Kinome-wide decoding of network-attacking mutations rewiring cancer signaling.

Cancer cells acquire pathological phenotypes through accumulation of mutations that perturb signaling networks. However, global analysis of these events is currently limited. Here, we identify six types of network-attacking mutations (NAMs), including changes in kinase and SH2 modulation, network rewiring, and the genesis and extinction of phosphorylation sites. We developed a computational platform (ReKINect) to identify NAMs and systematically interpreted the exomes and quantitative (phospho-)proteomes of five ovarian cancer cell lines and the global cancer genome repository. We identified and experimentally validated several NAMs, including PKCγ M501I and PKD1 D665N, which encode specificity switches analogous to the appearance of kinases de novo within the kinome. We discover mutant molecular logic gates, a drift toward phospho-threonine signaling, weakening of phosphorylation motifs, and kinase-inactivating hotspots in cancer. Our method pinpoints functional NAMs, scales with the complexity of cancer genomes and cell signaling, and may enhance our capability to therapeutically target tumor-specific networks.

Pembrolizumab plus chemotherapy in Japanese patients with persistent, recurrent or metastatic cervical cancer: Results from KEYNOTE-826.

Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-826 study. We report outcomes in patients enrolled in Japan. Patients received pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) with or without bevacizumab 15 mg/kg. Dual primary endpoints were PFS per RECIST v1.1 by investigator assessment and OS in the global population; these were evaluated in patients with tumors with PD-L1 combined positive score (CPS) ≥1, all-comers, and PD-L1 CPS ≥10. Fifty-seven patients from Japan were randomized (pembrolizumab plus chemotherapy, n = 35; placebo plus chemotherapy, n = 22). Pembrolizumab plus chemotherapy improved PFS versus placebo plus chemotherapy in patients with PD-L1 CPS ≥1 (n = 51; hazard ratio [HR; 95% CI], 0.36 [0.16-0.77]), all-comers (n = 57; 0.45 [0.22-0.90]), and patients with PD-L1 CPS ≥10 (n = 25; 0.36 [0.12-1.07]). HRs (95% CI) for OS were 0.38 (0.14-1.01), 0.41 (0.17-1.00), and 0.37 (0.10-1.30), respectively. Incidence of grade 3-5 AEs was 94% in the pembrolizumab group and 100% in the placebo group. Consistent with findings in the global KEYNOTE-826 study, pembrolizumab plus chemotherapy with or without bevacizumab may prolong survival versus placebo plus chemotherapy with or without bevacizumab and had a manageable safety profile in Japanese patients with persistent, recurrent, or metastatic cervical cancer.

Immunohistochemical analysis of the epithelial to mesenchymal transition in uterine carcinosarcoma.

OBJECTIVE: Uterine carcinosarcoma (UCS) is a highly aggressive neoplasm that is composed of an intricate admixture of carcinomatous and sarcomatous elements. The relationship between UCS and the epithelial to mesenchymal transition (EMT) has been reported. In this study, we examined how expression of E-cadherin was associated with the expression of EMT-related proteins in UCS. METHODS: UCS samples were histologically divided into three components: carcinomatous, transitional, and sarcomatous regions. Next, we examined the expression of E-cadherin and EMT-related proteins, including SNAI2, ZEB1, and TWIST1, in each component of the UCS using immunohistochemistry. The expression score was determined by combining the staining intensity and staining area of the target cells. RESULTS: The expression score of E-cadherin was significantly lower in transitional and sarcomatous components than in the carcinomatous component. In addition, a significant difference in the low expression score of E-cadherin between transitional and sarcomatous components (transitional > sarcomatous components) was found. There were significant differences between the expression scores of ZEB1 in the three components (sarcomatous > transitional > carcinomatous components). However, no difference in the expression of TWIST1 between the components was found. Conversely, the expression level of SNAI2 was higher in sarcomatous or transitional components than in the carcinomatous component. However, a significant difference between the transitional and sarcomatous components was not detected. CONCLUSION: These results suggest that the EMT plays an essential role in the pathogenesis of UCS.

