[Show abstract][Hide abstract] ABSTRACT: Background:In this study, we sought to identify a criterion for the intermediate-risk grouping of patients with cervical cancer who exhibit any intermediate-risk factor after radical hysterectomy.Methods:In total, 2158 patients with pathologically proven stage IB-IIA cervical cancer with any intermediate-risk factor after radical hysterectomy were randomly assigned to two groups, a development group and a validation group, at a ratio of 3 : 1 (1620 patients:538 patients). To predict recurrence, multivariate models were developed using the development group. The ability of the models to discriminate between groups was validated using the log-rank test and receiver operating characteristic (ROC) analysis.Results:Four factors (histology, tumour size, deep stromal invasion (DSI), and lymphovascular space involvement (LVSI)) were significantly associated with disease recurrence and included in the models. Among the nine possible combinations of the four variables, models consisting of any two of the four intermediate-risk factors (tumour size 3 cm, DSI of the outer third of the cervix, LVSI, and adenocarcinoma or adenosquamous carcinoma histology) demonstrated the best performance for predicting recurrence.Conclusion:This study identified a 'four-factor model' in which the presence of any two factors may be useful for predicting recurrence in patients with cervical cancer treated with radical hysterectomy.British Journal of Cancer advance online publication, 19 December 2013; doi:10.1038/bjc.2013.716 www.bjcancer.com.
British Journal of Cancer 12/2013; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this phase II study was to investigate the efficacy and toxicity of combined ifosfamide and cisplatin chemotherapy in patients with recurrent epithelial ovarian cancer (EOC).
Forty-seven patients with recurrent EOC were treated with ifosfamide 5 g/m(2) and cisplatin 50 mg/m(2) on day 1, every 3 weeks for 6 cycles. The primary outcomes were response rate (RR) and toxicity. Other measurements were duration of response, time to progression (TTP), and overall survival (OS).
All 47 patients with 160 cycles were assessed for response and toxicity. The overall RR was 31.9 %; there were 3 complete responses (6.4 %) and 12 partial responses (25.5 %). Grade 3 and 4 hematologic toxicities included neutropenia (23.6 %), anemia (12.8 %), and thrombocytopenia (10.7 %). Non-hematologic toxicities were mild, and no drug-related toxic deaths occurred. The median duration of response, TTP, and OS was 5.1, 4.8, and 17.0 months, respectively. In the initially platinum-sensitive group, RR and OS were 44.4 % and 20.4 months, while in the initially platinum-resistant group, these values were 15.0 and 8.7 months, respectively (P = 0.027 and P = 0.002, respectively).
Ifosfamide combined with cisplatin is a well-tolerated regimen with modest activity in recurrent EOC. In addition, this regimen was especially effective in patients whose disease was initially platinum-sensitive.
Cancer Chemotherapy and Pharmacology 08/2013; · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We designed this study to identify and suggest the reasonable timing of adjuvant radiotherapy in the treatment of uterine carcinosarcoma according to the surgical intent and patterns of progression.
We retrospectively analyzed a total of 50 carcinosarcoma patients diagnosed between 1995 and 2010. Among these 50 patients, 32 underwent curative surgery and 13 underwent maximal tumor debulking surgery. The remaining five patients underwent biopsy only. Twenty-six patients received chemotherapy, and 15 patients received adjuvant radiotherapy.
The median follow-up period was 17.3 months. Curative resection (p < 0.001) and stage (p < 0.001) were statistically significant factors affecting survival. During follow-up, 30 patients showed progression. Among these, eight patients (16.0%) had loco-regional progression only. The patients who had received adjuvant radiotherapy did not show loco-regional progression, and radiotherapy was a significant negative risk factor for loco-regional progression (p = 0.01). The time to loco-regional progression was much earlier for non-curative than curative resection (range, 0.7 to 7.6 months vs. 7.5 to 39.0 months).
Adjuvant radiotherapy in the treatment of carcinosarcoma might be related to a low loco-regional progression rate. Radiotherapy should be considered in non-curatively resected patients as soon as possible.
[Show abstract][Hide abstract] ABSTRACT: We compared the prognostic value of volume-based metabolic parameters determined using fluorine 18 (F) fluorodeoxyglucose (FDG) positron emission tomography (PET) (F-FDG PET) (with other prognostic parameters in uterine cervical cancer.
