Desfechos reprodutivos e de sobrevida em adolescente tratada com cirurgia preservadora de fertilidade por tumor borderline de ovário em estádio avançado: relato de caso e revisão da literatura / Reproductive and survival outcomes in an adolescent treated with fertility- sparing surgery for advanced stage borderline ovarian tumor: case report and review of the literature

Existem poucos dados na literatura sobre os resultados obstétricos e oncológicos de adolescentes com tumores borderline de ovário em estádio avançado trata- das com cirurgia preservadora da fertilidade. Uma adolescente de 15 anos com diagnóstico de tumor borderline de ovário estádio IIIc foi inicialmente tratada com tumorectomia ovariana bilateral e quimioterapia adjuvante com esquema de platina/taxano (seis ciclos). Durante o seguimento, foi submetida a outras três tumorectomias devido a tumor borderline de ovário (duas vezes) e cistadenoma ovariano (uma vez). Outra recidiva de tumor borderline de ovário ocorreu seis anos após o diagnóstico inicial, quando ela estava grávida; foi tratada com tumorecto- mia realizada durante a cesariana. Em sua última consulta ambulatorial, a mulher de 27 anos não apresentava evidência da doença e tinha um filho saudável. Mesmo em estádio avançado, a cirurgia de preservação da fertilidade foi segura e factível nessa paciente com tumor borderline de ovário.

There are few data in the literature regarding obstetric and oncological outcomes of adolescents with advanced-stage borderline ovarian tumors treated with fertility spa- ring surgery. A 15 years old adolescent who was diagnosed with a stage IIIc borderline ovarian tumor, was treated with bilateral ovarian tumorectomies and adjuvant chemotherapy with platinum/taxane regimen (six cycles). During follow up she was submitted to other three tumorectomies due to borderline ovarian tumor(twice) and ovarian cysta- denoma (once). Another borderline ovarian tumorrecurren- ce occurred six years after initial diagnosis, when she was pregnant; treated with tumorectomy performed during ce- sarean section. At her last outpatient visit, the 27-year-old woman had no evidence of disease and a had healthy child. Even at an advanced stage, fertility sparing surgery was safe and feasible in this patient with borderline ovarian tumor.

Signal transducer and activator of transcription 3 and cancer associated fibroblasts jointly generate chemo-resistance and affect prognosis in epithelial ovarian cancer / 中华妇产科杂志

Objective: To investigate the mechanism of signal transducer and activator of transcription 3 (STAT3) and cancer associated fibroblasts (CAF) jointly generate chemo-resistance in epithelial-ovarian cancer and their effect on prognosis. Methods: A total of 119 patients with high-grade ovarian serous cancer who received surgery in Cancer Hospital of Chinese Academy of Medical Sciences from September 2009 to October 2017 were collected. The clinico-pathological data and follow-up data were complete. Multivariate Cox regression model was used to analyze the prognostic factors. Ovarian cancer tissue chips of patients in our hospital were prepared. EnVision two-step method immunohistochemistry was used to detect the protein expression levels of STAT3, the specific markers of CAF activation, fibroblast activating protein (FAP), and type Ⅰ collagen (COL1A1) secreted by CAF. The relationship between the expression of STAT3, FAP, COL1A1 protein and drug resistance and prognosis of ovarian cancer patients was analyzed, and the correlation between the expression of three proteins was analyzed. These results were verified through the gene expression and prognostic information of human ovarian cancer tissues collected in the GSE26712 dataset of gene expression omnibus (GEO) database. Results: (1) Multivariate Cox regression model analysis showed that chemotherapy resistance was an independent risk factor for overall survival (OS) of ovarian cancer (P<0.001). (2) The expression levels of STAT3, FAP, and COL1A1 proteins in chemotherapy resistant patients were significantly higher than those in chemotherapy sensitive patients (all P<0.05). Patients with high expression of STAT3, FAP, and COL1A1 had significantly shorter OS than those with low expression (all P<0.05). According to the human ovarian cancer GSE26712 dataset of GEO database, patients with high expression of STAT3, FAP, and COL1A1 also showed shorter OS than patients with low expression (all P<0.05), the verification results were consistent with the detection results of ovarian cancer patients in our hospital. (3) Correlation analysis showed that the protein level of STAT3 was positively correlated with FAP and COL1A1 in our hospital's ovarian cancer tissue chips (r=0.47, P<0.001; r=0.30, P=0.006), the analysis of GEO database GSE26712 dataset showed that the expression of STAT3 gene and FAP, COL1A1 gene were also significantly positively correlated (r=0.31, P<0.001; r=0.52, P<0.001). Conclusion: STAT3 and CAF could promote chemotherapy resistance of ovarian cancer and lead to poor prognosis.

Primary Ovarian Small Cell Carcinoma of Pulmonary Type: Analysis of 6 Cases and Review of 31 Cases in the Literatures / 中国医学科学杂志(英文版)

Objective Primary ovarian small cell carcinoma of pulmonary type (SCCOPT) is a rare ovarian tumor with a poor prognosis. The platinum-based chemotherapy is the standard treatment. However, there is little research on the clinical characteristics of SCCOPT and the potential benefits of other treatments due to its low incidence. The study aims to investigate clinicopathological characteristics and treatment of SCCOPT.Methods We summarized the clinical, imaging, laboratorical and pathological characteristics of 37 SCCOPT cases, in which 6 cases were admitted to the Gansu Provincial Hospital from the year of 2008 to 2022 and 31 cases reported in 17 English and 3 Chinese literatures.Results The median age of the studied SCCOPT cases (n=37) was 56.00 (range, 22-80) years. Almost 80% of them had a stage Ⅲ or Ⅳ tumor. All patients underwent an operation and postoperative chemotherapy. Nevertheless, all cases had a poor prognosis, with a median overall survival time of 12 months. Immunohistochemically, the SCCOPT of all patients showed positive expressions of epithelial markers, such as CD56 and sex-determining region of Y chromosome-related high-mobility-group box 2 (SOX-2), and negative expressions of estrogen receptor, progesterone receptor, vimentin, Leu-7, and somatostatin receptor 2. The tumor of above 80% cases expressed synaptophysin. Only a few cases expressed neuron-specific enolase, chromogranin A, and thyroid transcription factor-1. Conclusions SCCOPT had a poor prognosis. SOX-2 could be a biomarker to be used to diagnose SCCOPT.