An open-label, randomized, phase II trial evaluating the efficacy and safety of standard of care with or without bevacizumab in platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer patients previously treated with bevacizumab for front-line or platinum-sensitive ovarian cancer: rationale, design, and methods of the Japanese Gynecologic Oncology Group study JGOG3023.

BACKGROUND: We present the study rationale and design of the JGOG3023 study, an open-label, parallel-arm, randomized, phase II trial that aimed to assess the efficacy and safety of chemotherapy with or without bevacizumab in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were previously treated with bevacizumab for front-line or platinum-sensitive ovarian cancer. We hypothesize that patients treated with a combination of single-agent chemotherapy and bevacizumab will show improved progression-free survival (PFS) compared with those treated with single-agent chemotherapy alone, in the setting beyond disease progression following prior bevacizumab treatment. METHODS/DESIGN: A total of 106 patients who have recurrence or progression of ovarian cancer, while receiving chemotherapy or within 6 months after the final dose of platinum, after completing at least three cycles of bevacizumab plus platinum chemotherapy will be randomized in a 1:1 ratio to treatment with single-agent chemotherapy or single-agent chemotherapy combined with bevacizumab. For chemotherapy, one of the following four drugs will be chosen by an investigator: pegylated liposomal doxorubicin, topotecan, paclitaxel, or gemcitabine. The primary endpoint is investigator-assessed PFS. The secondary endpoints are overall survival, objective response rate, number of paracentesis, and response rate by CA125. Safety will be evaluated by the incidence of adverse events. DISCUSSION: This study will assess the efficacy and safety of bevacizumab in combination with single-agent chemotherapy, which could be used continuously after disease progression following standard platinum-based chemotherapy with bevacizumab. TRIAL REGISTRATION: UMIN000017247 (registered April 22, 2015).

Targeting of Aberrant αvß6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells.

Expression of the αvß6 integrin is upregulated in several solid tumors. In contrast, physiologic expression of this epithelial-specific integrin is restricted to development and epithelial re-modeling. Here, we describe, for the first time, the development of a chimeric antigen receptor (CAR) that couples the recognition of this integrin to the delivery of potent therapeutic activity in a diverse repertoire of solid tumor models. Highly selective targeting αvß6 was achieved using a foot and mouth disease virus-derived A20 peptide, coupled to a fused CD28+CD3 endodomain. To achieve selective expansion of CAR T cells ex vivo, an IL-4-responsive fusion gene (4αß) was co-expressed, which delivers a selective mitogenic signal to engineered T cells only. In vivo efficacy was demonstrated in mice with established ovarian, breast, and pancreatic tumor xenografts, all of which express αvß6 at intermediate to high levels. SCID beige mice were used for these studies because they are susceptible to cytokine release syndrome, unlike more immune-compromised strains. Nonetheless, although the CAR also engages mouse αvß6, mild and reversible toxicity was only observed when supra-therapeutic doses of CAR T cells were administered parenterally. These data support the clinical evaluation of αvß6 re-targeted CAR T cell immunotherapy in solid tumors that express this integrin.

Measurement of endometrial thickness in premenopausal women in office gynecology.

Purpose: To define the median endometrial thickness (ET) in office gynecology is thought to be important for clinical practice. However, there are few reports about ET that have included the general female population on a large scale. The median ET was determined prospectively in premenopausal women who attended office gynecology for cervical cancer screening. Methods: In total, 849 women were enrolled. The median ET was determined by using transvaginal ultrasound and the relationships between the ET and various clinical factors were analyzed. Results: The participants' median age was 38.5 years. The median ET was 8.6 mm (90% and 95% quantiles: 13.8 and 15.8 mm). The ET was not related to their age, symptoms, obstetric history, geographical location, or risk factors for endometrial cancer. In the women with a menstrual cycle length of 28-30 days, the ET was 7 mm on days 1-6, but it increased from 5.4 mm immediately after menstruation (day 7 or 8) to 9.2 mm on days 13-14. Subsequently, the ET increased further to 11.1 mm on day 18. Conclusion: In all the women, the upper limit of the ET was 13.8 mm and 15.8 mm in the 90% and 95% quantile, respectively, in office gynecology.

Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours. METHODS: Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols. RESULTS: Alterations to the switch/sucrose non-fermentable (SWI/SNF) subunit, the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway, and the receptor tyrosine kinase (RTK)/Ras signalling pathway were found in 51%, 42%, and 29% of OCCC tumours, respectively. The 3-year overall survival (OS) rate for patients with an activated PI3K/Akt signalling pathway was significantly higher than that for those with inactive pathway (91 vs 40%, hazard ratio 0.24 (95% confidence interval (CI) 0.10-0.56), P=0.0010). Similarly, the OS was significantly higher in patients with the activated RTK/Ras signalling pathway than in those with the inactive pathway (91 vs 53%, hazard ratio 0.35 (95% CI 0.13-0.94), P=0.0373). Multivariable analysis revealed that activation of the PI3K/Akt and RTK/Ras signalling pathways was an independent prognostic factor for patients with OCCC. CONCLUSIONS: The PI3K/Akt and RTK/Ras signalling pathways may be potential prognostic biomarkers for OCCC patients. Furthermore, our whole-genome sequencing data highlight important pathways for molecular and biological characterisations and potential therapeutic targeting in OCCC.

Inhibition of Aurora Kinase A Synergistically Enhances Cytotoxicity in Ovarian Clear Cell Carcinoma Cell Lines Induced by Cisplatin: A Potential Treatment Strategy.

OBJECTIVE: This study aims to clarify the incidence of Aurora kinase A (Aurora-A) protein expression and its correlation with clinical parameters in ovarian clear cell carcinoma (OCCC) tumor tissues. In addition, we assessed the efficacy of ENMD-2076, a novel selective Aurora-A inhibitor, in combination with chemotherapeutic agents for the treatment of OCCC. METHODS/MATERIALS: Aurora-A protein expression was determined by immunohistochemical staining of OCCC specimens from 56 patients to evaluate its correlation with clinical outcomes in OCCC. In the in vitro study, 6 OCCC cell lines were exposed to ENMD-2076 in combination with cisplatin, SN38, doxorubicin, or paclitaxel, and cell proliferation, cell cycle distribution, and apoptosis were assessed. RESULTS: The 5-year survival rates of International Federation of Gynecology and Obstetrics stages IC3 to IV patients with intermediate or strong Aurora-A expression were significantly lower than those of patients with negative or weak Aurora-A expression. Increased Aurora-A expression was associated with significantly worse overall survival of International Federation of Gynecology and Obstetrics stages IC3 to IV patients (21% vs 77%). Multivariate analysis revealed that Aurora-A expression was an independent prognostic factor for stages IC3 to IV OCCC patients. Furthermore, synergistic effects were observed with ENMD-2076 in combination with cisplatin or SN-38 in 4 of the 6 tested cell lines. ENMD-2076 dramatically enhanced apoptosis and cell cycle arrest at the G2/M phase induced by cisplatin. CONCLUSIONS: Aurora-A is a promising biomarker that is predictive of patient outcomes and a potential target for OCCC. The results suggested that chemotherapy, including ENMD-2076 in combination with cisplatin, is a potential treatment modality for patients with OCCC.

Serum Vascular Endothelial Growth Factor-A as a Prognostic Biomarker for Epithelial Ovarian Cancer.

