Yuri Matsumoto

Pretreatment leukocytosis is an indicator of poor prognosis in patients with cervical cancer

OBJECTIVES The aim of this study was to investigate the prognostic value of pretreatment leukocytosis in patients with cervical cancer in relation to well-established conventional risk factors. METHODS The baseline characteristics and outcome data from 536 patients treated for cervical cancer between 1996 April to 2007 March were collected and reviewed. Cox proportional hazards regression model was used to identify independent prognostic factors for overall survival. Subsequently, the prognostic significance of pretreatment WBC count was prospectively investigated in 156 patients newly diagnosed cervical cancer from 2007 April to 2010 March. RESULTS In a retrospective analysis, patients with leukocytosis (WBC ≥ 10,000/μl) showed significantly higher treatment failure rate (P < 0.0001) and shorter OS (P < 0.0001) than the patients without leukocytosis. Tumors from patients with leukocytosis showed significantly stronger immunoreactivity for G-CSF than those obtained from patients without leukocytosis. Multivariate analyses revealed that clinical stage, tumor diameter, histology, and elevated WBC count (≥ 10,000/μl) were significant prognostic factors in terms of overall survival. In a prospective investigation, patients with leukocytosis showed significantly higher treatment failure rate (P < 0.0001), shorter PFS (P < 0.0001), and higher serum G-CSF concentrations (p = 0.001) than the patients without leukocytosis. Multivariate analyses revealed that clinical stage, tumor diameter, and elevated WBC count were significant prognostic factors in terms of PFS. CONCLUSION Pretreatment leukocytosis is an independent prognostic factor in patients with cervical cancer. Our finding can be used to identify patients with poor prognosis and to design future tailored clinical trials.

Uterine Cervical Cancer Displaying Tumor-Related Leukocytosis : A Distinct Clinical Entity With Radioresistant Feature

BACKGROUND Tumor-related leukocytosis (TRL) is occasionally found in patients with nonhematopoietic malignancies. We investigated the clinical implication of TRL and individualized treatment for TRL-positive cervical cancer, as well as the underlying biological mechanism. METHODS Clinical data from 258 cervical cancer patients treated with definitive radiotherapy were analyzed to investigate the association between TRL and treatment outcome. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms responsible for TRL in cervical cancer, focusing on the role of tumor-derived granulocyte colony-stimulating factor (G-CSF) and myeloid-derived suppressor cells (MDSCs). All statistical tests were two-sided. RESULTS TRL was statistically significantly associated with younger age (Wilcoxon rank sum test, P = .03), larger tumor size (Wilcoxon rank sum test, P = .006), advanced clinical stage (χ(2) test, P = .01), and shorter overall survival (Cox proportional hazard modeling and Wald tests, P < .001). Among cervical cancer patients, TRL was associated with upregulated tumor G-CSF expression (χ(2) test, P < .001), elevated serum G-CSF levels (Student t test, P = .03), larger spleens (Student t test, P = .045), and increased MDSC frequencies in the blood (Student t test, P < .001) compared with the TRL-negative patients. In vitro and in vivo experiments revealed that tumor-derived G-CSF was involved in the underlying causative mechanism of TRL and MDSCs induced by tumor-derived G-CSF are responsible for the rapidly progressive and radioresistant nature of TRL-positive cervical cancer. The administration of anti-Gr-1 neutralizing antibody or the depletion of MDSCs by splenectomy (n = 6 per group) inhibited tumor growth and enhanced radiosensitivity in TRL-positive cervical cancer xenografts (Wilcoxon rank sum test, P = .008 and P = .02, respectively). CONCLUSIONS TRL is associated with resistance to radiotherapy among cervical cancer patients, and MDSC-targeting treatments may have therapeutic potential in these patients.