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.

Cytopathological characterization of ascites for the diagnosis of serous ovarian carcinoma / 中华肿瘤杂志

Objective: To investigate the cytomorphological and immunocytochemical features of tumor cells in the ascites of ovarian plasmacytoma (SOC). Methods: Specimens of serous cavity effusions were collected from 61 tumor patients admitted to the Affiliated Wuxi People's Hospital of Nanjing Medical University from January 2015 to July 2021, including ascites from 32 SOC, 10 gastrointestinal adenocarcinomas, 5 pancreatic ductal adenocarcinomas, 6 lung adenocarcinomas, 4 benign mesothelial hyperplasia and 1 malignant mesothelioma patients, pleural effusions from 2 malignant mesothelioma patients and pericardial effusion from 1 malignant mesothelioma. Serous cavity effusion samples of all patients were collected, conventional smears were made through centrifugation, and cell paraffin blocks were made through centrifugation of remaining effusion samples. Conventional HE staining and immunocytochemical staining were applied to observe and summarize cytomorphological characteristics and immunocytochemical characteristics. The levels of serum tumor markers carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were detected. Results: Of the 32 SOC patients, 5 had low-grade serous ovarian carcinoma (LGSOC) and 27 had high-grade serous ovarian carcinoma (HGSOC). 29 (90.6%) SOC patients had elevated serum CA125, but the difference was not statistically significant between them and patients with non-ovarian primary lesions included in the study (P>0.05); The serum CEA was positive in 9 patients with gastrointestinal adenocarcinoma and 5 patients with lung adenocarcinoma, and the positive rate was higher than that in SOC patients (P<0.001); The serum CA19-9 was positive in 5 patients with gastrointestinal adenocarcinoma and 5 patients with pancreatic ductal adenocarcinoma, and the positive rate was higher than that in SOC patients (P<0.05). The serum CA125, CEA and CA19-9 were within the normal range in 4 patients with benign mesothelial hyperplasia. LGSOC tumor cells were less heterogeneous and aggregated into small clusters or papillary pattern, and psammoma bodies could be observed in some LGSOC cases. The background cells were fewer and lymphocytes were predominant; the papillary structure was more obvious after making cell wax blocks. HGSOC tumor cells were highly heterogeneous, with significantly enlarged nuclei and varying sizes, which could be more than 3-fold different, and nucleoli and nuclear schizophrenia could be observed in some cases; tumor cells were mostly clustered into nested clusters, papillae and prune shapes; there were more background cells, mainly histiocytes. Immunocytochemical staining showed that AE1/AE3, CK7, PAX-8, CA125, and WT1 were diffusely positively expressed in 32 SOC cases. P53 was focally positive in all 5 LGSOCs, diffusely positive in 23 HGSOCs, and negative in the other 4 HGSOCs. Most of adenocarcinomas of the gastrointestinal tract and lung had a history of surgery, and tumor cells of pancreatic ductal adenocarcinoma tend to form small cell nests. Immunocytochemistry can assist in the differential diagnosis of mesothelial-derived lesions with characteristic "open window" phenomenon. Conclusion: Combining the clinical manifestations of the patient, the morphological characteristics of the cells in the smear and cell block of the ascites can provide important clues for the diagnosis of SOC, and the immunocytochemical tests can further improve the accuracy of the diagnosis.

A phase 2 trial of short-course Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) at interval cytoreductive surgery (iCRS) for advanced ovarian cancer / Quimioterapia Intraperitoneal Hipertérmica (HIPEC) de curta duração ao tempo da cirurgia citorredutora de intervalo (iCRS) para câncer de ovário avançado: ensaio clínico de fase 2

ABSTRACT Objective: to report the final analysis of a phase 2 trial assessing the efficacy and safety of short-course hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with advanced epithelial ovarian cancer (EOC). Methods: this was an open-label, multicenter, single-arm trial of HIPEC in patients with advanced EOC who underwent interval cytoreductive surgery (iCRS) after neoadjuvant chemotherapy (NACT). HIPEC was performed as a concentration-based regimen of platinum-based chemotherapy for 30 minutes. Primary endpoint was the rate of disease progression occurring at nine months following iCRS plus HIPEC (PD9). Secondary endpoints were postoperative complications, time to start adjuvant chemotherapy, length of hospital and ICU stay, quality of life (QoL) over treatment, and ultimately 2-year progression-free survival (PFS) and overall survival (OS). Analysis was by intention-to-treat with final database lock for survival outcomes on February 23, 2021. Results: fifteen patients with stage III EOC were enrolled between February 2015 and July 2019, in four centers. The intention to treat PD9 was 6.7%. With a median follow-up of 33 months (IQR, 24.3-46.5), the median PFS was 18.1 months and corresponding 2-year rates of PFS and OS was 33.3% and 93.3%, respectively. Three patients (20%) experienced graded III complications. Median length of hospital and ICU stay was 5 (IQR, 4-6.5) and 1 (IQR, 1-1) days, respectively. Time to restart systemic chemotherapy was 39 (IQR, 35-49.3) days and no significant difference over time in QoL was observed. Conclusions: we demonstrate preliminary efficacy and safety of short-course HIPEC in patient with advanced EOC.

