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Background: Endometrioid epithelial ovarian cancer (EEOC) is frequently diagnosed in conjunction with endometriosis and is suggested to arise during the process of endometriosis. This study evaluates the clinical manifestations, including endometriosis-related symptoms and their relationships according to the coexistence of endometriosis. Methods: Using medical records, a retrospective analysis was conducted on 221 patients treated for EEOC at four tertiary educational hospitals between 2000 and 2008. The initial presenting symptoms, particularly those related to endometriosis, were examined in relation to the coexistence of endometriosis or other clinical variables. Results: Endometriosis was identified in 82 (37.1%) of the 221 patients with EEOC. The most common symptoms were pelvic pain followed by gastrointestinal symptoms, palpable mass, abdominal distension, vaginal bleeding, and newly developed or exacerbated dysmenorrhea (18.1%) and dyspareunia (13.6%). Notably, dysmenorrhea and dyspareunia were frequently observed in patients with endometriosis. Among 210 patients identified with pretreatment serum CA-125, 54 (25.7%) displayed normal CA-125 levels ( Conclusions: In this large series of patients with EEOC, the main presenting symptoms were pelvic pain followed by gastrointestinal symptoms, palpable mass, abdominal distension, vaginal bleeding, and newly developed or exacerbated dysmenorrhea and dyspareunia. Dyspareunia and dysmenorrhea were more frequently detected in patients with endometriosis. Normal CA-125 levels cannot be applied as a marker to exclude EEOC, particularly at the early stages. Cancer Epidemiol Biomarkers Prev; 19(2); 398–404

Myoblast fusion depends on mitochondrial integrity and intracellular Ca2+ signaling regulated by various ion channels. In this study, we investigated the ionic currents associated with [Ca2+]i regulation in normal and mitochondrial DNA-depleted (ρ0) L6 myoblasts. The ρ0 myoblasts showed impaired myotube formation. The inwardly rectifying K+ current (IKir) was largely decreased with reduced expression of KIR2.1, whereas the voltage-operated Ca2+ channel and Ca2+-activated K+ channel currents were intact. Sustained inhibition of mitochondrial electron transport by antimycin A treatment (24 h) also decreased the IKir. The ρ0 myoblasts showed depolarized resting membrane potential and higher basal [Ca2+]i. Our results demonstrated the specific downregulation of IKir by dysfunctional mitochondria. The resultant depolarization and altered Ca2+ signaling might be associated with impaired myoblast fusion in ρ0 myoblasts.

To determine the incidence of lymph node (LN) metastasis in patients with apparently early carcinosarcoma of the uterus, to analyze the clinicopathologic factors associated with LN metastasis, and to evaluate the role of pelvic and/or para-aortic lymphadenectomy in treatment of such conditions.We retrospectively analyzed 41 patients with carcinosarcoma intraoperatively confined to the uterus who underwent complete staging procedures including pelvic and/or para-aortic lymphadenectomy.After surgery, two patients (4.9%) were upstaged to stage IIIA because of positive peritoneal washing cytology, and 13 (31.7%) were upstaged to stage IIIC as a result of LN metastasis. Five patients had pelvic, three had paraaortic, and five had both pelvic and para-aortic LN metastases. The mean number of metastatic LNs was 3.7 (range 1-15). On multivariate analysis, myometrial invasion1/2 [odds ratio (OR) 8.50; 95% confidence interval (CI) 1.57-45.92; P = 0.013] and lymphovascular space invasion (LVSI) (OR 8.50; 95% CI 1.57-45.92; P = 0.013) were significantly predictive of LN metastasis. After a median follow-up interval of 32 months (range 3-179 months), the 2-year disease-free survival (DFS) and overall survival (OS) rates were 73% and 84%, respectively, and the 5-year DFS and OS rates were 73% and 69%, respectively. Patients with LVSI or LN metastasis had significantly poorer DFS and OS.Pelvic and para-aortic lymphadenectomy should be performed in patients with apparently early carcinosarcoma of the uterus, especially in those with myometrial invasion1/2 or LVSI.

Although cancer survivors are at increased risk for developing cancers at other sites, little is known about the current status of second cancer (cancers other than the index cancer) screening practices and related factors in cervical cancer survivors. We enrolled 809 cervical cancer survivors aged ≥40 years who had been treated at six hospitals from 1983 to 2004. Subjects filled out a questionnaire that included the practices of second cancer screening (breast, stomach, and colorectum) and other sociodemographic variables. Among subjects, 38.9% had been recommended to receive screening for other cancers from health care providers, and 27.4% reported that they thought they had lower risk of other cancer than general population. Older (age ≥65 years) and poor (family income

Mouse B cells and their cell line (WEHI-231) express large-conductance background K+ channels (LKbg) that are activated by arachidonic acids, characteristics similar to TREK-2. However, there is no evidence to identify the molecular nature of LKbg; some properties of LKbg were partly different from the reported results of TREK type channels. In this study, we compared the properties of cloned TREK-2 and LKbg in terms of their sensitivities to ATP, phosphatidylinositol 4,5-bisphosphate (PIP2), intracellular pH (pHi), and membrane stretch. Similar to the previous findings of LKbg, TREK-2 showed spontaneous activation after membrane excision (i-o patch) and were inhibited by MgATP or by PIP2. The inhibition by MgATP was prevented by wortmannin, suggesting membrane-delimited regulation of TREKs by phosphoinositide (PI) kinase. The same was observed with the property of LKbg; the activation of TREK-2 by membrane stretch was suppressed by U73122 (PLC inhibitor). As with the known properties of TREK-2, LKbg were activated by acidic pHi and inhibited by PKC activator. Finally, we confirmed the expression of TREK-2 in WEHI-231 by using RT-PCR and immunoblot analyses. The amplitude of background K+ current and the TREK-2 expression in WEHI-231 were commonly decreased by genetic knockdown of TREK-2 using small interfering RNA. The downregulation of TREK-2 attenuated Ca2+-influx induced by arachidonic acid in WEHI-231. As a whole, these results strongly indicate that TREK-2 encodes LKbg in mouse B cells. We also newly suggest that the low activity of TREK-2 in intact cells is due to the inhibition by intrinsic PIP2.

