavirus vaccination and screening programmes is urgently needed. FUNDING: Union for International Cancer Control, WHO Regional Office for Europe, and Ministry of Health of Ukraine.


Asunto(s)
Neoplasias de la Mama/patología , Neoplasias del Cuello Uterino/patología , Adolescente , Adulto , Anciano , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/epidemiología , Detección Precoz del Cáncer , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Persona de Mediana Edad , Estadificación de Neoplasias , U.R.S.S./epidemiología , Neoplasias del Cuello Uterino/clasificación , Neoplasias del Cuello Uterino/epidemiología , Adulto Joven
20.
Molecules ; 26(3)2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33572896

RESUMEN

The search for novel anti-cancer compounds which can circumvent chemotherapeutic drug resistance and limit systemic toxicity remains a priority. 2-Ethyl-3-O-sulphamoyl-estra-1,3,5(10)15-tetraene-3-ol-17one (ESE-15-one) and 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16) are sulphamoylated 2-methoxyestradiol (2-ME) analogues designed by our research team. Although their cytotoxicity has been demonstrated in vitro, the temporal and mechanistic responses of the initiated intracellular events are yet to be determined. In order to do so, assays investigating the compounds' effects on microtubules, cell cycle progression, signalling cascades, autophagy and apoptosis were conducted using HeLa cervical- and MDA-MB-231 metastatic breast cancer cells. Both compounds reversibly disrupted microtubule dynamics as an early event by binding to the microtubule colchicine site, which blocked progression through the cell cycle at the G1/S- and G2/M transitions. This was supported by increased pRB and p27Kip1 phosphorylation. Induction of apoptosis with time-dependent signalling involving the p-JNK, Erk1/2 and Akt/mTOR pathways and loss of mitochondrial membrane potential was demonstrated. Inhibition of autophagy attenuated the apoptotic response. In conclusion, the 2-ME analogues induced a time-dependent cross-talk between cell cycle checkpoints, apoptotic signalling and autophagic processes, with an increased reactive oxygen species formation and perturbated microtubule functioning appearing to connect the processes. Subtle differences in the responses were observed between the two compounds and the different cell lines.


Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Estrona/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Antineoplásicos/farmacología , Apoptosis/genética , Autofagia/genética , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Línea Celular Tumoral , Estrenos/farmacología , Estrona/análogos & derivados , Estrona/química , Femenino , Células HeLa , Humanos , Microtúbulos/química , Metástasis de la Neoplasia , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacología , Neoplasias del Cuello Uterino/patología
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