RESUMO Objetivo: apresentar a análise final de ensaio clínico de fase 2 que avaliou a eficácia e a segurança da quimioterapia intraperitoneal hipertérmica (HIPEC) de curta duração em pacientes com câncer epitelial de ovário avançado (EOC). Métodos: estudo aberto, multicêntrico, de braço único avaliando a HIPEC em pacientes com EOC avançado submetidos a cirurgia citorredutora de intervalo (iCRS) após quimioterapia neoadjuvante (NACT). A HIPEC foi realizada como regime baseado na concentração de cisplatina, perfundida por 30 minutos. O desfecho primário foi a taxa de progressão da doença 9 meses após a iCRS com HIPEC (PD9). Os desfechos secundários foram complicações pós-operatórias, tempo para iniciar a quimioterapia adjuvante, tempo de internação e permanência em UTI, qualidade de vida (QoL) ao longo do tratamento e, finalmente, sobrevida cumulativa livre de progressão (PSF) e global (OS) em 2 anos. As análises foram em intenção de tratar (ITT) com fechamento dos dados para análise da sobrevida em 23 de fevereiro de 2021. Resultados: quinze pacientes com EOC em estágio III foram incluídos no estudo entre fevereiro de 2015 e julho de 2019 em quatro centros recrutadores. A PD9 por ITT foi de 6,7%. Com acompanhamento mediano de 33 meses (IQR, 24,3-46,5), a PFS mediana foi de 18,1 meses e as taxas correspondentes de PFS e OS em 2 anos foram 33,3% e 93,3%, respectivamente. Três pacientes (20%) apresentaram complicações grau III. O tempo mediano de internamento hospitalar e em UTI foi de 5 (IQR, 4-6,5) e 1 (IQR, 1-1) dias, respectivamente. O tempo para reinício da quimioterapia sistêmica foi de 39 dias (IQR, 35-49,3) e não foi observada diferença significativa na QoL ao longo do tratamento. Conclusões: demonstrou-se eficácia e segurança preliminares da HIPEC de curta duração em pacientes com EOC avançado.

Effect of RBP2 gene silencing on proliferation, migration and invasion of ovarian epithelial cancer SKOV3/DDP cells and its mechanism / 中华肿瘤杂志

Objective: To explore the effect of down-regulation of retinol binding protein 2 (RBP2) expression on the biological characteristics of ovarian cancer cells and its mechanism. Methods: Knockdown of RBP2 and cisplatin (DDP)-resistant ovarian cancer cell line SKOV3/DDP-RBP2i was established, the negative control group and blank control group were also set. Cell counting kit 8 (CCK-8) was used to detect the cell proliferation ability, flow cytometry was used to detect cell apoptosis, scratch test and Transwell invasion test were used to detect cell migration and invasion ability, real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) and western blot were used to detect the expressions of molecular markers related to epithelial-mesenchymal transition (EMT). The effect of RBP2 on the growth of ovarian cancer was verified through experiment of transplanted tumors in nude mice, and the relationships between RBP2 expression and tumor metastasis and patient prognosis were analyzed using the clinical data of ovarian cancer in TCGA database. Results: After down-regulating the expression of RBP2, the proliferation ability of SKOV3/DDP cell was significantly reduced. On the fifth day, the proliferation activities of SKOV3/DDP-RBP2i group, negative control group and blank control group were (56.67±4.16)%, (84.67±3.51) and (87.00±4.00)% respectively, with statistically significant difference (P<0.001). The apoptosis rate of SKOV3/DDP-RBP2i group was (14.19±1.50)%, higher than (8.77±0.75)% of the negative control group and (7.48±0.52)% of the blank control group (P<0.001). The number of invasive cells of SKOV3/DDP-RBP2i group was (55.20±2.39), lower than (82.60±5.18) and (80.80±7.26) of the negative control group and the blank control group, respectively (P<0.001). The scratch healing rate of SKOV3/DDP-RBP2i group was (28.47±2.72)%, lower than (50.58±4.06)% and (48.92±4.63)% of the negative control group and the blank control group, respectively (P<0.001). The mRNA and protein expressions of E-cadherin in the SKOV3/DDP-RBP2i group were higher than those in the negative control group (P=0.015, P<0.001) and the blank control group (P=0.006, P<0.001). The mRNA and protein expression of N-cadherin in SKOV3/DDP-RBP2i group were lower than those in the negative control group (P=0.012, P<0.001) and the blank control group (P=0.005, P<0.001). The mRNA and protein expressions of vimentin in SKOV3/DDP-RBP2i group were also lower than those in the negative control group (P=0.016, P=0.001) and the blank control group (P=0.011, P=0.001). Five weeks after the cells inoculated into the nude mice, the tumor volume of SKOV3/DDP-RBP2i group, negative control group and blank control group were statistically significant different. The tumor volume of SKOV3/DDP-RBP2i group was smaller than those of negative control group and blank control group (P=0.001). Bioinformatics analysis showed that the expression of RBP2 in patients with metastatic ovarian cancer was higher than that without metastasis (P=0.043), and the median overall survival of ovarian cancer patients with high RBP2 expression was 41 months, shorter than 69 months of low RBP2 expression patients (P<0.001). Conclusion: Downregulation of the expression of RBP2 in SKOV3/DDP cells can inhibit cell migration and invasion, and the mechanism may be related to the inhibition of EMT.