BACKGROUND: Bevacizumab, which targets vascular endothelial growth factor (VEGF)-A, has recently been proven to be effective for the treatment of epithelial ovarian cancer (EOC). Thus, interest in VEGF-A has increased. There are few reports on concomitant detection of both ligands and its soluble receptors in serum samples, and the significance of serum VEGF-A in EOC is unclear, unlike the situation with tissue samples. We conducted the present study to explore the levels of serum VEGF family and its receptors and to evaluate their utility as prognostic biomarkers. METHODS: A total of 128 patients with EOC, who were consecutively treated at Tottori University Hospital between 2006 and 2012, were included. Blood samples were collected before initial surgery. Serum concentrations of VEGF-A, VEGF-C, VEGFR-1, and VEGFR-2 were analyzed by enzyme-linked immunosorbent assay. We also examined the mRNA and protein expression of VEGF-A in tumor tissue from 30 cases by real-time reverse transcription polymerase chain reaction and immunohistochemistry. RESULTS: The levels of VEGF-A in patients with stage III/IV disease were significantly higher than those with stage I/II disease (P = 0.0036). On the other hand, the level of VEGFR-2 in stage III/IV was significantly lower than that in stage I/II (P = 0.0026). With the cutoff value of VEGF/VEGFRs at the median level, the overall survival (OS) for patients with high VEGF-A levels was significantly lower than those with low levels (P = 0.015). Patients with high VEGFR-2 levels showed better prognosis than those with low VEGFR-2 levels (P = 0.023). Multivariate analysis revealed that International Federation of Gynecology and Obstetrics stage and serum VEGF-A were independent prognostic factors for OS [hazard ratio 2.01, 95% confidence interval (1.13-3.63), P = 0.017]. There was no significant correlation between mRNA or protein expression and serum levels of VEGF-A. CONCLUSIONS: Serum VEGF-A is an independent prognostic factor for OS in patients with EOC, implying that serum VEGF-A is a prognostic biomarker for EOC. Further study to validate the data is needed.

Apparent diffusion coefficient (ADC) measurement in ovarian tumor: Effect of region-of-interest methods on ADC values and diagnostic ability.

PURPOSE: To investigate the difference in apparent diffusion coefficient (ADC) measurements of differently shaped regions of interest (ROIs) in ovarian tumors, and to investigate the diagnostic ability of differently shaped ROIs in differentiating benign from malignant ovarian tumors. MATERIALS AND METHODS: Fifty-four patients with ovarian tumors with a solid component were evaluated. The patients underwent magnetic resonance (MR) examinations including diffusion-weighted imaging using a 3.0T MR system. Two readers measured ADCs using four ROI methods: freehand, square, round, and five small round ROIs. The interclass correlation coefficient (ICC) and repeated-measures analysis of variance were used to assess their measurement reliability and to compare ADCs for each ROI method. Receiver operating characteristic curve analysis and unpaired t-test on each ROI were used to differentiate benign and malignant ovarian tumors and assess the diagnostic ability. RESULTS: All ROI methods except the square ROI (0.56) showed good or excellent correlations (0.70-0.91). Minimum and mean ADC values differed significantly between the ROIs (P < 0.05). When using the freehand ROI, the minimum and mean ADC values were the lowest and highest, respectively. The optimal cutoff minimum and mean ADC values of each ROI for differentiating benign and malignant tumors were 0.81-1.06 × 10(-3) mm(2) /s and 1.15-1.52 × 10(-3) mm(2) /s, respectively. The areas under the curve showed no significant differences among the ADCs in the different ROI methods (P > 0.05). Minimum and mean ADCs from all ROIs showed significant differences between benign and malignant tumors (P < 0.05). CONCLUSION: The ROI shape influences ADC values and the optimal cutoff ADC values for differentiating benign from malignant ovarian tumors.

Fertility-sparing surgery for uterine cervical cancer.

The standard treatment for early cervical cancer of the uterus (CC) is radical hysterectomy with resection of the parametrium and pelvic lymphadenectomy. At least 40% of patients develop early-stage CC during child-bearing age, therefore preserving the uterus to maintain fertility has been an important consideration. Several surgical procedures including conization and vaginal or abdominal radical trachelectomy have been reported. These procedures are safe for removing lymph node negative CC tumors with <2 cm diameter. Recently, less radical surgical procedures that maintain fertility, such as conization, simple trachelectomy, minimally invasive surgery and neoadjuvant chemotherapy, have been indicated for tumors greater than 2 cm in diameter. In this review, we discuss the currently accepted surgical approaches for treating CC while maintaining fertility.

