Aging affects regrowth of stealthperitoneal dissemination of advanced ovarian cancer: a multicenter retrospective cohort study.

Ovarian cancer (OvCa) is one of the most lethal gynecological malignancies, and most patients are diagnosed at advanced stage with peritoneal dissemination. Although age at diagnosis is considered an independent prognostic factor, its impact on peritoneal recurrence after combined cytoreductive surgery and chemotherapy is not clear. The objective of this study was to investigate the impact of aging on peritoneal recurrence from stealth dissemination and gain insight of the pathophysiology of OvCa in elderly patients. A total of 243 patients with pT2b-pT3 epithelial ovarian who achieved complete surgery, no-residual tumor at first surgery, were selected to be analyzed the risk of peritoneal seeding and recurrence. We found that age over 65 years was independently associated with an increased risk of peritoneum-specific (PS) recurrence (. Furthermore, pT3 stages and positive ascites cytology also worsen the PS-relapse-free survival. Collectively, our findings suggest that age, especially over 65 years, predicts reduced peritoneum-specific tumor recurrence in patients with advanced ovarian cancer after complete cytoreduction surgery, particularly those with pT3 tumors and positive ascites cytology.

Elucidation of the role of XBP1 in the progression of complete hydatidiform mole to invasive mole through RNA-seq.

OBJECTIVE: A complete hydatidiform mole (CHM) is a common disease and is known to develop post-molar gestational trophoblast neoplasia (GTN). However, the molecular mechanisms underlying the progression of CHM to post-molar GTN remain largely unknown. In this study, we investigated the molecular factors associated with the progression using RNA-seq. METHODS: We included 13 patients with CHM and performed RNA-seq using freshly frozen samples. We identified differentially expressed genes between patients who developed GTN (GTN group) and those who achieved spontaneous remission after uterine evacuation (SR group), and performed pathway analysis. Then, functional analyses were performed on choriocarcinoma (JAR and JEG-3) and CHM (Hmol1-3B and Hmol1-2C) cells. Moreover, we evaluated the in vivo tumorigenicity of XBP1-overexpressed Hmol1-3B cells. RESULTS: The gene expression profiles were separated into two groups, and an upstream regulator analysis was performed using 281 differentially expressed genes. We focused on transcription factors and identified that 33 transcription factors were activated in the GTN group. Then, excluding those with low expression levels in clinical samples and cell lines, XBP1 was selected for further analysis. Additionally, XBP1 downregulation significantly decreased the migration and invasive abilities of choriocarcinoma cells, whereas XBP1 overexpression significantly increased the migration and invasive abilities of CHM cells. Furthermore, animal experiments showed that tumor weight and blood human chorionic gonadotropin (hCG) levels were significantly higher in the XBP1-overexpressing Hmol1-3B-bearing mice than those in the control mice. CONCLUSION: RNA-seq identified XBP1 as a key factor in post-molar GTN, suggesting it contributes to the development of post-molar GTN.

Update on the oncologic and obstetric outcomes of medroxyprogesterone acetate treatment for atypical endometrial hyperplasia and endometrial cancer.

AIMS: To evaluate the safety and effectiveness of high-dose oral medroxyprogesterone acetate (MPA) therapy as a fertility-sparing treatment for patients diagnosed with atypical endometrial hyperplasia (AEH) and endometrioid carcinoma G1 without myometrial invasion (G1EC). Particular attention was given to the extended administration and readministration of MPA for patients with persistent disease following initial treatment and those with recurrence. METHODS: We conducted a retrospective analysis of data from 79 patients who underwent daily oral MPA treatment between 2005 and 2024 at Nagoya University Hospital. Patient characteristics, treatment outcomes, factors contributing to recurrence, and post-MPA therapy pregnancies were examined. RESULTS: MPA therapy achieved a remarkable complete response (CR) rate of 91.1%. The median time to achieve CR was 26.0 and 40.0 weeks for AEH and G1EC patients, respectively. Importantly, 27 patients (39.7%) attained CR after more than 6 months of treatment, including 8 patients (11.8%) who achieved CR after more than a year of treatment. The recurrence rates were 52.9% for AEH and 64.7% for G1EC. Twenty eight patients resumed MPA treatment, and 23 achieved second CR. Notably, recurrence was not associated with clinical factors such as age, body mass index, or post-CR pregnancy. Among patients who attempted pregnancy after achieving CR, 22 live births were successfully achieved. CONCLUSIONS: High-dose oral MPA therapy demonstrated both safety and efficacy for preserving fertility in patients with AEH and G1EC, resulting in a high CR rate. MPA extension and readministration proved to be beneficial strategies for managing patients with recurrence and persistent disease following initial treatment.

