Self-delivery of a metal-coordinated anti-angiogenic nanodrug with GSH depleting ability for synergistic chemo-phototherapy.

Synergistic chemo-phototherapy has offered tremendous potential in cancer treatment. Nevertheless, nanosystems usually suffer from the complexity of multicomponents (polymeric or inorganic materials), which results in carrier-related toxicity issues. Moreover, the GSH over-expression of tumor cells seriously compromises ROS therapeutic efficiency. Herein, we designed a self-delivered nanodrug via Cu(II) coordination-driven co-self-assembly of celastrol (CST, a chemo-drug with anti-angiogenesis activity) and indocyanine green (ICG, a photosensitizer) for synergistic chemo-phototherapy with GSH depletion. The nanodrug was further cloaked by an erythrocyte membrane (RBC) to prolong the circulation time. Within the tumor microenvironment, the nanodrug would be disassembled upon intracellular GSH triggering. Moreover, the released Cu(II) could efficiently deplete the GSH, thus damaging the ROS-scavenging system and amplifying the phototherapeutic efficiency upon laser irradiation. The in vivo experiments validated the highly effective accumulation at tumor sites, potent tumor growth inhibition, and inappreciable systemic toxicity. The tumor microenvironment-responsive coordination-driven self-assembled biomimetic nanodrug may hold potential applications in tumor theranostics.

Management and prognosis comparison between incidental and nonincidental intravenous leiomyomatosis: a retrospective single-center real-life experience.

Background: Intravenous leiomyomatosis (IVL) is a rare, difficult-to-treat type of smooth muscle tumor that originates from the uterine myoma. However, its clinical characteristics, management, and prognosis are not clearly understood. Moreover, the 2 different methods used to diagnose IVL-incidental and nonincidental-result in completely different treatments. Methods: We conducted a single-center, retrospective study. Our real-life case series included patients pathologically diagnosed with IVL between July 2011 and December 2020. All patients with IVL were divided into 2 groups: an incidental group and a nonincidental group. Medical records of patients, including clinical characteristics, primary treatment, treatment after recurrence, and prognosis, were reviewed. Results: A total of 39 patients were included in the study, with a median patient age of 47 years. Of the 39 cases, 15 (38.5%) were incidentally diagnosed with only intrapelvic tumors. Among the 24 patients with IVL in the nonincidental group, tumor spread in the inferior vena cava, right heart, and pulmonary artery was identified in 4, 17, and 3 patients, respectively. The most common symptoms were abnormal uterine bleeding in the incidental group and chest distress and dyspnea in the nonincidental group. Among the 15 patients in the incidental group, ovary-preserving surgery was performed in 6 young women (≤40 years old), of whom 3 underwent myomectomy. All 24 patients with IVL in the nonincidental group underwent thrombectomy without uterine or ovary preservation by multidisciplinary surgical treatment. Only 1 patient in each group underwent postoperative adjuvant therapy. During the median follow-up of 36.0 months, recurrence was recorded in 5 (12.8%) cases in the incidental group, with no deaths recorded. Only 1 patient was lost to follow-up. No recurrence was noted in the cases in the nonincidental group. Among the 5 patients who experienced recurrence, 4 received secondary surgical treatment and 1 received hormone therapy. All patients were alive as of this report. Conclusions: Patients with IVL who are diagnosed incidentally have a higher recurrence risk than those who are diagnosed nonincidentally and undergo complete tumor resection. However, patients incidentally diagnosed with IVL can still experience long disease-free survival rates following secondary surgical treatment after recurrence.

Immune Subtypes Characterization Identifies Clinical Prognosis, Tumor Microenvironment Infiltration, and Immune Response in Ovarian Cancer.

