Adjuvant chemotherapy versus adjuvant concurrent chemoradiotherapy after radical surgery for early-stage cervical cancer: a randomized, non-inferiority, multicenter trial / 医学前沿

We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB-IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant chemotherapy group and 164 in the adjuvant CCRT group. The median follow-up was 72.1 months. The three-year PFS rates were both 91.9%, and the five-year OS was 90.6% versus 90.0% in adjuvant chemotherapy and CCRT groups, respectively. No significant differences were observed in the PFS or OS between groups. The adjusted HR for PFS was 0.854 (95% confidence interval 0.415-1.757; P = 0.667) favoring adjuvant chemotherapy, excluding the predefined non-inferiority boundary of 1.9. The chemotherapy group showed a tendency toward good quality of life. In comparison with post-operative adjuvant CCRT, adjuvant chemotherapy treatment showed non-inferior efficacy in patients with early-stage cervical cancer having pathological risk factors. Adjuvant chemotherapy alone is a favorable alternative post-operative treatment.

Principais implicações terapêuticas à qualidade de vida de pacientes com câncer de colo uterino: uma revisão narrativa / Therapeutic implications to the quality of life of cervical cancer's patients: a narrative review

O câncer de colo uterino é o quarto tipo mais incidente e fatal entre as mulheres no Brasil e no mundo, o que representa mundialmente em torno de 600 mil novos casos e mais de 300 mil mortes a cada ano. Assim como o diagnóstico, o tratamento da doença pode impactar de forma significativa a qualidade de vida dessas pacientes. A aplicação de questionários que avaliem os diferentes aspectos da qualidade de vida das mulheres afetadas por esse câncer é uma ferramenta relevante, pois auxilia na compreensão e identificação dos principais danos relacionados ao tratamento. Este trabalho visa analisar a literatura atual que investiga e relata os principais efeitos à qualidade de vida de mulheres com câncer de colo uterino associados a diferentes modalidades terapêuticas e, desse modo, contribuir nas escolhas de tratamento e manejo clínico que resultem em menores impactos à qualidade de vida dessas mulheres.(AU)

Cervical cancer is the fourth most incident and fatal cancer type among women in Brazil and worldwide. This data represents around 600 thousand new cases worldwide each year and more than 300 thousand lives lost. Both diagnosis and treatment can significantly impact the quality of life of cervical cancer patients. The application of questionnaires that assess the different aspects of the quality of life of women affected by this cancer is a relevant tool, as it helps to understand and identify the main damages related to the treatment. This article aims to analyze the current literature that reports the main effects on the quality of life of women with cervical cancer associated with different therapeutic modalities. In this way, the review could assist in the treatment choices that imply less impact on the quality of life of these women.(AU)

Epidermal growth factor receptor regulates fibrinolytic pathway elements in cervical cancer: functional and prognostic implications

Epidermal growth factor receptor (EGFR) signaling and components of the fibrinolytic system, including urokinase-type plasminogen activator (uPA) and thrombomodulin (TM), have been implicated in tumor progression. In the present study, we employed cBioPortal platform (http://www.cbioportal.org/), cancer cell lines, and an in vivo model of immunocompromised mice to evaluate a possible cooperation between EGFR signaling, uPA, and TM expression/function in the context of cervical cancer. cBioPortal analysis revealed that EGFR, uPA, and TM are positively correlated in tumor samples of cervical cancer patients, showing a negative prognostic impact. Aggressive human cervical cancer cells (CASKI) presented higher gene expression levels of EGFR, uPA, and TM compared to its less aggressive counterpart (C-33A cells). EGFR induces uPA expression in CASKI cells through both PI3K-Akt and MEK1/2-ERK1/2 downstream effectors, whereas TM expression induced by EGFR was dependent on PI3K/Akt signaling alone. uPA induced cell-morphology modifications and cell migration in an EGFR-dependent and -independent manner, respectively. Finally, treatment with cetuximab reduced in vivo CASKI xenografted-tumor growth in nude mice, and decreased intratumoral uPA expression, while TM expression was unaltered. In conclusion, we showed that EGFR signaling regulated expression of the fibrinolytic system component uPA in both in vitro and in vivo settings, while uPA also participated in cell-morphology modifications and migration in a human cervical cancer model.

The anti-neoplastic activities of aloperine in HeLa cervical cancer cells are associated with inhibition of the IL-6-JAK1-STAT3 feedback loop / 中国天然药物

Cervical cancer (CC) is recognized as the most common neoplasm in the female reproductive system worldwide. The lack of chemotherapeutic agents with outstanding effectiveness and safety severely compromises the anti-cipated prognosis of patients. Aloperine (ALO) is a natural quinolizidine alkaloid with marked anti-cancer effects on multiple malignancies as well as favorable activity in relieving inflammation, allergies and infection. However, its therapeutic efficacy and underlying mechanism in CC are still unclear. In the current study, MTT assay was employed to evaluate the viability of HeLa cells exposed to ALO to preliminarily estimate the effectiveness of ALO in CC. Then, the effects of ALO on the proliferation and apoptosis of HeLa cells were further investigated by plate colony formation and flow cytometry, respectively, while the migration and invasion of ALO-treated HeLa cells were evaluated using Transwell assay. Moreover, nude mice were subcutaneously inoculated with HeLa cells to demonstrate the anti-CC properties of ALO in vivo. The molecular mechanisms underlying these effects of ALO were evaluated by Western blot and immunohistochemical analysis. This study experimentally demonstrated that ALO inhibited the proliferation of HeLa cells via G2 phase cell cycle arrest. Simultaneously, ALO promoted an increase in the percentage of apoptotic HeLa cells by increasing the Bax/Bcl-2 ratio. Additionally, the migration and invasion of HeLa cells were attenuated by ALO treatment, which was considered to result from inhibition of epithelial-to-mesenchymal transition. For molecular mechanisms, the expression and activation of the IL-6-JAK1-STAT3 feedback loop were markedly suppressed by ALO treatment. This study indicated that ALO markedly suppresses the proliferation, migration and invasion and enhances the apoptosis of HeLa cells. In addition, these prominent anti-CC properties of ALO are associated with repression of the IL-6-JAK1-STAT3 feedback loop.