Safety assessments and clinical features of PARP inhibitors from real-world data of Japanese patients with ovarian cancer.

Poly (ADP-ribose) polymerase inhibitors have been increasingly used in ovarian cancer treatment. However, the real-world safety data of these drugs in Japanese patients are limited. This retrospective study included 181 patients with ovarian cancer who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Regarding patient backgrounds, the olaparib group had higher proportions of patients with serous carcinoma, BRCA positivity, homologous recombination deficiency, and those receiving maintenance therapy after recurrence treatment than the niraparib group. Regarding toxicity properties, the most common reasons for discontinuation in the olaparib group were anemia, fatigue, and nausea, while the reason in the niraparib was thrombocytopenia. Thrombocytopenia caused by niraparib treatment occurred earlier than anemia caused by olaparib treatment. Patients with a low body mass index or who had undergone several previous treatment regimens were more likely to discontinue treatment within the first 3 months. Although we analyzed blood collection data, predicting treatment interruptions due to blood toxicity was challenging. In this study, we revealed the characteristics of patients and the timing of interruptions for each drug, highlighting the importance of carefully managing adverse effects.

Combined use of tyrosine kinase inhibitors with PD-(L)1 blockade increased the risk of thyroid dysfunction in PD-(L)1 blockade: a prospective study.

BACKGROUND: Anti-programmed cell death-1 (ligand-1) antibody [PD-(L)1-Ab] can cause destructive thyroiditis and/or hypothyroidism. In addition, tyrosine kinase inhibitors (TKIs) frequently induce hypothyroidism. The aim of this prospective study is to examine the incidence and clinical characteristics of thyroid dysfunction induced by combination therapy of a PD-(L)1-Ab and TKI [PD-(L)1-Ab/TKI]. METHODS: A total of 757 patients treated with PD-(L)1-Ab or PD-(L)1-Ab/TKI were evaluated for anti-thyroid antibodies (ATAs) at baseline and for thyroid function for 48 weeks after treatment initiation and then observed until the last visit. RESULTS: The cumulative incidences of destructive thyroiditis [4/23 (17.4%) vs. 45/734 (6.1%) patients, p < 0.001], isolated hypothyroidism [10/23 (43.5%) vs. 29/734 (4.0%) patients, p < 0.001], and all thyroid dysfunction [14/23 (60.9%) vs. 74/734 (10.1%) patients, p < 0.001] were significantly higher in the PD-(L)1-Ab/TKI group than PD-(L)1-Ab group, respectively. All patients positive for ATAs at baseline developed thyroid dysfunction after PD-(L)1-Ab/TKI treatment, a significantly higher incidence than that in those negative for ATAs at baseline [4/4 (100%) vs. 10/19 (52.6%) patients, p = 0.026]. CONCLUSIONS: The addition of TKIs increased the risk of thyroid dysfunction induced by PD-(L)1-Ab, with the risk being higher in patients positive for baseline ATAs.

Factors affecting the long-term prognosis of patients in the AYA generation with epithelial ovarian cancer: A multicenter propensity score matching analysis.

OBJECTIVE: Ovarian carcinoma (OvCa) is more common in the elderly, but also affects the adolescent and young adult (AYA) generation, which refers to those aged 15-39 years. Although the characteristics of OvCa may differ between AYAs and non-AYAs, limited information is currently available on differences in prognostic factors. Therefore, we herein investigated prognostic factors for and the prognosis of OvCa in AYAs. We also examined the prognostic impact of fertility-sparing surgery in a subgroup analysis. METHODS: We retrospectively collected data on 4897 patients with OvCa from the databases of multiple institutions and ultimately included 1161 patients with epithelial ovarian cancer (EOC). We performed a survival analysis to compare AYAs and non-AYAs with backgrounds that conformed to those of AYAs using the propensity score (PS) matching method. A Cox regression analysis was also conducted to evaluate each predictor of recurrence-free survival (RFS) and overall survival (OS) in the original population. As a subgroup analysis, a multivariate analysis stratified by the AYA and non-AYA generations was performed. RESULTS: In total, 119 AYA patients were included in this study. After PS adjustments, no significant differences were observed in RFS or OS between AYAs and non-AYAs. Prognostic factors differed between AYAs and non-AYAs, particularly in histology and cytology. A multivariate analysis stratified by the AYA and non-AYA generations described that uterine-preserving surgery (UPS) did not have a significant impact on the prognosis of AYAs or non-AYAs. In cases with recurrence, no significant differences were observed in RFS and recurrent sites in the two groups. CONCLUSION: Characteristic prognostic factors for EOC in AYAs were identified. The present results indicate the limited prognostic impact of UPS for EOC in AYAs.