OBJECTIVE To estimate the effectiveness of the human papillomavirus (HPV) test performed after conization in predicting residual disease in patients who subsequently underwent hysterectomy. METHODS A total of 115 patients who underwent hysterectomy after conization caused by cervical intraepithelial neoplasia grade 3 (CIN 3) and microinvasive cervical cancer (IA1 cancer) were included in this prospective study. All patients underwent HPV testing with a liquid hybridization assay immediately before hysterectomy. Differences in sensitivity, specificity, and accuracy between resection margin and the HPV test in predicting residual disease in subsequent hysterectomy samples were estimated using the McNemar exact test. RESULTS Univariable analysis showed that age, parity, menopausal status, glandular extension, and severity of disease were not predictive for residual disease, but positive resection margin and positive HPV tests were significant factors for predicting residual disease. These factors were also significant in a multivariable analysis (positive resection margin 45.5%, odds ratio [OR] 3.09, 95% confidence interval [CI] 1.19-8.03, P=.021; positive HPV test 57.6%, OR 11.05, 95% CI 4.01-30.49, P

Objectives To evaluate the occurrence of residual or recurrent disease after loop electrosurgical excisional procedure (LEEP) for adenocarcinoma in situ (AIS) of the uterine cervix. Study design Records of 78 patients with a histological diagnosis of AIS of uterine cervix on LEEP who were treated and followed at our center between 1992 and 2008 were, retrospectively, reviewed. Results Of 78 patients who underwent LEEP, 47 had negative and 31 had positive resection margins. Of the 47 patients with negative margins, 30 underwent subsequent hysterectomy and residual AIS, including 1 invasive adenocarcinoma, was present in 17% (5/30) of patients. The remaining 17 had no additional procedures. Of the 31 patients with positive margins, 29 patients underwent subsequent hysterectomy and residual AIS, including 4 invasive adenocarcinomas, was present in 48% (14/29) of patients. The remaining two had no additional procedures. After a mean follow-up time of 28 months (range, 1–74 months), no recurrences were observed among the 19 patients who did not undergo hysterectomy. Conclusions The incidence of residual disease in patients with negative margins after LEEP for AIS of the uterine cervix is low but not negligible. Therefore, conservative management in these patients seems to be feasible but careful surveillance is required. However, positive resection margin carries a higher risk for residual AIS or occult invasive adenocarcinoma, warranting additional LEEP or hysterectomy in these patients.

The increase of cytoplasmic Ca2+ concentration (Delta[Ca2+]c) in response to antigenic stimulation is a critical step of signals activating immune responses. In addition, the voltage-gated K+ channels (Kv) in T lymphocytes draw attention as an effective target of immune-modulation. Caffeic acid phenethyl ester (CAPE), an active component of propolis, shows strong anti-inflammatory effects and T cell suppression. Although various mechanisms have been suggested for the action of CAPE, the effects of CAPE on intracellular Ca2+ signaling and ion channels are unknown. Here we investigated the effects of CAPE on Delta[Ca2+](c), Ca2+-release activated Ca2+ current (I(CRAC)), and Kv current (I(Kv)) in Jurkat T cells, and on Ca2+-activated K+ channel current (I(SK4)) overexpressed in HEK-293 cells. I(CRAC) was induced by dialyzing T cells and Orai1/STIM1 overexpressing HEK293 cells with InsP(3)/BAPTA-containing pipette solution. CAPE concentration-dependently decreased both T cell receptor (CD3)- and thapsigargin-induced Delta[Ca2+](c). The phosphorylation of PLCgamma(1) by CD3 stimulation was not affected by CAPE. I(CRAC) was almost completely blocked by 25 microM CAPE. CAPE also inhibited the I(Kv) and I(SK4). Albeit the strong inhibition of Ca2+ influx via CRAC, the suppression of IL-2 secretion by CAPE was similarly observed in human peripheral T cells when the CRAC pathway was circumvented by ionomycin. Although the unspecific inhibition of ion channels by CAPE suggested an intriguing mechanism, the effects of CAPE on signaling pathways other than I(CRAC) seem to play dominant roles in the immunomodulation by CAPE.

Menthol, a naturally occurring compound from peppermint oil, binds and activates the TRPM8 Ca(2+)-permeable channel that exhibits abnormal expression patterns in prostate cancer, suggesting that TRPM8 links Ca(2+) transport pathways to tumor biology. We thus investigated the cellular responses of prostate cancer cells to menthol. Here we found that menthol increases [Ca(2+)](i) via Ca(2+) influx mechanism(s) independent of TRPM8 in PC-3 cells. We demonstrated that menthol induces cell death at supramillimolar concentrations in PC-3 cells and the cell death is not suppressed by low extracellular Ca(2+) condition which indicates that menthol-induced cell death is not associated with Ca(2+) influx pathways. In addition, we showed that menthol increases a phosphorylated form of c-jun N-terminal kinase (JNK) in PC-3 cells through TRPM8-independent mechanisms. Thus, our data indicate that there is an apparent lack of causality between TRPM8 activation and menthol-induced cell death and that menthol can regulate TRPM8-independent Ca(2+)-transport and cellular processes.

Objective. To investigate the efficacy of conization followed by conservative management for treating stage IA1 microinvasive carcinoma of the uterine cervix. Design/Setting. Retrospective study. Population. Seventy-five patients treated for stage IA1 microinvasive carcinoma of the cervix. Patients underwent conization followed by hysterectomy (Group 1, 53 patients), or were followed by conservative management (Group 2, 22 patients). Methods. Medical and histopathological record review. Results. For Group 1, pathology results showed that 30 had no residual tumor, one had cervical intraepithelial neoplasia (CIN) I, 11 had CIN III/cervical carcinoma in situ (CIS), nine had microinvasive carcinomas, and one had an invasive carcinoma (outcome for one patient not recorded). For Group 2, secondary procedures involved only cervical smears for 12 (48%) patients, of whom nine had normal cytology, one had low-grade squamous intraepithelial lesion and two had high-grade squamous intraepithelial lesions. For 13 (52%) patients in Group 2, secondary procedures involved repeat conization on whom six had no residual tumor, one had CIN II, four CIN III/CIS, and two microinvasive carcinoma and a negative resection margin. Therefore, conization followed by conservative management was an effective treatment for 90.9% (20/22) of Group 2. In neither group was recurrence recorded. There was no relation between lymphovascular invasion and follow-up cytology or pathology results, or between resection margin status and follow-up examination results. Conclusion. Conization alone with careful follow-up appears to be an effective and safe treatment for patients with stage IA1 microinvasive carcinoma of the uterine cervix, regardless of resection margins status or lymphovascular invasion.

From January 1995 to December 2000, medical records of 196 patients were collected from 14 hospitals nationwide and were reviewed retrospectively. We evaluated the clinicopathologic characteristics of malignant germ cell tumors in the ovaries of South Korean women and determined the prognostic factors affecting recurrence. The mean patient age was 23.8 years (range, 4-63 years), and the median follow-up period was 67 months (range, 1-128 months). The distribution of the International Federation of Gynecology and Obstetrics stage was as follows: 128 cases (65.3%) in stage I, 27 cases (13.8%) in stage II, 39 cases (19.9%) in stage III, and 2 cases (1.0%) in stage IV. Histologically, immature teratoma was the most common tumor type (n = 68), followed by dysgerminoma (n = 54), endodermal sinus tumor (n = 38), mixed form (n = 24), and choriocarcinoma (n = 12). A fertility-sparing operation was performed in 134 patients, staging operation in 43 patients, and hysterectomy and bilateral salpingo-oophorectomy in 19 patients. Postoperative chemotherapy was administered in 166 patients, and the most common regimen was bleomycin, etoposide, and cisplatin (n = 120). Recurrence was observed in 13 patients (6.8%) and was influenced by the stage of the tumor and patient age (>40 years). The 5-year survival rate was 96.7%. During the follow-up period, 20 patients had 22 pregnancies that resulted in 17 normal deliveries at term and 5 abortions. The results of this study demonstrate that most malignant germ cell tumors of the ovary in Korean women are detected in the early stage and have excellent survival outcomes with conservative operation and platinum-based chemotherapy.