Preparation of paclitaxel-loaded and folic acid-modified poly (lactic-co-glycolic acid) nano-micelles and in vitro anticancer effect on cervical cancer HeLa cells / 中国中药杂志

The paclitaxel-loaded and folic acid-modified poly(lactic-co-glycolic acid) nano-micelles(PTX@FA-PLGA-NMs) were prepared by the emulsion solvent evaporation method, and the parameters of paclitaxel-loaded nano-micelles were optimized with the particle size and PDI as evaluation indexes. The morphology of the nano-micelles was observed by transmission electron microscopy(TEM), and the stability, drug loading and encapsulation efficiency were systematically investigated. In vitro experiments were performed to study the cytotoxic effects of nano-micelles, apoptosis, and cellular uptake. Under the optimal parameters, the nano-micelles showed the particle size of(125.3±1.2) nm, the PDI of 0.086±0.026, the zeta potential of(-20.0±3.8) mV, the drug loading of 7.2%±0.75%, and the encapsulation efficiency of 50.7%±1.0%. The nano-micelles were in regular spherical shape as observed by TEM. The blank FA-PLGA-NMs exhibited almost no inhibitory effect on the proliferation and growth of tumor cells, while the drug-loaded nano-micelles and free PTX exhibited significant inhibitory effects. The IC_(50) of PTX@FA-PLGA-NMs and PTX was 0.56 μg·mL~(-1) and 0.66 μg·mL~(-1), respectively. The paclitaxel-loaded nano-micelles were potent in inhibiting cell migration as assessed by the scratch assay. PTX@FA-PLGA-NMs had good pro-apoptotic effect on cervical cancer HeLa cells and significantly promoted the uptake of HeLa cells. The results of in vitro experiments suggested that PTX@FA-PLGA-NMs could target and treat cervical cancer HeLa cells. Therefore, as nanodrug carriers, PTX@FA-PLGA-NMs with anti-cancer activity are a promising nano-system for improving the-rapeutic effects on tumors.

Braquiterapia adaptativa guiada por resonancia magnética para el cáncer cervical localmente avanzado: experiencia del Hospital Carlos Van Buren / MRI-guided adaptive brachytherapy for locally advanced cervical cancer: experience at Carlos Van Buren Hospital

Introducción y objetivos: El tratamiento estándar para pacientes con cáncer cervical localmente avanzado (CCLA) se basa en radioterapia externa y quimioterapia concomitante seguida de braquiterapia adaptativa guiada por imágenes (BTAGI). El objetivo de este estudio fue describir los resultados del protocolo de BTAGI de resonancia magnética del Servicio de Oncología del Hospital Carlos Van Buren. Métodos: En pacientes con CCLA tratadas con Radioquimioterapia concomitante seguida de BTAGI de resonancia magnética se evaluó la reducción tumoral, parámetros dosimétricos y la toxicidad aguda. Resultados: Se evaluó la reducción tumoral entre el diagnóstico y el momento de la braquiterapia en 34 pacientes. Todas las pacientes completaron el tratamiento de radioterapia externa. Veinticuatro pacientes recibieron 3 sesiones de braquiterapia. Dosis equivalentes totales > 80 Gy se logro en todos los pacientes. Doce pacientes presentaron reducción del volumen tumoral mayor al 70%. La mediana de las dosis equivalentes totales prescritas al D2cc de vejiga fue 73.9 Gy, al recto 65.6 Gy y al intestino fue de 69.1 Gy. Una paciente presento toxicidad gastrointestinal grado ≥ 3. No hubo diferencias estadísticamente significativas al comparar pacientes que recibieron dosis equivalentes totales desde los 85 Gy con las que recibieron menor dosis respecto a toxicidad gastrointestinal (p=0.33) y genitourinaria (p=0.97). Conclusión: La braquiterapia adaptativa guiada por resonancia magnética se puede realizar en el sistema público de salud y cumplir con las recomendaciones internacionales requeridas para el tratamiento estándar del CCLA.

Introduction and purpose: External beam radiation therapy with concomitant chemotherapy followed by adaptive image-guided brachytherapy (IGABT) is the standard of care for patients with locally advanced cervical cancer (LACC). The purpose of this study was to describe the local outcomes of the magnetic resonance IGABT protocol at the radiation oncology department of the Carlos Van Buren Hospital. Methods: Tumor reduction, dosimetric parameters and acute toxicity were evaluated in patients with LACC treated with concomitant radiochemotherapy followed by magnetic resonance IGABT. Results: Tumor reduction between diagnosis and brachytherapy was evaluated in 34 patients. All patients completed external radiation therapy treatment. Twenty-four patients received 3 sessions of brachytherapy. All patients received a total equivalent dose > 80 Gy. Twelve patients showed a tumor volume reduction greater than 70%. The median total equivalent dose prescribed to the bladder D2cc was 73.9 Gy, the rectum 65.6 Gy, and the intestine 69.1 Gy. One patient presented grade ≥ 3 gastrointestinal toxicity. No statistically significant differences were found when comparing patients who received total equivalent doses larger than 85 Gy with those who received lower doses regarding gastrointestinal (p = 0.33) and genitourinary (p = 0.97) toxicity. Conclusion: MRI-guided adaptive brachytherapy can be performed in the public health system and achieve the international recommendations required as standard of care treatment of LACC.

Standard treatment with bevacizumab as targeted therapy in cervical cancer

ABSTRACT Metastatic, recurrent, or persistent disease in cervical cancer has a poor prognosis. Historically, this group of patients has had limited treatment options, even with the best cytotoxic treatments (platinum-based chemotherapy [CT] doublets). Therefore, investigating new medications that help improve the patient's quality of life and survival has been essential. Angiogenesis has been shown to play a critical role in tumor cell growth and survival. Bevacizumab is a recombinant humanized monoclonal G1 immunoglobulin targeted against vascular endothelial growth factor. The combination of CT and bevacizumab is associated with an increase in overall survival as well as in progression-free survival and response rates.