Spatial distribution of tumor-resident macrophages as predictive biomarkers in endometrial cancer.

BACKGROUND: To investigate the role of CD47 expression and its relationship with tumor-resident macrophages, specifically at the tumor margin, in patients with type II endometrial cancer. This study aims to elucidate whether CD47 could serve as a prognostic marker and to understand the dynamics between CD47 and macrophages, which could inform new therapeutic strategies. METHODS: A retrospective cohort study was conducted involving 75 patients of type II endometrial. Immunohistochemical analysis was performed to assess CD47 expression and macrophage markers (CD68 and CD163). RESULTS: The study found no direct correlation between CD47 expression levels and overall survival (p = 0.32), challenging its role as an independent prognostic marker in type II endometrial cancer. The higher expression of CD47 had significantly less incidence of endometrioid carcinoma G3 (p = 0.047). The negative correlation between CD47 H-score and the density of CD68-positive macrophages at tumor margin was statistically significant (p = 0.049). A high density of CD68-positive macrophages at the tumor margin but a low density of CD163-positive macrophages at the tumor margin were associated with poorer prognosis (p = 0.036). CONCLUSIONS: The complex interaction between CD47 and macrophages, particularly at the tumor margin, suggests new avenues for targeted therapy in type II endometrial cancer.

Real-world data of poly (ADP-ribose) polymerase inhibitor response in Japanese patients with ovarian cancer.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors have been increasingly used in the treatment of ovarian cancer, with BRCA positivity and homologous recombination deficiency (HRD) being common biomarkers used for predicting their efficacy. However, given the limitations of these biomarkers, new ones need to be explored. METHODS: This retrospective study included 181 ovarian cancer patients who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Patient characteristics, treatment history, and predictability of treatment duration based on blood data before treatment initiation were examined. RESULTS: High-grade serous carcinoma, BRCA positivity, HRD, and maintenance therapy after recurrence treatment were observed more frequently in the olaparib group than in the niraparib group. The most common reasons for treatment interruption were anemia, fatigue, and nausea in the olaparib group and thrombocytopenia in the niraparib group. Regarding response to olaparib treatment, complete response to the most recent treatment, maintenance therapy after the first chemotherapy, high-grade serous carcinoma, and germline BRCA positivity were observed significantly more frequently among responders than among non-responders. Furthermore, neutrophil counts were significantly higher among responders than among non-responders. CONCLUSIONS: Inflammation-related blood data, such as neutrophil count, obtained at the initial pre-treatment visit might serve as potential predictors for prolonged olaparib treatment. While this study offers valuable insights into potential indicators for prolonged olaparib treatment, it underscores the need for more expansive research to strengthen our understanding of PARP inhibitors and optimize treatment strategies in ovarian cancer.

An update of oncologic and obstetric outcomes of radical trachelectomy for early-stage cervical cancer: The need for further minimally invasive treatment.

AIMS: To investigate the oncologic and obstetric outcomes of radical trachelectomy (RT) in patients with early-stage cervical cancer and to evaluate the potential role of fertility-preserving treatments in improving pregnancy outcomes while oncologic status is stable. METHODS: In this single-institution study, we analyzed the oncologic and obstetric outcomes of 67 patients with early-stage cervical cancer who underwent RT at Nagoya University Hospital. RESULTS: The cancer recurrence rate (6.0%) and the mortality rate (1.5%) were comparable with those of previous studies. Of the 46 patients who attempted to conceive after RT, 19 (41.3%) became pregnant, and 16 gave birth. Of these 37.5% delivered at term, and delivery at less than 28 weeks of gestation occurred in 31.3% of pregnancies. CONCLUSIONS: RT is a viable treatment option for selected patients with early-stage cervical cancer. However, the use of less invasive techniques, such as conization/simple trachelectomy and pelvic lymph node dissection, may improve pregnancy outcomes while oncologic status is stable.

