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1.
Drugs Today (Barc) ; 57(3): 187-197, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33729216

RESUMO

The use of monoclonal antibodies directed against programmed cell death protein 1 (PD-1) and its ligand, programmed cell death 1 ligand 1 (PD-L1), widely extends to a large number of tumors such as melanoma, non-small cell lung, renal or lymphomas, among others. Some of them are already approved as first- or second-line treatment, as pembrolizumab, nivolumab or cemiplimab. Dostarlimab is an investigational humanized anti-PD-1 that is being developed both in monotherapy and as combination therapy, for gynecological tumors but also for lung cancer or melanoma. The preliminary results, particularly in endometrial cancer, show a high affinity against PD-1 with encouraging clinical activity. Here we summarize the development of this compound as well as the current preclinical and clinical data and potential future development.


Assuntos
Antineoplásicos Imunológicos , Neoplasias do Endométrio , Neoplasias Pulmonares , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1 , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico
2.
Support Care Cancer ; 29(1): 213-222, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32338316

RESUMO

PURPOSE: To compare rates of complete response (no emesis, retching, or rescue antiemetics) in the late phase (days 4-7 post-chemotherapy) of cycle 1 between transdermal granisetron and oral ondansetron in cervical, endometrial, or vaginal cancer survivors undergoing chemoradiation at The University of Texas MD Anderson Cancer Center and LBJ Hospital in Houston, TX. METHODS: In this non-blinded parallel design trial, eligible patients received a granisetron patch replaced every 7 days or 8 mg of ondansetron thrice daily continued for 72 h after chemotherapy completion. Data were collected on medication compliance, episodes of chemotherapy-induced nausea and vomiting (CINV), use of rescue antiemetics, and effects of CINV on quality of life. RESULTS: Seventy-five survivors receiving chemoradiation for cervical (n = 61), endometrial (n = 12), or vaginal (n = 2) cancer were electronically randomized to transdermal granisetron (n = 41) or oral ondansetron (n = 34). In the late phase of cycle 1, the rate of complete response was 49.8% (95% CI, 35.2-64.3%) for transdermal granisetron and 39.7% (95% CI, 24.4-56.1%) for oral ondansetron. The posterior probability that transdermal granisetron achieved a higher success rate in controlling late-onset CINV compared with oral ondansetron was 82%. During the acute phase (day 1 post-chemotherapy) of cycles 2 and 3, transdermal granisetron patients used more rescue antiemetics than oral ondansetron patients (p = 0.006 and p = 0.003, respectively). Otherwise, no between-group differences in CINV events were observed. Medication compliance and the effect of CINV on quality of life were similar between groups. CONCLUSION: Transdermal granisetron was 82% more like to control CINV than oral ondansetron in the late phase of cycle 1 and performed similarly to oral ondansetron in all other cycles. Transdermal granisetron should be considered an option as prophylactic antiemetic therapy for gynecologic cancer survivors undergoing chemoradiation.


Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Granisetron/uso terapêutico , Náusea/prevenção & controle , Ondansetron/uso terapêutico , Vômito/prevenção & controle , Administração Cutânea , Adulto , Antineoplásicos/uso terapêutico , Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Granisetron/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Ondansetron/administração & dosagem , Qualidade de Vida/psicologia , Indução de Remissão , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias Vaginais/tratamento farmacológico , Vômito/induzido quimicamente , Vômito/tratamento farmacológico
3.
Zhonghua Fu Chan Ke Za Zhi ; 55(12): 857-864, 2020 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-33355761