Objective: Because of the modest immunotherapeutic response among ovarian carcinoma (OC) patients, it is significant to evaluate antitumor immune response and develop more effective precision immunotherapeutic regimens. Here, this study aimed to determine diverse immune subtypes of OC. Methods: This study curated the expression profiles of prognostic immunologically relevant genes and conducted consensus clustering analyses for determining immune subtypes among OC patients in TCGA cohort. With Boruta algorithm, characteristic genes were screened for conducting an immune scoring system through principal component analysis algorithm. The single-sample gene set enrichment analysis and ESTIAMTE methods were adopted for quantifying the immune infiltrates and responses to chemotherapeutic agents were estimated with pRRophetic algorithm. Two immunotherapeutic cohorts were used for investigating the efficacy of immune score in predicting therapeutic benefits. Results: Two immune subtypes were conducted among 377 OC patients. Immune subtype 2 was characterized by worse clinical prognosis, more frequent genetic variations and mutations, enhanced immune infiltrates, and increased expression of MHC molecules and programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1). In total, 30 prognosis-relevant characteristic immune subtype-derived genes were identified for constructing the immune score of OC patients. High immune score was linked with more dismal prognosis, decreased immune infiltrations, and expression of MHC molecules. High immune score presented favorable sensitivity to doxorubicin and vinorelbine and reduced sensitivity to cisplatin. In addition, immune score possessed the potential in predicting benefits from anti-PD-1/PD-L1 therapy. Conclusion: Collectively, our findings propose two complex and diverse immune subtypes of OC. Quantitative assessment of immune subtypes in individual patients strengthens the understanding of tumor microenvironment features and promotes more effective immunotherapeutic regimens.

Surgical treatment strategies for extra-pelvic intravenous leiomyomatosis.

BACKGROUND: Extra-pelvic intravenous leiomyomatosis (IVL) extending into inferior vena cava (IVC) or heart (i.e. intracardiac leiomyomatosis, ICL) is an extremely rare benign disease. No consensus has been reached on the optimal surgical strategy. The aim of this study is to introduce four types of one-stage surgical strategies including less invasive options and a guideline to select patient-specific strategy for this disease. METHODS: Twenty-four patients of extra-pelvic IVLs receiving one-stage resections at the Zhongshan Hospital from July 2011 to November 2019 were reviewed retrospectively. Base on the initial experiences of the indiscriminate choices of tumor thrombectomies through sterno-laparotomy under cardiopulmonary bypass (CPB) in 6 ICLs, an anatomy-based guideline for four types of surgical strategies was developed and applied for the next 18 patients. RESULTS: Under the direction of guideline, tumor thrombectomies through single laparotomy were applied without CPB in 2 ICLs and 4 IVLs confined in IVC, or with CPB in 7 ICLs. Guideline-directed double-incisions with CPB were applied in only 5 ICLs, including 1 receiving mini-thoracotomy and 4 receiving sternotomy because of tumor adherences with right atriums in 2 and with pulmonary arteries in 2. All 24 patients accomplished one-stage panhysterectomy, bilateral adnexectomy and complete resections of intracaval and intracardiac tumors. For residual pelvic intravenous tumors in 19 patients, 17 received macroscopically complete resections while the other 2 failed because of high risk of hemorrhage. Intraoperative blood losses, operation time and hospitalization expense in the single-laparotomy non-CPB group were significantly lesser than the other groups. In CPB groups, inpatient stay and hospitalization expense in the single-incision group were significantly lesser than the double-incisions group. All patients were alive and free of recurrences during a mean follow-up of 35.4 ± 27.2 months (range, 1-100 months). The pelvic tumor residues in 2 patients remained unchanged for 51 and 52 months since operation, respectively. CONCLUSIONS: For various extra-pelvic IVLs, the 4 types of surgical strategies including less invasive options are feasible, providing these are selected by a guideline base on the tumor extension and morphology. The proposed guideline is believed to accommodate more patients receiving less invasive surgery without compromising the curative effect.

Survival benefits of dose-dense early postoperative intraperitoneal chemotherapy in front-line therapy for advanced ovarian cancer: a randomised controlled study.