The subjects were 73 female patients who had an initial diagnosis of uterine cervical cancer and who underwent F-FDG PET. Various metabolic or volume-based PET parameters including maximum and average standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) were measured in primary cervical tumors. Survival analysis for disease-free survival or progression-free survival was performed with a Kaplan-Meier method using PET parameters and other clinical variables. For determining independent prognostic factors, Cox regression analysis was performed.
Recurrence or disease progression occurred in 23 patients (31.5%). In univariate analysis, patient age (cutoff, 57 years, P < 0.05), International Federation of Gynecology and Obstetrics stage (P = 0.07), primary tumor size (cutoff, 6.7 cm; P < 0.05), lymph node status on PET (P < 0.005), treatment method (P < 0.01), metabolic tumor volume (cutoff, 82 cm; P = 0.001), and TLG (cutoff, 7600; P = 0.005) were significant predictors of recurrence or progression. In multivariate analysis, both lymph node status on PET (hazard ratio, 1.042 [negative vs intrapelvic metastasis only], 7.008 [negative vs extrapelvic metastasis]; P < 0.001) and TLG (cutoff, 7600; hazard ratio, 2.981; P < 0.05) were independent prognostic factors for predicting recurrence.
In uterine cervical cancer, TLG, a volume-based metabolic parameter, and lymph node status on PET may be significant independent prognostic factors for event-free survival.
International Journal of Gynecological Cancer 07/2012; 22(7):1226-33. · 1.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human Fas associated factor 1 (hFAF1) is a pro-apoptotic scaffolding protein containing ubiquitin-associating (UBA), ubiquitin like 1 and 2 (UBL1, UBL2), and ubiquitin regulatory X (UBX) domains. hFAF1 interacts with polyubiquitinated proteins via its N-terminal UBA domain and with valosin containing protein (VCP) via its C-terminal UBX domain. Overexpression of hFAF1 or its N-terminal UBA domain significantly increases cell death by increasing the degradation of polyubiquitinated proteins. In this study, we investigated whether hFAF1, whose expression level is reduced in cervical cancer, plays a role in tumor formation. We found that HeLa cells overexpressing full-length hFAF1 or the hFAF1 UBA domain alone, significantly suppressed the anchorage independent tumor growth in soft agar colony formation, increased cell death, and activated JNK and caspase 3. Employing UBA-specific tandem immunoprecipitation, we identified moieties specifically interacting with UBA domain of hFAF1, and found that polyubiquitinated Hsp70s are recruited to UBA domain. We also demonstrated that hFAF1 overexpression promotes Hsp70 degradation via the proteasome. We further found that mutating the UBA domain (I41N), as well as knocking down hFAF1 with specific RNAi, abolishs its ability to increase the proteasomal degradation of Hsp70. These findings suggest that hFAF1 inhibits tumor formation by increasing the degradation of Hsp70 mediated via its UBA domain.
PLoS ONE 01/2012; 7(8):e40361. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In cervical cancer, the prognostic significance of bladder wall invasion on MRI without pathological evidence of mucosal invasion is not known. From 454 consecutive patients with cervical cancer who were treated with radiation, we reviewed images and analysed the outcome of 92 patients with the Federation of International Gynecology and Obstetrics (FIGO) stage IIIB-IVA. We analysed the patients in three groups, normal, wall (muscle and/or serosal) invasion and mucosal invasion, according to the findings on the MRI. Kaplan-Meier life table analysis and the log-rank test were used to assess the survival rates and differences according to prognostic factors. MRI detected abnormalities in the bladder wall in 42 patients (45.6%): wall invasion in 24 and mucosal invasion in 18. 5 of 18 patients, suspected on MRI to have mucosal invasion, showed no pathological evidence of mucosal invasion. Median follow-up period was 34 months. 3-year cause-specific survival (CSS) in the normal group compared with the wall invasion group was 76.2% vs 71.4% (p = 0.48). 3-year CSS for the wall invasion group compared with the mucosal invasion group was 71.4% vs 54.3% (p = 0.04). Mucosal invasion on MRI (p = 0.03) and concurrent chemoradiotherapy (p = 0.01) was significant for CSS. The prognosis for patients with cervical cancer with evidence of muscle and/or serosal invasion of the bladder on MRI may not differ from that for patients without abnormality on MRI. In patients with the MRI finding of bladder mucosal invasion, further studies should be conducted regarding the role of cystoscopy to determine the need for pathological confirmation.