RESUMO

Objective: To analyze the pregnancy outcome, influencing factors and recurrence of fertility-preserving therapy for women with atypical endometrial hyperplasia (AEH) or endometrial carcinoma (EC). Methods: The multi-center retrospective study included 107 women with AEH or EC for fertility-preserving therapy in 10 hospitals from January 1st, 2009 to December 31st, 2018. The clinical pregnancy rate, live birth rate and recurrence of 66 patients with urgent child-bearing requirements after fertility-preserving treatment were analyzed. Results: (1) Among the 66 AEH and EC women with urgent child bearing requirements, 24 women chose spontaneous pregnancy, the clinical pregnancy rate was 54.2% (13/24) and the live birth rate was 41.7% (10/24), the median time from fertility-preserving therapy withdrawal to clinical pregnancy was 5.5 months. Forty-two women chose assisted reproductive technology (ART), the clinical pregnancy rate was 59.5% (25/42) and the live birth rate was 35.7% (15/42), the median time from fertility-preserving therapy withdrawal to clinical pregnancy was 19.5 months. The time from fertility-preserving therapy withdrawal to pregnancy in women receiving ART was significantly longer than that in women with spontaneous pregnancy (P=0.048). (2) Age and intrauterine adhesions were independent factors affecting the clinical pregnancy rate (P<0.05). (3) Among 107 patients with AEH or EC, the recurrence rate was 27.1% (29/107). Among the 42 cases who chose ART, 9 of them recurred before ART treatment, who received the fertility-preserving therapy again and then ART treatment, 8 women got clinical pregnancy,5 of them delivered at least a live birth. Conclusions: Women with AEH or EC could achieved satisfactory clinical pregnancy rate and live birth rate after fertility-preserving therapy. Age and intrauterine adhesions are independent factors affecting clinical pregnancy rate. The women with recurrent AEH or EC could be treated with fertility-preserving therapy again and get a satisfactory pregnancy outcome.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Hiperplasia Endometrial/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Preservação da Fertilidade , Tratamentos com Preservação do Órgão , Resultado da Gravidez/epidemiologia , Adulto , Antineoplásicos Hormonais/administração & dosagem , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/patologia , Endométrio/efeitos dos fármacos , Endométrio/patologia , Feminino , Fertilidade , Humanos , Nascimento Vivo , Recidiva Local de Neoplasia , Gravidez , Taxa de Gravidez , Técnicas de Reprodução Assistida , Estudos Retrospectivos , Resultado do Tratamento
4.
Int J Mol Sci ; 21(24)2020 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-33352687

RESUMO

Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Metilação de DNA , Mutação , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Adulto , Idoso , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Prognóstico , Regiões Promotoras Genéticas , Estudos Retrospectivos , Taxa de Sobrevida
5.
Artigo em Inglês | MEDLINE | ID: mdl-32824293

RESUMO

Background: to elucidate the predictors of progression-free survival (PFS) and overall survival (OS) in high-risk endometrial cancer patients. Methods: the medical records of all consecutivewomen with high-risk endometrial cancer were reviewed. Results: among 92 high-risk endometrial cancer patients, 30 women experienced recurrence, and 21 women died. The 5-year PFS and OS probabilities were 65.3% and 75.9%, respectively. Multivariable Cox regression revealed that body mass index (hazard ratio (HR) = 1.11), paraaortic lymph node metastasis (HR = 11.11), lymphovascular space invasion (HR = 5.61), and sandwich chemoradiotherapy (HR = 0.15) were independently predictors of PFS. Body mass index (HR = 1.31), paraaortic lymph node metastasis (HR = 32.74), non-endometrioid cell type (HR = 11.31), and sandwich chemoradiotherapy (HR = 0.07) were independently predictors of OS. Among 51 women who underwent sandwich (n = 35) or concurrent (n = 16) chemoradiotherapy, the use of sandwich chemoradiotherapy were associated with better PFS (adjusted HR = 0.26, 95% CI = 0.08-0.87, p = 0.03) and OS (adjusted HR = 0.11, 95% CI = 0.02-0.71, p = 0.02) compared with concurrent chemoradiotherapy. Conclusion: compared with concurrent chemoradiotherapy, sandwich chemoradiotherapy was associated with better PFS and OS in high-risk endometrial cancer patients. In addition, high body mass index, paraaortic lymph node metastasis, and non-endometrioid cell type were also predictors of poor OS in high-risk endometrial cancer patients.


