Masayoshi Hosaka

Treatment of cervical cancer with adjuvant chemotherapy versus adjuvant radiotherapy after radical hysterectomy and systematic lymphadenectomy

Aim:  To compare the clinical efficacy focused on post‐treatment morbidity between adjuvant chemotherapy (CT) and pelvic radiotherapy (RT) after radical hysterectomy for patients with cervical cancer.

The impact of microRNA-mediated PI3K/AKT signaling on epithelial-mesenchymal transition and cancer stemness in endometrial cancer

Activation of the PI3K/AKT pathway, a common mechanism in all subtypes of endometrial cancers (endometrioid and non-endometrioid tumors), has important roles in contributing to epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) features. MicroRNAs (miRNAs) are small non-coding RNA molecules that concurrently affect multiple target genes, and regulate a wide range of genes involved in modulating EMT and CSC properties. Here we overview the recent advances revealing the impact of miRNAs on EMT and CSC phenotypes in tumors including endometrial cancer via regulating PI3K/AKT pathway. MiRNAs are crucial mediators of EMT and CSC through targeting PTEN-PI3K-AKT-mTOR axis. In endometrial cancer cells, miRNAs can activate or attenuate EMT and CSC by targeting PTEN and other EMT-associated genes, such as Twist1, ZEB1 and BMI-1. More detailed studies of miRNAs will deepen our understanding of the molecular basis underlying PI3K/AKT-induced endometrial cancer initiation and progression. Targeting key signaling components of PI3K/AKT pathway by restoring or inhibiting miRNA function holds promise as a potential therapeutic approach to suppress EMT and CSC in endometrial cancer.

Clinical efficacy of paclitaxel/cisplatin as an adjuvant chemotherapy for patients with cervical cancer who underwent radical hysterectomy and systematic lymphadenectomy.

The aim of this study was to compare the clinical efficacy of paclitaxel/cisplatin (TP) as an adjuvant chemotherapy to adjuvant radiotherapy (RT) after radical hysterectomy and systematic lymphadenectomy for patients with cervical cancer.

Identification of KLF17 as a novel epithelial to mesenchymal transition inducer via direct activation of TWIST1 in endometrioid endometrial cancer

Krüppel-like factor 17 (KLF17), a member of the KLF transcription factor family, has been shown to inhibit the epithelial-mesenchymal transition (EMT) and tumor growth. However, the expression, the cellular function and the mechanism of KLF17 in endometrioid endometrial cancer (EEC; a dominant type of endometrial cancer) remain elusive. Here, we report that among the KLF family members, KLF17 was consistently upregulated in EEC cell lines compared with immortalized endometrial epithelial cells. Overexpression of KLF17 in EEC cell lines induced EMT and promoted cell invasion and drug resistance, resulting in increased expression of TWIST1. In contrast, KLF17 suppression reversed EMT, diminished cell invasion, restored drug sensitivity and suppressed TWIST1 expression. Luciferase assays, site-directed mutagenesis and transcription factor DNA-binding analysis demonstrated that KLF17 transactivates TWIST1 expression by directly binding to the TWIST1 promoter. Knockdown of TWIST1 prevented KLF17-induced EMT. Consistent with these results, both KLF17 and TWIST1 levels were found to be elevated in EECs compared with normal tissues. KLF17 expression positively correlated with tumor grade but inversely correlated with estrogen and progesterone receptor expression. Thus, KLF17 may have an oncogenic role during EEC progression via initiating EMT through the regulation of TWIST1.

Clusterin is a potential molecular predictor for ovarian cancer patient's survival: targeting Clusterin improves response to paclitaxel