Lopinavir and curcumin directly alters BAX/BCL2 and VEFG165b mRNA levels to suppress human squamous cervical carcinoma cell growth / Lopinavir y curcumina alteran directamente los niveles de ARNm de BAX/ BCL 2 y VEFG165 para suprimir el crecimiento de células de carcinoma cervical escamoso humano

Following the success of the highly active antiretroviral therapy, the potential of multidrug combination regimen for the management of cancer is intensely researched. The anticancer effects of curcumin on some human cell lines have been documented. Lopinavir is a FDA approved protease inhibitor with known apoptotic activities. Dysregulated apoptosis is important for the initiation of cancer while angiogenesis is required for cancer growth and development, this study therefore investigated the effects of the combination of lopinavir and curcumin on cell viability, apoptosis and the mRNA expression levels of key apoptotic and angiogenic genes; BAX, BCL2 and VEGF165b in two human cervical cell lines; human squamous cell carcinoma cells - uterine cervix (HCS-2) and transformed normal human cervical cells (NCE16IIA). The two human cervical cell lines were treated with physiologically relevant concentrations of the agents for 120 h following which BAX, BCL2 and VEGF165b mRNA expression were determined by Real Time qPCR. The Acridine Orange staining for the morphological evaluation of apoptotic cells was also performed. The combination of lopinavir and curcumin up-regulated pro-apoptotic BAX and antiangiogenic VEGF165b but down-regulated the mRNA levels of anti-apoptotic BCL2 mRNA in the human squamous cell carcinoma (HCS-2) cells only. The fold changes were statistically significant. Micrographs from Acridine Orange staining showed characteristic evidence of apoptosis in the human squamous cell carcinoma (HCS-2) cells only. The findings reported here suggest that the combination of curcumin and the FDA approved drug-lopinavir modulate the apoptotic and angiogenic pathway towards the inhibition of cervical cancer.

Tras el éxito de la terapia antirretroviral altamente activa, se investiga intensamente el potencial del régimen de combinación de múltiples fármacos para el tratamiento del cáncer. Se han documentado los efectos anticancerígenos de la curcumina en algunas líneas celulares humanas. Lopinavir es un inhibidor de proteasa aprobado por la FDA con actividades apoptóticas conocidas. La apoptosis disrregulada es importante para el inicio del cáncer, mientras que la angiogénesis es necesaria para el crecimiento y desarrollo del cáncer. Por lo tanto, este estudio investigó los efectos de la combinación de lopinavir y curcumina sobre la viabilidad celular, la apoptosis y los niveles de expresión del ARNm de genes apoptóticos y angiogénicos clave: BAX, BCL2 y VEGF165b en dos líneas celulares cervicales humanas; células de carcinoma de células escamosas humanas: cérvix uterino (HCS-2) y células cervicales humanas transformadas (NCE16IIA). Las dos líneas celulares cervicales humanas se trataron con concentraciones fisiológicamente relevantes de los agentes durante 120 horas, después de lo cual la expresión de ARNm de BAX, BCL2 y VEGF165b se determinó mediante qPCR en tiempo real. También se realizó la tinción con naranja de acridina para la evaluación morfológica de células apoptóticas. La combinación de lopinavir y curcumina reguló incrementando BAX proapoptósicos y VEGF165b antiangiogénicos, pero reguló a la baja los niveles de ARNm del BCL2 antiapoptótico en células de carcinoma de células escamosas humanas (HCS-2) únicamente. Los cambios en el pliegue fueron estadísticamente significativos. Las micrografías de la tinción con naranja de acridina mostraron evidencia característica de apoptosis solo en las células del carcinoma de células escamosas humanas (HCS-2). Los hallazgos reportados aquí sugieren que la combinación de curcumina y el fármaco aprobado por la FDA lopinavir modulan la vía apoptótica y angiogénica hacia la inhibición del cáncer cervical.

Fatores prognósticos de resposta à quimioterapia em tumores avançados do colo uterino: o papel da neoangiogênese / Prognostic factors for response to chemotherapy in advanced tumors of the uterine cervix: the role of neoangiogenesis

RESUMO Objetivo: analisar a expressão do Fator de Crescimento do Endotélio Vascular (VEGF), seu receptor (VEGFR-2), idade e tipo histológico de carcinomas avançados de colo uterino com relação à resposta clínica à quimioterapia neoadjuvante. Métodos: foram incluídas 40 pacientes com diagnóstico de carcinoma de colo uterino (IB2 e IVA), com biópsias prévias ao tratamento. Todas as pacientes foram submetidas à quimioterapia neoadjuvante e avaliadas quanto à resposta clínica e à expressão do VEGF. Considerou-se boa resposta clínica uma regressão tumoral total ou maior do que 50%. Resultados: em relação à resposta à quimioterapia, 18 pacientes (45%) apresentaram boa resposta e 22 (55%), má resposta. Quanto à expressão do VEGF, em 16 pacientes foi considerada positiva e em 24, negativa. Quando os casos foram analisados separadamente em relação à resposta à quimioterapia, somente a expressão positiva de VEGF foi associada à boa resposta clínica (p=0,0157). Conclusão: a expressão de VEGF mostrou ser isoladamente, um importante marcador de boa resposta ao tratamento quimioterápico neoadjuvante das pacientes com carcinoma avançado de colo uterino.

ABSTRACT Objective: to analyze the expression of Vascular Endothelial Growth Factor (VEGF), its receptor (VEGFR-2), age and histological type of advanced cervical carcinomas with respect to the clinical response to neoadjuvant chemotherapy. Methods: we studied 40 patients with cervical carcinoma (IB2 and IVA) diagnosed by biopsies prior to treatment. All patients underwent neoadjuvant chemotherapy and evaluation for clinical response and expression of VEGF. We considered a tumor regression greater than 50% as a good clinical response. Results: eighteen patients (45%) had good response to chemotherapy, and 22 (55%), poor response. VEGF expression was positive in 16 patients and negative in 24. When analyzed separately for response to chemotherapy, only the positive expression of VEGF was associated with good clinical response (p=0.0157). Conclusion: VEGF expression alone was an important marker of good response to neoadjuvant chemotherapy in patients with advanced carcinoma of the cervix.

