Outcome of robot-assisted surgery for stage IA endometrial cancer compared to open and laparoscopic surgeries: a retrospective study at a single institution.

Few studies have compared the efficacy of robot-assisted, laparoscopic, and open surgeries for endometrial cancer. When considering the position of robotic surgery in Japan, it was necessary to determine whether it was effective or not. We aimed to compare the efficacy and safety of these three types of surgeries for early-stage endometrial cancer. In total, 175 patients with endometrial cancer of preoperative stage IA, who had undergone laparotomic (n = 80), laparoscopic (n = 40), or robot-assisted (n = 55) modified radical hysterectomy at our hospital from 2010 to 2022, were included; surgical outcomes, perioperative complications, and prognoses were compared. Total operative and console times for robot-assisted surgery between patients who did or did not undergo pelvic lymphadenectomy were assessed. The robot-assisted group had the shortest total operative time. The estimated blood loss was lower in the laparoscopic and robot-assisted groups than in the laparotomy group. In advanced postoperative stage IA cases, there were no differences in progression-free and overall survival among the three groups. In the robot-assisted group, the operative time decreased as the number of operations increased; the learning curve was reached after 10 cases each of patients with and without pelvic lymphadenectomy. The frequency of perioperative complications of Clavien-Dindo classification Grade 1 or higher was the lowest in the robot-assisted group (p = 0.02). There were no complications of Clavien-Dindo classification Grade 2 or higher in the robot-assisted group. Robot-assisted surgery for stage IA endometrial cancer, a minimally invasive procedure, has fewer operative times and complications than those of laparoscopic and open surgeries in a single institution in Japan.

Proposal for Classifying the Emetogenicity of Oral Anticancer Agents with a Focus on PARP Inhibitors: A Prospective, Observational, Multicenter Study (JASCC-CINV 2002).

Background: Olaparib and niraparib (poly adenosine diphosphate [ADP]-ribose polymerase [PARP] inhibitors) have significant antitumor action in patients with ovarian cancer. However, the incidence of nausea and vomiting among patients on these drugs in clinical trials is rather high. There are no guidelines on antiemetic treatment for nausea caused by oral anticancer agents. This study aimed to investigate the incidence of nausea and vomiting caused by PARP inhibitors and the actual situation of antiemetic therapy in patients with gynecologic cancer. Methods: Patients with gynecologic cancer who were scheduled to receive PARP inhibitors were enrolled. Data on PARP inhibitor-induced nausea and vomiting were collected from patient diaries for 21 days. The primary endpoint was the incidence of vomiting during the 21 days after starting olaparib and niraparib. Results: Overall, between January 2020 and March 2023, 134 patients were enrolled. Of the 129 patients who were evaluated, 28 (21.7%) received prophylactic antiemetics for 21 days, and 101 (78.3%) did not. The overall incidence of PARP inhibitor-induced vomiting was 16.3%. The incidence of vomiting in the group that did not receive antiemetic prophylaxis was 13.9%. On dividing the group that did not receive antiemetic prophylaxis into the olaparib and niraparib subgroups, the incidence of vomiting was found to be 18.6% for the olaparib group and 10.3% for the niraparib group. Conclusion: The incidence of emesis without antiemetic prophylaxis among patients on olaparib and niraparib ranged from 10% to 30%. Therefore, olaparib and niraparib can be classified in the low emetogenic risk and prophylactic antiemetic therapy at the time of treatment initiation may be unnecessary.

Malignant Pericardial Tamponade Secondary to Ovarian Clear Cell Carcinoma.

Malignant pericardial effusion is an uncommon metastatic manifestation of ovarian carcinoma. Few cases of ovarian serous carcinoma have been previously reported. Ovarian clear cell carcinoma is the second most common histologic subtype in East Asian countries and is a relatively rare in Western countries. Here, we report the case of cardiac tamponade secondary to Ovarian clear cell carcinoma. A 46-year-old woman with recurrent Ovarian clear cell carcinoma presented with worsening cough, palpitations, and shortness of breath during chemotherapy. Chest radiography and computed tomography confirmed a pleural effusion with cardiac tamponade. The patient underwent pericardial fenestration and drainage for cardiac tamponade. Pericardial fluid cytology showed malignant cells forming papillary and ball-like clusters with irregular stacking. The cells had a mirror ball-like appearance and collagenous stroma, in which a homogenous hyaline core was observed in the center of most tumor cell clusters. Based on these findings, a diagnosis of Ovarian clear cell carcinoma metastasis was made. She received palliative care and died 5 months after the operation without recurrent cardiac tamponade. This case suggests that cytological findings from pericardial effusion are useful in diagnosing Ovarian clear cell carcinoma metastasis.