Effect of exosome derived from ovarian cancer cell on the differentiation of fibroblast / 中华肿瘤杂志

Objective: To study the effects of exosome secreted by ovarian cancer (OC) cell on the differentiation and metastasis of normal fibroblasts (NFs). Methods: NFs were collected from patients who underwent hysteromyoma resection in the Affiliated Hospital of Qingdao University from May to December 2019. Exosome was extracted from the culture supernatant of SKOV3 cells by using ultra-high-speed centrifugation. The NFs were co-cultured with condition medium (CM), exosome of SKOV3 (SKOV3-exo) and control medium. The expression levels of fibroblast activation protein (FAP) and α-smooth muscle actin (α-SMA) were detected by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot. The metastatic ability of NFs was detected by Transwell array. Results: Under the transmission electron microscope, the extracellular vesicles extracted from the culture supernatant of SKOV3 were 30-100 nm in diameter with cup holder-like bilayer membrane structure, and the protein expression levels of TSG101 and HSP27 in exosomes (1.00±0.05 and 1.12±0.13) were higher than those of ovarian cancer SKOV3 cells (0.22±0.21 and 0.36±0.14, respectively, P<0.05). PKH67 fluorescently labeled exosomes could be taken up by NFs. The expression levels of α-SMA and FAP mRNA in CM group(2.91±0.15 and 3.21±0.33)and SKOV3-exo group (3.50±0.21 and 4.63±0.24, respectively) were higher than that in blank group (1.00±0.06 and 1.00±0.13, P<0.05). The protein expression levels of α-SMA and FAP in CM group and SKOV3-exo group (0.89±0.11 and 1.25±0.09, 0.81±0.09 and 1.20±0.12) were higher than those in the blank group (0.12±0.31 and 0.11±0.19, respectively, P<0.05). The migrated numbers of cells in the CM group and SKOV3-exo group [(215.01±14.80) and (389.72±19.43), respectively] were higher than that in the blank group [(113.73±4.70), P<0.05]. Conclusion: The exosome secreted by SKOV3 cells can be taken up by NFs, which makes it to differentiate into cancer associated fibroblasts (CAFs) and significantly enhances its metastatic ability, indicating that OC cells may promote the transformation of normal ovarian mesenchymal fibroblasts to CAFs through exosome pathways, and then promote the development of ovarian cancer.

MUC16: The Novel Target for Tumor Therapy / 中国肺癌杂志

Mucin16 (MUC16), also known as carbohydrate antigen 125 (CA125), is a glycoprotein antigen that can be recognized by the monoclonal antibody OC125 detected from epithelial ovarian carcinoma antigen by Bast et al in 1981. CA125 is not present in normal ovarian tissue but is usually elevated in the serum of epithelial ovarian carcinoma patients. CA125 is the most commonly used serologic biomarker for the diagnosis and recurrence monitoring of epithelial ovarian carcinoma. MUC16 is highly expressed in varieties of tumors. MUC16 can interact with galectin-1/3, mesothelin, sialic acid-binding immunoglobulin-type lectins-9 (Siglec-9), and other ligands. MUC16 plays an important role in tumor genesis, proliferation, migration, invasion, and tumor immunity through various signaling pathways. Besides, therapies targeting MUC16 have some significant achievements. Related preclinical studies and clinical trials are in progress. MUC16 may be a potential novel target for tumor therapy. This article will review the mechanism of MUC16 in tumor genesis and progression, and focus on the research actuality of MUC16 in tumor therapy. This article also provides references for subsequent tumor therapy studies targeting MUC16.
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TIM-3 gene is highly expressed in ephithelial ovarian cancer to promote proliferation and migration of ovarian cancer cells / 南方医科大学学报

OBJECTIVE@#To analyze the expression of immunoglobulin mucin molecule 3 (TIM-3) in epithelial ovarian cancer (EOC) and the effects of TIM-3 knockdown and overexpression on proliferation and migration of ovarian cancer cells.@*METHODS@#We analyzed TIM-3 expression in EOC and normal ovarian tissues using GEPIA database. We also detected TIM-3 expression levels in 82 surgical specimens of EOC and 18 specimens of normal ovarian tissues using immunohistochemistry, and analyzed the correlation of TIM-3 expression with clinicopathological parameters and survival outcomes of the patients. The expression of TIM-3 and Wnt1 mRNA in the tissues were detected using qRT-PCR. We constructed SKOV3 cell models of TIM-3 knockdown and overexpression and examined the changes in proliferation, apoptosis, migration and invasion of the cells using MTT assay, Annexin V-FITC/PI staining, scratch test and Transwell assay. The activity of Wnt/β-catenin pathway in the transfected was detected using dual luciferase reporter assay, and the mRNA levels of TCF-7, TCCFL-2 and CD44 were detected using qPCR. The protein expressions of MMP-9, CD44, Wnt1, β-catenin and E-cad in the transfected cells were detected with Western blotting.@*RESULTS@#The positive expression rate of TIM-3 was significantly higher in EOC tissues than in normal ovarian tissues (P < 0.05). The expression of TIM-3 was significantly correlated with FIGO stage, histological differentiation and lymph node metastasis, and was positively correlated with Wnt1 level (P < 0.05). In SKOV3 cells, TIM-3 knockdown significantly lowered the activity of Wnt/ β-catenin pathway, inhibited cell proliferation, migration and invasion, and promoted cell apoptosis. TIM-3 knockdown significantly down-regulated the mRNA levels of TCF-7, TCFL-2 and CD44 and the protein levels of MMP-9, CD44, Wnt1 and β-catenin, and significantly up-regulated the expression level of E-cad (P < 0.05). Overexpression of TIM-3 caused opposite effects in SKOV3 cells.@*CONCLUSION@#TIM-3 is highly expressed in EOC tissue to promote malignant behaviors of the tumor cells possibly by activating the Wnt/β-catenin signal pathway.