Antineoplastic potential of the aqueous crude extract of Eugenia uniflora L. in human cervical cancer

Abstract Considering the high prevalence of human cervical cancer and the adverse effects of the available treatments, it is important to develop studies involving plants. Eugenia uniflora L. is a Brazilian native plant widely used in folk medicine and some biological effects have already been described. In this study, we investigated the biologicals effects of the aqueous crude extract of E. uniflora leaves in relation to the viability of human cervical cancer cells (SiHa), non-tumorigenic cells HaCaT and human lymphocytes. Our results demonstrated that different concentrations of E. uniflora's extract significantly inhibited the viability of the Siha cell line at 24, 48 and 72 hours of treatment, but did not induce significant changes in the HaCat cell line and human lymphocytes. Tumor cells had adhesion capacity, migration processes, ability of colony forming and the potential to recover its viability after treatment. withdrawal, significantly reduced. The nuclear morphology revealed chromatin condensation, and the flow cytometry showed predominantly cell death by apoptosis in the treated tumor cells. Therefore, the E. uniflora's extract may contribute for future studies aiming at new therapeutic perspectives for human cervical cancer.

Oxidative stress: therapeutic approaches for cervical cancer treatment

OBJECTIVES: Oxidative stress results from an imbalance between the generation and elimination of oxidant species. This condition may result in DNA, RNA and protein damage, leading to the accumulation of genetic alterations that can favor malignant transformation. Persistent infection with high-risk human papillomavirus types is associated with inflammatory responses and reactive oxygen species production. In this context, oxidative stress, chronic inflammation and high-risk human papillomavirus can act in a synergistic manner. To counteract the harmful effects of oxidant species, protective molecules, known as antioxidant defenses, are produced by cells to maintain redox homeostasis. In recent years, the use of natural antioxidants as therapeutic strategies for cancer treatment has attracted the attention of the scientific community. This review discusses specific molecules and mechanisms that can act against or together with oxidative stress, presenting alternatives for cervical cancer prevention and treatment.

Influence of chemoradiotherapy on nutritional status, functional capacity, quality of life and toxicity of treatment for patients with cervical cancer / Influência da quimiorradioterapia no estado nutricional, capacidade funcional, qualidade de vida e toxicidade do tratamento para pacientes com câncer cervical

Introduction: The adverse effects provoked by antineoplastic therapy may aggravate preexisting alterations of the nutritional status and can result in a larger chance of toxicity, bringing about other adverse consequences, such as a diminished response and tolerance of the treatment and reduction of quality of life (QoL). Objective: The objective of this study was to assess the influence of chemoradiotherapy on the nutritional status, functional capacity, and quality of life (QoL), associating these indicators with toxicity and interruption of oncologic treatment in women with cervical cancer. Methods: Prospective cohort study performed on 49 women, who underwent treatment between August 2015 and January 2016. For data collection, two appointments took place with the researcher in charge: the first one occurring the day before the first chemotherapy session (T0) and the other one after 35 days (T1). Nutritional status was measured by anthropometry and computed tomography (skeletal muscle index ­ SMI), functional capacity by handgrip strength (HGS) and Karnofsky Perfomace Status (KPS), and application of QoL questionnaire (EORTC QLQ-C30). Results: There was significant reduction in weight, BMI, HGS, KPS and QoL between T0 and T1. The interruption of chemotherapy was significantly associated with the variables of nutritional status assessed, in addition to a significant QoL reduction according to worsening nutritional status. Women that interrupted their treatment due to acute toxicity also had an SMI median significantly smaller in relation to those who concluded the treatment and 83% of these patients presented cachexia. Conclusion: Chemoradiotherapy treatment in patients with cervical cancer had changed negatively nutritional parameters, function capacity and QoL.(AU)

Introdução: Os efeitos adversos provocados pela terapia antineoplásica podem agravar alterações preexistentes do estado nutricional, que resultam em maior chance de toxicidade, além de outras consequências adversas, como diminuição da resposta e tolerância ao tratamento e redução da qualidade de vida (QV). Objetivo: O objetivo do estudo foi avaliar a influência da quimiorradioterapia sobre o estado nutricional, capacidade funcional e QV, associando esses indicadores à toxicidade e interrupção do tratamento oncológico em mulheres com câncer de colo uterino. Método: Foi realizado um estudo de coorte prospectivo com 49 mulheres submetidas ao tratamento quimiorradioterápico entre agosto de 2015 e janeiro de 2016. Para coleta de dados, foram realizadas duas consultas com o pesquisador responsável: a primeira ocorreu no dia anterior à primeira sessão de quimioterapia (T0) e a outra após 35 dias (T1). Em ambas as consultas, o estado nutricional foi avaliado por antropometria, a capacidade funcional pela força de preensão palmar (FPP) e pelo Karnofsky Performance Status (KPS) e foi aplicado um questionário específico para QV (EORTC QLQ-C30). Adicionalmente, foi utilizada a tomografia computadorizada para avaliação da massa magra (índice de músculo esquelético - IME) disponível no T0. Resultados: Houve redução significativa no peso, IMC, FPP, KPS e QV entre T0 e T1. A interrupção da quimioterapia foi significativamente associada às variáveis de estado nutricional, além de uma redução significativa da QV de acordo com a piora do estado nutricional. As mulheres que interromperam seu tratamento devido à toxicidade aguda também apresentavam mediana de IME significativamente menor em relação àquelas que concluíram o tratamento e 83% dessas pacientes apresentaram caquexia. Conclusão: O tratamento quimiorradioterápico em pacientes com câncer de colo uterino impactou negativamente nos parâmetros nutricionais, na capacidade funcional e na QV.(AU)

Manejo terapéutico y supervivencia del cáncer de cuello uterino en el Instituto Nacional de Oncología y Radiobiología (2004-2010) / Therapeutic management and survival of cervical cancer at the National Institute of Oncology and Radiobiology (2004-2010)

