Borderline ovarian tumors: a review of its biology, molecular profile, and management / Tumores borderline de ovário: uma revisão de sua biologia, perfil molecular e manejo

Borderline ovarian tumors typically exhibit indolent behavior and boast a favorable prognosis; however, a subset of patients experiences disease recurrence and progression to low-grade ovarian carcinoma. The complex biology underlying these phenomena has been illuminated through molecular analyses. KRAS and BRAF mutations have emerged as recurrent ?ndings in borderline ovarian tumors. Speci?cally, KRAS mutations have been linked to a higher risk of recurrence and progression to low-grade ovarian carcinoma, while BRAF mutations seem to confer a protective e?ect, inducing a senescent state that mitigates the likelihood of progression. In this comprehensive review, we explore the biology and the molecular pro?le of borderline ovarian tumors, shedding light on recent discoveries that have enriched our comprehension. Additionally, we discuss the current state of borderline ovarian tumors management. Surgery remains the cornerstone of treatment. While cytotoxic therapies role is limited so far, molecular characterization emphasizes the imminent potential for personalized therapeutic approaches.

Os tumores borderline de ovário geralmente exibem comportamento indolente e apresentam prognóstico favorável; no entanto, um subconjunto de pacientes apresenta recorrência da doença e progressão para carcinoma de ovário de baixo grau. A biologia complexa subjacente a estes fenômenos foi iluminada através de análises moleculares. Mutações KRAS e BRAF surgiram como achados recorrentes em tumores borderline de ovário. Especificamente, as mutações KRAS têm sido associadas a um maior risco de recorrência e progressão para carcinoma de ovário de baixo grau, enquanto as mutações BRAF parecem conferir um efeito protetor, induzindo um estado senescente que mitiga a probabilidade de progressão. Nesta revisão abrangente, exploramos a biologia e o perfil molecular dos tumores borderline de ovário, lançando luz sobre descobertas recentes que enriqueceram nossa compreensão. Além disso, discutimos o estado atual do manejo de tumores borderline de ovário. A cirurgia continua sendo o pilar de tratamento. Embora o papel das terapias citotóxicas seja limitado até o momento, a caracterização molecular enfatiza o potencial iminente para abordagens terapêuticas personalizadas.

Sobreuso de ecografía transvaginal en un hospital universitario privado de Argentina: estudio de corte transversal / Transvaginal ultrasound overuse in a private university hospital in Argentina: a cross-sectional study

Introducción. Si bien contamos con recomendaciones basadas en la evidencia en contra de realizar tamizaje de cáncer ovárico con ecografía transvaginal debido a que aumenta el riesgo de resultados falsamente positivos y de cascadas diagnósticas, sin disminuir la mortalidad por esta enfermedad, su solicitud en mujeres sanas es frecuente. Sin embargo, no conocemos la magnitud de la implementación de esta práctica, que constituye un cuidado de bajo valor. Objetivo. Documentar el sobreuso de ecografías transvaginales realizadas en forma ambulatoria en un hospital universitario privado de Argentina. Métodos. Estudio de corte transversal de una muestra aleatoria de ecografías realizadas en forma ambulatoria durante 2017 y 2018. Mediante revisión manual de las historias clínicas, la solicitud de cada ecografía fue clasificada como apropiada cuando algún problema clínico justificaba su realización, o inapropiada cuando había sido realizada con fines de control de salud o por una condición clínica sin indicación de seguimiento ecográfico. Resultados. De un total de 1.997 ecografías analizadas, realizadas a 1.954 mujeres adultas (edad promedio 50 años),1.345 (67,4 %; intervalo de confianza [IC] 95 % 65,2 a 69,4) habían sido solicitadas en el contexto de un control de saludo sin un problema asociado en la historia clínica y otras 54 (8,3 %; IC 95 % 6,3 a 10,7), por condiciones de salud para las que no hay recomendaciones de realizar seguimiento ecográfico. Conclusiones. Esta investigación documentó una alta proporción de sobre utilización de la ecografías transvaginales en nuestra institución. Futuras investigaciones permitirán comprender los motivos que impulsan esta práctica y ayudarán a diseñar intervenciones para disminuir estos cuidados de bajo valor. (AU)

Background. Although we have evidence-based recommendations against screening for ovarian cancer with transvaginalultrasound because it increases the risk of false positive results and diagnostic cascades without reducing mortality from this disease, its request in healthy women is frequent. However, we do not know the magnitude of the implementation of this practice, which constitutes low-value care. Objective. To document the overuse of transvaginal ultrasounds performed on an outpatient basis in a private university hospital in Argentina. Methods. Cross-sectional study of a random sample of outpatient ultrasounds performed during 2017 and 2018. Through a manual review of the medical records, the request for each ultrasound was classified as appropriate when a clinical problem justified its performance or inappropriate when it was carried out for health control purposes or for a clinical condition that had no indication for ultrasound follow-up. Results. Of a total of 1997 ultrasounds analyzed, performed on 1954 adult women (average age 50 years), 1,345 (67.4 %;95 % confidence interval [CI] 65.2 to 69.4) had been requested in the context of a health check-up or without a documented problem in the medical history that would support its performance, and another 54 (8.3 %; 95 % CI 6.3 to 10.7), for health conditions for which there are no treatment recommendations to perform ultrasound follow-up. Conclusions. This research documented a high proportion of overuse of transvaginal ultrasound in our institution. Future research will allow us to understand the reasons that drive this practice and will help design interventions to reduce thislow-value care. (AU)