Dose-dense early postoperative intraperitoneal chemotherapy (DD-EPIC) significantly increased non-progression rate in advanced ovarian cancer (OC) patients. We report final overall survival (OS) results to further strengthen the efficacy of DD-EPIC in the front-line therapy. In this phase 2 trial, 218 patients with FIGO IIIC-IV OC were randomly allocated to receive DD-EPIC followed by intravenous (IV) chemotherapy (DD-EPIC group), or IV chemotherapy alone (IV group). The study was prespecified to detect differences in progression-free survival (PFS) and OS. At a median follow-up period of 69.1 months, the median OS was 67.5 and 46.3 months in the DD-EPIC and IV group, respectively. The probability rate of OS at 5 years was 61.0% with DD-EPIC, and 38.2% with IV (hazard ratio [HR] for death from OC, 0.70; 95% confidence interval [CI], 0.49-1.00). DD-EPIC was associated with a prolonged PFS compared with the IV group (the estimated rate of PFS at 5 years, 26.0% vs. 8.5%; HR for disease progression, 0.64; 95% CI, 0.47-0.86). DD-EPIC was associated with a longer OS than IV chemotherapy alone. It may be considered as a valuable option of the front-line therapy for advanced ovarian cancer.Trial registration: ClinicalTrials.gov, NCT01669226 (date of registration: August 20, 2012).

Addition of intraperitoneal cisplatin and etoposide to first-line chemotherapy for advanced ovarian cancer: a randomised, phase 2 trial.

BACKGROUND: We assessed the efficacy of adding intraperitoneal (IP) chemotherapy to standard first-line intravenous (IV) chemotherapy in epithelial ovarian cancer (EOC) patients. METHODS: Patients with stage IIIC-IV EOC who underwent optimal debulking surgery were randomly assigned to four cycles of weekly IP chemotherapy with cisplatin (50 mg/m2) and etoposide (100 mg/m2) followed by six cycles of IV chemotherapy every 3 weeks (IP/IV arm), or were administered IV chemotherapy alone (IV arm). The primary endpoint for this study was the 12-month non-progression rate (NPR). RESULTS: Between 4/2009 and 9/2015, 218 patients were randomised, of whom 215 initiated treatment. In the IP/IV arm, 90.6% of patients completed 4 cycles of IP chemotherapy. The 12-month NPRs were 81.9% and 64.2% in the IP/IV and IV groups, respectively (HR 0.48 (95% CI 0.27-0.82)). The median progression-free survival (PFS) was increased in the IP/IV arm compared with that in the IV arm (22.4 vs. 16.8 months; HR 0.66 (0.48-0.91)) and in a subgroup with no gross cytoreduction (31.1 vs. 16.8 months; HR 0.46 (0.26-0.82)). Similar findings were detected with regard to time to first subsequent anticancer therapy (TFST) (25.9 vs. 18.0 months; P = 0.009) and time to second subsequent anticancer therapy (TSST) (40.8 vs. 30.1 months; P = 0.042). Grade 3/4 leukopenia, anaemia and gastrointestinal events were more common in the IP/IV arm, but the treatment burden was considered acceptable. CONCLUSIONS: IP chemotherapy prior to IV chemotherapy was associated with an increased 12-month NPR and a longer TSST than IV alone in patients with EOC, albeit with acceptable toxic effects. Long-term follow-up is warranted to identify the effects of IP therapy on overall survival.

Expression Profiles of Endometrial Carcinoma by Integrative Analysis of TCGA Data.

BACKGROUND: This study was to explore the expression profile of endometrial carcinoma (EC) and identify the potential molecular mechanism and therapeutic targets. METHODS: Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified in EC using mRNA and miRNA sequencing data released by the Cancer Genome Atlas database; then, gene function and pathway of DEGs were analyzed based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases; finally, the transcription factors (TFs) latently regulating the DEGs and DEMs were predicted and a TF-miRNA-Gene network was then established to summarize the regulatory links between TFs, DEMs and DEGs. RESULTS: One thousand five hundred and forty two upregulated and 1,885 downregulated DEGs, 34 upregulated and 12 downregulated DEMs were identified. The principal DEGs-enriched functions were cell differentiation, cell migration, and cell surface receptor signaling pathway. The DEGs-enriched cell signaling pathways including the MAPK, Wnt signaling pathway, and the p53 signaling pathway. As shown in the TF-miRNA-Gene network, TFs such as CPBP and GKLF, miRNAs such as miR-141-3p and miR-130b-3p, regulated most of DEGs and DEMs. CONCLUSION: These results may contribute to the study of the molecular mechanism and therapeutic targets in EC, and facilitate the discovery of new biomarkers for screening, diagnosis and monitoring.