We have investigated structural and vibrational properties of Na nanoclusters self-assembled on the Si(1 1 1)-7×7 surface at room temperature mainly using high-resolution electron-energy-loss spectroscopy. We observe three characteristic loss peaks L1, L2, and L3 ascribed to an interband transition, a local atomic vibration, and another interband transition from an Na nanocluster-induced state, respectively. The spectral change of L1 with Na coverage θ suggests that the S1 dangling bond band is gradually filled up to open a band gap with increasing θ up to 1.1 eV when all three loss peaks completely disappeared. The relatively high loss energy El=243meV of L2 with a narrow linewidth of 32 meV indicates the only Na–Si atomic vibrational mode with Na atoms occupying the tilted on-top sites above Si rest atoms. Furthermore the extremely weak loss peak L3 visible at a coverage range unique only to the Na nanoclusters proves the presence of a Na nanoclusters-induced electronic state N2. These observations provide explanation to most unresolved spectral behavior of earlier photoemission study and evidence for the atomic structure of the Na nanocluster.

Background To evaluate the toxicity and efficacy of a newly developed topoisomerase I inhibitor, CKD-602 in second-line therapy of ovarian cancer. Methods We enrolled 24 patients with recurrent ovarian cancer, of median age 54 years (range, 39–64). Eleven patients had measurable lesions on CT scan, and the other 13 had increased serum CA-125 levels. Eighteen patients had platinum-sensitive disease (minimum treatment free interval≥6 months) and 6 had platinum-resistant disease (minimum treatment free interval 2 /day) was administered intravenously for 5 days every 3 weeks. The median number of courses per patient was 6 (range, 1 to 12). Response was evaluated by the evaluation of the size of the mass by CT scan and CA-125 response. Results The overall response rate was 45.0% (9/20), with 4 patients exhibiting partial responses and 5 patients exhibiting 75% CA-125 responses in 20 evaluable patients. Of the 9 responsive patients, 8 were platinum-sensitive (8/15, 53.3%) and 1 was platinum-resistant (1/5, 20.0%). An additional 5 patients showed stable disease, whereas 6 patients exhibited progressive lesions. Of 24 patients, the most common toxicity was hematological, with grades 3 or 4 neutropenia developing in all 24 patients (100%) and in 94 cycles (71.7%). Grade 3 thrombocytopenia developed in 4 patients (16.7%) and 6 cycles (4.6%). None of the patients experienced grades 3 and 4 gastrointestinal toxicities, including nausea, vomiting, and anorexia. Conclusions The newly developed topoisomerase I inhibitor, CKD-602, showed activity against both platinum-sensitive and -resistant ovarian cancer, with acceptable toxicity.

Uterine sarcoma is a rare malignancy with the worst prognosis of all uterine cancers. This study evaluated the prognostic factors and treatment outcomes of patients with this disease. A retrospective analysis was performed on 127 patients with histologically verified uterine sarcoma who were treated and followed at the Asan Medical Center (Seoul, Korea) from 1989 to 2007. Histological analyses revealed that 37 patients had endometrial stromal sarcoma, 44 had malignant mixed mullerian tumors and 46 had leiomyosarcoma. Surgical stages, as defined by the International Federation of Gynecology and Obstetrics (FIGO) system, were I in 82 patients, II in 6 patients, III in 18 patients and IV in 19 patients. All patients underwent surgical treatment and 72 patients received adjuvant therapy. The 10-year disease-free survival (DFS) rate was 30% and the 10-year overall survival (OS) rate was 48%, with a mean follow-up time of 38 months (ranging from 1 to 212 months). Adjuvant radiation and chemotherapy had limited impact on the outcome of early-stage disease. However, patients with advanced-stage disease who received adjuvant chemotherapy had significantly longer OS times. A multivariate analysis revealed that FIGO stage (P = 0.025), depth of myometrial invasion (P = 0.004), and complete cytoreduction (P = 0.030) were significantly associated with DFS, while menopausal status (P = 0.044), FIGO stage (P = 0.016), depth of myometrial invasion (P = 0.029), and lymph-vascular space invasion (LVSI) (P = 0.020) were significantly associated with OS. This study suggests that complete cytoreduction is important and adjuvant chemotherapy can help achieve favorable prognoses in patients with advanced stage disease. However, postmenopausal status, advanced FIGO stage, deep myometrial invasion, and positive LVSI were associated with poor prognosis.

Objective To evaluate the clinical accuracy and clinical impact of positron emission tomography (PET) or positron emission tomography/computed tomography (PET/CT) in detecting and treating tumor recurrence in patients with treated uterine sarcoma. Methods Results of 36 patients who underwent PET or PET/CT in post-therapy surveillance of uterine sarcoma were retrospectively assessed. Histopathologic confirmation or clinical/radiological outcome at least 6 months after PET or PET/CT was standard of reference. Results The 36 patients underwent 48 PET or PET/CT scans as part of post-therapy surveillance. Thirty scans (8 PET and 22 PET/CT) were performed due to suspicion of disease recurrence on CT, whereas 18 scans (4 PET and 14 PET/CT) were performed as part of routine post-therapy surveillance in asymptomatic patients. The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of PET or PET/CT were 92.9%, 100%, 94.4%, 100% and 80%, respectively, in patients with suspected recurrence and 87.5%, 95.5%, 93.3%, 87.5% and 95.5%, respectively, in asymptomatic patients. PET or PET/CT influenced the management of 12 patients (33.3%), by initiation of previously unplanned treatment in 8 patients and by avoidance of previously planned treatment in 4 patients. Conclusion PET or PET/CT was highly effective in discriminating true recurrence in patients with suspected recurrence and was highly sensitive in detecting recurrence in asymptomatic patients. It had impacts on clinical decision making in a high proportion of patients.

Objective. To compare positron emission tomography/computed tomography (PET/CT) with magnetic resonance imaging (MRI) in the preoperative detection of primary lesions and lymph node (LN) and distant metastases in patients with uterine corpus cancer. Methods. The patient cohort consisted of 53 women with uterine corpus cancer who underwent preoperative workup, including both MRI and PET/CT scans, and underwent surgical staging, including pelvic and/or paraaortic LN dissection, between October 2004 and June 2007 at Asan Medical Center, Seoul, Korea. Pathologic data from surgical staging were compared with the preoperative MRI and PET/CT results. For area specific analysis, LNs were divided into paraaortic, right pelvic and left pelvic areas. Results. In detecting primary lesions, MRI and PET/CT showed no differences in sensitivity (91.5% vs. 89.4%), specificity (33.3% vs. 50.5%), accuracy (84.9% vs. 84.9%), positive predictive value (PPV) (91.5% vs. 93.3%) and negative predictive value (NPV) (33.3% vs. 37.5%). With MRI, the sensitivity, specificity, accuracy, PPV and NPV for detecting metastatic LNs on LN area-by-area analysis were 46.2%, 87.9%, 83.9%, 28.6% and 94.0%, respectively; With PET/CT, those were 69.2%, 90.3%, 88.3%, 42.9%, and 96.6%, respectively. PET/CT showed higher sensitivity, but it did not reach statistical significance ( p =0.250). There were also no differences in specificity, accuracy, PPV and NPV. In detecting distant metastasis, the sensitivity, specificity, accuracy, PPV and NPV of PET/CT were 100%, 93.8%, 92.5%, 62.5% and 100%, respectively. Conclusion. In patients with uterine corpus cancer, PET/CT had moderate sensitivity, specificity and accuracy in detecting primary lesions and LN metastases, indicating that this method cannot replace surgical staging. The primary benefit of PET/CT is its sensitivity in detecting distant metastases. Because of its high NPV in predicting LN metastasis, PET/CT may also have advantages in selected patients who are poor candidates for surgical staging.