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.

Feasibility study on combination chemotherapy using nogitecan hydrochloride (topotecan) and cisplatin for patients with metastatic, persistent, or recurrent uterine cervical cancer.

BACKGROUND: The standard chemotherapeutic regimen for stage IVB, persistent, or recurrent uterine cervical cancer is platinum-based combination chemotherapy such as cisplatin (CDDP)/paclitaxel and CDDP/nogitecan hydrochloride (NGT, topotecan). Because it is unclear whether the CDDP/NGT combination chemotherapy is tolerable for Japanese patients, we conducted the present study to assess the feasibility of CDDP/NGT combination chemotherapy. METHODS: Between June 2012 and April 2014, 15 patients with stage IVB, persistent, or recurrent uterine cervical cancer were enrolled in this study. Patients underwent six cycles of NGT at a dose of 0.75 mg/m2, followed immediately by CDDP at a dose of 50 mg/m2 on day 1 by intravenous infusion, and then NGT at a dose of 0.75 mg/m2 on days 2 and 3. RESULTS: Of 15 patients, 9 patients underwent at least 6 cycles of NGT/CDDP combination chemotherapy. Of a total of 83 cycles, 70 cycles (84.3 %) of NGT/CDDP combination chemotherapy could be continued at the starting dose of NGT (0.75 mg/m2). Grade 3/4 hematological toxicities included leukopenia in 10 patients (66.7 %), neutropenia in 15 (100 %), anemia in 6 (40.0 %), thrombocytopenia in 4 (26.7 %), and febrile neutropenia in 4 (26.7 %). The response rate according to RECIST was 27 % (3/11), with partial response in 3 patients. CONCLUSIONS: NGT/CDDP combination chemotherapy may be a tolerable and effective regimen for Japanese patients with stage IVB, persistent, or recurrent uterine cervical cancer. Based on the results of this study, NGT/CDDP combination chemotherapy was approved in Japan in November 2015.

Clinical tumor diameter and prognosis of patients with FIGO stage IB1 cervical cancer (JCOG0806-A).

OBJECTIVE: In order to determine indications for less radical surgery such as modified radical hysterectomy, the risk of pathological parametrial involvement and prognosis of FIGO stage IB1 cervical cancer patients undergoing standard radical hysterectomy with pre-operatively assessed tumor diameter≤2 cm were investigated. METHODS: We conducted a retrospective multi-institutional chart review of patients with FIGO stage IB1 cervical cancer who underwent primary surgical treatment between 1998 and 2002. The eligibility criteria for the analyses were (i) histologically-proven squamous cell carcinoma, adenocarcinoma or, adenosquamous cell carcinoma, (ii) radical hysterectomy performed, (iii) clinical tumor diameter data available by MR imaging or specimens by cone biopsy, and (iv) age between 20 and 70. Based on the clinical tumor diameter, patients were stratified into those with the following tumors: i) 2 cm or less (cT≤2 cm) and ii) greater than 2 cm (cT>2 cm). We expected 5-year OS of ≥95% and parametrial involvement<2-3% for patients with cT≤2 cm who underwent radical hysterectomy. RESULTS: Of the 1269 patients enrolled, 604 were eligible for the planned analyses. Among these, 571 underwent radical hysterectomy (323 with cT≤2 cm and 248 with cT>2 cm). Parametrial involvement was present in 1.9% (6/323) with cT≤2 cm and 12.9% (32/248) with cT>2 cm. Five-year overall survivals were 95.8% (95% CI 92.9-97.6%) in cT≤2 cm and 91.9% (95% CI 87.6-94.8%) in cT>2 cm patients. CONCLUSION: Patients with cT≤2 cm had lower risk of parametrial involvement and more favorable 5-year overall survival. They could therefore be good candidates for receiving less radical surgery.

Fibroblast growth factor receptor 2 is associated with poor overall survival in clear cell carcinoma of the ovary and may be a novel therapeutic approach.