Assuntos
Quimioterapia Adjuvante , Neoplasias do Endométrio , Idoso , Intervalo Livre de Doença , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos
6.
Crit Rev Oncol Hematol ; 153: 103016, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32563900

RESUMO

For many decades, the Bokhman dualist vision was used to stratify endometrial cancer (EC) in good or bad tumors. Nowadays, a more robust and reliable molecular stratification is taking place with the The Cancer Genome Atlas Research Network (TCGA) classification bringing new and important information in the field. Collaborative groups are replicating TCGA using accessible tools with immunohistochemistry. It's time to move on and include this information along with pathology features to better delineate adjuvant treatment in EC.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Imuno-Histoquímica
9.
Hum Cell ; 33(3): 801-809, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32388810

RESUMO

Endometrial cancer (EC) is one of the most common cancers among females worldwide. Advanced stage patients of EC have poor prognosis. Inevitable side effects and treatment tolerance of chemotherapy for EC remain to be addressed. Our results in this study showed that EC cells with higher tumor necrosis factor receptor-associated factor 4 (TRAF4) expression have lower sensitivity to poly ADP-ribose polymerase 1 (PARP1) inhibitors. Upon TRAF4 knockdown, the colony numbers of EC cells were markedly down-regulated, and the markers of DNA double-strand breakage were significantly up-regulated after the treatment of olaparib, a PARP1 inhibitor. TRAF4 knockdown reduced the phosphorylation of protein kinase B (Akt), promoted DNA double-strand breakage, and decreased levels of DNA repair related proteins, including phosphorylated-DNA-dependent protein kinase (p-DNA-PK) and RAD51 recombinase (RAD51). In addition, TRAF4's effect on the sensitivity of EC cells to olaparib was further found to be mainly mediated by Akt phosphorylation. Moreover, in vivo results showed that TRAF4 knockdown enhanced the sensitivity of EC to PARP1 inhibitors using a mouse xenograft model. Collectively, our data suggest that combined application of TRAF4 knockdown and PARP1 inhibition can be used as a promising strategy for synthetic lethality in EC treatment.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Técnicas de Silenciamento de Genes , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Quebras de DNA de Cadeia Dupla , Modelos Animais de Doenças , Neoplasias do Endométrio/patologia , Feminino , Expressão Gênica , Humanos , Camundongos , Terapia de Alvo Molecular , Fosforilação/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator 4 Associado a Receptor de TNF/genética , Fator 4 Associado a Receptor de TNF/metabolismo , Células Tumorais Cultivadas
10.
Jpn J Clin Oncol ; 50(7): 753-765, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32463094

RESUMO

Endometrial cancer frequently occurs in post-menopausal women, and the endometrium is a well-known site of cancer affecting women. Endometrial cancer is found with genital bleeding and often at an early stage. However, there are some risks of recurrence after hysterectomy. As a medical treatment after the diagnosis of endometrial cancer, appropriate adjuvant therapy is considered to lead to a decrease in the rate of recurrence and improvement of prognosis according to the determination of the cancer stage from the surgical and histopathological results. In this review, we describe post-operative adjuvant therapy administered for endometrial cancer and advanced disease, focusing on chemotherapy, radiation therapy and the combination of both. These treatments are divided according to the risk of recurrence as based primarily on the reported evidence.


Assuntos
Quimioterapia Adjuvante/métodos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Feminino , Humanos , Prognóstico
11.
Zhonghua Fu Chan Ke Za Zhi ; 55(5): 327-332, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32464721