Linfoma no Hodgkin difuso de células B grande como linfoma primario de ovario. Presentación de caso / Diffuse large B-cell non-Hodgkin's lymphoma as primary ovarian lymphoma. Case presentation

Fundamento: Los linfomas primarios de ovario son poco frecuentes; el 1 % de estos se presenta en ovario y el 1.5 % de los tumores malignos de ovario son linfomas. Los tipos histológicos más frecuentes es el linfoma no Hodgkin difuso de células B grande y el BurKitt; el tratamiento consiste en cirugía combinada con quimioterapia. Objetivo: Reportar un caso de un linfoma no Hodgkin difuso de células B grande primario de ovario. Presentación de caso: Se presentó el caso de una paciente de 39 años de edad, con antecedentes patológicos personales de salud; la cual fue al cuerpo de guardia de ginecología por presentar dolor abdominal difuso que no se aliviaba con analgésicos. En la exploración física presentaba dolor a la palpación superficial y profunda en hipocondrio y fosa ilíaca derecha con masa tumoral palpable. Ecografía hacia proyección anexial derecha se observó una imagen de baja ecogenicidad y en la laparoscopia de urgencia se concluyó como una formación de aspecto tumoral que parecía corresponderse con ovario derecho. Se le realizó una histerectomía con doble anexectomía. El diagnóstico anatomopatológico fue un linfoma no Hodgkin primario de ovario. Conclusiones: La paciente del caso presentado tuvo una clínica oligosintomática y la confirmación de la enfermedad fue a partir de una muestra quirúrgica, lo que expresa que el diagnóstico del linfoma no Hodgkin de células B es difícil y aunque es poco frecuente siempre se debe tener en cuenta en el diagnóstico diferencial de las tumoraciones unilaterales de ovario.

Background: Primary ovarian lymphomas are uncommon, 1% of these malignancies occur in the ovary, and 1.5% of all ovarian malignancies are lymphomas. The most common histologic types are diffuse large B-cell non-Hodgkin's lymphoma and BurKitt's lymphoma; treatment consists of surgery combined with chemotherapy. Objective: To report a case of primary ovarian diffuse large B-cell non-Hodgkin lymphoma. Case presentation: A 39-year-old female case is presented, with a personal pathological history; she went to the gynecology emergency service because she presented diffuse abdominal pain that was not relieved by analgesics. Physical examination revealed superficial and deep pain on palpation in the hypochondrium and right illiac fossa with a palpable tumor mass. Right adnexal ultrasound showed an image of low echogenicity and at the emergency laparoscopy, it was diagnosed as a tumor-like formation that appeared to correspond to the right ovary. She underwent a hysterectomy with double adnexectomy. The anatomopathologic diagnosis was primary ovarian non-Hodgkin's lymphoma. Conclusions: The patient in the presented case had an oligosymptomatic clinical presentation. Confirmation of the disease was obtained from a surgical sample, which means that B-cell non-Hodgkin's lymphoma is difficult to diagnose and although it is uncommon, it should always be considered in the differential diagnosis of unilateral ovarian tumors.

Tumor del seno endodérmico ovárico bilateral en adolescente / Bilateral ovarian yolk sac tumor in adolescent i: en

Se presenta el caso clínico de una adolescente de 15 años de edad, quien fue asistida en el Hospital Provincial Pediátrico Universitario José Luis Miranda de Villa Clara, remitida desde su área de salud, por presentar dolor pélvico intenso desde hacía 3 días, náuseas y fiebre de 38,5 °C. Luego de realizados el examen clínico y los estudios complementarios pertinentes, se decidió practicar la resección completa del tumor. Durante el procedimiento se tomó muestra para estudio histológico que confirmó la existencia de un tumor del seno endodérmico ovárico, por lo cual fue reintervenida para extirpar el ovario contralateral y el epiplón infiltrados. Posteriormente se indicó poliquimioterapia según el protocolo y la evolución postratamiento fue satisfactoria.

The case report of a 15-years-old adolescent is presented, who was assisted at José Luis Miranda University Pediatric Provincial Hospital from Villa Clara, referred from her health area due to an intense pelvic pain for 3 days, nausea and fever of 38.5 °C. After carrying out the clinical exam and the pertinent laboratory tests, it was decided to practice the complete tumor resection. During the procedure a sample for histologic study was taken that confirmed the existence of an ovarian yolk sac tumor, reason why she was operated again to extirpate the contralateral ovary and the infiltrated omentum. Later on polychemotherapy was indicated according to the protocol and the post-treatment clinical course was satisfactory.

Fibrotecoma de ovario y embarazo. Presentación de un caso / Ovarian fibrothecoma and pregnancy. A case report

El fibrotecoma ovárico es una neoplasia poco frecuente. Se observa, por lo general, como un tumor sólido unilateral, de tamaño variable, en mujeres premenopáusicas. En su mayoría es benigno y puede ser funcional. En el artículo se describe el diagnóstico y tratamiento de esta rara enfermedad. Se presenta un caso de fibrotecoma ovárico gigante en una paciente adolescente de 18 años de edad, con un embarazo de 34 semanas, a quien se le practicó una cesárea y la exéresis de la lesión, sin complicaciones interoperatorias ni postoperatorias.