Introducción: el cáncer de cuello uterino es uno de los principales problemas de la salud pública en el mundo por sus altas tasas de incidencia y mortalidad en la mujer. Objetivos: describir el manejo de las pacientes diagnosticadas con cáncer cérvico uterino admitidas y atendidas en el Instituto Nacional de Oncología y Radiobiología. Método: estudio descriptivo, retrospectivo en una serie de 853 pacientes diagnosticadas con cáncer de cuello uterino (estadios IA-IVA, FIGO 2009). Se realizaron pruebas de hipótesis y análisis de supervivencia. Para la estimación de la supervivencia se utilizó el método estadístico de Kaplan-Meier. Se aplicó la prueba de Long Rank para comparar la supervivencia por estratos. Se consideró como diferencia estadísticamente significativa p< 0,05. Resultados: edad promedio de las pacientes, 49,7 años (DS: ± 13,9), 56,6 por ciento no se habían realizado la citología cervical. El seguimiento citológico, según establece el Programa de Diagnóstico Precoz del Cáncer de Cuello Uterino, se cumplió por 84,1 por ciento de las mujeres pesquisadas; en 15,9 por ciento de los casos, el periodo de seguimiento citológico fue superior a los 3 años. El carcinoma epidermoide fue la variedad histológica más frecuente (88,2 por ciento). Del total de pacientes, 87,1 por ciento fueron diagnosticadas en estadios localmente avanzados (FIGO IB2-IVA). La modalidad terapéutica más empleada fue la quimio radioterapia concurrente. La tasa de supervivencia global al diagnóstico fue de 47,2 por ciento. La mediana de supervivencia fue de 4 años. La edad al diagnóstico y el estadio del tumor mostraron una asociación estadísticamente significativa con la supervivencia global (p< 0,005). Conclusiones: la incidencia y mortalidad de cáncer de cuello uterino, así como su estabilidad en el último quinquenio, exigen la realización de estudios de mayor alcance e investigaciones dirigidas a la evaluación de los programas, sistemas y servicios de salud implicados(AU)

Introduction: cervical cancer is one of the main public health problems in the world due to its high incidence and mortality rates in women. Objective: to describe the management of patients diagnosed with uterine cervical cancer admitted and treated at the National Institute of Oncology and Radiobiology. Method: descriptive, retrospective study in a series of 853 patients diagnosed with cervical cancer (stages IA-IVA, FIGO 2009). Hypothesis testing and survival analysis were performed. The Kaplan-Meier statistical method was used to estimate survival. The Long Rank test was used to compare survival by strata. Statistically significant difference was considered p < 0.05. Results: mean age of the patients, 49.7 years (DS: ± 13.9), 56.6 percent had not performed the cervical cytology. Cytological follow-up, according to the Early Diagnosis Program of Cervical Cancer, was met by 84.1 percent of the women surveyed; in 15.9 percent of the cases, the cytological follow-up period was superior to 3 years. Epidermoid carcinoma was the most frequent histological variety (88.2 percent). Of the total number of patients, 87.1 percent were diagnosed in locally advanced stages (FIGO IB2-IVA). The most commonly used therapeutic modality was concurrent chemo radiotherapy. The overall survival rate at diagnosis was 47.2 percent. The median survival was 4 years. Age at diagnosis and tumor stage showed a statistically significant association with overall survival (p < 0.005). Conclusion: cervical cancer incidence and mortality, as well as its stability over the last five years, require more extensive studies and research aimed at evaluating the health programs, systems and services involved(AU)

TMPYP4 exerted antitumor effects in human cervical cancer cells through activation of p38 mitogen-activated protein kinase

BACKGROUND: The aim of the present study was to investigate the potential effects of the 5,10,15,20-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP4) on the proliferation and apoptosis of human cervical cancer cells and the underlying mechanisms by which TMPyP4 exerted its actions. RESULTS: After human cervical cancer cells were treated with different doses of TMPyP4, cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) method, the apoptosis was observed by flow cytometry (FCM), and the expression of p38 mitogen-activated protein kinase (MAPK), phosphated p38 MAPK (p-p38 MAPK), capase-3, MAPKAPK2 (MK-2) and poly ADP-ribose polymerase (PARP) was measured by Western blot analysis. The analysis revealed that TMPyP4 potently suppressed cell viability and induced the apoptosis of human cervical cancer cells in a dose-dependent manner. In addition, the up-regulation of p-p38 MAPK expression levels was detected in TMPyP4-treated human cervical cancer cells. However, followed by the block of p38 MAPK signaling pathway using the inhibitor SB203580, the effects of TMPyP4 on proliferation and apoptosis of human cervical cancer cells were significantly changed. CONCLUSIONS: It was indicated that TMPyP4-inhibited proliferation and -induced apoptosis in human cervical cancer cells was accompanied by activating the p38 MAPK signaling pathway. Taken together, our study demonstrates that TMPyP4 may represent a potential therapeutic method for the treatment of cervical carcinoma.

Seguimento de pacientes após a realização de biópsia excisional da zona de transformação do colo uterino: análise de fatores associados a doença persistente ou recorrente / Follow-up of patients after excisional biopsy of the transformation zone of uterine cervix: analysis of factors associated with persistent or recurrent disease

O câncer de colo uterino é mundialmente o quarto tipo de câncer entre as mulheres, e a neoplasia intraepitelial cervical (NIC) é a lesão precursora deste tipo de câncer, sendo importante a análise de fatores que estariam relacionados à persistência ou recorrência deste tipo de lesão. O presente estudo realizou o levantamento das biópsias excisionais da zona de transformação do colo uterino realizadas no Hospital Universitário da Universidade Federal de Juiz de Fora, no período de 2009 a 2012, a fim de se analisar o grau histológico das lesões (neoplasia intraepitelial cervical grau I, II ou III) e status da margem destas, correlacionando estes dados à possível detecção de doença recorrente ou persistente. Trata-se de um estudo retrospectivo que analisou resultados histopatológicos de material da excisão da zona de transformação (EZT) do colo uterino de pacientes com diagnóstico de neoplasia intraepitelial cervical grau I, II ou III, realizados entre os anos de 2009 a 2012, levando-se em consideração tipo de lesão diagnosticada neste exame, status da margem, presença de substituição glandular e ocorrência de doença persistente/recorrente, esta última avaliada através de exames citológicos e histopatológicos feitos até 24 meses após a excisão da zona de transformação. A média de idade das pacientes foi de 32 anos. Verificou-se que a maior parte das pacientes que tiveram margem comprometida apresentou NICIII como lesão ao diagnóstico da EZT. Assim, nesta análise, o tipo de lesão ao diagnóstico da biópsia excisional (EZT) interfere em se ter a margem comprometida ou não. A maioria das pacientes (63%) não apresentou recidiva e não teve margem comprometida (76%) e entre as pacientes que recidivaram (36%), grande parte também não possuía margem comprometida (70,7%), o que chama atenção para o fato de que mesmo pacientes com margens livres de lesão devem realizar seguimento adequado.