Tratamiento de tumores malignos epiteliales de ovario en estadios avanzados. Experiencia del Hospital Italiano de Buenos Aires / Treatment of advanced epithelial ovarian tumor. Hospital Italiano de Buenos Aires experience

Resumen El cáncer de ovario ocupa el tercer lugar en frecuencia entre los cánceres ginecológicos en Argentina. Existe un déficit de información de esta enfermedad en nuestro país respecto al tratamiento y evolución oncológica de las pacientes. El objetivo de nuestro trabajo fue evaluar los resultados perioperatorios y oncológicos, en pacientes con tumor epitelial de ovario con estadios avanzados. Presentamos una cohorte retrospectiva en la que se evaluó la supervivencia libre de enfermedad y la supervivencia global en pacientes con tumores epiteliales de ovario tratadas en el Hospital Italiano de Buenos Aires entre junio del 2009 a junio del 2017. De 170 pacientes incluidas en el estudio, 72 (42.4%) fueron tratadas con una cirugía de citorreducción primaria (CCP), mientras que 98 (57.6%) recibieron neoadyuvancia y luego cirugía del intervalo (CI). La tasa de citorreducción óptima fue de 75% y de 79% respectivamente. No se encontraron diferencias en los resultados perioperatorios, ni en las complicaciones graves entre ambos grupos. La mediana de SLE en el grupo de CCP fue de 2.5 años (IC 95% 1.6-3.1) mientras que en el grupo de CI fue de 1.4 (IC 95% 1.2-1.7) p < 0.001. La mediana de supervivencia global fue de 5.8 años en CCP, y de 3.5 años en CI. En pacientes adecuadamente seleccionadas la CCP presenta mejores resultados oncológicos a la neoadyuvancia y CI. La selección correcta de las pacientes para tratamiento primario es fundamental para definir la conducta terapéutica.

Abstract Ovarian cancer represents the third gynecological cancer in frequency in Argentina. There is a lack of information on this pathology in our country regarding the treatment and evolution of patients who suffer it. The aim of this study was to evaluate the perioperative and oncological results in patients with advanced epithelial ovarian tumor. We present a retrospective cohort in which we evaluated disease-free survival and overall survival in patients with epithelial ovarian tumor treated at the Hospital Italiano de Buenos Aires between June 2009 and June 2017. Of 170 patients included in the study, 72 (42.4%) received primary debulking surgery (CCP), while 98 (57.6%) received neoadjuvant therapy and interval surgery (CI). The optimal cyto-reduction rate was 75% and 79% respectively. No differences were found in perioperative outcomes, or in severe complications between the two groups. The median disease-free survival in the CCP group was 2.5 years (95% CI 1.6-3.1) while in the CI group it was 1.4 (95% CI 1.2-1.7) p < 0.001. The median overall survival was 5.8 years in CPP, and 3.5 years in CI. Faced with a meticulous selection by a group of experts, patients with advanced ovarian cancer treated with CCP present better oncological results than those who received neoadjuvant therapy and CI.

Phosphorylation of Cofilin-1 Enhances Paclitaxel Resistance of Epithelial Ovarian Cancer Cells by Inhibiting Apoptosis / 生物医学与环境科学（英文）

Objective@#To investigate the molecular mechanism of high phosphorylation levels of cofilin-1 (p-CFL-1) associated with paclitaxel resistance in epithelial ovarian cancer (EOC) cells.@*Methods@#Cells displaying varying levels of p-CFL-1 and CFL-1 were created by plasmid transfection and shRNA interference. Cell inhibition rate indicating paclitaxel efficacy was assessed by Cell Counting Kit-8 (CCK-8) assay. Apoptosis was assessed by flow cytometry and protein levels were detected by western blotting. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of phosphokinases and phosphatases of CFL-1. Survival analysis evaluated the correlation between the prognosis of EOC patients and the levels of p-CFL-1 and slingshot-1 (SSH-1).@*Results@#High levels of p-CFL-1 were observed in EOC cells that survived treatment with high doses of paclitaxel. SKOV3 cell mutants with upregulated p-CFL-1 showed impaired paclitaxel efficacy, as well as decreased apoptosis rates and pro-survival patterns of apoptosis-specific protein expression. Cytoplasmic accumulation of p-CFL-1 inhibited paclitaxel-induced mitochondrial apoptosis. SSH-1 silencing mediated CFL-1 phosphorylation in paclitaxel-resistant SKOV3 cells. Clinically, the high level of p-CFL-1 and the low level of SSH-1 in EOC tissues were closely related to chemotherapy resistance and poor prognosis in EOC patients.@*Conclusion@#The SSH-1/p-CFL-1 signaling pathway mediates paclitaxel resistance by apoptosis inhibition in EOC and is expected to be a potential prognostic predictor.

Role of miR-145-5p Targeting ARK5 in Regulating the Proliferation and Apoptosis of Human Epithelial Ovarian Cancer Cells / 中国医学科学院学报

Objective To explore the effect of miR-145-5p on the proliferation and apoptosis of human ovarian cancer cells and the possible molecular mechanisms involved.Methods Real-time quantitative PCR was performed to detect the expression of miR-145-5p in ovarian epithelial cells and ovarian cancer cells.CCK-8 and flow cytometry were used to detect the effects of miR-145-5p overexpression on the proliferation and apoptosis of ovarian cancer cells.TargetScan was employed to predict the target genes of miR-145-5p.Western blotting,dual luciferase reporter assay and rescue experiment were employed to predict and verify the underlying molecular mechanism of miR-145-5p function.Results The expression of miR-145-5p in ovarian cancer cells was significantly lower than that in normal ovarian epithelial cells(

Clinical laboratory features of Meigs' syndrome: a retrospective study from 2009 to 2018 / 医学前沿