Ovarian fibrothecoma is a rare neoplasm. It is usually seen as a unilateral solid tumor of variable size in premenopausal women. It is mostly benign and may be functional. This article describes the diagnosis and treatment of this rare disease. We present an 18-year-old female adolescent patient with a 34-week pregnancy and a giant ovarian fibrothecoma; she underwent a cesarean section and excision of the lesion without intra- or postoperative complications.

Leiomioma ovárico primario

El leiomioma es un tumor mesenquimal benigno común que puede desarrollarse allí donde haya músculo liso; raro como tumor ovárico primario, su origen aún es controversial. El leiomioma ovárico primario es uno de los tumores benignos más raros del ovario, representa 0,5% a 1% de los tumores benignos y suele observase en mujeres entre 20 y 65 años. Generalmente, son asintomáticos y se les encuentra de forma incidental durante el examen pélvico o la cirugía por otra causa, pero en ocasiones puede manifestarse por dolor abdominal y masa palpable. El diagnóstico definitivo es difícil antes de la extirpación quirúrgica. Debido a que no existen síntomas patognomónicos ni tiene imágenes características, los principales diagnósticos diferenciales incluyen fibroma, tecoma, tumor estromal esclerosante y leiomiosarcoma. La tinción inmunohistoquímica es fundamental para el diagnóstico preciso y debe considerarse en el diagnóstico diferencial de los tumores ováricos de células fusiformes. Se presenta un caso de leiomioma ovárico primario.

Leiomyoma is a common benign mesenchymal tumor that can develop wherever smooth muscle is present; rare as a primary ovarian tumor, its origin is still controversial. Primary ovarian leiomyoma is one of the rarest benign ovarian tumors, accounting for 0.5% 1% of benign tumors and is usually seen in women between 20 and 65 years of age. They are usually asymptomatic and appear incidentally during a pelvic examination or surgery for another cause but can occasionally manifest by abdominal pain and palpable mass. Definitive diagnosis is difficult before surgical removal. Because there are no pathognomonic symptoms and no characteristic imaging, the main differential diagnoses include fibroma, thecoma, sclerosing stromal tumor and leiomyosarcoma. Immunohistochemical staining is essential for accurate diagnosis and should be considered in the differential diagnosis of ovarian spindle cell tumors. A case of primary ovarian leiomyoma is presented.

Análise de impacto orçamentário dos inibidores da PARP no tratamento do carcinoma de ovário avançado a partir de evidências de mundo real sob a perspectiva de um hospital federal referência em oncologia / Budget impact analysis of PARP inhibitors in the treatment of advanced ovarian cancer from on real-world evidence the perspective of a federal hospital reference in oncology

Objetivo: Avaliar o impacto orçamentário do tratamento com iPARP como primeira linha de manutenção, comparado ao tratamento-padrão a partir de evidências de mundo real sob a perspectiva de um hospital público referência em oncologia no Rio de Janeiro. Métodos: Foi aplicada uma análise de impacto orçamentário para estimar a introdução das tecnologias iPARP, olaparibe e niraparibe, em comparação com o cenário referência, utilizando dados de eficácia e evidências de mundo real, e considerando os custos globais de tratamento da doença em cinco anos. Este estudo foi aprovado pelo Comitê de Ética em Pesquisa, CAAE: 95157018.9.0000.5274. Resultados: A análise demonstrou que o cenário referência apresentou um impacto orçamentário no valor de R$ 3.578.768,04 em cinco anos. No cenário alternativo, o custo incremental do olaparibe chegou a ser 23,8% maior, comparado ao niraparibe, atingindo um custo de R$ 23.736.459,20 versus R$ 18.076.951,81, respectivamente. Os parâmetros que apresentaram maior impacto nas análises para a tecnologia olaparibe foram a difusão da tecnologia e o preço do medicamento. Contudo, para o niraparibe, os parâmetros de maior impacto foram a duração do tratamento, a difusão da tecnologia e a dose utilizada, demonstrando maior suscetibilidade de variação. Conclusão: Os iPARP no tratamento de pacientes com carcinoma de ovário avançado, apesar de apresentarem custo incremental de aproximadamente R$ 23 milhões em cinco anos, apontam para uma potencial redução de custos associados à progressão da doença.

Objective: Assess the budgetary impact of treatment with iPARP as a first line of maintenance, compared to standard treatment based on real-world evidence from the perspective of a public hospital reference in oncology at Rio de Janeiro. Methods: A budget impact analysis was applied to estimate the introduction of iPARP, olaparib and niraparib technologies, compared to the reference scenario, using efficacy data and real-world evidence, and considering the global costs of treating the disease in five years. This study was approved by the Research Ethics Committee, CAAE: 95157018.9.0000.5274. Results: The analysis showed that the reference scenario presented a budgetary impact of R$ 3,578,768.04 in five years. In the alternative scenario, the incremental cost of olaparib reached 23.8% higher compared to niraparib, reaching a cost of R$ 23,736,459.20 versus R$ 18,076,951.81, respectively. The parameters that had the greatest impact on the analyzes for the olaparib technology were technology diffusion and drug price. However, for niraparib, the parameters with the greatest impact were the duration of treatment, the diffusion of the technology and the dose used, demonstrating greater susceptibility to variation. Conclusion: iPARP in the treatment of patients with advanced ovarian carcinoma, despite having an incremental cost of approximately R$ 23 million in five years, point to a potential reduction in costs associated with disease progression.