BackgroundClusterin is a cytoprotective chaperone protein involved in numerous physiological processes, carcinogenesis, tumor growth and tissue remodelling. The purpose of this study was to investigate whether clusterin (CLU), an antiapoptotic molecule, could be a potential predictor molecule for ovarian cancer and whether or not targeting this molecule can improve survival of ovarian cancer patients.MethodsClusterin expression was compared between ten primary and their recurrent tumors from same patients immunohistochemically. We analyzed prognostic significance of CLU expression in another 47 ovarian cancer tissue samples by immunohistochemistry. We used small interference RNA to knock down CLU in the chemo-resistant ovarian cancer cell lines. KF-TX and SKOV-3-TX, paclitaxel-resistant ovarian cancer cells, were established from parental KF and SKOV-3 chemo-sensitive cell lines, respectively. Either siRNA or second generation antisense oligodeoxynucleotide against CLU (OGX-011), which is currently evaluated in clinical phase II trials in other cancer s, was used to modulate sensitivity to paclitaxel (TX) in ovarian cancer cells in vitro. Cellular viability assay, FACS analysis and annexin V staining were used to evaluate the comparative effect of CLU knocking down in ovarian cancer cells.ResultsImmunohistochemical analysis of CLU expression in primary ovarian cancer tissue specimens and their recurrent counterparts from same patients demonstrated higher expression of CLU in the recurrent resistant tumors compared with their primary tumors. High expression of CLU by immunohistochemistry among 47 surgical tissue specimens of early-stage (stage I/II) ovarian cancer, who underwent complete cytoreduction as a primary surgery, significantly related to poor survival, while none of other clinicopathological factors analyzed were related to survival in this patient cohort. Secretory CLU (s-CLU; 60 KDa) expression was upregulated in TX-resistant ovarian cancer cells compared to parental cells. Transfection of siRNA or OGX-011 clearly reduced CLU expression. Cell viability assay, FACS analysis and annexin V staining demonstrated that targeting CLU expression by siRNA or OGX-011 sensitized ovarian cancer cells to TX.ConclusionWe conclude that CLU could be a potential molecular target to predict survival while targeting this s-CLU may improve survival of patients with ovarian cancer.

Risk factors for persistent low bladder compliance after radical hysterectomy.

Introduction: Bladder compliance deteriorates immediately after radical hysterectomy (RH), and low bladder compliance causes upper urinary tract dysfunctions such as progressive hydronephrosis. The aims of this study were to clarify risk factors for persistent low bladder compliance after RH and to propose a postsurgical management protocol for improved recovery of bladder function. Methods: A total of 113 consecutive patients who underwent RH with the intention to preserve the pelvic autonomic nerve system were included in this prospective study. Urodynamic studies were performed according to a planned schedule: presurgery and 1, 3, 6, and 12 months after surgery. Autonomic nerves were preserved at least unilaterally in 95 (84.1%) of the 113 patients, but this was not possible in the remaining 18 patients (15.9%). Postoperative adjuvant radiation therapy (RT) was performed in 14 patients. The relationships between bladder compliance and various clinical factors were investigated using logistic regression analysis. Covariates included age, nerve-sparing procedure, adjuvant RT, and maximum abdominal pressure during the voiding phase. Bladder compliance at 12 months after surgery was used as the dependent variable. Results: Radical hysterectomy with a non-nerve-sparing procedure (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.1-11.0), adjuvant RT (OR, 10.3; 95% CI, 2.5-43.5), and voiding with abdominal pressure at 3 months after surgery (OR, 2.9; 95% CI, 1.1-7.2) were risk factors for persistent low bladder compliance. Conclusions: A nerve-sparing procedure and prohibition of voiding with abdominal strain during the acute and subacute phases after RH resulted in improved recovery of bladder compliance. Adjuvant RT should be avoided in patients who undergo nerve-sparing RH if an alternative postoperative strategy is possible.

Multivariate prognostic analysis of adenocarcinoma of the uterine cervix treated with radical hysterectomy and systematic lymphadenectomy

Objective The aim of this study was to investigate the prognostic factors and treatment outcome of patients with adenocarcinoma of the uterine cervix who underwent radical hysterectomy with systematic lymphadenectomy. Methods A total of 130 patients with stage IB to IIB cervical adenocarcinoma treated with hysterectomy and systematic lymphadenectomy from 1982 to 2005 were retrospectively analyzed. Clinicopathological data including age, stage, tumor size, the number of positive node sites, lymphovascular space invasion, parametrial invasion, deep stromal invasion (>2/3 thickness), corpus invasion, vaginal infiltration, and ovarian metastasis, adjuvant therapy, and survival were collected and Cox regression analysis was used to determine independent prognostic factors. Results An estimated five-year survival rate of stage IB1 was 96.6%, 75.0% in stage IB2, 100% in stage IIA, and 52.8% in stage IIB. Prognosis of patients with one positive-node site is similar to that of those with negative-node. Prognosis of patients with multiple positive-node sites was significantly poorer than that of negative and one positive-node site. Multivariate analysis revealed that lymph node metastasis, lymphovascular space invasion, and parametrial invasion were independent prognostic factors for cervical adenocarcinoma. Survival of patients with cervical adenocarcinoma was stratified into three groups by the combination of three independent prognostic factors. Conclusion Lymph node metastasis, lymphovascular space invasion, and parametrial invasion were shown to be independent prognostic factors for cervical adenocarcinoma treated with hysterectomy and systematic lymphadenectomy.