Effect of radical trachelectomy on ovarian reserve: A single-institute prospective study.

AIM: Reduced responses to controlled ovarian stimulation (COS) after radical trachelectomy (RT) have been previously reported. We aimed to assess the effect of RT on ovarian reserve by measuring anti-Müllerian hormone (AMH) levels before and after the procedure in this prospective study. METHODS: We included 12 patients who underwent RT between September 2019 and December 2021 in this study. Serum AMH levels were measured preoperatively, 1 month postoperatively, and 6 months postoperatively. Differences in the AMH levels were assessed using a paired t-test. RESULTS: The median age of the patients was 30.6 years, and the median follow-up time was 30.1 months. AMH levels at 1 and 6 months postoperatively did not show a consistent trend. At 1 month postoperatively, the average AMH level decreased insignificantly but returned to preoperative levels at 6 months. The differences in AMH levels before and after RT were insignificant. CONCLUSION: Our findings indicate that RT did not affect ovarian reserve as measured by AMH levels. However, the relationship between unchanged ovarian reserve and reduced response to COS remains unclear. Further research with larger sample sizes and additional measures of ovarian function is needed to corroborate these results and investigate the long-term effects of RT on ovarian reserve. Understanding these mechanisms will help guide surgical practices and provide patients with valuable information about their reproductive outcomes after RT.

Establishment and characterization of a non-gestational choriocarcinoma patient-derived xenograft model.

BACKGROUND: Non-gestational choriocarcinoma (NGC) is a rare subtype of malignant germ cell tumour and there is no consensus on its treatment. The lack of suitable preclinical models for NGC is a challenge in drug discovery research. Patient-derived xenograft (PDX) models recapitulate the tumour microenvironment of the original cancer tissue. Therefore, they have received considerable attention for studies on rare cancer. Here, we aimed to establish a PDX model from a patient with recurrent NGC. METHODS: Fresh NGC tumour tissue was immediately transplanted into a severely immune-deficient mouse (NOD.Cg-Prkdcscid1l2rgtm1Wjl/SzJ) and maintained for more than three in vivo passages. Subsequently, we evaluated the molecular characteristics of the PDX model using immunohistochemistry, polymerase chain reaction, and RNA sequencing. Moreover, the PDX tumours were transplanted into BALB/c nude mice, and we evaluated their sensitivity for cisplatin and methotrexate. RESULTS: The PDX tumour maintained the morphological features of NGC. Moreover, Immunohistochemistry revealed that the human chorionic gonadotropin, cytokeratin 7, and EpCAM expression levels were similar to those in the primary tumour. Furthermore, serum human chorionic gonadotropin levels were elevated in both the primary tumour and the PDX models. Additionally, using PCR analysis with species-specific primers, we confirmed that the PDX tumour contained human genes and was derived from human tissue. Moreover, the gene expression profile of the NGC was compared with that of epithelial ovarian cancer samples and cell lines, and 568 dysregulated genes in the NGC were extracted. The expression of the dysregulated genes in PDX was significantly correlated with that in the primary tumour (R2 = 0.873, P < 0.001). Finally, we demonstrated that the PDX tumour was sensitive to cisplatin and methotrexate; therefore, its clinical response to the agents was similar to that of the primary tumour. CONCLUSIONS: We successfully established a PDX model of NGC, to the best of our knowledge, for the first time. The established PDX retained the molecular and transcriptome characteristics of the primary tumour and can be used to predict drug effects. It may facilitate further research and the development of novel therapeutic agents for NGC.

9-oxo-ODAs suppresses the proliferation of human cervical cancer cells through the inhibition of CDKs and HPV oncoproteins.