Ovarian hydatid cyst: an uncommon site of presentation

ABSTRACT Hydatid cyst is a parasitic infestation caused by Echinococcus larvae. Hydatid cyst of the ovary is a highly unusual presentation. Herein, we present a case of a young woman who complained of episodic lower abdominal pain. Ultrasound of the abdomen revealed a multi-cystic left adnexal mass measuring 86 mm x 67 mm. A possibility of ovarian cystic neoplasm was suggested. Unilateral salpingo-oophorectomy was performed. On histopathological examination, a cyst measuring 8.0 x 5.5 x 4.5 cm was found, replacing the entire ovary. The cyst cavity was filled with serous fluid and multiple pearly white membranous structures, giving a multiloculated appearance. Microscopic examination showed a cyst lined by a lamellar membrane containing protoscolices and hooklets. Hydatid disease is a zoonotic ailment caused by tapeworms (Echinococcus granulosus or, less commonly, Echinococcus multilocularis). The definitive hosts are carnivores. Humans are the accidental intermediate hosts. The hydatid cyst commonly affects the liver and the lungs. The primary hydatid cyst of the ovary is quite rare, with few case reports in the literature. In most cases, symptoms are vague, and the lesion is misdiagnosed as benign or malignant ovarian cystic neoplasm on clinical and radiological examination. Ovarian hydatid cyst is treated by surgery with ovarian cystectomy as the gold standard. The possibility of a hydatid cyst should be kept under differential diagnoses while evaluating the cystic diseases of the ovary.

The expression and significance of protease activated receptor 2 in ovarian epithelial carcinoma / 中华肿瘤杂志

Objective: To investigate the expression and significance of protease activated receptor 2 (PAR2) in ovarian epithelial carcinoma. Methods: PAR2 mRNA expression levels in 410 cases of epithelial ovarian carcinoma and 88 cases of human normal ovary were analyzed from cancer Genome Atlas (TCGA) database and tissue genotypic expression database (GTEx). Immunohistochemical (IHC) staining of PAR2 protein was performed in 149 patients with ovarian cancer who underwent primary surgical treatment at Cancer Hospital of Chinese Academy of Medical Sciences. Then the relationship between mRNA/protein expression of PAR2 and clinicopathological features and prognosis was analyzed. Gene functions and related signaling pathways involved in PAR2 were studied by enrichment analysis. Results: The mRNA expression of PAR2 in epithelial ovarian carcinoma was significantly higher than that in normal ovarian tissue (3.05±0.72 vs. 0.33±0.16, P=0.004). There were 77 cases showing positive and 19 showing strong positive of PAR2 IHC staining among the 149 patients, accounting for 64.4% in total. PAR2 mRNA/protein expression was closely correlated with tumor reduction effect and initial therapeutic effect (P<0.05). Survival analysis showed that the progression free survival time (P=0.033) and overall survival time (P=0.011) in the group with high PAR2 mRNA expression was significantly lower than that in the low PAR2 mRNA group. Multivariate analysis showed tumor reduction effect, initial therapeutic effect were independent prognostic factors on both progression-free survival and overall survival (P<0.05). The progression-free survival (P=0.016) and overall survival (P=0.038) of the PAR2 protein high expression group was significantly lower than that of the low group. Multivariate analysis showed PAR2 expression, initial treatment effect and chemotherapy resistance were independent prognostic factors on both progression-free survival and overall survival (P<0.05). Based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), PAR2 target genes were mainly enriched in function related to intercellular connection, accounting for 40%. Gene enrichment analysis (GSEA) showed that the Wnt/β-catenin signaling pathway (P=0.023), the MAPK signaling pathway (P=0.029) and glycolysis related pathway (P=0.018) were enriched in ovarian cancer patients with high PAR2 mRNA expression. Conclusions: PAR2 expression is closely related to tumor reduction effect, initial treatment effect and survival of ovarian cancer patients. PAR2 may be involved in Wnt/β-catenin signaling pathway and intercellular connection promoting ovarian cancer invasion and metastasis.

Activation of JAK/STAT in ovarian high-grade serous cancers and its prognostic significance / 北京大学学报(医学版)