The British journal of radiology 10/2010; 83(994):868-73. · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In cervical cancer, the prognostic significance of bladder wall invasion on MRI without pathological evidence of mucosal invasion is not known. From 454 consecutive patients with cervical cancer who were treated with radiation, we reviewed images and analysed the outcome of 92 patients with FIGO stage IIIB-IVA. We analysed the patients in three groups, normal, wall (muscle and/or serosal) invasion and mucosal invasion, according to the findings on the MRI. Kaplan-Meier life table analysis and the log-rank test were used to assess the survival rates and differences according to prognostic factors. MRI detected abnormalities in the bladder wall in 42 patients (45.6%): wall invasion in 24 and mucosal invasion in 18. 5 of 18 patients, suspected on MRI to have mucosal invasion, showed no pathological evidence of mucosal invasion. Median follow-up period was 34 months. 3 year cause-specific survival (CSS) in normal compared with wall invasion was 76.2% vs 71.4% (p = 0.48). 3 year CSS for wall invasion compared with mucosal invasion was 71.4% vs 54.3% (p = 0.04). Mucosal invasion on MRI (p = 0.03) and concurrent chemoradiotherapy (p = 0.01) were significant for CSS. The prognosis for cervical cancer patients with evidence of muscle and/or serosal invasion of the bladder on MRI may not differ from that for patients without abnormality on MRI. In patients with the MRI finding of bladder mucosal invasion, further studies should be conducted regarding the role of cystoscopy to determine the need for pathological confirmation.
The British journal of radiology 06/2010; · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although mutations in the insulin receptor have been causally implicated with leprechaunism, the full pathophysiology of the syndrome cannot be accounted for by malfunction of this gene alone. We sought to characterize a connection between Wnt-mediated cell signaling and the production of reactive oxygen species (ROS) which revealed a novel mechanistic basis for understanding the pathogenesis of leprechaunism. To identify candidate genes involved in this process, a PCR-based subtractive hybridization was performed. Candidate genes were examined for interaction with the Wnt signaling pathway and ROS generation. We found that Dickkopf 1 (Dkk1), a Wnt inhibitor, is overexpressed in skin fibroblast cells derived from three leprechaunism patients and that the cells showed an impaired response to Wnt2 in terms of beta-catenin-Tcf activation. Knockdown of Dkk1 in the patient cell lines rescued Wnt2-mediated Tcf activation. Concerted action of Wnt2 and knockdown of Dkk1 resulted in enhanced Nox4 expression and PDGF-induced ROS generation compared to parental patient cells. Furthermore, we found that NFATc2 was activated in response to Wnt2 stimulation and directly activates Nox4 expression. These data show a crosstalk between Wnt and ROS pathways which in turn provides new mechanistic insights at the molecular level into the pathogenesis of leprechaunism.
Molecules and Cells 01/2010; 29(1):63-9. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have previously reported that central repeated units (CRUs) of Ahnak act as a scaffolding protein networking phospholipase Cgamma and protein kinase C (PKC). Here, we demonstrate that an Ahnak derivative consisting of four central repeated units binds and activates PKC-alpha in a phosphatidylserine/1,2-dioleoyl-sn-glycerol-independent manner. Moreover, NIH3T3 cells expressing the 4 CRUs of Ahnak showed enhanced c-Raf, MEK, and Erk phosphorylation in response to phorbol 12-myristate 13-acetate (PMA) compared with parental cells. To evaluate the effect of loss-of-function of Ahnak in cell signaling, we investigated PKC activation and Raf phosphorylation in embryonic fibroblast cells (MEFs) of the Ahnak knock-out (Ahnak(-/-)) mouse. Membrane translocation of PKC-alpha and phosphorylation of Raf in response to PMA or platelet-derived growth factor were decreased in Ahnak null MEF cells compared with wild type MEFs. Several lines of evidence suggest that PKC-alpha activity is regulated through association with protein phosphatase 2A (PP2A). A co-immunoprecipitation assay indicated that the association of PKC-alpha with PP2A was disrupted in NIH3T3 cells expressing 4 CRUs of Ahnak in response to PMA. Consistently, Ahnak null MEF cells stimulated by PMA showed enhanced PKC-PP2A complex formation, and add-back expression of Ahnak into Ahnak null MEF cells abolished the PKC-PP2A complex formation in response to PMA. These data indicate that Ahnak potentiates PKC activation through inhibiting the interaction of PKC with PP2A.