OBJECTIVE: We previously found that gene and protein expression of fibroblast growth factor receptor (FGFR) 2 were increased in ovarian clear cell carcinoma (CCC); here, we examined FGFR2 expression in CCC tumor tissues and its correlation with clinical parameters. We also analyzed the effect of an FGFR inhibitor on the growth of CCC cells to investigate whether FGFR2 could be a therapeutic target for this disease. METHODS: We analyze the protein expression of FGFR2 by immunohistochemical staining in CCC from 112 patients and evaluated the association of these molecular parameters with clinical outcome. We treated the 11 CCC cell lines with an FGFR inhibitor, and then assessed cell viability, the expression of protein in FGFR2 signaling pathway, and cell cycle distribution. RESULTS: The expressions of FGFR2 were found in 96% of CCC. The 5-year survival rate for patients with a moderate or strong expression of FGFR2 was significantly lower than that for those with an absent or poor expression of FGFR2 (54% vs 79%). Multivariable analysis revealed that FGFR2 expression and disease stage were independent prognostic factors. The FGFR inhibitor effectively suppressed the growth of CCC cells with induction of G1 cell cycle arrest and down-regulated the expression of phosphorylated Akt and phosphorylated ERK. CONCLUSIONS: FGFR2 is an important biomarker predictive of patient outcome and is a potential target for CCC. Further study is warranted for FGFR inhibitor to treat CCC.

Loss of ARID1A expression is associated with poor prognosis in patients with stage I/II clear cell carcinoma of the ovary.

BACKGROUND: Recent studies have shown that somatic mutations in the AT-rich interactive domain 1A (SWI-like) gene (ARID1A) are the most common genetic changes in clear cell carcinoma of the ovary (CCC). A gene mutation of ARID1A was found in approximately half of CCC cases, and led to absence of the encoded protein and inactivation of the putative tumor suppressor. Here, we investigated whether ARID1A could be a prognostic biomarker for this disease. METHODS: We analyzed the protein expression of ARID1A in CCC from 112 patients by immunohistochemical staining, and evaluated the association of these molecular parameters with clinical outcome. RESULTS: The loss of ARID1A expression was found in 39 % (44/112) of CCC, and was not associated with patient age, FIGO stage, and status of residual tumor. The 5-year survival rate for FIGO stage I or II patients with negative tumor expression of ARID1A was lower than those with positive tumor expression of ARID1A (74 % vs 91 %), but this difference was not observed in FIGO stage III or IV patients. Multivariable analysis revealed that ARID1A expression was an independent prognostic factor in FIGO stage I or II CCC patients. CONCLUSION: ARID1A may be a biomarker that is predictive of the outcome of FIGO stage I and II CCC.

Incidence and risk factors for lower limb lymphedema after gynecologic cancer surgery with initiation of periodic complex decongestive physiotherapy.

BACKGROUND: Lower limb lymphedema (LLL) is one of the most frequent postoperative complications of retroperitoneal lymphadenectomy for gynecologic cancer. LLL often impairs quality of life, activities of daily living, sleep, and sex in patients with gynecologic cancer. We conducted this study to evaluate the incidence and risk factors for LLL after gynecologic cancer surgery in patients who received assessment and periodic complex decongestive physiotherapy (CDP). METHODS: We retrospectively reviewed 126 cases of gynecologic cancer that underwent surgery involving retroperitoneal lymphadenectomy at Tottori University Hospital between 2009 and 2012. All patients received physical examinations to detect LLL and underwent CDP by nurse specialists within several months after surgery. The International Society of Lymphology staging of lymphedema severity was used as the diagnostic criteria. RESULTS: Of 126 patients, 57 (45.2%) had LLL, comprising 45 and 12 patients with stage 1 and stage 2 LLL, respectively. No patient had stage 3 LLL. LLL was present in 37 (29.4%) patients at the initial physical examination. Multivariate analysis revealed that adjuvant concurrent chemoradiotherapy and age ≥ 55 years were independent risk factors for ≥ stage 2 LLL. CONCLUSIONS: To minimize the incidence of ≥ stage 2 LLL, gynecologic oncologists should be vigilant for this condition in patients who are ≥ 55 years and in those who undergo adjuvant chemoradiotherapy. Patients should be advised to have a physical assessment for LLL and to receive education about CDP immediately after surgery involving retroperitoneal lymphadenectomy for gynecologic cancer.