The learning curve of introduced robotic-assisted hysterectomy versus skilled laparoscopic hysterectomy for benign gynecologic diseases.

AIM: This study aimed to compare introduced robotic-assisted hysterectomy (RAH) and skilled total laparoscopic hysterectomy (TLH) for the treatment of benign gynecological diseases. METHODS: Patients who underwent RAH or TLH by two surgeons at the Tottori University Hospital between January 2018 and May 2022 were included in this retrospective study. Inclusion criteria were patients with 100-300 g of uterine weight. The exclusion criteria were patients with stage IV endometriosis. Mean operative time and learning curve were compared among the first-half RAH, second-half RAH, and TLH groups. RESULTS: There were 40 eligible cases (first-half RAH: 20 cases, second-half RAH: 20 cases) in the RAH group and 44 cases in the TLH group. The total operative time (TOT) of the second half of RAH was significantly shorter than that of the first half of RAH (p = 0.021) and was comparable to that of the TLH group. The operative time (OT) of the second half of RAH was shorter than that of TLH (p = 0.023). The preparation time of TLH was shorter than that of the RAH group (p < 0.01). The learning curve of the TOT in RAH crossed that of TLH on the 31st case of RAH. In contrast, both curves of the OT crossed on the 11th case of RAH. CONCLUSION: The TOT of the introduced RAH was equivalent to that of skilled TLH in approximately 30 cases since the first RAH. Furthermore, the OT of RAH was comparable to that of TLH in approximately 10 cases of surgery since the first RAH.

Prognostic Value of Human Papillomavirus Genotyping before and after Cervical Conization for Squamous Intraepithelial Lesion.

INTRODUCTION: We previously reported that preoperative human papillomavirus (HPV) type 16/18 positivity and postoperative high-risk (HR)-HPV test positivity are associated with abnormal postoperative cytology. In this study, we further examined whether preoperative and postoperative HR-HPV genotyping could predict cytological abnormalities and the risk of additional surgery. METHODS: Patients who underwent cervical conization at our hospital between July 2009 and June 2018 were enrolled. HPV genotyping was performed preoperatively for all patients with HPV-positive. The association among preoperative and postoperative HR-HPV genotyping results, the cumulative risk of cytological abnormalities, and additional surgery were evaluated. The endpoint approach was used to investigate the cumulative incidence of additional surgery owing to cytological abnormalities, such as low-grade squamous intraepithelial lesion positivity and recurrence 2 years after cervical conization. RESULTS: Positive and negative histological margins were observed in 21 and 287 of 308 cases, respectively. The cumulative incidence of abnormal cytology and additional surgery was significantly higher in margin-positive cases than that in margin-negative cases. Examination established according to the margin status demonstrated that the postoperative HR-HPV-positive group had a significantly worse prognosis than the HR-HPV-negative group. Additionally, 32 cases, wherein the same genotype detected before and after surgery, demonstrated significantly unfavorable outcomes. Fifteen patients with persistent HPV 16/18 had the worst prognosis than the other types. CONCLUSION: Preoperative and postoperative HR-HPV genotype tests were used to predict the cumulative incidence of abnormal cytology and additional surgery. Particularly, patients with suspected persistent HPV type 16/18 infection are at a high recurrence risk.

Robot-Assisted Total Hysterectomy of Extremely Unusual Pelvic Anatomy: A Case Report and Literature Review.

We report a case of robot-assisted total hysterectomy in a patient with extremely rare pelvic anatomy. Robot-assisted total laparoscopic hysterectomy was performed for lobular endocervical glandular hyperplasia on the left side of the uterus. The sigmoid colon was present between the two uterine corpora of a uterine didelphys and was attached to the bladder via the mesentery and fat. During surgery, the surgeon left the console and confirmed the magnetic resonance images. The surgery was then completed safely after the surgeon understood the anatomy. The postoperative condition was good, and the patient was discharged on postoperative day 5. Robot-assisted surgery has various advantages, including a good field of view, accuracy of instrument movement, and ease of viewing information in the medical record by pausing the operation. Robot assisted surgery improves not only safety and operational precision but also intraoperative convenience. Further studies are needed regarding the specific anatomy seen in this case.