Lymphocytes express voltage-gated (Kv) and Ca(2+)-activated (IKCa1) K(+) channels. Recently, we found that WEHI-231, an immature B cell line, expresses voltage-independent K(+) channels called large-conductance background K( + ) channels (LK(bg)). Arachidonic acid (AA) has attracted attention because of its potential regulatory roles in the apoptosis of immature B cells. To elucidate the functional targets of AA, we investigated the effects of AA on membrane currents, voltages, and cytoplasmic Ca(2+) concentration ([Ca(2+)](c)) of WEHI-231 and Bal-17 cells that represent immature and mature mouse B cells, respectively. In whole-cell patch clamp, both Kv and IKCa1 were inhibited by AA. On the other hand, AA activated LK(bg) current and non-selective cationic (NSC) current in WEHI-231 while only NSC current in Bal-17. Inside-out patch clamp study showed that AA directly activates LK(bg). AA induced hyperpolarization of WEHI-231 and depolarization of Bal-17 cells, respectively. The selective functional expression of LK(bg) and their activation by AA were also confirmed in the immature B cells (B220(+)/AA4.1(+)) freshly isolated from mouse spleen. In fura-2 spectrofluorimetry, AA induced persistent increase in [Ca(2+)](c) of WEHI-231 cells, which was attenuated by KCl-induced depolarization. In Bal-17 cell, however, AA induced only a transient increase of [Ca(2+)](c). In summary, the novel type of background K(+) channels (LK(bg)) in immature B cells is strongly activated while the other K(+) channels (Kv and IKCa1) commonly expressed in lymphocytes are inhibited by AA. The hyperpolarization and augmentation of Ca(2+) influx by LK(bg) activation might play a role in the response of immature B cells to AA.

K+ channels play critical roles in the proliferation and activation of lymphocytes. Mouse B cells express large-conductance background K+ channel (LK bg) in addition to the voltage-gated K+ channel (Kv) and Ca2+-activated K+ channel current (IKCa1). Mibefradil, a blocker of T-type Ca2+ channels, has been reported to affect the proliferation of immune cells. In this study, we investigated the effects of mibefradil on the membrane potential and ion channels in murine B cell lines, WEHI-231 and Bal-17. In the whole-cell patch clamp experiments, mibefradil blocked Kv and LK bg current with half inhibitory concentration (IC50), 1.9 and 2.3 microM, respectively. Interestingly, IKCa1 current was increased by mibefradil. In the inside-out patch clamp study with cloned murine IKCa1 (mIKCa1) in HEK-293, mibefradil increased both Ca2+ sensitivity and maximum activity of mIKCa1. At high concentrations (10 microM), mibefradil inhibited mIKCa1 in a voltage-dependent manner. Application of anti-IgM antibody to stimulate B cell receptors (BCR-ligation) induced transient hyperpolarization of Bal-17 and WEHI-231 cells, which became persistent with 1 microM mibefradil. The hyperpolarizing response was abolished by charybdotoxin, a selective blocker for SK4/IKCa1. In summary, our study firstly reports the ion channel-activating effects of mibefradil. The selective potent activation of IKCa1 suggests that mibefradil-derived drugs might be useful in the control of cell responses related with IKCa1.

Objectives: We aimed to investigate the prevalence of comorbidities in cervical cancer survivors compared with the general population and to identify risk factors and impact on their quality of life (QoL). Methods: 860 female cervical cancer survivors enrolled at six tertiary hospitals and 994 women from the general population were surveyed on current comorbidities and QoL (EORTC QLQ-C30 and QLQ-CX24). Results: Compared with the general female population, the cervical cancer survivors reported higher prevalence of comorbidities (0.93 ± 2.91 vs. 0.37 ± 0.67, p < 0.01), significantly more heart disease (adjusted odds ratio (aOR), 2.64; 95% confidence interval (CI), 1.38–5.07), liver disease (aOR, 3.29; 95% CI, 1.54–7.02), hypertension (aOR, 1.72; 95% CI, 1.30–2.27), gastrointestinal disease (aOR, 1.79; 95% CI, 1.37–2.33) and musculoskeletal disease (aOR, 1.94; 95% CI, 1.45–2.59). Heart and renal disease significantly influenced QoL in many subscales. Patients with diabetes or cerebrovascular disease had an increased likelihood of sexual problems. Conclusions: The cervical cancer survivors had more comorbidities than the general population, and that in turn affected their QoL. Vigilant follow-up of comorbidities should be incorporated into in the care of cancer survivors.

BACKGROUND. The purpose of this study was to identify problems related to long-term quality of life (QOL) and sexual function in cervical cancer survivors. METHODS. The authors enrolled 860 women (median time since diagnosis, 5.86 years) with a history of cervical cancer (stage I to IVa) who had been treated at any of 6 hospitals from 1983 through 2004 and 494 control subjects selected randomly from a representative sample of Korean women. Subjects filled out a questionnaire that included the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, its Cervical Cancer Module, and additional sexual function items. RESULTS. Cervical cancer survivors had clinically significant worse problems with social functioning, constipation, diarrhea, and difficulties with their finances than controls (P < .01). Survivors also reported more severe lymphedema and menopausal symptoms and worse body image, sexual and/or vaginal functioning, and sexual worry (P < .01). Anxiety about sexual performance was more problematic in survivors than in controls (P < .01), as was dyspareunia for women who received radiotherapy (P < .01). CONCLUSIONS. These findings can increase the awareness of healthcare providers to the potential need for counseling and other interventions among women who have been successfully treated for cervical cancer and could help them improve their impaired QOL. Cancer 2007. © 2007 American Cancer Society.