Circulating microRNAs as a fingerprint for endometrial endometrioid adenocarcinoma.

BACKGROUND: Endometrial cancer is the most common malignancy of the female genital tract worldwide, and endometrial endometrioid adenocarcinoma (EEC) is the major histological type of endometrial cancer. There is a great need for better markers with high sensitivity and specificity to permit early diagnosis and proper management of EEC. The aim of our study is to identify a miRNA classifier within plasma as a noninvasive biomarker for EEC diagnosis. METHODS: This study was a retrospective case-control analysis which contained two independent cohorts including 93 participants. First, we screened 375 miRNAs in 29 plasma samples. 9 of the miRNAs were selected to be evaluated their expression by quantitative reverse-transcriptase polymerase chain reaction. A stepwise logistic regression model was then used to establish a new classifier in the validation cohort. Area under the receiver operating characteristic curve was used to evaluate the diagnostic accuracy. Co-expression analysis was used to verify the independence of results. RESULTS: miR-15b, -27a, and -223 were found to be differentially expressed in the EEC plasma between the two cohorts and had few connections with other miRNAs. The areas under the curve (AUC) were 0.768, 0.813, and 0.768 for miR-15b, -27a, and 223, respectively. miR-27a and CA125 can be combined as a potential non-invasive biomarker for detecting EEC, with the AUC of 0.894. CONCLUSION: Our study demonstrated three miRNAs, including miR-15b, -27a, and -233 have a good clinical value in EEC diagnosis. The classifier, including miR-27a and CA125, demonstrated a high accuracy in the diagnosis of EEC and might serve as a novel non-invasive biomarker in the future.

High expression of UCH37 is significantly associated with poor prognosis in human epithelial ovarian cancer.

Ubiquitin carboxyl-terminal hydrolase 37 (UCH37) is a member of deubiquitinating enzymes. It can suppress protein degradation through disassembling polyubiquitin from the distal subunit of the chain. The aim of this study was to assess the value of UCH37 in predicting tumor recurrence after curative resection in epithelial ovarian cancer (EOC) patients. In this study, the expression level of UCH37 in 5 paired EOC and normal tissue was tested by Western blot. And the association of UCH37 expression and prognostic value was analyzed in 100 tumor specimens from EOC patients, who underwent curative resection between 2003 and 2011. We found that UCH37 was up-regulated in most of the tumor tissue and high expression of UCH37 was an independent significant predictor associated with the poor outcome and recurrence of EOC (p=0.0037 and p=0.0042 in overall and disease-free survival, respectively), especially in the advanced stage of EOC (p=0.0106 and p=0.0115 in overall and disease-free survival, respectively), and may become a novel predictor for prognosis of EOC patients after curative resection. Our data suggest for the first time that UCH37 overexpression is associated with advanced tumor progression and poor clinical outcome of EOC patients and may help physicians make informed decisions regarding adjuvant treatment following curative resection.

A ten-microRNA signature identified from a genome-wide microRNA expression profiling in human epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common gynecologic malignancy. To identify the micro-ribonucleic acids (miRNAs) expression profile in EOC tissues that may serve as a novel diagnostic biomarker for EOC detection, the expression of 1722 miRNAs from 15 normal ovarian tissue samples and 48 ovarian cancer samples was profiled by using a quantitative real-time polymerase chain reaction (qRT-PCR) assay. A ten-microRNA signature (hsa-miR-1271-5p, hsa-miR-574-3p, hsa-miR-182-5p, hsa-miR-183-5p, hsa-miR-96-5p, hsa-miR-15b-5p, hsa-miR-182-3p, hsa-miR-141-5p, hsa-miR-130b-5p, and hsa-miR-135b-3p) was identified to be able to distinguish human ovarian cancer tissues from normal tissues with 97% sensitivity and 92% specificity. Two miRNA clusters of miR183-96-183 (miR-96-5p, and miR-182, miR183) and miR200 (miR-141-5p, miR200a, b, c and miR429) are significantly up-regulated in ovarian cancer tissue samples compared to those of normal tissue samples, suggesting theses miRNAs may be involved in ovarian cancer development.