Journal of Biological Chemistry 04/2008; 283(10):6312-20. · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoradionecrosis (ORN) of the pelvic bone presenting as a progressive osteolytic lesion, following three-dimensional conformal radiotherapy (3DCRT) with concurrent chemotherapy, is a clinical diagnostic challenge that must be differentiated from an osseous metastasis. We report on a case with an unusual presentation of ORN mimicking bony metastasis that should be taken note of by physicians. A 46-year-old woman who had recurrent cervical cancer in the right pelvic sidewall underwent concurrent salvage chemoradiotherapy. She received 63 Gy 3DCRT. At 22 months, post-RT, an asymptomatic but enlarging osseous defect in the right ilium, located within the area covered by a 95% isodose line, was demonstrated on pelvic computed tomography (CT). ORN was confirmed by whole-body [18F] fluoro-2-deoxy-d-glucose (FDG)-positron emission tomography (PET) CT scan and CT-guided bone biopsy. A localized, growing ORN of pelvic bone after high-dose 3DCRT is an uncommon late complication. Differential diagnosis between ORN and bony metastasis may be possible with low FDG uptake of ORN on PET-CT scans.
Annals of Nuclear Medicine 03/2008; 22(2):139-41. · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to assess the efficacy and toxicities of a combination of paclitaxel, ifosfamide, and cisplatin (TIP) for recurrent carcinoma of the uterine cervix. Fifty-three patients with recurrent cervical carcinoma were treated with ifosfamide 1500 mg/m2 intravenously over 3 h on days 1–3, paclitaxel 135 mg/m2 as a 3-h intravenous infusion, and cisplatin 50 mg/m2 intravenously over 30 min on day 1. The chemotherapy was repeated every 3 weeks until there was disease progression or unacceptable toxicity. Forty-five patients received at least three courses of treatment and were evaluable for their response. Twenty-one patients (46.7%) showed objective responses, including 4.4% complete responses and 42.2% partial responses. The median time to progression and the overall survival for all the patients were 8.0 months (95% confidence interval [CI], 7.1–8.9 months) and 19.0 months (95% CI, 11.9–26.1 months), respectively. The median duration of response was 9.0 months. Patients who had previously been treated with another chemotherapy after tumor recurrence showed a moderate response rate (29.4%) but a shorter time to progression (6 vs 8 months, P= 0.0421) and a shorter survival (11 vs 39 months, P= 0.0018). Patients with good performance status showed a higher response rate (63.6% vs 30.4%, P= 0.026) and a longer time to progression (9 vs 7 months, P= 0.0049). Patients with recurrent disease only outside the previous radiotherapy (RT) field exhibited a slightly higher response without statistical significance (60.0% vs 36.0%, P= 0.109). Grade 3 or 4 toxicities included neutropenia in 13% of patients and neurotoxicity in 5%. Three deaths during treatment were observed, but two of them were due to disease progression. We conclude that the combination chemotherapy with TIP yields a high response rate with acceptable toxicity for patients with recurrent cervical carcinoma, including those patients who have failed to respond to prior platinum-based chemotherapy.
International Journal of Gynecological Cancer 04/2006; 16(3):1157 - 1164. · 1.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leprechaunism features a clinical constellation characterized by extreme insulin resistance, growth retardation, and several distinct developmental abnormalities. One puzzling observation about leprechaunism is that mutations in the insulin receptor gene frequently associated with this syndrome cannot account for the aberrant responses of cultured cells to other growth factors. Here we report that the generation of reactive oxygen species (ROS) is impaired in cells from leprechaunism patients, thus shedding new light on this issue. Stimulation of patients' skin fibroblast cells with platelet-derived growth factor (PDGF) resulted in a lower-level tyrosine phosphorylation of cytosolic proteins compared with that seen in normal cells. In addition, consistent with the hypothesis that ROS mediate the level of tyrosine phosphorylation of cytosolic proteins through inactivation of protein tyrosine phosphatases (PTPases), patient fibroblast cells showed a significantly higher phosphatase activity than normal cells. We further showed that the lower-level tyrosine phosphorylation in response to growth factors results from the downregulation of an NADPH oxidase, Nox4, which in turn results in the reduction of ROS generation. Ectopic expression of Nox4 in the patient fibroblast cells consistently restored PDGF-induced ROS production and regulation of PTPase activities. Taken together, these data provide insight into the mechanisms through which growth retardation is associated with leprechaunism syndrome.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the efficacy and toxicity of consolidation chemotherapy after concurrent chemoradiation (CCRT) with 5-fluorouracil (5-FU) and cisplatin in the treatment of high-risk, early stage cervical carcinoma after radical surgery.