OBJECTIVE@#The activation of Janus kinase (JAK) and signal transducers and activators of transcription (STAT) plays an important role in the prognosis and targeted therapy of ovarian high-grade serous carcinoma (HGSC). Utilizing simple and practicable technique, this study aimed to evaluate the activation of JAK/STAT signaling pathway in ovarian HGSC patients, and investigated the correlation between the activation of JAK/STAT signaling pathway and the prognosis of the HGSC patients.@*METHODS@#We performed immunohistochemistry of phosphorylated STAT3 (pSTAT3) and phosphorylated STAT5 (pSTAT5) on paraffin imbedded slides of 73 ovarian HGSC patients, and evaluated the expression level and range of both markers. According to the grading score of the immunostaining of pSTAT3 and pSTAT5, we divided the 73 ovarian HGSC cases into STAT3 low/high expression and STAT5 low/high expression groups, and analyzed the prognosis of the patients in different groups, in order to explore the relationship between the expression of pSTAT3 and pSTAT5 proteins and the prognosis of the HGSC patients.@*RESULTS@#Some of the ovarian HGSC cases showed high expression of pSTAT3 and pSTAT5 protein level, which was related to the poorer prognosis of the HGSC patients. There was a significant difference in the expression level of pSTAT3 and pSTAT5 between the patients with better prognosis (survival time ≥3 years) and poorer prognosis (survival time < 3 years). The patients with higher protein expression of pSTAT3, pSTAT5 or both markers might have poorer prognosis, with significant shorter progression-free survival time and overall survival time (P < 0.001).@*CONCLUSION@#Immunostaining of pSTAT3 and pSTAT5 proteins might be helpful to evaluate and predict the prognosis of the ovarian HGSC patients, and to identify the patients who might have higher chances to respond to the STAT inhibitors and anti-angiogenesis therapy.

Immunostaining of stromal CD56 cells in ovarian malignancies

SUMMARY OBJECTIVES: The aim of this study was to evaluate CD56 immunostaining in the stroma of benign and malignant ovarian epithelial neoplasms and associate the CD56 immunostaining with prognostic factors and survival in ovarian cancer. METHODS: Patients with ovarian epithelial neoplasia (n=77) were studied with a prospective cohort. The CD56 immunostaining was evaluated in the peritumoral stroma. Two groups were evaluated: benign ovarian neoplasms (n=40) and malignant ovarian neoplasms (n=37). Data were recorded for histological type and grade, International Federation of Gynecology and Obstetrics staging, molecular subtype, and lymph node metastases. Fisher's exact test and Kaplan-Meier survival curves were used, with a significance level of ≤0.05. RESULTS: We found greater CD56 stromal immunostaining in malignant neoplasms when compared to the group of benign neoplasms (p=0.00001). There was no significant difference in relation to the prognostic factors and survival. CONCLUSION: Malignant ovarian neoplasms showed higher stromal CD56 immunostaining. As the prognostic value of natural killer in ovarian cancer is controversial, knowing the specific function of each cell present both in the tumor tissue and systemically may help guide successful immunotherapies in the near future.

Prognostic Factors of Non-epithelial Ovarian Cancer in a Tertiary Hospital in Indonesia

@#Introduction: Non-epithelial is a rare type of ovarian cancer but the most common ovarian neoplasm in reproductive age. This study analyzed the correlation of clinical characteristics to disease-free survival (DFS) and 3-year survival in non-epithelial ovarian cancer. Methods: A cohort analysis of medical records of 30 patients with non-epithelial ovarian cancer from 2016 to 2017 at Dr. Soetomo General Academic Hospital. Survival analysis was performed using Kaplan–Meier test, log-rank test, and Cox regression to determine the correlation of characteristics including age, stage, tumor size, tumor residue, histopathology type and chemotherapy status as prognostic factors for recurrence and mortality. Results: DFS was significantly affected by stage (p=0.049), tumor residue (p<0.0001), and chemotherapy (p=0.005). Stage I, no residual disease, and adequate chemotherapy had the highest DFS and mean DFS rates (94.1% and 35.6 months; 95.5% and 35.7 months; 75% and 31.94 months, respectively). Highest recurrence rates were found in patients with unstaged disease (hazard ratio [HR]=10.08), residue >0 cm (HR=23.13), and inadequate chemotherapy (HR=6.55). Three-year survival was significantly affected by stage (p=0.001), tumor residue (p<0.0001), and chemotherapy (p<0.0001). Stage I, no residual disease, and adequate chemotherapy had the highest 3-year survival rate and mean survival time (94.1% and 35.47 months; 95.5% and 35.7 months; 87.5% and 33 months). The highest mortality were found in patients with unstaged disease (HR=19.99), residue >0 cm (HR=11.33), and inadequate chemotherapy (HR=11.71). Conclusion: Stage, tumor residue, and chemotherapy status in patients with non-epithelial ovarian cancer are significant prognostic factors for DFS and 3-year survival.

Effect of apatinib combined with fluzoparib on proliferation ability of human ovarian cancer cisplatin-resistant cells / 肿瘤研究与临床