Endometrial Cancer Arising in Adenomyosis That Could Not Be Diagnosed by Endometrial Biopsy: A Case Report.

Uterine adenomyosis is an estrogen-dependent tumor and one of the most common benign diseases in sexually mature women. The frequency of endometrial cancer associated with adenomyosis has been reported to be 18%-66%. On the other hand, endometrial cancer arising in adenomyosis (EC-AIA) is extremely rare. EC-AIA is now considered a different entity from and has a worse prognosis than endometrial cancer with adenomyosis (EC-A). In the present study, we report a case of endometrial cancer with adenomyosis in which endometrial biopsy failed to provide a definitive diagnosis. A 63-year-old female patient presented with endometrial thickening. Endometrial cytology was positive, and magnetic resonance imaging (MRI) showed small lesions suggestive of endometrial cancer with shallow invasion and adenomyosis. However, an endometrial biopsy showed only metaplasia, and careful follow-up was initiated. Subsequent endometrial cytology showed enlarged and round nuclei, uniform chromatin distribution, no thickening of nuclear margins, and abundant cytoplasm appearing in a sheet-like arrangement, suggesting atypical cells of endometrial glands with metaplasia. Three suspicious positive results and one positive result were observed, but repeated biopsies did not lead to the diagnosis of malignancy. The patient underwent diagnostic hysterectomy 19 months after the initial visit. The postoperative histopathological diagnosis was stage IA endometrial cancer (endometrioid carcinoma G1). This case of endometrial cancer associated with adenomyosis was difficult to diagnose. Our findings demonstrate that EC-AIA should be considered even if no lesions were detected by endometrial biopsy.

A simplified procedure of nerve-sparing radical hysterectomy.

AIM: We devised a simplified nerve-sparing radical hysterectomy that is simpler than commonly used procedures. METHODS: We retrospectively examined 16 cases of classical non-nerve-sparing radical hysterectomy (non-nerve-sparing group) and 16 cases of simplified nerve-sparing radical hysterectomy (nerve-sparing group) performed between 2019 and 2020. We examined and compared the duration of surgery, blood loss, perioperative complications, postoperative urinary function (presence or absence of urinary sensation, number of days with residual urine measurement, and frequency and duration of oral sustained release urapidil capsules and self-catheterization), and short-term prognosis between the two groups. RESULTS: Compared to conventional non-nerve-sparing radical hysterectomy, the duration of surgery for nerve-sparing radical hysterectomy was significantly shorter (407 [339-555] min vs. 212 [180-356] min; p < 0.001), and blood loss was significantly less. Compared to the nerve-sparing group, the non-nerve-sparing group had more cases of oral urapidil use and a higher frequency of clean intermittent catheterization. Clean intermittent catheterization was required in two cases in the nerve-sparing group; however, it was withdrawn at 180 and 240 days. Conversely, clean intermittent catheterization was still required in three cases in the non-nerve-sparing group. There were no statistically significant differences in progression-free survival and overall survival between the two groups. CONCLUSION: The simple nerve-sparing radical hysterectomy resulted in shorter duration of surgery and less blood loss as well as in a clear improvement in the postoperative urinary status and short-term prognosis. This technique simplifies nerve-sparing radical hysterectomy, which is commonly thought to be complicated, making it easier to understand.

Differential expression of estrogen receptor subtypes in ovarian high-grade serous carcinoma and clear cell carcinoma.