Mucosal human papillomavirus (HPV) subtypes 16 and 18 are causative agents of cervical cancer, a leading cause of cancer-related deaths among women worldwide. In Japan, eggplant calyx is a folk remedy used to treat common warts. 9-oxo-(10E,12E)-octadecadienoic acid, isolated from eggplant calyx, may have antitumor effects. This study investigated the antitumor effects of 9-oxo-(10E, 12Z)-octadecadienoic acid and 9-oxo-(10E,12E)-octadecadienoic acid (9-oxo-ODAs) on human cervical cancer cells. 9-oxo-ODAs suppressed the proliferation of human cervical cancer cell lines (HeLa, and SiHa) in a concentration-dependent manner (IC50 = 25-50 µM). FCM analysis revealed that 9-oxo-ODAs induced apoptosis. Transcriptome, proteomics, and enrichment analyses revealed that treatment with 9-oxo-ODAs significantly altered the cell cycle and p53 pathways and decreased cyclin-dependent kinase 1 (CDK1) protein expression. Real-time PCR analysis demonstrated that 9-oxo-ODAs reduced CDK1 mRNA expression in a concentration-dependent manner. In vitro, 9-oxo-ODAs reduced the HPV oncoprotein expression. In ex vivo human cervical cancer tissues, 9-oxo-ODAs decreased CDK1 expression and increased cleaved caspase 3, an apoptosis marker. Further, 9-oxo-ODAs showed the potential to suppressed metastatic formation and growth of cervical cancer in vivo. These findings suggest that 9-oxo-ODAs induce cell cycle arrest and apoptosis in HPV-positive human cervical cancer cells, and this process involves CDK1. Consequently, 9-oxo-ODAs may be potential therapeutic agents for cervical cancer.

Local hyperthermia with built-in endoscopy for radioresistant cervical cancer: a case series.

We evaluated the efficacy and safety of an endoscope-embedded transvaginal laser hyperthermia system for superficial cervical cancer that remained in the cervix after radiotherapy. We developed an innovative endoscope-embedded hyperthermia system consisting of a diode laser device, a temperature control unit, an endoscope control unit, and a transvaginal probe. Superficial lesions of recurrent or residual cervical cancer on the uterine cervix or vaginal wall after radiotherapy were eligible for this study. A total of four cases of three patients were eligible for this treatment. Case 1: The post-chemoradiotherapy residual tumor of a patient with stage IIB squamous cell carcinoma of the cervix was treated with the device. Two months after the laser hyperthermia treatment, the tumor's disappearance was confirmed. Case 2: A post-hysterectomy persistent tumor on the vaginal stump of a patient with stage IIB adenocarcinoma of the cervix was subjected to the laser hyperthermia treatment. Two months after the treatment, the stump's cytology was false positive. Case 3: As in case 2, this patient's recurrence in the anterior vaginal wall was subjected to laser hyperthermia treatment, but the tumor's growth was not controlled. Case 4: A tumor at the vaginal margin was identified during a salvage hysterectomy in a patient with stage IIB squamous cell carcinoma of the cervix who underwent chemoradiotherapy. After laser hyperthermia treatment, the tumor's disappearance was confirmed. Our new endoscope-embedded laser hyperthermia system can be a candidate for treating residual superficial cervical cancer after radiotherapy by accurately capturing superficial lesions.

Small Extracellular Vesicles from adipose-derived stem cells suppress cell proliferation by delivering the let-7 family of microRNAs in ovarian cancer.

INTRODUCTION: Ovarian cancer is the leading cause of death among women with gynecological cancer, and novel treatment options are urgently needed. Extracellular vesicles (EVs), including exosomes, may be one of the most promising therapeutic tools for various diseases. In this study, we aimed to investigate the therapeutic effects of adipose-derived stem cell-derived EVs (ADSC-EVs) on ovarian cancer cell lines. MATERIALS AND METHODS: ADSCs and the ovarian cancer cell lines SKOV3 and OV90 were used for analysis. ADSC-EVs were isolated through ultracentrifugation and validated using a cryotransmission electron microscope, nanoparticle tracking analysis, and western blotting. Then, the effect of ADSC-EVs on ovarian cancer cells was investigated using IncuCyte and microRNA sequencing. Moreover, the potential functions of miRNAs were evaluated by gain-of function analysis and in silico analysis. RESULTS: ADSC-EVs suppressed SKOV3 and OV90 cell proliferation. In particular, small EVs (sEVs) from ADSCs exhibited a stronger antitumor effect than ADSC-medium/large EVs (m/lEVs). Comparison of the miRNA profiles between ADSC-sEVs and ADSC-m/lEVs, along with downstream pathway analysis, suggested the involvement of the let-7 family. Overexpression of hsa-let-7b-5p and hsa-let-7e-5p significantly suppressed the proliferation of SKOV3 cells. In silico analysis revealed that four potential target genes of hsa-let-7b-5p and hsa-let-7e-5p were significantly associated with the prognoses of the patients. CONCLUSION: ADSC-sEVs had a stronger antitumor effect than ADSC-m/lEVs. Hsa-let-7b-5p and hsa-let-7e-5p, which are highly abundant in ADSC-sEVs, suppressed cell proliferation. These findings may open up new possibilities for therapeutic approaches using ADSC-sEVs.