The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer

Granulocyte-colony stimulating factor (G-CSF) producing malignant tumor has been reported to occur in various organs, and has been associated with poor clinical outcome. The aim of this study is to investigate the significance of tumor G-CSF expression in the chemosensitivity of uterine cervical cancer. The clinical data of recurrent or advanced cervical cancer patients who were treated with platinum-based chemotherapy were analyzed. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were employed to examine the mechanisms responsible for the development of chemoresistance in G-CSF-producing cervical cancer, focusing on myeloid-derived suppressor cells (MDSC). As a result, the tumor G-CSF expression was significantly associated with increased MDSC frequencies and compromised survival. In vitro and in vivo experiments demonstrated that the increased MDSC induced by tumor-derived G-CSF is involved in the development of chemoresistance. The depletion of MDSC via splenectomy or the administration of anti-Gr-1 antibody sensitized G-CSF-producing cervical cancer to cisplatin. In conclusion, tumor G-CSF expression is an indicator of an extremely poor prognosis in cervical cancer patients that are treated with chemotherapy. Combining MDSC-targeting treatments with current standard chemotherapies might have therapeutic efficacy as a treatment for G-CSF-producing cervical cancer.

Potential Role of mTORC2 as a Therapeutic Target in Clear Cell Carcinoma of the Ovary

The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and -resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2–AKT signaling was observed in RAD001-resistant CCC cells compared with the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the antitumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a first-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment. Mol Cancer Ther; 12(7); 1367–77. ©2013 AACR.

Squamous cell carcinoma of the uterine cervix producing granulocyte colony-stimulating factor: a report of 4 cases and a review of the literature.

Granulocyte colony-stimulating factor (G-CSF)-producing malignant tumor has been reported to occur in various organs, and most of which has been associated with poor clinical outcome. However, because of the rarity of the reported cases, information regarding the G-CSF-producing gynecological malignancies is limited. We report 4 cases of G-CSF-producing cervical cancers. At initial diagnosis, all of the 4 patients exhibited marked leukocytosis without an obvious sign of infection. Of the 4 patients, 3 had their disease initially treated with definitive radiotherapy, and one was treated with radical surgery. Despite the aggressive treatments, all of these patients experienced recurrences within 6 months. In all cases, the white blood cell count returned to the normal range in response to the initial treatment and then increased again with recurrences. Based on the facts that the tumor cells were positive for G-CSF, the serum level of G-CSF was elevated, and their clinical course correlated well with the white blood cell count, we concluded that these tumors were G-CSF-producing cancers. All patients died from disease progression in less than 15 months. These cases strongly indicate the aggressive nature of the G-CSF-producing cervical cancer.

Elevated white blood cell count at the time of recurrence diagnosis is an indicator of short survival in patients with recurrent cervical cancer.

Objectives The aim of this study was to investigate the prognostic significance of elevated white blood cell (WBC) count at the time of the diagnosis of cervical cancer recurrence. Methods The baseline characteristics and outcome data of 219 patients who had a diagnosis of recurrent cervical cancer between April 1996 and September 2010 were collected and reviewed. Survival after recurrence was compared between the leukocytosis group (WBC ≥9000/&mgr;L) and the nonleukocytosis group (WBC <9000/&mgr;L). A Cox proportional hazards regression model was used to investigate the prognostic significance of elevated WBC count in patients with recurrent cervical cancer. Results The patients in the leukocytosis group showed significantly shorter disease-free interval (P = 0.0005) and more frequently had multiple recurrences (P = 0.0101) than those in the nonleukocytosis group. The median survival after recurrence of the patients with elevated WBC count was 9 months, which was significantly shorter than the 21 months observed in the patients without normal WBC count (log rank; P < 0.0001). Multivariate analyses revealed that clinical stage, tumor diameter, histology, an elevated WBC count (≥9000/&mgr;L), and an elevated neutrophil count (≥6500/&mgr;L) were significant prognostic factors in survival after recurrence. Conclusion The elevated WBC count at the time of the diagnosis of recurrence is an independent prognostic factor in patients with recurrent cervical cancer.