PURPOSE: To investigate the role of estrogen receptors (ERs) in high-grade serous carcinoma (HGSC) and clear cell carcinoma (CCC) of the ovary and evaluate ERs as prognostic biomarkers for ovarian cancer. METHODS: This study included 79 patients with HGSC (n = 38) or CCC (n = 41) treated at our institution between 2005 and 2014. Immunohistochemistry examined protein expression of ERα, ERß, and G protein-coupled estrogen receptor-1 (GPER-1); relationships between ERα, ERß, and GPER-1 with patient survival were evaluated. Additionally, cell proliferation assay and phosphokinase proteome profiling were performed. RESULTS: In HGSC patients, expression of ERα, cytoplasmic GPER-1, or nuclear GPER-1 was associated with poor progression-free survival (PFS) (P = .041, P = .010, or P = .013, respectively). Cytoplasmic GPER-1 was an independent prognostic factor for PFS in HGSC patients (HR = 2.83, 95% CI = 1.03-9.16, P = .007). ER expressions were not associated with prognosis in CCC patients. GPER-1 knockdown by siRNA reduced the cells number to 60% of siRNA-control-treated cells (P < .05), and GPER-1 antagonist, G-15 inhibited two HGSC cell lines proliferation (KF and UWB1.289) in a dose-dependent manner. Phosphoprotein array revealed that GPER-1 silencing decreased relative phosphorylation of glycogen synthase kinase-3. CONCLUSIONS: High GPER-1 expression is an independent prognostic factor for PFS in HGSC patients, and GPER-1 may play a role in HGSC cell proliferation.

Long-term evaluation of renal function and neurogenic bladder following radical hysterectomy in patients with uterine cervical cancer.

OBJECTIVE: This study aimed to determine whether radical hysterectomy (RH) affects renal function. METHODS: Renal function was followed up in 83 patients with stage IB1-IIB cervical cancer who underwent RH during 2006-2015. Serum creatinine (sCre) levels were measured preoperatively and every year postoperatively. Estimated glomerular filtration rate (eGFR) was calculated using sCre levels. Patients who were unable to urinate by themselves or whose residual urine was ≥100 mL were referred to a urologist with the diagnosis of neurogenic bladder (NB). The relationship between NB occurrence and changes in sCre level or eGFR was evaluated respectively. RESULTS: Urological intervention was required in 45 patients (54.2%), and self-urethral catheterization was performed in 41 (49.3%) patients. The NB and clean intermittent catheterization (CIC) groups exhibited significant increases in sCre levels, which were not observed in the non-NB or non-CIC groups. In the non-NB group, eGFR did not change following surgery. However, in the NB group, significant decreases in eGFRs were observed at postoperative 2 and 3 years and at final follow-up. There was no difference in the incidence of cardiovascular events between patients with and without NB. CONCLUSION: In patients with NB following RH, a significant decrease in renal function was observed after postoperative 2 years.

Efficacy of panniculectomy-combined surgery in superobese patients with endometrial cancer: A case report and literature review.

INTRODUCTION: Panniculectomy is regarded as an effective approach in highly obese patients with endometrial cancer to improve surgical access or space of the surgical field. PRESENTATION OF CASE: A 66-year-old nulliparous woman was brought in from another hospital to our institute for newly diagnosed endometrial carcinoma. The patient was 158 cm in height and weighed 135.8 kg during the first visit to our hospital. Her body mass Index (BMI) was 54.4 kg/m2. Unfortunately, the patient developed an umbilical hernia and strangulation before the surgery. Emergency partial ileal resection and simple closure of the umbilical hernia were performed. We were finally able to perform simple hysterectomy, and bilateral salpingo-oophorectomy with panniculectomy. Her weight at the time of surgery was 115.5 kg which had been reduced by 20 kg from the time she was first brought in, and the BMI decreased from 54.4 to 45.3 kg/m2. The patient underwent follow-up without adjuvant therapy since she was in the low-risk group, and showed no signs of recurrence 12 months after surgery. DISCUSSION: There are various risks associated with surgery in highly obese patients. Diabetes mellitus, hypertension and smoking are reported to be risk factors of wound complication in panniculectomy, and it was reported that diabetes mellitus was an independent risk factor. CONCLUSION: The combination of panniculectomy was considered as an effective approach to perform safe surgery for obese patients.

Evaluating Chemotherapy-induced Nausea and Vomiting and Food Intake in Patients With Gynecologic Cancer.