Objective:To investigate the effect of apatinib and fluzoparib on the proliferation ability of cisplatin-resistant human ovarian cancer cells.Methods:Human ovarian cancer cells SKOV3 and cisplatin-resistant SKOV3/DDP cells of human ovarian cancer were treated with different concentrations of 1, 2, 4, 8, 16, 32, 64,128 μg/ml cisplatin at different times; CCK-8 method was used to detect the proliferation rate and half-inhibitory concentration ( IC50) of SKOV3 and SKOV3/DDP cells, and the drug-resistance fold of SKOV3/DDP cell was also calculated. SKOV3/DDP cells were treated with different concentrations of apatinib (4, 8, 16, 32, 64 μmol/L) and fluzoparib (148.15, 222.22, 333.33, 500.00, 750.00 μmol/L) for 24 h, 48 h and 72 h, respectively; the cell proliferation rate was determined by using CCK-8 method and IC50 was calculated. SKOV3/DDP cells were divided into the blank control group (cells untreated with drugs), cisplatin group, cisplatin + apatinib group, cisplatin + fluzoparib group, cisplatin + fluzoparib + apatinib group, and drug intervention was given in each group; the inhibition rate of cells in each group was detected by using CCK8 method. Results:The proliferation rate of SKOV3 cells treated with the same concentration of cisplatin for the same time was lower than that of SKOV3/DDP cells, and the differences were statistically significant (all P < 0.05). The IC50 of SKOV3/DDP cells treated with 4, 8, 16, 32, 64 μmol/L apatinib was 742.1μmol/L at 24 h, 156.8 μmol/L at 48 h, and 77.5 μmol/L at 72 h. Compared with the control group, the proliferation rate of SKOV3/DDP cells treated with apatinib at an effective concentration greater than 32 μmol/L was significantly decreased, and the differences were statistically significant (all P < 0.05). The IC50 of SKOV3/DDP cells treated with 148.15, 222.22, 333.33, 500.00, 750.00 μmol/L fluzoparib was 878.5 μmol/L at 24 h, 406.7 μmol/L at 48 h, and 283.3μmol/L at 72 h. When the effective concentration of fluzoparib was more than 333.33 μmol/L for 24 h, the proliferation rate of SKOV3/DDP cells was lower than that of the control group, and the differences were statistically significant (all P < 0.05). Compared with the control group, the proliferation rate of SKOV3/DDP cells was decreased when the effective concentration was more than 148.15 μmol/L at 48 h and 72 h, and the differences were statistically significant (all P < 0.05). The cell proliferation rate of 5 μg/ml cisplatin + 64 μmol/L apatinib group was lower than that of 5 μg/ml cisplatin group [(40.4±1.4)% vs. (62.7±1.4)%, t = 20.22, P < 0.001]. The cell proliferation rate of 5 μg/ml cisplatin + 290 μmol/L fluzoparib group was lower than that of 5 μg/ml cisplatin group [(5.2±0.4)% vs. (62.7±1.4)%, t = 52.04, P < 0.001]. The cell proliferation rate of 5 μg/ml cisplatin + 64 μmol/L apatinib + 290 μmol/L fluzoparib group was lower than that of 5 μg/ml cisplatin group [(0.3±0.8)% vs. (62.7±1.4)%, t = 53.98, P < 0.001]. The 5 μg/ml cisplatin + 64 μmol/L apatinib + 290 μmol/L fluzoparib group had the lowest proliferation rate of SKOV3/DDP cells, which was lower than that of 5μg/ml cisplatin + 64 μmol/L apatinib group and 5 μg/ml cisplatin + 290 μmol/L fluzoparib group (all P < 0.001). Conclusions:Apatinib and fluzoparib can enhance the sensitivity of human ovarian cancer cisplatin-resistant cells SKOV3/DDP to cisplatin, and the combination of drugs can produce the stronger inhibitory effects and reverse cisplatin resistance of ovarian cancer.

Effect of Yin Yang protein 1 transcriptionally regulating acetyl-CoA carboxylase 1 on the cell migration and lipogenesis in ovarian cancer / 肿瘤研究与临床

Objective:To investigate the expression of acetyl-CoA carboxylase 1 (ACC1) in ovarian cancer tissues and cells, and the related mechanisms of the effect of ACC1 on cell migration and lipogenesis in ovarian cancer.Methods:Samples including 1 case of normal ovarian tissue, 1 case of ovarian cancer primary lesion tissue and 1 case of ovarian cancer omentum metastatic tissue diagnosed by pathology examination of patients undergoing surgery resection who admitted to Linyi Cancer Hospital between January 2019 and December 2021 were collected. Immunohistochemistry was used to detect the protein levels of ACC1 and Yin Yang protein 1 (YY1) of all tissues. The PROMO database was used to predict the possible binding sites of YY1 and ACC1 promoter region. Through the assembled viral vector, the HEY cells of human ovarian cancer with ACC1 or YY1 expression [the untreated cells were treated as the negative control (NC)], or knocked down ACC1 or YY1 (the interference sequence sh1, sh2, sh3 was transferred to the target gene, and the negative control sequence shNC was transferred to the interference sequence). Double luciferase reporter gene assay was used to verify the binding sites of YY1 and ACC1 promoter and the activity of transcriptional regulation. Real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) and Western blot were used to detect the mRNA and protein expression levels of ACC1 and YY1 in the treated HEY cells, respectively. Transwell assay was used to detect the migration ability of HEY cells. Oil red O staining and Nile red staining were used to detect the lipid droplets in HEY cells.Results:The immunohistochemical scores of ACC1 and YY1 were 0, 2, 8 scores and 0, 4, 6 scores, respectively in normal ovarian tissue, primary lesion of ovarian cancer, and omentum metastatic tissue. Transwell assay showed that the number of invasive HEY cells in ACC1 overexpression group was more than that in NC group [(87.7±7.4) vs. (52.2±4.2), t = 5.19, P = 0.003]. The number of invasive HEY cells in ACC1-sh1 group, and ACC1-sh2 group with the knockdown of ACC1 was less than that in shNC group [(21.2±1.5), (29.7±2.3) vs. (56.2±5.3); t value was 6.41, 3.77; P < 0.001, P < 0.005]. The number of lipid droplets in HEY cells in the ACC1 overexpression group was more than that in the control NC group [Oil red O staining: (301±25) vs. (215±21); Nile red staining: (287±15) vs. (207±10); all P < 0.05]; the number of lipid droplets in HEY cells in ACC1-sh1 and ACC1-sh2 group with the knockdown of ACC1 was less than that in ACC1-shNC group [Oil red O staining: (113±8), (119±12) vs. (195±18); Nile red staining: (82±8), (117±11) vs. (165±17); all P < 0.05]. The result of dual luciferase reporter assay showed that overexpression of YY1 promoted the luciferase activity of the wild type ACC1 promoter region report gene ( P = 0.003), while the luciferase activity of the report gene was inhibited compared with the wild type after the mutation of binding sites of YY1 in ACCI promoter region ( P = 0.008). Western blot results showed that the expression levels of YY1 and ACC1 protein in HEY cells with YY1 overexpression group were higher than those in NC group, which indicated a synergistic increasing trend of both YY1 and ACC1; the expression levels of YY1 and ACC1 protein in YY1-sh1 group, YY1-sh2 group and YY1-sh3 group with the knockdown of YY1 were lower than those in the control YY1-shNC group, which indicated a synergistic decreasing trend of both YY1 and ACC1. Conclusions:ACC1 and YY1 are highly expressed in ovarian cancer metastatic tissues and both show a positive correlation trend. The expression level of ACC1 in vitro has an impact on cell migration and lipogenesis in ovarian cancer via YY1 transcriptionally regulating ACC1.