Avaliação da qualidade de vida de mulheres com carcinoma do colo do útero em quimioterapia paliativa / Evaluation of quality of life in women with cervical cancer undergoing palliative chemotherapy / Calidad de la vida de las mujeres en evaluación útero con carcinoma de cuello uterino en quimioterapia paliativa

Introdução: No câncer do colo do útero, a avaliação da qualidade de vida é de suma importância, pois identifica aspectos relacionados ao bem-estar físico, mental e social que são afetados pela doença. Objetivo: Avaliar o impacto do tratamento quimioterápico paliativo com carboplatina e paclitaxel na qualidade de vida relacionada à saúde de mulheres com câncer do colo uterino. Método: Trata-se de um estudo descritivo, não comparativo, sobre qualidade de vida de pacientes com câncer do colo do útero submetidas ao primeiro tratamento quimioterápico paliativo no período de 1 de abril a 30 de julho de 2015. Foram coletados dos prontuários dados sociodemográficos, e a qualidade de vida foi mensurada por meio da aplicação de questionário validado antes da realização do primeiro, segundo, quarto e sexto ciclos da quimioterapia. Para analisar a magnitude das alterações das variáveis, foram empregados os critérios estabelecidos por Osoba; e, para a análise de diferenças significativas entre as medidas, foi utilizado o teste de Wilcoxon. Resultados: Foi observado um impacto negativo nos sintomas da diarreia e neuropatia periférica, bem como melhora da capacidade emocional, física, funcional e social, além da minimização de sintomas como fadiga, dor, falta de apetite, náuseas e vômito e constipação. Contudo, não foi possível observar diferença estatística na alteração do estado geral de saúde ao longo do tratamento. Conclusão: Apesar do impacto positivo observado em diversos sintomas e funções, não foi possível observar melhora da qualidade de vida das pacientes avaliadas.

Introduction: In cervical cancer, evaluating quality of life, is very important because it identifies aspects related to physical, mental and social well-being that are affected by the disease. Objective: To evaluate the impact of palliative chemotherapy with carboplatin and paclitaxel on quality of life related to health in women with cervical cancer. Method: This is an observational prospective study of quality of life in patients with cervical cancer undergoing the first palliative chemotherapy in the period from 1 April to 30 July 2015. Sociodemographic data were collected from medical records and quality of life was measured by a validated questionnaire prior to undergoing the first, second, fourth and sixth chemotherapy cycles. To analyze the magnitude of the change of variables, the criteria established by Osoba were used and statistical significance analysis was performed using the Wilcoxon test. Results: A negative impact was observed in the symptoms of diarrhea, and peripheral neuropathy, as well as improvement in emotional, physical, functional and social capacity and minimizing of symptoms such as fatigue, pain, loss of appetite, nausea and vomiting and constipation. However, it was not possible to observe statistically significant differences in change in general health during the treatment. Conclusion: Despite the positive impact observed on various symptoms and functions, it was not possible to observe improvement in the quality of life of the patients evaluated.

Introducción: En el cáncer de cuello uterino, la evaluación de la calidad de vida, es muy importante, ya que identifica los aspectos relacionados con el bienestar físico, mental y social que se ven afectados por la enfermedad. Objetivo: Evaluar el impacto de la quimioterapia paliativa con carboplatino y paclitaxel en la calidad de vida relacionada con la salud de las mujeres con cáncer de cuello uterino. Método: Se realizó un estudio descriptivo no comparativo sobre la calidad de vida de pacientes con cáncer de cuello uterino, sometidas al tratamiento de quimioterapia paliativa en el período del 1 de abril al 30 de julio del año 2015 se obtuvieron de los registros médicos de datos sociodemográficos y de calidad de vida se midió mediante un cuestionario validado antes de el primer, segundo, cuarto y sexto ciclo de quimioterapia. Para analizar la magnitud del cambio de variables, se utilizaron los criterios establecidos por Osoba y para el análisis de diferencias significativas entre las medidas se realizó mediante el test de Wilcoxon. Resultados: Se observó un impacto negativo en los síntomas de diarrea, y la neuropatía periférica, así como la mejora de la capacidad emocional, problemas físicos, funcionales y sociales y la minimización de los síntomas tales como fatiga, dolor, pérdida de apetito, náuseas y vómitos y estreñimiento. Sin embargo, no fue posible observar diferencias estadísticamente significativas en el cambio en la salud general durante el tratamiento. Conclusión: A pesar del impacto positivo observado en diversos síntomas y funciones, no fue posible observar mejoría en la calidad de vida de las pacientes evaluadas.

Evaluación de seguridad de la vacuna contra el virus del papiloma humano / Safety assessment of the human papillomavirus vaccine