Mean platelet volume as a potential biomarker for survival outcomes in ovarian clear cell carcinoma.

OBJECTIVE: This study aimed to explore the prognostic value of mean platelet volume (MPV) in patients with ovarian clear cell carcinoma (OCCC) and evaluate the predictive performance of a random forest model incorporating MPV and other key clinicopathological factors. METHODS: A total of 204 patients with OCCC treated between January 2004 and December 2019 were retrospectively analyzed. Clinicopathological characteristics and preoperative laboratory data were collected, and survival outcomes were evaluated using the Kaplan-Meier method and Cox proportional hazards models. An optimal MPV cutoff was determined by receiver operating characteristic (ROC) curve analysis. A random forest model was then constructed using the identified independent prognostic factors, and its predictive performance was evaluated. RESULTS: The ROC analysis identified 9.3 fL as the MPV cutoff value for predicting 2-year survival. The MPV-low group had lower 5-year overall survival and progression-free survival rates than the MPV-high group (p = 0.003 and p = 0.034, respectively). High MPV emerged as an independent prognostic factor (p = 0.006). The random forest model, incorporating the FIGO stage, residual tumors, peritoneal cytology, and MPV, demonstrated robust predictive performance (area under the curve: 0.905). CONCLUSION: MPV is a promising prognostic indicator in OCCC. Lower MPV correlated with worse survival rates, advocating its potential utility in refining patient management strategies. The commendable predictive performance of the random forest model, integrating MPV and other significant prognostic factors, suggests a pathway toward enhanced survival prediction, thereby warranting further research.

Unclear tumor border in magnetic resonance imaging as a prognostic factor of squamous cell cervical cancer.

Magnetic resonance imaging (MRI) is used for pretreatment staging in cervical cancer. In the present study, we used pretreatment images to categorize operative cases into two groups and evaluated their prognosis. A total of 53 cervical cancer patients with squamous cell carcinoma who underwent radical hysterectomy were included in this study. Based on MRI, the patients were classified into two groups, namely clear and unclear tumor border. For each patient, the following characteristics were evaluated: overall survival; recurrence-free survival; lymph node metastasis; lymphovascular space invasion; and pathological findings, including immunohistochemical analysis of vimentin. The clear and unclear tumor border groups included 40 and 13 patients, respectively. Compared with the clear tumor border group, the unclear tumor border group was associated with higher incidence rates of recurrence (3/40 vs. 3/13, respectively), lymphovascular space invasion (24/40 vs. 13/13, respectively), lymph node metastasis (6/40 vs. 10/13, respectively), and positivity for vimentin (18/40 vs. 10/13, respectively). Despite the absence of significant difference in recurrence-free survival (p = 0.0847), the unclear tumor border group had a significantly poorer overall survival versus the clear tumor border group (p = 0.0062). According to MRI findings, an unclear tumor border in patients with squamous cell cervical cancer is linked to poorer prognosis, lymph node metastasis, and distant recurrence of metastasis.

The sarcopenia index measured using the lumbar paraspinal muscle is associated with prognosis in endometrial cancer.