RESUMO

Objective: To investigate the efficacy and pregnancy outcome of fertility-preserving treatment for patients with stage Ⅰa, grade 2 endometrial cancer (EC). Methods: Clinical data was retrospectively collected for EC or atypical endometrial hyperplasia (AEH) patients treated in Peking University People's Hospital, Foshan First People's Hospital of Guangdong Province and First Affiliated Hospital of Sun Yat-sen University, from 2010 to 2019. Inclusion criteria for fertility-preserving treatment included: (1) Age ≤45 years. (2) EC with histological differentiation of G(1), G(2) or endometrial AEH. (3) EC disease should be stage Ⅰa, confined to the endometrium without myometrial invasion, lymph node or extrauterine metastasis. Treatment regimen: patients were given oral progestin therapy and endometrial pathology was evaluated every three months. Patients were divided into three groups as G(2) EC group, G(1) EC group and AEH group based on the histological differentiation. Oncological and pregnancy outcomes were compared among them. Results: (1) Totally 57 eligible patients were included in this study, including 11 cases with G(2) EC, 22 cases with G(1) EC, and 24 cases with AEH. (2) Oncological outcome: among the three groups of G(2) EC, G(1) EC and AH, the complete remission rates (9/11, 91% and 96%, respectively) and recurrence rates (3/9, 30% and 22%, respectively) were not significantly different (all P>0.05). Median remission time was significantly longer in the G(2) EC group than those in the other two groups (8, 6 and 4 months; P=0.046). Among 9 G(2) EC patients who recurred after complete remission, three patients relapsed at 7, 18 and 53 months, respectively. All 3 patients chose fertility-sparing treatment again, and all achieved complete remission after retreatment. (3) Pregnancy outcome: among the three groups, the assisted reproduction technology rates (4/8, 5/18 and 36%, respectively) and pregnancy rates (6/8, 5/18 and 36%, respectively) had no significant difference (P>0.05). However, time interval to pregnancy was shorter in G(2) EC patientsthan the other two groups (4, 9 and 22 months, respectively; P=0.006). Conclusions: Fertility-preserving treatment for patients with stageⅠa, G(2) endometrial cancer, may obtain a relatively high remission rate and an acceptable pregnancy rate. However, further exploration is needed due to the limited number of cases.


Assuntos
Hiperplasia Endometrial/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Preservação da Fertilidade , Tratamentos com Preservação do Órgão , Progestinas/administração & dosagem , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Resultado do Tratamento
12.
Jpn J Clin Oncol ; 50(8): 882-888, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32322873

RESUMO

OBJECTIVE: This study compared the survival outcomes and the incidence of chemotherapy-related adverse events in endometrial cancer patients who received four and six cycles of adjuvant chemotherapy to examine the optimal number of adjuvant chemotherapy cycles. METHODS: A total of 112 patients with endometrial cancer with a high risk of recurrence were retrospectively enrolled; 46 patients received four cycles and 66 received six cycles of adjuvant chemotherapy. Between-group differences of overall survival, disease-free survival, hematological and non-hematological toxicities were analyzed. Baseline patient's background differences were assessed with inverse probability of treatment weighting using propensity score. RESULTS: Overall and disease-free survivals between the two groups were not significantly different. Paclitaxel + carboplatin, every 3-4 weeks was the most frequently used chemotherapy regimen in both groups. Patients in the six-cycle chemotherapy group developed neutropenia G4 or febrile neutropenia more frequently than those in the four-cycle group; odds ratio (95% confidence interval) is 4.07 (1.51-10.96). Peripheral sensory neuropathy was the most frequently observed non-hematological toxicity; the incidence of peripheral sensory neuropathy was not significantly different between four- and six-cycle chemotherapy group, P = 0.832. The result was same in the subgroup analysis in patients who received TC regimen, P = 0.455. CONCLUSION: This study implies a possible benefit of fewer cycles of adjuvant chemotherapy in endometrial cancer patients with a high risk of recurrence because of the lower incidence of hematological toxicities without impairing survival outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Endométrio/patologia , Recidiva Local de Neoplasia/patologia , Idoso , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Intervalo Livre de Doença , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Probabilidade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
13.
Am Soc Clin Oncol Educ Book ; 40: 1-11, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32239967

RESUMO

Worldwide, the incidence of endometrial cancer is increasing. Although the prognosis remains good for patients diagnosed with early-stage disease, for those diagnosed with recurrent or metastatic disease, options have been limited, and prognosis is short. Optimizing and identifying new well-tolerated treatments for women living with endometrial cancer is a top priority. A new era is dawning where we are starting to see the integration of clinically relevant genomic and pathologic data to inform and refine treatment strategies for women with endometrial cancer. Here, we focus on reviewing nonimmunotherapy-based targeted treatment options and emerging directions for women with endometrial cancer.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Redes Reguladoras de Genes , Terapia de Reposição Hormonal/métodos , Ensaios Clínicos como Assunto , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Medicina de Precisão , Prognóstico
14.
Orv Hetil ; 161(11): 425-433, 2020 Mar.
Artigo em Húngaro | MEDLINE | ID: mdl-32148096