Introducción: el cáncer de cuello uterino es en Colombia el segundo cáncer con mayor frecuencia y mortalidad en mujeres. Las vacunas contra el virus del papiloma humano (VPH) han mostrado efectividad para prevenir la infección por el virus y las lesiones precancerosas asociadas, sin embargo, se han reportado eventos negativos en salud, posiblemente asociados con la aplicación de la vacuna. Objetivo: examinar la seguridad del uso de la vacuna profiláctica contra el VPH. Metodología: se realizó una búsqueda sistemática en MEDLINE, EMBASE, Cochrane Database, IBECS, LILACS y fuentes complementarias. La selección de estudios se realizó por dos revisores independientes de acuerdo con criterios de elegibilidad predefinidos. Se incluyeron estudios experimentales, observacionales analíticos y observacionales descriptivos que reportaran desenlaces de seguridad y efectividad de la vacuna contra el VPH. La calidad de los estudios analíticos fue valorada mediante herramientas previamente definidas, de acuerdo a cada diseño. Los estudios descriptivos fueron considerados con alta probabilidad de sesgo. La calidad de la evidencia fue evaluada para cada desenlace reportado mediante la etodología Grading of Recommendations Assessment, Development and Evaluation (GRADE). Los resultados por cada desenlace fueron reportados de forma narrativa y presentados en perfiles de evidencia GRADE (estudios analíticos) y tablas de evidencia genéricas (estudios descriptivos). Resultados: fueron seleccionados 112 estudios que reportaron 305 resultados de desenlaces de seguridad reportados \r\nposterior a la aplicación de la vacuna contra el VPH, que incluyeron desenlaces para los cuales la vacunación mostró asociación estadísticamente significativa como factor de riesgo, desenlaces para los cuales la vacunación no mostró asociación como factor de riesgo, y desenlaces para los cuales la vacunación mostró resultados inconsistentes. La calidad de la evidencia fue baja y muy baja para la mayoría de los resultados reportados. Discusión y conclusión: Las principales debilidades de la evidencia identificada fueron falta de periodos adecuados de seguimiento para eventos de aparición tardía, falta de precisión de los resultados, y limitaciones en la medición de los desenlaces, verificación del periodo de latencia de \r\nlos mismos y control de los potenciales factores de confusión. Los determinantes más relevantes de \r\nla calidad fueron la falta de precisión de los resultados, probablemente por la baja frecuencia de los \r\neventos, y el carácter observacional de los estudios que evaluaron la mayor parte de los desenlaces \r\nreportados. Los resultados de asociación reportados no permiten establecer causalidad entre los \r\neventos y la vacunación. La baja calidad de la evidencia no implica que los resultados no sustenten \r\nla existencia, o no, de las asociaciones evaluadas; ni que los resultados no sean suficientes para \r\norientar decisiones; sino que es probable que estudios con mayor rigor metodológico muestren \r\nresultados diferentes. La mejor evidencia disponible hasta la fecha sustenta un adecuado perfil de \r\nseguridad de la vacuna contra el VPH, similar al reportado por la OMS para otras vacunas, que apoya \r\nsu utilización teniendo en cuenta los beneficios reportados en la literatura; sin que sea posible descartar la ocurrencia de eventos adversos graves raros, por lo cual es recomendable la \r\nimplementación de un sistema de vigilancia posvacunación, que garantice un apropiado reporte, \r\ndiagnóstico, seguimiento, análisis y retroalimentación a los usuarios, de los posibles eventos adversos de la vacunación, con enfoque en los eventos descritos en esta evaluación. (AU)

Evaluación de la citotoxicidad de extractos marinos sobre un panel de líneas celulares / Evaluation of cytotoxicity of different marine extracts in a cell line panel

Introducción: los extractos naturales provenientes de fuentes marinas representan una importante fuente en el descubrimiento de nuevos compuestos con potencialidades como anticarcinogénicos. Objetivos: determinar el efecto de cinco extractos provenientes de diferentes organismos marinos sobre la viabilidad de un panel de cinco líneas celulares (A549, HEp-2, MDA-MB-231, SiHa y MRC-5). Metodos: el efecto de los extractos (Physalia physali, Cassiopea xamachana, Tripneustes ventricosus, Echinometra lucunter) se determinó mediante el ensayo colorimétrico con el empleo de bromuro de 3(4,5 dimetil-2-tiazoil)-2,5-difeniltetrazolio. Mediante de RT-PCR se determinó adicionalmente el efecto del extracto de Echinometra lucunter sobre la expresión de los genes apoptóticos p53, survivin, bcl-xL y noxa en SiHa. Resultados: todos los extractos afectaron la viabilidad celular de la línea normal MRC-5 de pulmón humano. Sin embargo, no disminuyeron la viabilidad de las líneas celulares de origen tumoral con excepción del extracto de Echinometra lucunter. Este extracto solo afectó la viabilidad de la línea celular tumoral SiHa. Los valores de las concentraciones inhibitorias medias (CI50) mostraron que solo para el extracto de Echinometra lucunter, la línea celular tumoral SiHa evidenció una CI50 de 52,07±11 µg/mL que es significativamente inferior a MRC-5 con una CI50 de 98,6±14 µg/mL, por lo que se muestra selectividad frente a las células tumorales. Adicionalmente, el extracto disminuyó significativamente la expresión de los genes proapoptóticos lo que sugiere la muerte celular por necrosis en las células SiHa. Conclusiones: el extracto proveniente de Echinometra lucunter resultó selectivo frente a las células tumorales SiHa. Experimentos que incluyan otras líneas celulares de cáncer cérvicouterino podrían confirmar el potencial de este extracto frente a esta variedad histológica de cáncer(AU)

Introduction: natural extracts from marine sources represent an important source for the discovery of new compounds with anti-carcinogenic potentialities. Objectives: to determine the effect of five extracts from several marine organisms pm the viability of a panel of five cell lines (A549, HEp-2, MDA-MB-231, SiHa y MRC-5). Methods: the effects of the extracts (Physalia physali, Cassiopea xamachana, Tripneustes ventricosus, Echinometra lucunter) were then determined by using the colorimetric assay with 3 (4,5 dimethyl-2-tiazoil)/2,5-difeniltetrazolium bromide. Additionally, the effect of extract of Echinometra lucunter was determined on the expression of apoptotic genes p53, survivin, bcl-xL and noxa in SiHa. Results: all the extracts affected the cell viability of the normal cell line MRC-5 of the human lung. However, viability of tumoral cell lines did not decrease except for the extract from Echinometra lucunter. This extract just affected the viability of tumor cell line SiHa. The mean inhibitory concentrations (IC50) showed that only for Echinometra lucunter extract, the tumor cell line SiHa revealed a IC50 of 52,07±11 µg/mL that is significantly lower than that of MRC-5 with IC50 of 98,6±14 µg/mL, therefore the selectivity against the tumor cells was shown. Moreover, the extract markedly decreased the expression of propapoptosis genes, thus indicating the cell death from necrosis in SIHa cells. Conclusions: extract from Echinometra lucunter was selective against tumor cells SiHa. Other experiments that will include other cervix uterine cancer cell lines can confirm the potential of this extract to have an effect on this histological cancer type(AU)