Women with clinical stage IB and IIA cervical carcinoma, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes, positive margins, parametrial involvement, or all three, were divided into either a CCRT alone group or a consolidation chemotherapy after CCRT group. Three cycles of chemotherapy were given to the CCRT alone group, and six cycles to the consolidation chemotherapy group. Women in each group received 50.4 Gy external radiation in 28 fractions to a standard pelvic field. Chemotherapy consisted of cisplatin 60 mg/m2 (X 1) and 5-FU 1000 mg/m2/d (X 5) every 3 weeks, with the first and second cycles given concurrent with radiation. Survival and toxicity were compared between the two groups.
Forty women were evaluable (25 in the CCRT alone group and 15 in the consolidation chemotherapy group). The estimated 2-year progression-free survival was 87.7% in the CCRT alone group and 67.0% in the consolidation chemotherapy group. The estimated 2-year overall survival was 95.8% in the CCRT alone group and 100% in the consolidation chemotherapy group. However, no significant differences were found in progression-free and overall survival in the two groups (P = 0.17 and P = 0.29, respectively). Grade 2 or higher leukopenia and neutropenia were significantly more frequent in the consolidation chemotherapy group than in the CCRT alone group (P = 0.02 and P < 0.01, respectively).
Although the sample size was small, and this study was not randomised, these results suggest that consolidation chemotherapy may not improve survival. Rather, it may increase haematologic toxicities for women with high-risk, early stage cervical carcinoma who undergo radical surgery followed by CCRT.
[Show abstract][Hide abstract] ABSTRACT: Alveolar soft part sarcoma (ASPS) of the vagina is an exceptionally rare neoplasm. Furthermore, vaginal metastasis of ASPS has not been reported. A 28-year-old woman with a history of a right thigh mass diagnosed as ASPS excised 8 years ago presented to the emergency room with massive vaginal bleeding and anemia. Biopsy of a vaginal mass revealed that the tumor was a vaginal metastasis of ASPS. For control of intractable bleeding and preventing further transfusions, palliative radiation therapy was planned. She received a total of 39 Gy (daily 3 Gy, using 15-MV photons), and after 6-Gy irradiation, there was no more vaginal bleeding and no more transfusion needed. This is the first case of vaginal metastasis of ASPS reported in the literature that was manifested by intractable vaginal bleeding, which was controlled successfully with radiation therapy.
International Journal of Gynecological Cancer 01/2005; 15(6):1166-8. · 1.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have recently shown that phospholipase C-gamma (PLC-gamma) is activated by the central repeated units (CRUs) of the AHNAK protein in the presence of arachidonic acid. Here we demonstrate that four central repeated units (4 CRUs) of AHNAK act as a scaffolding motif networking PLC-gamma and PKC-alpha. Specifically, 4 CRUs of AHNAK bind and activate PKC-alpha, which in turn stimulates the release of arachidonic acid near where PLC-gamma1 is localized. Moreover, 4 CRUs of AHNAK interacted with PLC-gamma and the concerted action of 4 CRUs with arachidonic acid stimulated PLC-gamma activity. Stimulation of NIH3T3 cells expressing 4 CRUs of AHNAK with phorbol 12-myristate 13-acetate resulted in the increased generation of total inositol phosphates (IP(T)) and mobilization of the intracellular calcium. Phorbol 12-myristate 13-acetate-dependent generation of IP(T) was completely blocked in NIH3T3 cells depleted of PLC-gamma1 by RNA interference. Furthermore, bradykinin, which normally stimulated the PLC-beta isozyme resulting in the generation of a monophasic IP(T) within 30 s in NIH3T3 cells, led to a biphasic pattern for generation of IP(T) in NIH3T3 cells expressing 4 CRUs of AHNAK. The secondary activation of PLC is likely because of the scaffolding activity of AHNAK, which is consistent with the role of 4 CRUs as a molecular linker between PLC-gamma and PKC-alpha.
Journal of Biological Chemistry 07/2004; 279(25):26645-53. · 4.65 Impact Factor