RESUMO

Introduction: Endometrial cancer is the most common invasive gynecologic malignancy in developed countries. The best survival rates are expected after surgical removal, thus the aim of a complex treatment is to achieve resecability in locally and locoregionally advanced disease. Aim: The primary purpose of this study was to evaluate if the neoadjuvant systemic treatment leads to better overall survival compared to irradiation solely. Method: From January 2015 to December 2018, we enrolled 28 patients diagnosed with irresecable, locally and locoregionally advanced high-risk endometrial carcinoma. Patients were treated by neoadjuvant paclitaxel-carboplatin, then radical hysterectomy, bilateral oophorectomy and lymphadenectomy were performed. Results: After administration of 6 cycles of carboplatin-paclitaxel, the control MR test showed tumor shrinkage in all patients. Complete resection was achieved in the case of every patient. Tumor residuum in lymph nodes was verified in 4 cases by pathological evaluation. The 2-year survival and the 2-year progression-free survival rates were 65,1% and 66,1%, respectively. The median overall survival was 16,5 months. Conclusion: Neoadjuvant treatment can be an effective approach in providing the conditions for complete tumor resection, which may result in survival advantage. Despite multimodal treatment, prognosis is poor. Orv Hetil. 2020; 161(11): 425-433.


Assuntos
Carboplatina/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/cirurgia , Terapia Neoadjuvante , Paclitaxel/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino/uso terapêutico , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , Excisão de Linfonodo , Estadiamento de Neoplasias , Ovariectomia , Taxa de Sobrevida , Resultado do Tratamento
15.
Arch Biochem Biophys ; 684: 108327, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32142890

RESUMO

Endometrial carcinoma is a type of gynecological cancer that originates in the endometrial epithelial tissue. Due to its high proliferation and ability to invade muscle tissue, it is one of the most common malignant tumors in the female reproductive system. Fatostatin is a small molecule non-sterol diarylthiazole derivative that acts as a chemical inhibitor of the sterol regulatory-element binding protein (SREBP) pathway. Previous studies have shown that fatostatin has an anti-tumor effect in some cancers. In this study, we investigated the effect of fatostatin on the growth, proliferation, apoptosis, migration and cell cycle of human endometrial carcinoma cells (HEC-1A and AN3 CA cells) using cholecystokinin (CCK) -8 method, clonogenicity assay, wound closure assay, Transwell migration assay and flow cytometer. We also examined its effect on the expression of apoptosis-associated protein (Caspase-3, Caspase-8 and Caspase-9) and level of lipid metabolism-related proteins, free fatty acid, and total cholesterol in cells. The growth of endometrial carcinoma xenografts was measured to confirm the effect of fatostatin in vivo. Our results showed that fatostatin inhibited the growth and proliferation of human endometrial carcinoma cells, changed their cell cycle and induced apoptosis. Based on the preliminary animal experiments, fatostatin also exhibited antitumor activity. The present study adds a new dimension to our understanding of the antitumor effects of fatostatin and provides an experimental basis for its use, and supports its potential value for clinical application.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Piridinas/uso terapêutico , Tiazóis/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Feminino , Humanos , Camundongos Endogâmicos BALB C , Piridinas/farmacologia , Tiazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Clin Chem ; 66(4): 606-613, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32176763