Expression and clinical significance of BIRC6 in human epithelial ovarian cancer.

Baculoviral IAP repeat containing 6 (BIRC6), an unusually large member of the IAP family, may play an important role in oncogenesis. The aim of this study was to assess the value of BIRC6 in predicting tumor recurrence after curative resection in epithelial ovarian cancer (EOC) patients. In this study, the differences of BIRC6 expression in four paired EOC and normal tissue were performed by Western blot, and expression of BIRC6 protein was analyzed in 100 clinicopathologically characterized EOC cases from those who underwent curative resection between 2003 and 2011 by immunohistochemistry. Kaplan-Meier survival estimates and log-rank tests were used to assess the prognostic significance. It was found that BIRC6 expression was higher in the carcinoma tissue than in normal control tissue at protein level by Western blot. There was a significant difference of BIRC6 expression in patients categorized according to tumor differentiation (p = 0.016). Univariate analyses and multivariate analyses revealed that BIRC6 was an independent significant predictor for overall survival and disease-free survival. A prognostic significance of BIRC6 was also found by Kaplan-Meier method. The expression of BIRC6 in the cytoplasm is associated with EOC differentiation and may be a novel predictor for poor prognosis of EOC patients after curative resection.

Multimodality treatment of two cases of intracardiac leiomyomatosis with enormous mass in the abdominopelvic cavity.

Difficulties in the preoperative preparation and surgical management of patients with intravenous leiomyomatosis involving the heart and pulmonary artery resulting in intracardiac leiomyomatosis necessitate further investigation of this condition. In this report, we describe the interdisciplinary treatment of two cases of intracardiac leiomyomatosis with enormous mass in the abdominopelvic cavity. A single-stage surgical procedure with a combined thoracic and abdominal approach was performed in both cases and the tumors were successfully excised. The procedure also involved removal of the atrial, caval and other venular extensions, and total hysterectomy with bilateral salpingo-oophorectomy. Postoperative pathology findings confirmed the diagnosis of intravenous leiomyomatosis. Neither patient died perioperatively, and no complications were observed.

Gestrinone inhibits growth of human uterine leiomyoma may relate to activity regulation of ERα, Src and P38 MAPK.

The study was to investigate the effect of gestrinone on the growth of human uterine leiomyoma cells and on the levels and activity of p38, Src and estrogen receptor alpha (ERα). Human uterine leiomyoma cells were cultured and treated with dimethylsulfoxide (DMSO) or a gestrinone concentration gradient. Morphological changes were observed and apoptosis was evaluated. Levels of p38 and phosphorylated-p38 (pp38) were assayed by enzyme-linked immunosorbent assay (ELISA). Levels of ERα and Src were analyzed using real-time RT-PCR and Western blotting. The result showed that gestrinone significantly inhibited the growth of cultured human uterine leiomyoma cells in a concentration- and time-dependent manner, with a 50% inhibitory concentration (IC(50)) value and corresponding 95% confidence intervals (CI) of 43.67 (23.46∼81.32), 27.78 (12.51∼61.68) and 15.25 (7.17∼32.43) µmol/L at 20, 40 and 60h, respectively. Compared with control-treated leiomyoma cells, gestrinone significantly reduced both the expression of ERα (P<0.05) and the levels of phospho-Ser167-ERα (P<0.05). Gestrinone also markedly suppressed the level of phospho-Tyr416-Src (P<0.05). Moreover, gestrinone significantly increased the ratio of phospho-p38/p38 mitogen-activated protein kinase (MAPK) (P<0.05). However, no significant increase in apoptosis or cell cycle arrest was observed (P>0.05) in response to the tested concentrations of 0.1 to 3.0µmol/L. As a conclusion, gestrinone suppresses the proliferation of uterine leiomyoma cells mainly by regulating the activity of ERα/Src/p38 MAPK in a concentration-dependent manner at a low concentration of 0.1∼3.0µM, but not significantly regulating apoptosis. Gestrinone opposes the growth of uterine leiomyoma through multiple genes.