Preclinical Efficacy for AKT Targeting in Clear Cell Carcinoma of the Ovary

The aim of this study was to determine the role of AKT as a therapeutic target in ovarian clear cell carcinoma (CCC), an aggressive, chemoresistant histologic subtype of ovarian cancer. AKT activation was assessed by immunohistochemistry (IHC) using human tissue microarrays of primary ovarian cancers, composed of both CCC and serous adenocarcinoma (SAC). The growth-inhibitory effect of AKT-specific targeting by the small-molecule inhibitor, perifosine, was examined using ovarian CCC cell lines in vitro and in vivo. Finally, the activity of perifosine was examined using in CCC-derived tumors that had acquired resistance to anti-VEGF or chemotherapeutics such as bevacizumab or cisplatin, respectively. Interestingly, AKT was frequently activated both in early-stage and advanced-stage CCCs. Treatment of CCC cells with perifosine attenuated the activity of AKT–mTORC1 signaling, inhibited proliferation, and induced apoptosis. The effect of perifosine was more profound under conditions of high AKT activity compared with low AKT activity. Increased AKT activation and enhanced sensitivity to perifosine were observed in the context of cisplatin-resistant CCC. Treatment with perifosine concurrently with cisplatin significantly enhanced the antitumor effect of cisplatin. Moreover, perifosine showed significant antitumor activity in CCC-derived tumors that had acquired resistance to bevacizumab or cisplatin. Collectively, these data reveal that AKT is frequently activated in ovarian CCCs and is a promising therapeutic target in aggressive forms of ovarian cancer. Implications: AKT-targeted therapy has value in a first-line setting as well as a second-line treatment for recurrent disease developing after platinum-based chemotherapy or bevacizumab treatment. Mol Cancer Res; 13(4); 795–806. ©2014 AACR.

Prognostic significance of systemic neutrophil and leukocyte alterations in surgically treated endometrial cancer patients: A monoinstitutional study

OBJECTIVE The aim of this study was to investigate the prognostic significance of an elevated neutrophil count at the time of the initial diagnosis in patients with surgically treated endometrial cancer. METHODS The baseline characteristics and outcome data of patients who were diagnosed with endometrial cancer between January 2000 and December 2010 were collected and retrospectively reviewed. The patients were separated into two groups according to their neutrophil counts. The clinicopathological characteristics and overall survival rates of the two groups were compared. A Cox proportional hazard regression model was used to investigate the prognostic significance of an elevated neutrophil count among patients with surgically treated endometrial cancer. RESULTS An elevated neutrophil count was found to be associated with an advanced clinical stage (P<0.0001), lymphovascular space involvement (P=0.0003), cervical involvement (P=0.0049), the proportion of patients that received adjuvant therapy (P=0.0020), elevated NLR (P<0.0001), and treatment failure (P<0.0001). Multivariate analyses demonstrated that age (hazard ratio (HR)=2.23, 95% confidence interval (95% CI)=1.30 to 3.91; P=0.0035), clinical stage (HR=4.72, 95% CI=2.61 to 8.90; P<0.0001), lymphovascular space involvement (HR=3.15, 95% CI=1.60 to 6.68; P=0.0007), an elevated neutrophil count (HR=2.76, 95% CI=1.43 to 5.03; P=0.0033), and an elevated white blood cell count (HR=2.79, 95% CI=1.50 to 4.96; P=0.0017) were significant predictors of survival. CONCLUSION The elevated neutrophil or leukocyte counts at the time of the initial diagnosis are independent prognostic factors in patients with surgically treated endometrial cancer.

The first 2 cases of granulocyte colony-stimulating factor producing adenocarcinoma of the uterine cervix.

Granulocyte colony-stimulating factor (G-CSF)-producing nonhematopoietic malignancies have been reported in various organs, and most of them have been associated with poor clinical outcome. However, because of the rarity of the reported cases, information regarding the G-CSF-producing gynecological malignancies is limited. We report the first 2 cases of G-CSF-producing cervical adenocarcinomas, which exhibited an aggressive clinical course. At initial diagnosis, both patients exhibited marked leukocytosis without an obvious sign of infections. Of these, one was initially treated with definitive radiotherapy and the other was treated with radical surgery. However, both of these patients experienced recurrences in a short period and died from disease progression in less than 6 months. According to the facts that the tumor cells were positive for G-CSF, the elevated serum level of G-CSF, and their clinical course correlated well with the white blood cell count, we concluded that these tumors were G-CSF-producing cancers. These cases strongly indicate the aggressive nature of the G-CSF-producing cervical adenocarcinomas.

Cysteine sulfinic acid decarboxylase regulation: A role for farnesoid X receptor and small heterodimer partner in murine hepatic taurine metabolism

Bile acid synthesis is regulated by nuclear receptors including farnesoid X receptor (FXR) and small heterodimer partner (SHP), and by fibroblast growth factor 15/19 (FGF15/19). We hypothesized that hepatic cysteine sulfinic acid decarboxylase (CSAD) (a key enzyme in taurine synthesis) is regulated by bile acids (BA). The aim of this study was to investigate CSAD regulation by BA dependent regulatory mechanisms.