OBJECTIVE: The number of type-II endometrial cancer patients has been increasing and the prognosis is not favorable. We aim to investigate whether sarcopenia index in any of several different muscles could serve as a novel biomarker of prognosis in patients with type-II endometrial cancer. METHODS: We retrospectively investigated a total of 194 patients at four hospitals. Ninety patients were treated as derivation set and the other 104 patients as validation set. Using preoperative computed tomography images, we measured the horizontal cross-sectional area at the third lumbar spine level: the (i) psoas major, (ii) iliac and (iii) paraspinal muscle. The clinical information including recurrence-free survival and overall survival were retrospectively collected. These results were validated with external data sets of three hospitals. RESULTS: The median values of the sarcopenia index (cm2/m2) ± standard deviation with the first data of 90 patients using the psoas, iliac and paraspinal muscle were 3.4 ± 1.0, 1.7 ± 0.6 and 12.6 ± 3.2, respectively. In univariate analyses, the sarcopenia indexes measured using the psoas or paraspinal muscle were associated with recurrence-free survival and overall survival. On the other hand, in multivariate analyses, only the sarcopenia index using paraspinal muscle was significantly related to recurrence-free survival (hazard ratio = 3.78, 95% confidence intervals = 1.29-5.97, P = 0.009) and overall survival (hazard ratio = 3.13, 95% confidence interval = 1.18-8.26, P = 0.022). Paraspinal sarcopenia index was also related to overall survival (hazard ratio = 3.74, 95% confidence interval = 1.31-10.72, P = 0.014) even in patients with advanced stage. Serum albumin was significantly correlated with the sarcopenia index (P = 0.012). Within the analysis of the validation set, sarcopenia index using paraspinal muscle was related to recurrence-free survival (hazard ratio = 2.06, P = 0.045) in multivariate analysis and recurrence-free survival (P = 0.009) in patients with advanced stage. CONCLUSIONS: The sarcopenia index using the paraspinal muscle, not psoas, could be a suitable index to predict recurrence-free survival and overall survival in patients with type-II endometrial cancer even in advanced stage.

The prognostic significance of DDIT4 in endometrial cancer.

BACKGROUND: Despite extensive research on endometrial cancer and tumor hypoxic microenvironment, there are no reports exploring the role of DDIT4 in endometrial cancer. OBJECTIVE: This study aimed to elucidate the significance of DDIT4, as a prognostic biomarker for endometrial cancer by immunohistochemical staining and statistical analysis. METHODS: Four endometrial cancer cells were cultured under normoxia and hypoxia, and the differentially expressed genes were examined using RNA-seq. Immunohistochemical staining for DDIT4 and HIF1A was performed in 86 patients with type II endometrial cancer treated at our hospital, and their correlation with other clinicopathological factors and the prognostic role was analyzed using statistical methods. RESULTS: The expression analysis of hypoxia-inducible genes using four types of endometrial cancer cells revealed that DDIT4 was among the 28 genes that were upregulated in all cells. Based on our results of immunohistochemistry of DDIT4 expression in endometrial cancer tissues, univariate and multivariate analyses based on COX regression analysis showed that high DDIT4 expression significantly correlated to favorable prognosis in both progression-free survival and overall survival. Limited to recurrent cases, metastasis to only lymph nodes was significantly related to high DDIT4 expression, whereas metastasis to other parenchymal organs was significantly dominant in patients with low DDIT4 expression. CONCLUSIONS: The expression of DDIT4 enables to predict survival and recurrence in type II endometrial cancer.

Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway.

OBJECTIVES: Ovarian cancer constitutes one of the most common causes of cancer-related deaths, and preventing chemotherapy resistance and recurrence in patients with ovarian cancer remains a challenge. Herein, we aimed to identify the effect of luteolin, a novel therapeutic agent targeting vaccinia-related kinase 1 (VRK1), on high-grade serous ovarian cancer (HGSOC). METHODS: Phosphokinase array, RNA sequencing, and cell cycle and apoptosis assays were conducted to determine the underlying mechanism of the effect of luteolin on HGSOC cells. The anticancer effects of oral and intraperitoneal luteolin administration were assessed in patient-derived xenograft models via several methods, including the assessment of tumor size and immunohistochemistry of phospho-p53, phosphor-HistoneH3 and cleaved caspase 3. RESULTS: Luteolin reduced HGSOC cell proliferation and increased apoptosis and cell cycle arrest at G2/M. Compared with controls, several genes were dysregulated in luteolin-treated cells, and luteolin activated the p53 signaling pathway. The human phosphokinase array revealed distinct p53 upregulation in luteolin-treated cells, as confirmed by p53 phosphorylation at ser15 and ser46 using western blot analysis. In patient-derived xenograft models, oral or intraperitoneal luteolin administration substantially suppressed tumor growth. Moreover, combination treatment involving luteolin and cisplatin inhibited tumor cell proliferation, especially in cisplatin-resistant HGSOC cell lines. CONCLUSIONS: Luteolin demonstrated considerable anticancer effect on HGSOC cells, reduced VRK1 expression, and activated the p53 signaling pathway, thereby inducing apoptosis and cell cycle arrest in G2/M and inhibiting cell proliferation. Furthermore, luteolin exhibited a synergistic effect with cisplatin both in vivo and in vitro. Thus, luteolin can be considered a promising cotreatment option for HGSOC.