Ion channels play critical roles in immunological responses. Although the most widely known players are Ca2+-permeable channels (Gallo et al. 2006), K+ channels provide the electrical driving force required for Ca2+ influx, cell volume regulation, and for apoptotic volume decrease (Beeton & Chandy, 2005). B cells are the principal cellular mediators of specific humoral immune response to infection. In a mouse B cell line (WEHI-231), we previously reported novel voltage-independent, large conductance background-type, K+ (LKbg) channels that are inhibited by phosphatidyl inositol 4,5-bisphosphate (PIP2). While LKbg was originally named BKbg (Nam et al. 2004), the acronym was changed to LKbg here to prevent confusion with the calcium-activated K+ channel (BKCa, maxi-K). LKbg channels show low activity in the intact cell membrane while their activity increases spontaneously after excising the membrane (inside-out (i-o) configuration). In i-o patches, LKbg channels are reversibly inhibited by applying MgATP to the cytoplasmic side, and the inhibition was found to be blocked by wortmannin, an inhibitor of phosphoinositide (PI)-kinase. Thus, it has been suggested that the molecular systems that regulate PIP2 levels are tightly associated with LKbg channels (Nam et al. 2004). PIP2 is increasingly being recognized as a key physiological regulator of ion channel/transporters (Hilgemann et al. 2001; Horowitz et al. 2005; Suh & Hille, 2005). While most PIP2-sensitive ion channels are positively regulated, LKbg channels are inhibited by PIP2 along with TRPV1 and cyclic nucleotide-gated cation channels (Hilgemann et al. 2001; Suh & Hille, 2005). In spite of the conspicuous large conductance (∼300 pS), LKbg-like channels with PIP2 sensitivity have not yet been found in other types of cells, and the molecular identity is still unknown. Although LKbg were originally termed ‘background’ K+ channels due to their voltage independence, their activity in the intact resting B cells is very low, which is most likely due to the PIP2 generated from the phosphorylation of phosphoinositides (Nam et al. 2004). Therefore, in pilot studies, we explored the activating conditions for LKbg channels. In these trials we found that mechanical stimulation by negative pressure of patch pipette or osmotic swelling of B cells reversibly activates LKbg channels. It has been recently reported that osmotic swelling and shear stress activate tyrosine kinase (Syk) in DT40 B cells (Miah et al. 2004; Qin et al. 1997), and elevate [Ca2+]i in mouse B cells by activating phospholipase Cγ (PLCγ) and non-selective cation channels (Liu et al. 2005; Zhu et al. 2005). The PLC-mediated hydrolysis of PIP2 by membrane receptor activation is a widely observed regulatory mechanism of PIP2-sensitive ion channels (Suh & Hille, 2005). Considering that membrane stretch is also an activating condition for PLC (Moore et al. 2002; Ruwhof et al. 2001; Zhu et al. 2005; Liu et al. 2005), ion channels regulated by PIP2 might be affected by membrane stretch in a PLC-dependent manner. However, no study has been performed to investigate whether stretch-dependent PLC activation regulates the PIP2-sensitive ion channels. Since cells are exposed to various levels of mechanical stimuli, the elucidation of any such signalling mechanism would provide an intriguing insight into ion channel regulation. In the present study, we propose that the mechanosensitive activation of LKbg channels are mediated by PLC-dependent hydrolysis of PIP2.

Na adsorption at room temperature causes the Na/Si(1 1 1)3 × 1 surface with Na coverage of 1/3 monolayer (ML) to transit into the Na/Si(1 1 1)6 × 1 surface at 1/2 ML and sequentially into the Na/Si(1 1 1)3 × 1 surface at 2/3 ML. The phase transition was studied by Si 2p core-level photoemission spectroscopy. The detailed line shape analysis of the Si 2p core-level spectrum of the Na/Si(1 1 1)3 × 1 surface (2/3 ML) is presented and compared to the Na/Si(1 1 1)3 × 1 surface (1/3 ML) which is composed of Si honeycomb chain-channel structures. This suggests that as additional Na atoms form atomic chains resulting in the Na/Si(1 1 1)3 × 1 surface (2/3 ML), the inner atoms of the Si honeycomb chain-channel structure is buckled due to the additional Na atoms.

Ginger extract is used as an analeptic in herbal medicine and has been reported to exert antioxidant effects. Transient receptor potential (TRP) canonical 5 (TRPC5), TRP cation channel, subfamily M, member 7 (TRPM7; melastatin 7), and TRP cation channel, subfamily A, member 1 (TRPA1; ankyrin 1) are non-selective cation channels that are modulated by reactive oxygen/nitrogen species (ROS/RNS) and subsequently control various cellular processes. The aim of this study was to evaluate whether ginger and its pungent constituents modulate these channels and exert antioxidant effects. It was found that TRPC5 and TRPA1 currents were modulated by ginger extract and by its pungent constituents, [6]-gingerol, zingerone and [6]-shogaol. In particular, [6]-shogaol markedly and dose-dependently inhibited TRPC5 currents with an IC50 of value of ~18.3 µM. Furthermore, the strong dose-dependent activation of TRPA1 currents by [6]-shogaol was abolished by A‑967079 (a selective TRPA1 inhibitor). However, ginger extract and its pungent constituents had no effect on TRPM7 currents. These results suggest the antioxidant effects of ginger extract and its pungent constituents are mediated through TRPC5 and TRPA1, and that [6]-shogaol is predominantly responsible for the regulation of TRPC5 and TRPA1 currents by ginger extract.

Objective To compare the validities of magnetic resonance imaging (MRI) and 18 F-fluoro-deoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in preoperative evaluation of uterine carcinosarcoma. Methods Pathologic results of primary tumor lesions and paraaortic and pelvic lymph node (LN) areas were compared with the preoperative image findings. Differences in the validity parameters of both images were compared using McNemar test. Results For detecting primary tumor lesions ( n =56), the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for 18 F-FDG PET/CT versus MRI were 98.1% versus 98.1% ( P =1.000), 33.3% versus 100% ( P =0.157), 94.6% versus 98.2% ( P =0.500), 96.3% versus 100%, and 50% versus 75%, respectively. For paraaortic LN areas, the values were 77.8% versus 51.9% ( P =0.016), 90.2% versus 100% ( P =0.025), 85.9% versus 83.3% ( P =0.774), 80.8% versus 100%, and 88.5% versus 79.7%, respectively. For pelvic LN areas, the values were 61.1% versus 50% ( P =0.125), 86.8% versus 89.5% ( P =0.727), 78.6% versus 76.8% ( P =0.774), 68.8% versus 69.2%, and 82.5% versus 79.1%, respectively. For extrauterine disease, the patient-based values for 18 F-FDG PET/CT were 100%, 78.9%, 85.7%, 69.2%, and 100%, respectively. Conclusion In patients with uterine carcinosarcoma, 18 F-FDG PET/CT is comparable to MRI in detecting primary uterine lesions. For predicting LN metastases, though 18 F-FDG PET/CT might be insufficient for replacing lymphadenectomy or MRI, it might allow lymphadenectomy to be omitted in poor surgical candidates. For detecting extrauterine metastases, it could also be useful to identify unsuspected disease.

In traditional Korean/Asian medicine, Salvia plebeia R.Br. (S. plebeia) leaves are used to treat inflammatory diseases, including dermatitis, cough, asthma and toothache. Recently, S. plebeia leaves have been applied in skin care, as they promote skin lightening and elasticity. Therefore, the present study investigated the anti-aging effects of S. plebeia leaf methanolic extract and its fractions (dichloromethane, ethylacetate and n-butanol). The results of a whole-cell patch clamp analysis indicated that the methanolic extract mediated ultraviolet (UV)-induced photoaging-associated ion channels, transient receptor potential vanilloid 1 (TRPV1) and calcium release-activated calcium channel protein 1 (ORAI1) channel activity in HEK293T cells overexpressing TRPV1 or ORAI1 and STIM1. Electrophysiological analysis revealed that the butanol fraction inhibited capsaicin-induced TRPV1 (84±8% at −60 mV/86±1% at 100 mV at 100 µg/ml) and ORAI1 (87±2% at −120 mV at 100 µg/ml) currents. Furthermore, the dichloromethane and hexane fractions inhibited tyrosinase activity by 32.4±0.69 and 22.6±0.96% at 330 µg/ml, respectively. Furthermore, the ethylacetate and butanol fractions inhibited elastase activity by 65.2±1.30 and 31.7±1.23% at 330 µg/ml, respectively. Tyrosinase and elastase, which are UV-induced photoaging-associated enzymes, regulate skin pigmentation and wrinkle formation, respectively. The results of the present study indicated that S. plebeia leaves may be a novel treatment for UV-induced photoaging.