Survival and failure pattern of patients with endometrial cancer after extensive surgery including systematic pelvic and para-aortic lymphadenectomy followed by adjuvant chemotherapy.

We investigated the survival and the failure pattern of 288 patients with endometrial cancer treated with extensive surgery including systematic pelvic and para-aortic lymphadenectomy followed by cisplatin-based chemotherapy from 1982 to 2002. We correlated the failure pattern with various clinicopathologic factors to find the predictors of recurrence sites. The 5-year overall survival rates were 97.5% for stage I, 87.5% for stage II, 85.2% for stage III, and 12.5% for stage IV. Notably, the 5-year survival rate was 76.5% for patients with stage IIIC disease. Among patients with a low risk (n = 92) for recurrence who received no adjuvant chemotherapy, 2 (2.2%) showed recurrent disease. Among those with intermediate (n = 98) and high (n = 98) risks for recurrence who received adjuvant chemotherapy, 9 (9.2%) and 20 (20.4%) showed recurrent disease, respectively. The recurrence sites were described as follows: distant (n = 12), vaginal (n = 8), peritoneal (n = 7), pelvic (n = 2), and lymphatic (n = 2). Lymphatic failure was found beyond the area of lymphadenectomy. Architectural and nuclear grades; myometrial, lymph-vascular space, and cervical invasions; and lymph node metastasis were predictors of distant failure. Cervical invasion and lymph node metastasis were predictors of vaginal failure. For patients with stage I/II cancer, the architectural and nuclear grades were related to distant failure. Seven (63.6%) of 11 patients with a low or intermediate risk survived after relapse, whereas only 1 (4.8%) of 21 patients with a high risk survived after a recurrence. We conclude that we need to further test the efficacy of systemic adjuvant therapy using new chemotherapeutic regimens to prevent distant failure and to improve the survival of patients with endometrial cancer.

New revised FIGO 2008 staging system for endometrial cancer produces better discrimination in survival compared with the 1988 staging system.

The aim of this study was to analyze the stage migration and survival of endometrial cancer by the revised FIGO 2008 staging system compared with the 1988 staging system.

Clusterin Expression Inversely Correlates with Chemosensitivity and Predicts Poor Survival in Patients with Locally Advanced Cervical Cancer Treated with Cisplatin-Based Neoadjuvant Chemotherapy and Radical Hysterectomy

Overexpression of clusterin, an antiapoptotic molecule, has been reported to induce resistance to chemotherapy in a variety of cancer cell types. The aim of this study was to evaluate the significance of clusterin expression to predict response to platinum-based neoadjuvant chemotherapy and survival of patients with invasive cervical cancer who subsequently underwent radical hysterectomy. Biopsy specimens of invasive cervical cancer before neoadjuvant chemotherapy were obtained from 46 patients who subsequently underwent radical hysterectomy at Hokkaido University Hospital and Gunma University Hospital from 1994 to 2007. The expression of clusterin protein was analyzed by immunohistochemistry. Findings were evaluated in relation to several clinicopathological factors. Survival analyses were performed by the Kaplan-Meier curves and the log-rank test. Independent prognostic factors were determined by multivariate Cox regression analysis. Clusterin protein was mainly present in the cytoplasm of cervical cancer cells. The expression of clusterin protein in cervical cancer tissues before neoadjuvant chemotherapy was significantly related to poor response to chemotherapy among factors analyzed. Univariate analysis on prognostic factors showed that response to chemotherapy (p = 0.01), lymph node metastasis (p = 0.02), and clusterin expression (p = 0.02) were related to survival. Multivariate analysis revealed that lymph node metastasis (p = 0.03), and clusterin expression (p = 0.03) were independent prognostic factors for survival of cervical cancer patients. We conclude that clusterin expression could be a new molecular marker to predict response to platinum-based chemotherapy and survival of patients with cervical cancer treated with neoadjuvant chemotherapy and radical hysterectomy.