Efficacy and safety of triple therapy with aprepitant, palonosetron, and dexamethasone for preventing nausea and vomiting induced by cisplatin-based chemotherapy for gynecological cancer: KCOG-G1003 phase II trial.

PURPOSE: Prevention of chemotherapy-induced nausea and vomiting (CINV) is crucial for maintaining the quality of life of cancer patients. Female patients have been underrepresented in previous clinical studies of aprepitant or palonosetron. We performed a prospective multicenter study to investigate the efficacy and safety of triple therapy comprising these two agents and dexamethasone in female cancer patients receiving chemotherapy that included cisplatin (≥ 50 mg/m(2)). METHODS: Aprepitant was administered at a dose of 125 mg before chemotherapy on day 1 and at 80 mg on days 2 and 3. Palonosetron (0.75 mg) was given before chemotherapy on day 1. Dexamethasone was administered at a dose of 9.9 mg before chemotherapy on day 1 and at 6.6 mg on days 2-4. The primary endpoint was the the proportion of patients with a complete response (CR no vomiting and no use of rescue medication) throughout the overall period (0-120 h post-chemotherapy). RESULTS: Ninety-six women (median age 55 years) were enrolled. The overall CR rate was 54.2 %. CR was obtained during the acute phase (0-24 h post-chemotherapy) and the delayed phase (24-120 h post-chemotherapy) in 87.5 and 56.3 % of the patients, respectively. The most common adverse reactions were constipation and fatigue (reported by three patients each). CONCLUSIONS: Exhibition of a favorable overall CR rate over existing two-drug combinations suggests that the triple therapy regimen used in the present study is effective and tolerable in patients with gynecological malignancies receiving cisplatin-based chemotherapy. Female patients may have a higher risk of developing CINV.

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.

Checkpoint kinase inhibitor AZD7762 overcomes cisplatin resistance in clear cell carcinoma of the ovary.

OBJECTIVE: Checkpoint kinase (Chk) inhibitors are thought to increase the cytotoxic effects of DNA-damaging agents and are undergoing clinical trials. The present study was aimed to assess the potential to use the Chk1 and Chk2 inhibitor, AZD7762, with other anticancer agents in chemotherapy to treat ovarian clear cell carcinoma. METHODS: Four ovarian clear cell carcinoma cell lines were used in this study. We treated the cells with AZD7762 and anticancer agents, then assessed cell viability, cell cycle distribution, apoptosis, and the expression of protein in apoptotic pathways and molecules downstream of the Chk signaling pathways. We also investigated the effects of these drug combinations on tumor growth in a nude mouse xenograft model. RESULTS: Synergistic effects from the combination of AZD7762 and cisplatin were observed in all 4 cell lines. However, we observed additive effects when AZD7762 was combined with paclitaxel on all cell lines tested. AZD7762 effectively suppressed the Chk signaling pathways activated by cisplatin, dramatically enhanced expression of phosphorylated H2A.X, cleaved caspase 9 and PARP, decreased the proportion of cells in the gap 0/ gap 1 phase and the synthesis-phase fraction, and increased apoptotic cells. Combinations of small interfering RNA against Chk 1 and small interfering RNA against Chk2 enhanced the cytotoxic effect of cisplatin in both RMG-I and KK cells. Finally, treating mice-bearing RMG-I with AZD7762 and cisplatin significantly suppressed growth of tumors in a xenograft model. CONCLUSIONS: The present study indicates that chemotherapy with AZD7762 and cisplatin should be explored as a treatment modality for women with ovarian clear cell carcinoma.