Progress of anterior gradient protein 2 and anterior gradient protein 3 in the diagnosis and treatment of ovarian cancer / 肿瘤研究与临床

Ovarian cancer ranks the third among gynecological malignancies, while its mortality rate is the highest. Even though recent treatment progress has been made after using PARP inhibitors, the prognosis is still poor. Anterior gradient protein 2 (AGR2) may be a marker for early diagnosis of ovarian cancer, and the expression of AGR2 suggests that the prognosis of ovarian cancer is better. However, Anterior gradient protein 3 (AGR3) could be used to differentiate high-grade and low-grade ovarian cancer, but its influence on prognosis is still controversial. AGR2 and AGR3 may be therapeutic targets for ovarian cancer. This article introduces the research progress of AGR2 and AGR3 in the diagnosis and treatment of ovarian cancer.

Clinical molecular diagnosis of breast and female reproductive system tumors / 中华检验医学杂志

The gynecological tumours such as Breast cancer or female reproductive system tumors are a serious threat to female health. With the development of molecular diagnosis, the genomic changes of gynecological tumours have been revealed continuously, and the diagnosis and treatment modes of tumors have gradually changed. The detection of molecular targets which potentially participated in the transformation or progress of disease has become an important section of the management of female reproductive tumors, and accurate identification of molecular targets of tumors plays an important role in disease diagnosis, monitoring of metastasis, prediction of recurrence and treatment. This review briefly discusses the risk assessment, molecular typing, targeted therapy, toxic and side effects, and prognosis evaluation of breast and female reproductive system tumors by molecular diagnosis.

Research and application progress of molecular detection technology in female tumor diagnosis / 中华检验医学杂志

The molecular detection technology shows a better application prospect and broad development in the early screening of female tumors, guiding the selection of therapeutic drugs, predicting prognosis and monitoring the efficacy of treatment. Numerous studies have demonstrated that molecular detection has great impact on the diagnosis and treatment strategies of female tumors such as breast cancer, cervical cancer, endometrial cancer and ovarian cancer. Previously, human papilloma virus detection has laid a foundation for clinical application for cervical cancer screening and breast cancer 1/2 mutation susceptibility gene detection to predict the risk of breast cancer and give drug guidance. These studies show the clinical application prospect of new molecular detection in the diagnosis and treatment of female tumors in the future.

Analysis of factors for serious early complications after primary debulking surgery in elderly patients with advanced epithelial ovarian cancer / 中华老年医学杂志

Objective:To investigate the factors for serious complications within 30 days after surgery in elderly patients with advanced epithelial ovarian cancer(EOC)who undertook primary debulking surgery(PDS).Methods:The clinical data of International Federation of Gynecology and Obstetrics(FIGO)stage ⅢC/Ⅳ EOC patients aged≥60 years who received PDS in gynecological department of National Cancer Center and National Center of Gerontology between January 2014 and December 2018 were retrospectively analyzed.Clavien-Dindo scoring system was applied to grade the complications within 30 days after surgery.The serious early postoperative complications were those of grade Ⅲ or above occurred within 30 days after surgery.Multivariate Logistic regression analysis was used to screen the independent risk factors of serious complications within 30 days after surgery.Results:A total of 133 patients were included in this study and serious complications rated 11.3%(15/133). The mean age of patients in severe complication group was significantly higher than that in the control group[(69.80±6.56) vs.(65.87±5.14), t=2.699, P=0.008]. The proportion of patients with preoperative ECOG score≥2 was significantly higher in the severe complication group than that in the control group[26.7%(4/15) vs.5.9%(7/118), χ2=4.985, P=0.026], and the proportion of preoperative hypoalbuminemia(<35 g/L)was significantly higher in the severe complication group[20.0%(3/15) vs.3.4%(4/118), χ2=4.897, P=0.027]. However, there was no significant difference in intraoperative bleeding, R0 resection rate as well as surgical complexity( χ2=1.964, 0.330, 4.637, all P>0.05)between the two groups.Multivariate Logistic regression analysis showed that the independent factors for serious early postoperative complications were age≥70 years( OR=4.345, P=0.028), ECOG score≥2( OR=25.619, P=0.008)and preoperative albumin <35 g/L( OR=6.733, P=0.040). Conclusions:In the elderly ovarian cancer patients, individualized perioperative management should be strengthened for the patients with factors associated with serious early postoperative complications, in order to reduce severe complications and improve the prognosis.