BACKGROUND/AIM: Treatments for controlling delayed nausea after chemotherapy are inadequate, potentially inciting malnutrition. We sought to determine the incidence of nausea, anorexia, and food intake after chemotherapy. PATIENTS AND METHODS: Subjects were females with gynecological cancers who underwent chemotherapy between 2008 and 2013. Nausea, anorexia, and food intake in the acute (day 1) and delayed phases (days 2 and 3) were retrospectively evaluated. RESULTS: Subjects included 156 females. Chemotherapies were highly (HEC; n=24) and moderately emetogenic (MEC; n=132). There were no significant between-group differences for anorexia control during either the acute or the delayed phase and both groups demonstrated significantly worse control of nausea during the delayed phase. In the HEC group, food intake was significantly reduced on days 2 and 3 compared with day 1. CONCLUSION: Rates of nausea, anorexia, and food intake significantly worsened over time, particularly in the MEC group. Current supportive therapies appear inadequate and should be improved.

Serum vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 as prognostic biomarkers for uterine cervical cancer.

BACKGROUND: There are few studies on serum vascular endothelial growth factors and receptors (VEGF/VEGFRs) in patients with uterine cervical cancer (CC). The aim of this study was to determine whether VEGF/VEGFRs could be used as prognostic biomarkers in patients with CC. METHODS: A total of 107 patients with stage IB to IIB CC, who underwent radical hysterectomy at Tottori University Hospital between 2006 and 2015, were included in this study. Serum samples were collected prior to radical hysterectomy, and levels of VEGF-A, VEGF-C, VEGFR-1, and VEGFR-2 were analyzed by enzyme-linked immunosorbent assays. We evaluated the association between the levels of these angiogenic factors and clinicopathologic variables. Survival analysis of 93 patients treated between 2006 and 2013 was performed. RESULTS: The levels of VEGF-A in patients with bulky tumor, pelvic lymph-node involvement (PLNI), and parametrial infiltration (PI) were significantly higher than those in patients without these factors (P = 0.022, P = 0.020, and P = 0.0013, respectively). The overall survival (OS) of patients with high VEGF-A and VEGFR-2 defined by median levels was significantly lower than the OS of patients with low levels of VEGF-A and VEGFR-2 (P = 0.014, P = 0.012, respectively). Multivariate analysis revealed that PLNI, serum VEGF-A levels, and serum VEGFR-2 levels were independent prognostic factors for OS (hazard ratio for VEGF-A 3.42, 95% CI 1.07-13.2; hazard ratio for VEGFR-2 6.37, 95% CI 1.59-43.5). CONCLUSION: Our results suggest that serum VEGF-A and VEGFR-2 may be promising prognostic biomarkers for CC.

Recurrent colon perforation after discontinuation of bevacizumab for ovarian cancer.

Bevacizumab (Bev) is an antiangiogenic drug used to treat various malignances, including ovarian cancer (OC). Bev is generally well-tolerated; however, it has a characteristic toxicity profile. In particular, gastrointestinal perforation (GIP) is a rare but serious side effect that can be lethal. A 55-year-old woman with recurrent OC had an episode of GIP during third-line chemotherapy comprising Bev and topotecan (TPT). Bev was discontinued while TPT was continued as monotherapy. Three months after discontinuation of Bev, the patient presented with left lower abdominal pain and was diagnosed with a second GIP. She had emergent surgery. One year later, she is still alive and healthy, and is continuing TPT. This is the first report of recurrent GIP after discontinuation of Bev. Our case suggests that physicians should be aware of GIP even after the discontinuation of Bev.

Significance of High-Risk Human Papillomavirus Testing for Atypical Glandular Cells on Cervical Cytology.

OBJECTIVES: The aim of this study was to evaluate the diagnostic significance of high-risk human papillomavirus (hrHPV) testing for managing women with atypical glandular cells (AGC) and to explore the distribution of hrHPV genotypes. METHODS: We analyzed cytologic and histopathologic diagnoses in patients referred to our institution due to AGC or atypical squamous cells of undetermined significance (ASC-US). All patients underwent hrHPV testing and genotyping, and positive (PPV) and negative predictive values (NPV) for cervical intraepithelial neoplasia (CIN) 2 or worse [CIN2+/adenocarcinoma in situ (AIS)+] were calculated. RESULTS: Among 41 cases previously diagnosed with AGC, 22 (53%) were classified as CIN2+ (2 squamous cell carcinomas), whereas only 2 were AIS or adenocarcinoma. Twenty-seven (65.8%) cases in the AGC group were hrHPV positive. The most frequent genotypes in both the ASC-US and AGC groups were HPV16 and HPV52. The PPV of hrHPV testing for CIN2+/AIS+ was significantly higher in the AGC than in the ASC-US group (74.1 vs. 35.0%; p = 0.0005). The NPV for CIN2+/AIS+ was significantly lower in the AGC than in the ASC-US group (74.4 vs. 100%; p = 0.0441). CONCLUSION: In patients with AGC, both glandular and squamous lesions must be monitored. hrHPV testing is useful for detecting CIN2+/AIS+ in AGC.