Meigs' syndrome (MS), a rare complication of benign ovarian tumors, is easily misdiagnosed as ovarian cancer (OC). We retrospectively reviewed the clinical laboratory data of patients diagnosed with MS from 2009 to 2018. Serum carbohydrate antigen 125 and HE4 levels were higher in the MS group than in the ovarian thecoma-fibroma (OTF) and healthy control groups (all P < 0.05). However, the serum HE4 levels were lower in the MS group than in the OC group (P < 0.001). A routine blood test showed that the absolute counts and percentages of lymphocytes were significantly lower in the MS group than in the OTF and control groups (all P < 0.05). However, these variables were higher in the MS group than in the OC group (both P < 0.05). The neutrophil-to-lymphocyte ratio (NLR) was also significantly lower, whereas the lymphocyte-to-monocyte ratio was higher in the MS group than in the OC group (both P < 0.05). The NLR, platelet-to-lymphocyte ratio, and systemic immune index were significantly higher in the MS group than in the OTF and control groups (all P < 0.05). The hypoxia-inducible factor-1 mRNA levels were also significantly higher, whereas the glucose transporter 1, lactate dehydrogenase, and enolase 1 mRNA levels were lower in peripheral CD4

Clinical significance of p27 Kip1 expression in advanced ovarian cancer

Background: Ovarian cancer is the most common gynecological malignancy. In patients with advanced ovarian cancer, some biological parameters have prognostic implementations. P27kip1 is an inhibitor of a cycline-dependent kinase, its loss, can contribute to tumor progression. Objective: This study aimed to examine the importance of P27KIP1 protein in predicting the prognosis and response to neoadjuvant chemotherapy in patients with advanced ovarian epithelial cancer and to compare the outcomes of immunohistochemistry with Quantitative Real-time PCR. Patients and methods: We have studied P27KIP1expression by both immunohistochemistry and Quantitative Realtime PCR from 88 patients with advanced ovarian carcinomas undergone radical debulking surgery and received Paclitaxel followed by Cisplatin every 3 weeks for a total of 6 cycles. We also studied their association with both chemotherapy response and patient survival. Results: Nuclear expression of p27KIP1 protein was intense in 86 normal ovarian tissues and 42 of 88 carcinomas. The P27kip1mRNA expression level by qRT-PCR was very low in ovarian cancer tissues relative to its adjacent normal tissues. The results were statistically significant by both methods of determination. p27KIP1 expression was significantly related to good prognostic parameters as low stage tumors, differentiated tumors, absence of ascites, residual disease < 2 cm, and response to chemotherapy but not with histopathological type in case of determination by immunohistochemistry. Comparison of P27kip1 by both immunohistochemistry and qRTPCR with different prognostic parameters revealed no significant difference between both methods in the assessment of these parameters. In 4 years of follow-up, 20.5% of patients were alive without evidence of disease. 6.8% were alive with disease. The disease-related four -year survival rate for the whole group was 28.2%. In multivariate analysis, residual disease, histological type, tumor differentiation, ascites was of independent prognostic significance. Conclusion: In ovarian cancer, patients with loss of p27KIP1 expression are at a greater likelihood of disease progression, p27KIP1 may be used as a molecular marker to predict response to chemotherapy and prognosis. Both immunohistochemistry and qRT-PCR have equal reliability in the determination of p27 KIP1

Cáncer de Ovario: Tamizaje y diagnóstico imagenológico / Ovarian Cancer: Screening and imaging diagnosis

Resumen El cáncer de ovario se ha caracterizado por ser la neoplasia ginecológica de peor pronóstico. Lo anterior es consecuencia del curso silente de la enfermedad que ocasiona que la mayoría de las veces el diagnóstico se realice en etapas avanzadas. La información recolectada señala que los avances terapéuticos no han demostrado ser efectivos en mejorar la sobrevida de las pacientes con cáncer de ovario, lo cual orienta a la búsqueda constante de un método (o conjunto de éstos), que permita llevar a cabo el tamizaje y la detección temprana de dicha patología. Sin embargo, debido a que actualmente no se ha logrado identificar un método que sea costo-efectivo para el tamizaje, el mismo no se aplica a la población general y se reserva para casos específicos, como mujeres con antecedentes familiares de la enfermedad o que presentan síndromes hereditarios. Esta revisión incluye además información sobre las diferentes técnicas de imagen utilizadas tanto para el estudio y caracterización de masas anexiales, como para el estadiaje y pronóstico del cáncer de ovario. De las técnicas estudiadas, el ultrasonido (US) demostró ser la mejor opción para el abordaje inicial de masas anexiales; sin embargo, a la hora de realizar el estadiaje resultó ser inferior a la tomografía computarizada (TC) y la resonancia magnética (RM).

Abstract Ovarian cancer is the gynecological malignancy with the worst prognosis. Due to the silent course of the disease the diagnosis is made mainly in advanced stages. The literature reviewed showed that the therapeutic advances have not shown any major improvement in patient´s survival with ovarian cancer, therefore there is a constant research for a technique (or a set of them) that allows a proper screening and early detection of the disease. However, a cost effective method has not been found for screening, therefore it is not recommended for general population and it is reserved for specific cases, such as women with family history of ovarian cancer and with hereditary syndromes. This review also includes information about the different imaging techniques available not only for the study and characterization of neoplasms, but also for staging and prognosis of ovarian cancer. The ultrasound proved to be the best option for the initial approach of adnexal masses, however it has shown to be inferior for staging than CT-Scan and MRI.