Análisis retrospectivo institucional de tratamiento quimio-radioterápico definitivo en cáncer de cuello uterino localmente avanzado / Institutional retrospective analysis of definitive chemo-radiotherapy treatment in locally advanced cervical cancer

El objetivo fue analizar retrospectivamente, en pacientes con cáncer de cuello uterino localmente avanzado tratados en nuestro centro, el perfil de toxicidad de la radioterapia concurrente con platinos mono droga o combinados con gemcitabine y su impacto en el tratamiento. Estudio descriptivo, retrospectivo y observacional de pacientes con cáncer de cuello uterino localmente avanzado (estadios IIa/IVa) desde marzo de 2011 a febrero de 2016. Se analizaron características patológicas, dosis de tratamiento radiante y quimioterápico, así como toxicidades graves (GIII/IV) y su impacto en el tratamiento, observado como reducción o suspensión de dosis y/o split de radioterapia (RT). Se evaluaron 60 pacientes, edad mediana 47 años (17-75), 93% PS0-1. Histología: escamoso (89%) y adenocarcinoma (8%). Estadio IIb 24 (40%) y IIIb 16 (27%). Dosis de RT utilizada 5040cGy; 35 (58%) realizaron boost y 47 (78%) braquiterapia posterior. Cuarenta y cinco realizaron tratamiento concurrente con PLA y 15 con platinos/gemcitabine (PLA/GEM). En el grupo que recibió PLA, uno requirió reducción de dosis de quimioterapia (QT), dos suspendieron algún ciclo por toxicidad y tres realizaron split de RT. El 100% completó el tratamiento de quimioradioterapia (QRT) concurrente. En el grupo que recibió PLA/GEM: 9 requirieron reducción de dosis de QT, 11 suspendieron algún ciclo y 4 no completaron el esquema por toxicidad; 4 hicieron split de RT, y 87% completó el tratamiento de RT. En este estudio, el esquema concurrente con quimioterapia combinada muestra mayor toxicidad que impacta en el cumplimiento del tratamiento, 15% no lo completó por toxicidades graves. No obstante, un correcto manejo institucional de toxicidades, permite utilizar la combinación de tratamiento para obtener potenciales beneficios (AU)

This is a retrospective analysis of profile toxicity and treatment impact of gemcitabine plus platinum radiotherapy in patients with locally advanced cervix cancer, treated at our Centre. Descriptive, retrospective and observational study of patients with locally advanced cervix cancer (Ila/IVa stages), since March 2011 until February 2016. The analysis included the pathological characteristics, chemo radiotherapy doses, as well as severs toxicity (GIII/V) and it impact in treatment observed as reduction or suspension of doses and/or radiotherapy (RT) split. There were evaluated 60 patients of 47 median age (17-75), 93-5 PS0-1. Histology: 89% of squamous cell carcinoma and 8% of adenocarcinoma. 40% of IIb 24 and 27% of IIIB 16 stages. RT doses used 5040cGy; 35 pts (58%) did boost and 47 pts (78%) followed with brachytherapy. 45pts took PLA concurrent treatment, 15pts gemcitabine plus platinum (PLA/GEM). Regarding PLA group, one required a doses reduction of chemotherapy (QT), 2pts suspended a cycle due to toxicity and 3pts did RT split. 100% pts completed chemo radiotherapy (QRT) concurrent treatment. Regarding PLA/GEM group: 9pts required QT doses reduction, 11pts suspended a cycle due to toxicity and 4 didn´t complete the cycle due to toxicity; 4 did RT split and 87% completed RT. The study shown that the scheme of concurrent combined chemotherapy presents higher toxicity that impacts in the fulfillment of treatment, 66 ONCOLOGÍA CLÍNICA - Vol. 21 Nº 3 - Diciembre 2016 15% couldn´t complete due to sever toxicity. However, a correct institutional manage of toxicities allows to use treatment combination to obtain potential benefits (AU)

In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells

BACKGROUND: Computer-based technology is becoming increasingly essential in biological research where drug discovery programs start with the identification of suitable drug targets. 2-Methoxyestradiol (2ME2) is a 17ß-estradiol metabolite that induces apoptosis in various cancer cell lines including cervical cancer, breast cancer and multiple myeloma. Owing to 2ME2's poor in vivo bioavailability, our laboratory in silico-designed and subsequently synthesized a novel 2ME2 analogue, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol), using receptor- and ligand molecular modeling. In this study, the biological effects of ESE-15-ol (180 nM) and its parent molecule, 2ME2 (1 µM), were assessed on morphology and apoptosis induction in cervical cancer cells. RESULTS: Transmission electron microscopy, scanning electron microscopy and polarization-optical transmitted light differential interference contrast (PlasDIC) images demonstrated morphological hallmarks of apoptosis including apoptotic bodies, shrunken cells, vacuoles, reduced cell density and cell debris. Flow cytometry analysis showed apoptosis induction by means of annexin V-FITC staining. Cell cycle analysis showed that ESE-15-ol exposure resulted in a statistically significant increase in the G2M phase (72%) compared to 2ME2 (19%). Apoptosis induction was more pronounced when cells were exposed to ESE-15-ol compared to 2ME2. Spectrophotometric analysis of caspase 8 activity demonstrated that 2ME2 and ESE-15-ol both induced caspase 8 activation by 2- and 1.7-fold respectively indicating the induction of the apoptosis. However, ESE-15-ol exerted all of the above-mentioned effects at a much lower pharmacological concentration (180 nM) compared to 2ME2 (1 µM physiological concentration). CONCLUSION: Computer-based technology is essential in drug discovery and together with in vitro studies for the evaluation of these in silico-designed compounds, drug development can be improved to be cost effective and time consuming. This study evaluated the anticancer potential of ESE-15-ol, an in silico-designed compound in vitro. Research demonstrated that ESE-15-ol exerts antiproliferative activity accompanied with apoptosis induction at a nanomolar concentration compared to the micromolar range required by 2ME2. This study is the first study to demonstrate the influence of ESE-15-ol on morphology, cell cycle progression and apoptosis induction in HeLa cells. In silico-design by means of receptor- and ligand molecular modeling is thus effective in improving compound bioavailability while preserving apoptotic activity in vitro.