Establishment and characterization of a novel ovarian clear cell carcinoma cell line, TU-OC-2, with loss of ARID1A expression.

A new cell line of human ovarian clear cell carcinoma (CCC), TU-OC-2, was established and characterized. The cells were polygonal in shape, grew in monolayers without contact inhibition and were arranged in islands like pieces of a jigsaw puzzle. The chromosome numbers ranged from 41 to 96. A low rate of proliferation was observed and the doubling time was 37.5 h. The IC50 values of cisplatin, 7-ethyl-10-hydroxycamptothecin (SN38), which is an active metabolite of camptothecin, and paclitaxel were 7.7 µM, 17.7 nM and 301 nM, respectively. The drug sensitivity assay indicated that TU-OC-2 was sensitive to SN38, but resistant to cisplatin and paclitaxel. Mutational analysis revealed that TU-OC-2 cells have no mutations of PIK3CA in exons 9 and 20 and of TP53 in exons 4-9. We observed the loss of ARID1A protein expression in TU-OC-2 cells by western blot analysis and in the original tumor tissue by immunohistochemistry. This cell line may be useful for studying the chemoresistant mechanisms of CCC and exploring novel therapeutic targets such as the ARID1A-related signaling pathway.

Human papillomavirus type-specific persistence and reappearance after successful conization in patients with cervical intraepithelial neoplasia.

OBJECTIVE: To assess the relationship between pre- and postoperative high-risk human papillomavirus (hrHPV) genotypes and hrHPV type-specific persistence and reappearance of abnormal cytology after successful conization. METHODS: A retrospective analysis was performed of 211 patients who were undergoing conization after hrHPV genotype testing at Tottori University Hospital between July 2009 and June 2013. Of the 211 women, 129 underwent pre- and postoperative hrHPV genotype testing and were diagnosed with cervical intraepithelial neoplasia (CIN) grades 1-3 with negative margins. RESULTS: The postoperative pathological diagnosis was CIN 1 in 8 patients, CIN 2 in 12, CIN 3 in 108 and adenocarcinoma in situ in 1 patient. Before conization, the most frequent hrHPV genotypes were HPV16 (n = 52; 40.3 %), followed by HPV52 (n = 32; 24.8 %) and HPV58 (n = 28; 21.7 %), while HPV18 was detected in 6 cases (4.7 %). Of the 23 postoperative hrHPV-positive cases, the same genotypes were detected in 10 cases while a different genotype was detected in 11 cases; type did not affect the frequency of persistent postoperative infection. The 3-year cumulative risk for the reappearance of abnormal cytology was significantly higher in postoperative hrHPV-positive patients than in postoperative hrHPV-negative patients (31.6 vs 9.7 %, P = 0.0014). A high-grade squamous intraepithelial lesion (HSIL) was observed during the follow-up period in one patient with persistent HPV16 infection. CONCLUSIONS: Postoperative hrHPV infection was a significant positive predictor for the reappearance of abnormal cytology and HPV16 infection-induced HSIL after treatment. Therefore, our study suggests that hrHPV genotype testing may be useful to follow-up CIN patients.

Establishment and mutation analysis of a novel malignant peritoneal mesothelioma cell line, TU-MM-1, using whole genome sequencing.

A new cell line of human malignant peritoneal mesothelioma (MPM), TU-MM-1, was established and characterized. The cells showed polygonal morphology, grew in monolayers without contact inhibition and were arranged like a jigsaw puzzle. The chromosome numbers ranged from 41 to 44. A low rate of proliferation was observed and the doubling time was 67.9 h. Genomic DNA sequencing revealed that TU-MM-1 cells harbored missense mutations in APC, LATS2, BRCA1/2, and TP53, and mutation of a splice donor site in BAP1 and loss of CDKN2A gene. We observed the absence of BAP1 and p16(INK4a) proteins, underexpression of LATS2 protein, and overexpression of p53 protein in TU-MM-1 cells in western blot analysis. Heterotransplantation to nude mice produced tumors that had the characteristics of the original tumor. This cell line may be useful for studying biological properties and contribute to novel treatment strategies.