Overexpression of long noncoding RNA PTPRG-AS1 is associated with poor prognosis in epithelial ovarian cancer

SUMMARY OBJECTIVE Long noncoding RNAs (lncRNAs) have been shown to play a critical role in tumor progression. Abnormal expression of LncRNA PTPRG antisense RNA 1 (PTPRG-AS1) has been reported in several tumors. Hence, we aimed to determine the expression and clinical significance of PTPRG-AS1 in epithelial ovarian cancer (EOC) patients. METHODS The expressions of PTPRG-AS1 were assessed in 184 pairs of EOC tumor specimens and adjacent normal tissues. The levels of target lncRNAs and GAPDH were examined using standard SYBR-Green methods. The relationships between the expressions of PTPRG-AS1 and the clinicopathological features were analyzed using the chi-square test. Multivariate analysis using the Cox proportional hazards model was performed to assess the prognostic value of PTPRG-AS1 in EOC patients. RESULTS We confirmed that the expressions of PTPRG-AS1 were distinctly higher in the EOC tissue compared with the adjacent non-tumor specimens (p < 0.01). Higher levels of PTPRG-AS1 in EOC patients were associated with advanced FIGO stage (p = 0.005), grade (p = 0.006), and distant metastasis (p = 0.005). Survival analyses revealed that patients with high expressions of PTPRG-AS1 had a distinctly decreased overall survival (p = 0.0029) and disease-free survival (p = 0.0009) compared with those with low expressions of PTPRG-AS1. Multivariate assays indicated that PTPRG-AS1 expression was an independent prognostic factor for both overall survival and disease-free survival in EOC (Both p < 0.05). CONCLUSIONS Our study suggests that PTPRG-AS1 may serve as a novel prognostic biomarker for EOC patients.

RESUMO OBJETIVO Sabe-se que RNAs longos não codificantes (lncRNAs) desempenham um papel crítico na progressão tumoral. A expressão anormal do RNA 1 anti-senso LncRNA PTPRG (PTPRG-AS1) já foi relatada em diversos tumores. Assim, buscamos determinar a expressão e significância clínica do PTPRG-AS1 em pacientes com câncer de ovário epitelial (COE). METODOLOGIA As expressões do PTPRG-AS1 foram avaliadas em 184 pares de amostras tumorais de COE e tecidos normais adjacentes. Os níveis de lncRNAs e GAPDH alvo foram examinados usando o método padrão de SYBR Green. As relações entre as expressões do PTPRG-AS1 e as características clínico-patológicas foram analisadas através do teste qui-quadrado. Uma análise multivariada utilizando o modelo de riscos proporcionais de Cox foi realizada para avaliar o valor prognóstico do PTPRG-AS1 em pacientes com COE. RESULTADOS Constatou-se que as expressões do PTPRG-AS1 foram nitidamente maiores nos tecidos de COE em relação aos espécimes adjacentes não tumorosos (p<0,01). Níveis mais elevados do PTPRG-AS1 em pacientes com COE foram associados a um estágio avançado de FIGO (p = 0,005), grau (p = 0,006) e metástases à distância (p = 0,005). As análises de sobrevida revelaram que pacientes com expressões elevadas do PTPRG-AS1 tiveram uma diminuição significativa da sobrevida global (p = 0,0029) e da sobrevida livre de doença (p = 0,0009) em relação àqueles com baixas expressões do PTPRG-AS1. As análises multivariadas indicaram que a expressão do PTPRG-AS1 foi um fator de prognóstico independente tanto para a sobrevida global quanto para a sobrevida livre de doença em pacientes com EOC (p < 0,05). CONCLUSÃO Nosso estudo sugere que o PTPRG-AS1 pode ser um novo biomarcador prognóstico para pacientes com COE.

Primary broad ligament adenocarcinoma

Primary broad ligament carcinoma is a very rare occurrence with 28 reported cases worldwide, to date. The epidemiology, treatment strategy and prognosis are still uncertain because of the scarcity of cases. Currently, all broad ligament carcinomas are managed similar to epithelial ovarian cancer. We report the case of a 43-year-old female with a prolonged complaint of abdominal pain and intermittent urinary retention, requiring frequent catheterization. She was diagnosed with obstructive right hydroureteronephrosis. The abdominal Contrast Enhanced Computed Tomography (CECT) revealed a well-defined heterogeneous lesion of 2.1х3х3.2cm size in the right lateral and posterior wall of the cervix. An ultrasound (USG)-guided Fine Needle Aspiration Cytology (FNAC) of the mass was done and it was suspected to be malignant. The patient underwent total abdominal hysterectomy, right salpingo-oophorectomy, pelvic lymph-nodal sampling, and peritoneal washing. Histological examination depicted an endometrioid adenocarcinoma of the broad ligament. She received adjuvant chemotherapy, followed by hormonal therapy. It has been five years since her surgery, and she is now alive and disease free.

Diseño de un panel de citometría de flujo para muestras de sangre, ascitis y tejido ovárico / Design of a multicolored flow cytometry panel for blood, ascites and ovarian tissue samples

Introducción: El cáncer epitelial de ovario (CEO) ocupa el sexto lugar en incidencia y mortalidad a nivel mundial y en Cuba, el quinto en incidencia. Este cáncer es inmunogénicoy sus células malignas crecen en interacción conlas células inmunitarias. Su curso clínico depende del infiltrado inflamatorio acompañante del tumor. La citología e histopatología son los métodos diagnóstico de elección. Sin embargo, la citometría de flujo emerge como una tecnología de mayor sensibilidad, objetividad y rapidez. Objetivo: Diseñar un panel multicolor de citometría de flujo para inmunofenotipar el infiltrado linfocitario de tres tipos de muestras de pacientes con CEO. Métodos: Se realizó un diseño experimental, para la creación y evaluación de un panel multicolor de citometríade flujo, en el laboratorio de Inmunología del Instituto Nacional de Oncología y Radiobiología. El panel se diseñó en sangre de 3 sujetos sanos y se optimizó para sangre periférica en 33 sujetos sanos y, en sangre periférica, ascitis y tejido tumoral ovárico de tres pacientes con CEO. En cada muestra se inmunofenotiparon varias poblaciones linfocitarias. Resultados: Se seleccionaron 11 marcadores antigénicos para el inmunofenotipo, el panel quedó conformado por 4 tubos de citometría. La metodología se pudo aplicar a las muestras de ascitis y tejido tumoral sin interferencias, se obtuvieron porcentajes de las subpoblaciones linfocitarias dentro de los valores esperados. Conclusiones: El panel diseñado permitió inmunofenotipar linfocitos en distintos tipos de muestras de pacientes con CEO, con resultados confiables y reproducibles. Esta metodología puede extenderse a la realización de inmunofenotipaje en otras enfermedades(AU)