We investigated the effect of gintonin, a novel ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand, on the pacemaker activity of the interstitial cells of Cajal (ICC) in ...

LPSs are widely used to stimulate TLR4, but their effects on ion channels in immune cells are poorly known. In THP-1 cells and human blood monocytes treated with LPS, inwardly rectifying K+ channel current (IKir,LPS) newly emerged at 1 h, peaked at 4 h (−119 ± 8.6 pA/pF), and decayed afterward (−32 ± 6.7 pA/pF at 24 h). Whereas both the Kir2.1 and Kir2.2 mRNAs and proteins were observed, single-channel conductance (38 pS) of IKir,LPS and small interfering RNA–induced knockdown commonly indicated Kir2.2 than Kir2.1. LPS-induced cytokine release and store-operated Ca2+ entry were commonly decreased by ML-133, a Kir2 inhibitor. Immunoblot, confocal microscopy, and the effects of vesicular trafficking inhibitors commonly suggested plasma membrane translocation of Kir2.2 by LPS. Both IKir,LPS and membrane translocation of Kir2.2 were inhibited by GF109203X (protein kinase C [PKC] inhibitor) or by transfection with small interfering RNA–specific PKCε. Interestingly, pharmacological activation of PKC by PMA induced both Kir2.1 and Kir2.2 currents. The spontaneously decayed IKir,LPS at 24 h was recovered by PI3K inhibitors but further suppressed by an inhibitor of phosphatidylinositol(3,4,5)-trisphosphate (PIP3) phosphatase (phosphatase and tensin homolog). However, IKir,LPS at 24 h was not affected by Akt inhibitors, suggesting that the decreased phosphatidylinositol(4,5)-bisphosphate availability, that is, conversion into PIP3 by PI3K, per se accounts for the decay of IKir,LPS. Taken together, to our knowledge these data are the first demonstrations that IKir is newly induced by TLR4 stimulation via PKC-dependent membrane trafficking of Kir2.2, and that conversion of phosphatidylinositol(4,5)-bisphosphate to PIP3 modulates Kir2.2. The augmentation of Ca2+ influx and cytokine release suggests a physiological role for Kir2.2 in TLR4-stimulated monocytes.

Objective To evaluate the clinical role of adjuvant chemotherapy (AC) in FIGO stage IB-IIA cervical cancer patients. Study Design A cohort of 262 patients with cervical cancer who received radical hysterectomy (RH) and adjuvant therapy at Asan Medical Center between 1992 and 2012 was enrolled. In this cohort, 85 patients received adjuvant chemotherapy (AC), and 177 received adjuvant radiotherapy or concurrent chemoradiation therapy (AR). Oncologic outcomes and adverse events in both treatment arms were compared using weighted Cox proportional hazards regression models with inverse-probability-of-treatment weighting (IPTW) to reduce the impact of treatment selection bias and potential confounding factors. Results During a 46.8-month median follow-up duration, 39 patients (14.9%) had recurrences, and 18 patients (6.9%) died of disease. In multivariate analysis, the hazard ratio (HR) for recurrence and death was not significantly different in patients in either treatment arm (p=0.62 and 0.12, respectively). Also, after IPTW matching, the HR for recurrence did not significantly differ between the arms (HR 1.57, 95% CI 0.68-3.62, p=0.29). Similarly, disease-free survival and overall survival were not significantly different between the arms (p=0.47 and 0.13, respectively). In addition, patients with AC had a much lower prevalence of long-term complications (lymphedema: n=8 (9.4%) vs. 46 (26.0%), p=0.03; ureteral stricture: n=0 vs. 9 (6.2%), p=0.05). Conclusion Patients with FIGO stage IB-IIA cervical cancer can benefit from AC after RH with fewer long-term complications and non-inferior therapeutic effect to AR. Chemotherapy may therefore be an alternative adjuvant treatment option for cervical cancer, particularly in younger patients.

The Asian Society of Gynecologic Oncology International Workshop 2014 on gynecologic oncology was held in Asan Medical Center, Seoul, Korea on the 23rd to 24th August 2014. A total of 179 participants from 17 countries participated in the workshop, and the up-to-date findings on the management of gynecologic cancers were presented and discussed. This meeting focused on the new trends in the management of cervical cancer, fertility-sparing management of gynecologic cancers, surgical management of gynecologic cancers, and recent advances in translational research on gynecologic cancers.

Gestational diabetes mellitus (GDM) is a transient metabolic disorder that is a strong predictor of type 2 diabetes and cardiovascular disease. Previously, GDM was associated with reduced red cell long-chain omega-6 and omega-3 fatty acids in population (British) with high intake of total and saturated fat. The aim of the study was to examine blood fatty acids status of GDM patients (n=12) and normoglycaemic women (control, n=12) from South Korea where typical diet retains high omega-3 fat with low total fat intake. Subjects were matched for BMI and gestation week. Blood obtained at delivery were analyzed for plasma triacylglycerols (TG), phosphatidylcholine (PC), sphingomyelin (SM), and red cell PC, phosphatidylethanolamine (PE) and SM fatty acids. GDM patients had lower total saturated fatty acids (SFA) in the plasma TG (p0.05) and PC (p0.0001), and higher omega-6 and omega-3 metabolites in the plasma PC (p0.05) than the controls. Conversely, the red cell PC and PE of the GDM contained higher proportions of palmitic (p0.05) and SFA (p0.05) but lower arachidonic (p0.05) and docosahexaenoic (p0.05) acids compared with the controls. Interestingly, red cell PC arachidonic acid level was comparable between Korean and British women whereas docosahexaenoic acid level decreased in the order of Korean control (5.5+/-0.9)Korean GDM (3.5+/-2.1)=British control (3.9+/-2.9)British GDM (2.8+/-2.3) (p0.05). The similarity in the plasma and red cell fatty acids profile between Korean and British cohort suggests that the reduced membrane arachidonic and docosahexaenoic acids in GDM might be attributed to the effect of the disease itself regardless of ethnicity, obesity, or diet.