The PI3K/mTOR dual inhibitor NVP-BEZ235 reduces the growth of ovarian clear cell carcinoma.

Patients with clear cell carcinoma of the ovary (OCCC) have poor survival due to resistance to standard chemotherapy. OCCC has frequent activating mutations of the PIK3CA gene. The present study was conducted to clarify the efficacy of the inhibition of the PI3K-AKT-mTOR pathway in OCCC. We used 8 OCCC cell lines and 5 ovarian serous adenocarcinoma (OSAC) cell lines. The mutation status of the PIK3CA and KRAS genes was examined by direct sequencing. The IC50 values of NVP-BEZ235 (BEZ235) and temsirolimus were determined by WST-8 assay. Protein expression levels of PI3K-AKT-mTOR pathway molecules were examined by western blotting. Cell cycle distribution was analyzed by flow cytometry. Annexin V staining was used for detecting apoptosis. We also investigated the effects of BEZ235 on OCCC tumor growth in a nude mouse xenograft model. Four of the 8 OCCC cell lines showed a PIK3CA mutation while none of the 5 OSAC cell lines showed a mutation. The IC50 values of BEZ235 for the OCCC cell lines were lower than these values for the OSAC cell lines. The IC50 value of temsirolimus was higher than BEZ235 in the OCCC cell lines. The PIK3CA mutation was more frequently noted in OCCC than OSAC cells, but the sensitivity of these cell lines to BEZ235 or temsirolimus was not related to the mutation status. pHER3 and pAkt proteins were expressed more frequently in OCCC compared with OSAC. However, protein expression levels were distributed widely, and were not related to the sensitivity. Treatment with BEZ235 suppressed expression of pAkt, although treatment with temsirolimus did not. OCCC cells exhibited G1 phase arrest after treatment with BEZ235 and apoptosis with a higher concentration of the agent. BEZ235 significantly inhibited tumor growth in mice bearing OVISE and TU-OC-1 cell tumors. The present study indicated that the PI3K-AKT-mTOR pathway is a potential target for OCCC, and that BEZ235 warrants investigation as a therapeutic agent.

Dual inhibition of phosphatidylinositol 3'-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach for mucinous adenocarcinoma of the ovary.

Ovarian mucinous adenocarcinoma (MAC) resists standard chemotherapy and is associated with poor prognosis. A more effective treatment is needed urgently. The present study assessed the possibility of molecular-targeted therapy with a novel dual inhibitor of phosphatidylinositol 3'-kinase (PI3K) and mammalian target of rapamycin (mTOR), NVP-BEZ235 (BEZ235) to treat of MAC. Seven human MAC cell lines were used in this study. The sensitivity of the cells to BEZ235, temsirolimus, and anticancer agents was determined with the WST-8 assay. Cell cycle distribution was assessed by flow cytometry, and the expression of proteins in apoptotic pathways and molecules of the PI3K/Akt/mTOR signaling pathways was determined by Western blot analysis. We also examined the effects of BEZ235 on tumor growth in nude mice xenograft models. The cell lines showed half-maximal inhibitory concentration values of BEZ235 from 13 to 328 nmol/L. Low half-maximal inhibitory concentration values to BEZ235 were observed in MCAS and OMC-1 cells; these 2 lines have an activating mutation in the PIK3CA gene. NVP-BEZ235 down-regulated the protein expression of phosphorylated (p-) Akt, p-p70S6K, and p-4E-BP1, suppressed cell cycle progression, up-regulated the expression of cleaved PARP and cleaved caspase 9, and increased apoptotic cells. Synergistic effects were observed on more than 5 cell lines when BEZ235 was combined with paclitaxel or cisplatin. The treatment of mice bearing OMC-1 or RMUG-S with BEZ235 significantly suppressed tumor growth in MAC xenograft models without severe weight loss. We conclude that the PI3K/Akt/mTOR pathway is a potential therapeutic target and that BEZ235 should be explored as a therapeutic agent for MAC.