Introduction: Epithelial ovarian cancer occupies the 6th place in incidence and mortality in women worldwide. In Cuba, it occupies the 5th place in incidence in females. This cancer is immunogenic and its malignant cells grow in interaction with multiple cells from immune system. Its clinical course depends largely on the type of inflammatory infiltrate accompanying the tumor. Cytology and histopathology are gold standard as diagnostic methods. However, flow cytometry emerges as a technology with greater sensitivity, objectivity and speed. Objective: To design a multicolored flow cytometry panel to immunophenotype the lymphocytic infiltrate of three types of samples for patients with ovarian cancer. Methods: An experimental design was carried out in vitro for the creation and evaluation of a multicolored flow cytometry panel in the Immunology laboratory of the National Institute of Oncology and Radiobiology of Cuba. The panel was designed in the blood of three healthy subjects; then it was optimized for blood in 33 healthy volunteers and blood, ascites and ovarian tumor tissue, from three patients with epithelial ovarian cancer. Several lymphocytes lineages were immunophenotypedin each sample. Results: Eleven markers were selected for the immunophenotype and the panel was made up of four multiparameter cytometry tubes. The methodology created could be applied to the samples of ascites and tumor tissue without interferences and percentages of different lymphocyte subpopulations were obtained within the expected values. Conclusions: The designed panel allowed immunophenotyping of lymphocytes in different types of ovarian cancer patient samples and reliable and reproducible results were obtained. This methodology could be employed for others diseases(AU)

Supervivencia de pacientes con cáncer epitelial de ovario en el Instituto Nacional de Cancerología, resultados a partir del registro hospitalario de cáncer (2005-2014) / Survival of patients with epithelial ovarian cancer, results of the hospital-based cancer registry of the National Cancer Institute (2005-2014)

Resumen Objetivo: Proporcionar características demográficas y clínicas, así como estimaciones de supervivencia global a tres años de pacientes con cáncer epitelial de ovario (CEO) tratadas entre 2005 y 2014 en el Instituto Nacional de Cancerología de Colombia (INC). Métodos: Se incluyeron 783 pacientes diagnosticadas y tratadas por primera vez en el INC por CEO en los periodos 2005-2008, 2009-2011 y 2012-2014 sin un diagnóstico previo de otro cáncer. Se cruzaron datos del registro hospitalario de cáncer con bases de datos gubernamentales para obtener información de seguimiento. Utilizando el método Kaplan-Meier se estimó la probabilidad de sobrevivir a 36 meses a partir de la fecha de ingreso, evaluando diferencias en supervivencia entre grupos con la prueba de rango logarítmico. Se utilizaron modelos multivariados de riesgos proporcionales de Cox para evaluar: el efecto relativo de edad, el estadio clínico, el subtipo histológico y el tipo de tratamiento inicial en la supervivencia. Resultados: La probabilidad de supervivencia global a 36 meses fue de 56,5% (IC 95%: 53,0; 60,0), que se mantuvo estable en los tres periodos. La edad avanzada, el estadio clínico y el subtipo histológico afectaron significativamente la supervivencia global a tres años: 49,5% (IC 95%: 43; 55,6) para mujeres >59 años; 21,9% (IC 95%: 14,7; 29,2) para la enfermedad en estadio IV y 56,3% (IC 95%: 37,5; 54,3) para los tumores serosos. Las estimaciones de hazard fueron significativamente más altas en pacientes de 59 años o más (HR 1,54 (IC del 95%: 1,04 a 2,27)) y en cánceres con estadio avanzado (HR 13,47 (IC 95%: 7,92-22,92)); la cirugía más quimioterapia tuvo una reducción en el riesgo en comparación con otros tratamientos (HR 0,84 (IC 95% 0,52-1,36). Conclusiones: La supervivencia del cáncer epitelial de ovario se mantuvo estable con el tiempo. La variación se presentó en factores como: la edad, el estadio clínico y el primer tratamiento.

Abstract Aims: To provide demographical and clinical characteristics and estimations of 3-year overall survival of epithelial ovarian cancer (EOC) patients treated at the Colombian National Cancer Institute (INC) between 2005 and 2014. Methods: All 783 patients first treated at INC for EOC in the three periods: (2005-2008, 2009-2011, 2012-2014), without a prior cancer diagnosis, were included in this study. Follow-up was realized by cross-linkage with governmental databases using person identification numbers. Probability of surviving 36 months since the date of entry at INC was estimated using Kaplan-Meier methods, using the log-rank test to evaluate differences between groups. We used multivariate Cox proportional hazard models to evaluate the relative effect of age, clinical stage, histological subtype and treatment first on survival. Results: The overall survival probability at 36 months was 56.5% (95% CI: 53.0, 60.0), which was stable over time. Advanced age and clinical stage significantly affected 3-year overall survival, being 49.5°% (95°% CI: 43.4, 55.6) for age > 59, 21.9°% (95°% CI: 14.7, 29.2) for stage IV disease and 56.3% (95% CI: 37.5, 54.3) for serous tumors. Hazard ratios were significantly higher for patients aged 59 and over (HR 1.54 (95%CI 1.04-2.27)) and advanced stage cancers (HR 13.47 (95%CI 7.92-22.92)), whereas patients with surgery plus chemotherapy had a strongly reduced risks compared to other treatments (HR 0.84 (95%CI 0.52-1.36)). Conclusions: Survival of epithelial ovarian cancer was stable over time, with a variation according to age, clinical stage and first treatment.