RESUMO

BACKGROUND: Microsatellite instability (MSI) has recently emerged as a predictive pan-tumor biomarker of immunotherapy efficacy, stimulating the development of diagnostic tools compatible with large-scale screening of patients. In this context, noninvasive detection of MSI from circulating tumor DNA stands as a promising diagnostic and posttreatment monitoring tool. METHODS: We developed drop-off droplet-digital PCR (ddPCR) assays targeting BAT-26, activin A receptor type 2A (ACVR2A), and defensin beta 105A/B (DEFB105A/B) microsatellite markers. Performances of the assays were measured on reconstitution experiments of various mutant allelic fractions, on 185 tumor samples with known MSI status, and on 72 blood samples collected from 42 patients with advanced colorectal or endometrial cancers before and/or during therapy. RESULTS: The 3 ddPCR assays reached analytical sensitivity <0.1% variant allelic frequency and could reliably detect and quantify MSI in both tumor and body fluid samples. High concordance between MSI status determination by the three-marker ddPCR test and the reference pentaplex method were observed (100% for colorectal tumors and 93% for other tumor types). Moreover, the 3 assays showed correlations with r ≥ 0.99 with other circulating tumor DNA markers and their dynamic during treatment correlated well with clinical response. CONCLUSIONS: This innovative approach for MSI detection provides a noninvasive, cost-effective, and fast diagnostic tool, well suited for large-scale screening of patients that may benefit from immunotherapy agents, as well as for monitoring treatment responses.


Assuntos
Neoplasias Colorretais/genética , Neoplasias do Endométrio/genética , Biópsia Líquida , Instabilidade de Microssatélites , Reação em Cadeia da Polimerase/métodos , Receptores de Activinas Tipo II/genética , Biomarcadores Tumorais , Linhagem Celular Tumoral , DNA Tumoral Circulante/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Reações Falso-Positivas , Feminino , Marcadores Genéticos , Humanos , Limite de Detecção , Repetições de Microssatélites , beta-Defensinas/genética
17.
Asian Pac J Cancer Prev ; 21(3): 733-741, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32212801

RESUMO

OBJECTIVE: To compare the Ki-67 index of endometrial cancer cells before and after treatment between the metformin and placebo group in women with endometrial cancer (EC). METHODS: This study was a randomized, double-blind, placebo-controlled trial conducting in non-diabetic women who diagnosed with endometrioid EC and had a schedule for elective surgical staging at Rajavithi Hospital between August 2018 and June 2019. Tissue specimens were obtained via endometrial curettage at the time of initial diagnosis (pre-treatment) and hysterectomy (post-treatment) to assess the value of the Ki-67 index by immunochemistry. Patients were randomly assigned into 2 groups: metformin and placebo group. Metformin 850 mg or placebo 1 tab were administered once daily for at least 7 days, starting on the first morning after recruitment until one day before surgery. Baseline characteristics (e.g., age, body mass index, co-morbidities) including surgical and pathological characteristics were recorded. The metabolic effect of metformin was also evaluated by a recording of fasting blood sugar, HbA1C and potential adverse events including nausea, vomiting, dizziness, and hypoglycemic symptom. RESULTS: A total of 49 EC patients were included in this study. Twenty-five patients were assigned to the metformin group and 24 patients were assigned to the placebo group. Baseline demographic, surgical, and pathological characteristics between the 2 groups were similar. Metformin significantly changed the Ki-67 index relative to placebo, with a mean decrease of 23.3% (p=0.001) and a mean proportional decrease of 39.1% (p=0.006) before and after treatment. Additionally, no significant differences were detected in metabolic effects and adverse events between the metformin and the placebo groups. CONCLUSION: Short-term treatment with an oral metformin significantly reduced a proliferative marker Ki-67 index in women with endometrioid EC awaiting surgical staging. This study supports the biological effect of metformin in EC and potential applications in the adjuvant treatment in EC patients.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Metformina/uso terapêutico , Biomarcadores/análise , Proliferação de Células , Método Duplo-Cego , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade
18.
Am Soc Clin Oncol Educ Book ; 40: 1-7, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32213091