To estimate the efficacy of laparoendoscopic single-site (LESS) ovarian cystectomy in ovarian endometrioma.Retrospective study. Canadian Task Force Classification II-2.University hospital.Three hundred forty-three premenopausal women with previously untreated ovarian endometrioma.The surgical and follow-up outcomes were compared between LESS (n = 154) and conventional laparoscopic ovarian cystectomy (n = 189).Four patients (2.6%) in the LESS group but no patients in conventional group required additional ports (p = .040). No patient in either group required conversion to laparotomy. Operating times, estimated blood loss, perioperative hemoglobin level changes, and transfusions did not differ between groups. However, the length of postoperative hospital stay was significantly shorter in the LESS group (2 ± .4 days vs 2.3 ± .8 days, p = .001) and significantly more patients in this group were discharged within 2 days of surgery (93.5% vs 79.4%, p.001). Perioperative complications occurred in 1 patient (0.6%) in the LESS group and in 2 patients (1.1%) in the conventional group (p.999). The LESS group showed significantly lower pain scores at 16 (3.2 vs 3.6, p.001), 24 (2.8 vs 3, p = .004), and 30 hours (2.7 vs 3, p = .040) after surgery. The requirement for additional analgesics was significantly lower in the LESS group (27.9% vs 45%, p = .001). After a median follow-up time of 48 months, 11 patients (7.1%) in the LESS group and 21 patients (11.1%) in the conventional group showed recurrent endometrioma (p = .209).LESS ovarian cystectomy has similar feasibility and efficacy with conventional laparoscopic surgery in the management of endometrioma. However, LESS is associated with less postoperative pain, lower analgesic requirement, and earlier discharge.

To investigate the interaction between the ion channels and transporters in the salivary fluid secretion, we measured the membrane voltage ( Vm) and intracellular concentrations of Ca2+, Na+([Na+]c), Cl−, and H+(pHi) in rat submandibular gland acini (RSMGA). After a transient depolarization induced by a short application of acetylcholine (ACh; 5 μM, 20 s), RSMGA showed strong delayed hyperpolarization ( Vh,ACh; −95 ± 1.8 mV) that was abolished by ouabain. In the HCO3−-free condition, the Vh,AChwas also blocked by bumetanide, a blocker of Na+-K+-2Cl−cotransporter (NKCC). In the presence of HCO3−(24 meq, bubbled with 5% CO2), however, the Vh,AChwas not blocked by bumetanide, but it was suppressed by ethylisopropylamiloride (EIPA), a Na+/H+exchanger (NHE) inhibitor. Similarly, the ACh-induced increase in [Na+]cwas totally blocked by bumetanide in the absence of HCO3−, but only by one-half in the presence of HCO3−. ACh induced a prominent acidification of pHiin the presence of HCO3−, and the acidification was further increased by EIPA treatment. Without HCO3−, an application of ACh strongly accelerated the NKCC activity that was measured from the decay of pHiduring the application of NH4+(20 mM). Notably, the ACh-induced activation of NKCC was largely suppressed in the presence of HCO3−. In summary, the ACh-induced anion secretion in RSMGA is followed by the activation of NKCC and NHE, resulting an increase in [Na+]c. The intracellular Na+-induced activation of electrogenic Na+/K+-ATPase causes Vh,ACh. The regulation of NKCC and NHE by ACh is strongly affected by the physiological level of HCO3−.

This study was designed to establish a more effective and safe culture system for adoptive immunotherapy by investigating the use of homologous cord blood plasma (HCBP) instead of fetal bovine serum (FBS), which has various limitations including ethical problems for the ex vivo expansion of human umbilical T lymphocytes. Fresh human umbilical mononuclear cell fractions were isolated by Ficoll-Hypaque density centrifugation. Nonadherent mononuclear cell fractions were cultured with anti-CD3 antibody (5 microg/ml), IL-2 (175 U/ml), and either 10% FBS or 10% HCBP. On day 8, the cellular proliferation rate and cell surface markers were assessed. There was no significant difference in proliferation when human umbilical cord blood T lymphocytes were grown in medium supplemented with FBS or HCBP (p0.05). In medium containing FBS, the proportion of CD3(+)CD4(+) (markers for helper T cell), CD3(+)CD8(+) (cytotoxic T cell), CD3(+)CD25(+) (activated T cell), CD3(+)CD38(+) (immature T cell), and CD3(+)CD45RO(+) (memory T cell) cells was significantly increased (p0.05), whereas proportion of CD3(+)CD45RA(+) (naive T cell) and CD16(+)CD56(+) (NK cell) cells was significantly decreased (p0.05). In HCBP supplemented medium, the proportion of CD3(+)CD8(+), CD3(+)CD25(+), CD3(+)CD45RA(+), and CD3(+)CD45RO(+) cells was significantly increased (p0.05). The proportion of CD3(+)CD4(+), CD3(+)CD45RO(+) and CD3(+)CD38(+) cells was significantly higher, but proportion of CD3(+)CD45RA(+) and CD3(+)CD8(+) cells was significantly lower in FBS compared with HCBP supplemented medium (p0.05). Our results support the feasibility of ex vivo expansion of human umbilical cord blood T lymphocytes in medium supplemented with HCBP for future adoptive cellular immunotherapy.

Layered double hydroxides (LDH) were incorporated into polyelectrolyte membranes in order to investigate the electrochemical reaction processes affected by transport rates of methanol and protons in direct methanol fuel cell (DMFC) applications. Depending on different ion exchange capacities and its compositions of LDH, the polyelectrolyte membranes gave different diffusion coefficients of methanol and proton conductivities, which were successfully correlated with the maximum power density of a single-cell DMFC. Decreasing the diffusion coefficient of methanol, the open circuit voltage was increased and the overall performance of DMFC was improved by incorporating LDH nanoparticles. An optimal property condition was observed when the proton conductivity and the diffusion coefficient were balanced in a desirable manner providing a 24% increment of the maximum power density compared with the pristine Nafion membrane at 5 M of methanol feed concentration. The developed nanocomposite technique identified the effects of the diffusion coefficient and proton conductivity of polyelectrolyte membranes in the electrochemical reactions of DMFC. Keywords: Fuel cell, Layered double hydroxide, Diffusion coefficient, Ionic conductivity, Methanol crossover

We studied the intracellular events associated with pancreatic beta cell apoptosis by IFN-gamma/TNF-alpha synergism. IFN-gamma/TNF-alpha treatment of MIN6N8 insulinoma cells increased the amplitude of high voltage-activated Ca(2+) currents, while treatment with IFN-gamma or TNF-alpha alone did not. Cytosolic Ca(2+) concentration ([Ca(2+)](c)) was also increased by IFN-gamma/TNF-alpha treatment. Blockade of L-type Ca(2+) channel by nifedipine abrogated death of insulinoma cells by IFN-gamma/TNF-alpha. Diazoxide that attenuates voltage-activated Ca(2+) currents inhibited MIN6N8 cell death by IFN-gamma/TNF-alpha, while glibenclamide that accentuates voltage-activated Ca(2+) currents augmented insulinoma cell death. A protein kinase C inhibitor attenuated MIN6N8 cell death and the increase in [Ca(2+)](c) by IFN-gamma/TNF-alpha. Following the increase in [Ca(2+)](c), calpain was activated, and calpain inhibitors decreased insulinoma cell death by IFN-gamma/TNF-alpha. As a downstream of calpain, calcineurin was activated and the inhibition of calcineurin activation by FK506 diminished insulinoma cell death by IFN-gamma/TNF-alpha. BAD phosphorylation was decreased by IFN-gamma/TNF-alpha because of the increased calcineurin activity, which was reversed by FK506. IFN-gamma/TNF-alpha induced cytochrome c translocation from mitochondria to cytoplasm and activation of caspase-9. Effector caspases such as caspase-3 or -7 were also activated by IFN-gamma/TNF-alpha treatment. These results indicate that IFN-gamma/TNF-alpha synergism induces pancreatic beta cell apoptosis by Ca(2+) channel activation followed by downstream intracellular events such as mitochondrial events and caspase activation and also suggest the therapeutic potential of Ca(2+) modulation in type 1 diabetes.