The consistency and application value of MRI-based ovarian-adnexal reporting and data system in the diagnosis of ovarian adnexal masses / 中华放射学杂志

Objective:To explore the consistency of MRI-based ovarian-adnexal report and data system (O-RADS) score and its diagnostic value for ovarian adnexal masses.Methods:The MRI data of 309 patients with ovarian adnexal masses confirmed by pathology were retrospectively collected from January 2017 to August 2021 in the Second Affiliated Hospital of Soochow University, including 327 lesions consisted of 250 benign lesions, 21 borderline lesions, and 56 malignant lesions confirmed by pathology. Borderline and malignant lesions were classified into the malignant group ( n=77) and benign lesions were classified as benign group ( n=250). Two radiologists scored all lesions according to the MRI-based O-RADS, and scored again after 6 months. The proportion of borderline/malignant lesions in each MRI-based O-RADS score was calculated. The weighted Kappa test was used to assess the intra-reader and inter-reader consistency of the image interpretation results. The receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic efficacy of MRI-based O-RADS classification for distinguishing benign and malignant ovarian adnexal masses. Results:The weighted Kappa value of the MRI-based O-RADS score between the two radiologists was 0.810 (95%CI 0.764-0.855), and the weighted Kappa values of the two radiologists′ scores at different times were 0.848 (95%CI 0.806-0.889) and 0.875 (95%CI 0.835-0.914), respectively. The borderline/malignant lesions accounted for 0/16, 0.8% (1/127), 10.1% (10/99), 76.0% (57/75), 9/10 and 0/17, 0 (0/122), 8.0% (8/100), 76.2% (48/63), and 84.0% (21/25) of the lesions in the two radiologists based on the MRI O-RADS score of 1, 2, 3, 4, and 5, respectively. When adopting O-RADS score>3 as a cut-off value, the area under the ROC curve of the two radiologists for distinguishing benign and malignant ovarian adnexal masses was 0.928 (95%CI 0.895-0.954) and 0.942 (95%CI 0.911-0.965), respectively. The sensitivity was 0.857 and 0.896, the specificity was 0.924 and 0.924, and the accuracy was 0.908 and 0.917 respectively.Conclusion:The MRI-based O-RADS yields high diagnostic efficiency in the evaluation of benign and malignant ovarian adnexal masses, and the intra-reader and inter-reader consistency of the image interpretation is strong.

Establishment and preliminary application of organoids in ovarian cancer / 中华妇产科杂志

Objective:To explore the establishment and application of ovarian cancer organoids.Methods:Fresh ovarian tumor tissues, obtaining from patients underwent surgery in the First Affiliated Hospital of Nanjing Medical University between October 2021 and March 2022, were collected, enzymatic degraded, digested, and embedded into matrigel to establish organoids. A total of 32 ovarian cancer samples were collected. Hematoxylin eosin (HE) staining and immunofluorescence (IF) procedure were used to verify the morphological structure of organoids and their expression of molecular markers. 3D cyto-live or dead assay was used to detecte the live or dead cells in organoids. Carboplatin with a concentration ranging from 5 to 80 μmol/L (5, 10, 20, 40, 80 μmol/L) was added to organoids to calculate the 50% inhibitory concentration (IC 50) in different organoids. Results:(1) Organoids from a total of 32 patients were established, of which 18 cases could be passaged stably in the long term in vitro, while 14 could be passaged in the short time. The average amplification time of long-term passage in vitro was over 3 months, and the longest reached 9 months. (2) In HE staining, significant nuclei atypia and local micropapillary structures were observed in organoids. IF staining revealed that ovarian cancer organoids expressed molecular markers similar to primary tumor tissues, such as Pan cytokeratin (Pan-CK), p53, paired box gene 8 (PAX8), and Wilms tumor gene 1 (WT1). (3) In 3D cyto-live or dead assay, a large number of apoptotic cells were observed inside and around the organoids after added carboplatin. The sensitivity to carboplatin varied in 18 organoids could amplify in the long term, with an average IC 50 of (29.5±15.8) μmol/L. Moreover, IC 50 values of 4 organoids derived from patients received neoadjuvant chemotherapy were much higher than the 14 organoids which did not received neoadjuvant chemotherapy [(48.7±11.3) μmol/L vs (24.0±12.1) μmol/L; t=3.429, P=0.022]. Conclusions:Organoids recapitulate ovarian cancers in vitro and could be stably passaged. Organoids derived from patients received neoadjuvant chemotherapy have higher resistance to carboplatin.