RESUMO

Approximately 30% of primary endometrial cancers are microsatellite instability high/hypermutated (MSI-H), and 13% to 30% of recurrent endometrial cancers are MSI-H or mismatch repair deficient (dMMR). Given the presence of immune dysregulation in endometrial cancer as described, immune checkpoint blockade (ICB) has been explored as a therapeutic mechanism, both as monotherapy and in combination with cytotoxic chemotherapy, other immunotherapy, or targeted agents. In MSI-H or dMMR advanced endometrial cancers, PD-1 inhibitors dostarlimab and pembrolizumab have shown response rates of 49% and 57%, respectively, whereas PD-L1 inhibitors avelumab and durvalumab have shown response rates of 27% and 43%, respectively. In microsatellite stable (MSS) or PD-L1-positive advanced endometrial cancers, modest activity of PD-1 inhibitors nivolumab and dostarlimab and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab has been seen, with response rates ranging from 3% to 23%. Based on substantial activity in a phase Ib/II study, the U.S. Food and Drug Administration (FDA) granted lenvatinib and pembrolizumab combination therapy accelerated approval in 2019 for the treatment of advanced endometrial cancer that is not MSI-H or dMMR and has progressed following prior therapy. Although these developments have been highly impactful, a more robust understanding of the molecular and immunologic drivers of response and resistance will be critical to optimally design next-generation studies in endometrial cancer.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Feminino , Humanos , Fatores de Risco
19.
Gynecol Oncol ; 157(2): 348-356, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32085863

RESUMO

OBJECTIVE: Our objectives were 1) to compare the efficacy of progestin therapy combined with metformin (Prog-Met) to Prog alone as primary fertility sparing treatment in women with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) or early-stage endometrioid carcinoma (EC), and 2) to analyze the proportion of women achieving live birth following treatment. METHODS: A retrospective cohort study of all reproductive-aged women with AH/IN or EC treated with Prog ± Met from 1999-2018 was conducted. Complete response (CR) was assessed and Kaplan-Meier analysis used to calculate time to CR. Comparison of potential response predictors was performed with multivariable Cox regression models. RESULTS: Ninety-two women met criteria; 59% (n = 54) were treated for AH/EIN and 41% (n = 38) for EC. Their median age, body mass index, and follow up time was 35 years, 37.7 kg/m2, and 28.4 months, respectively. Fifty-eight women (63%) received Prog and 34 (37%) received Prog-Met. Overall, 79% (n = 73) of subjects responded to treatment with a CR of 69% (n = 63). There was no difference in CR (p = 0.90) or time to CR (p = 0.31) between the treatment cohorts. Overall, 22% experienced a disease recurrence. On multivariable analysis, EC histology was the only covariate associated with a decreased Prog response (HR 0.48; p = 0.007). Only 17% of the cohort achieved a live-birth pregnancy, the majority of which required assisted reproductive technologies (81%) and occurred in the Prog treatment group. CONCLUSIONS: Our study does not support the use of Prog-Met therapy for treatment of AH/EIN or EC. Additionally, fewer than 20% of women achieved a live-birth pregnancy during the study period, with most requiring ART.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma in Situ/tratamento farmacológico , Hiperplasia Endometrial/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Preservação da Fertilidade/métodos , Nascimento Vivo , Adulto , Carcinoma in Situ/patologia , Estudos de Coortes , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Metformina/administração & dosagem , Recidiva Local de Neoplasia/patologia , Gravidez , Resultado da Gravidez , Progestinas/administração & dosagem , Estudos Retrospectivos
20.
Oncology ; 98(4): 195-201, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32036368

RESUMO

PURPOSE: The objective of this study was to evaluate the impact of hormone replacement therapy (HRT) on the prognosis in endometrial cancer (EC) survivors. METHODS: The research was conducted using the following electronic databases: MEDLINE (PubMed), Web of Science, ClinicalTrial.gov, and Cochrane Library. We performed a review of studies published from January 1986 to January 2019. We selected studies that included EC patients submitted to surgery with curative intent and postoperative use of HRT. RESULT: Seven of 1,332 abstracts considered were eligible: 4 retrospective series, 1 prospective study, 1 randomized controlled trial, and 1 population study. Globally in the observed studies there was not a significant increase in the recurrence rate, measured by the relative risk, in the EC survivors using HRT compared with the controls in tumour stages I and II. The bias was that HRT was prescribed only to low-risk patients, who were young and had a low stage of disease. CONCLUSION: This systematic review shows that HRT use had no negative effect on prognosis in EC survivors in tumour stages I and II.


Assuntos
Sobreviventes de Câncer , Neoplasias do Endométrio/mortalidade , Terapia de Reposição Hormonal , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Recidiva Local de Neoplasia/epidemiologia , Prognóstico
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