BACKGROUND The prostate gland contains numerous neuroendocrine cells (PNECs) innervated by adrenergic neurons. PNECs are believed to influence the growth and physiological function of the prostate gland via paracrine release of hormones. MATERIALS AND METHODS Using fura-2 fluorescence measurement and patch-clamp techniques, we investigated the effects of adrenergic stimulation on cytosolic concentration of Ca2+ ([Ca2+]c) and high voltage-activated Ca2+ channel currents (HVA-ICa) of the putative rat prostate neuroendocrine cells (RPNECs) freshly isolated by an enzymic digestion. RESULTS Noradrenaline (NA, 1 μM) induced a sharp, transient increase of [Ca2+]c measured by the fura-2 fluorescence. Pharmacological studies showed that α1-adrenoceptors (α1-ARs) coupled with PLC/IP3 signaling pathway induce the release of stored Ca2+, which subsequently recruits store-operated Ca2+ entry pathways. In the whole-cell voltage clamp experiment, NA decreased the amplitude of HVA-ICa by 40%, which was mimicked by an α2-AR agonist (UK14304) but not by an α1-AR agonist (phenyleprine). After selective blockade of N-type Ca2+ channels by ω-conotoxin GVIA, the addition of NA showed no further inhibition on the remaining L-type Ca2+ channel currents. The adrenergic inhibition of HVA-ICa was partially prevented by the pretreatment with pertussis toxin (PTX) (5 μg/ml, 4 hr, 37°C). CONCLUSIONS RPNECs express both α1- and α2-ARs, signaling the release of stored Ca2+ and the inhibition of N-type Ca2+ channels, respectively. Prostate 57: 99–110, 2003. © 2003 Wiley-Liss, Inc.

PURPOSE A prospective, randomized phase III, clinical trial was performed to assess treatment related acute toxicity, early response and survival difference, between a monthly 5-FU cisplatin, and a weekly cisplatin group alone, for concurrent chemoradiotherapy in the locally advanced uterine cervical carcinoma patients. MATERIALS AND METGODS: Between March 1998 and March 2000, 35 patients, with locally advanced (FIGO stage IIB to IVA) cervical carcinoma, were studied, but 5 patients were excluded inform the analysis due to their refusal of treatment. The patients were randomly assigned to 'monthly 5-FU cisplatin' (arm I), or 'weekly cisplatin' (arm II), groups. The patients of arm I received 5-FU cisplatin (5-FU 1,000 mg/m2/day cisplatin 20 mg/m2/day, IV continuous infusion, for 5 days, 3 cycles with 4-week intervals) with radiation therapy. Those of arm II received only cisplatin (cisplatin 30 mg/m2/day, IV bolus, 6 cycles with 1-week intervals) with radiation therapy. The radiation therapy consisted of external beam irradiation of 41.4~50.4 Gy/23~28 fractions, and high dose rate intracavitary treatments, delivering a dose of 30~35 Gy to point A in 6~7 fractions. During intracavitary radiation, a parametrial boost was delivered for a point B dose of 60 Gy in the non-thickened side, and 65 Gy in the thickened side. Treatment related acute toxicities were assessed using Radiation Therapy Oncology Group (RTOG) acute morbidity scoring criteria. The response to treatment, and survival, were analyzed. The median follow-up period was 19 months. RESULTS The FIGO stage distributions of arm I (n=16) and arm II (n=14) were as follows; IIB 10, IIIA 1, IIIB 4, IVA 1 in arm I, 12, 0, 1 and 1 in arm II respectively. The compliance of both arms were 80.0% and 93.3%, respectively (p=0.37). During radiation therapy, the incidences of leukopenia, greater than RTOG grade 2, were 25.0%, 14.3%, respectively. There were no patients with gastrointestinal or genitourinary toxicity greater than RTOG grade 2. The complete response rates at 3 months, following radiation therapy, were 87.5% and 92.9% respectively. Two-year disease free survival rates were 81.3%, 85.7%, respectively, for each arms. CONCLUSION There was no significant difference in response to treatment, or patterns of failure, between the monthly FP and weekly cisplatin arms. Although there were no statistically significant differences, the patients of the weekly cisplatin arm had better compliance. More patients, and a longer follow up, are needed for improved evaluation of the regimen.

5578 Background: In experimental studies, adrenergic hormones are involved in tumorigenesis of ovarian cancer and its progression. We investigated the impact of beta adrenergic blocker on survival outcome of ovarian cancer since few studies have investigated its relevance. Methods: Data of Korean National Health Insurance Service was analyzed (n = 866). We analyzed the impact of beta blocker on survival outcome of ovarian cancer according to the duration on medication and age groups of patients. Cox proportional hazards regression was used to analyze hazard ratios (HR) for all-cause mortality with 95% confidence intervals (CI) adjusting for confounding factors. Results: Median years of follow-up was 5.98 and 6.71 for non-users and users, respectively. Among the 866 patients, 206 (23.8%) were users and 660 (76.2%) were non-users. In total, there was no survival difference between the 2 groups. But, when patietns were grouped according to the duration of medication, patients with longer duration of medication (≥1 year) showed better survival outcome (adjusted HR 0.305 [95% CI: 0.187-0.500], P < 0.001). Also, beta blocker use in patients with > 60 years showed better survival compared to younger patients (adjusted HR 0.579 [95% CI: 0.408-0.822], P = 0.002). In patients with > 60 years, medication longer than 720 days was associated with better survival outcome (adjusted HR 0.267 [95% CI: 0.140-0.511], P < 0.001). Both selective and non-selective beta blocker showed identical survival benefit in these settings without difference between each other. Conclusions: Beta blocker medication was associated with favorable survival outcome in ovarian cancer, especially when used in older patients and in long term duration.

Supplemental Digital Content is available in the text, To identify prognostic factors for overall survival after recurrence (OSr) in endometrioid endometrial cancer (EC) patients and categorize patient subgroups that predict outcomes using these variables. Consecutive patients with recurrent endometrioid EC seen in our institution from 1989 to 2013 were retrospectively reviewed. Cox regression models were used to identify the clinicopathological factors associated with OSr. By summing scores proportionate to the hazard ratio (HR) for each significant variable, we stratified patients into 3 risk groups. Enrolled patients (n = 108) had a median time to recurrence of 15 (range, 3–163) months after initial treatment and a median OSr of 22 (range, 1–207) months. Twenty patients (18.5%) had locoregional recurrence, and 88 (81.5%) distant. One hundred three patients underwent salvage therapy; 51 (47.2%) received chemotherapy only, 22 (20.3%) received radiotherapy either alone or combined with chemotherapy, and 29 (26.9%) underwent salvage cytoreductive surgery. Multivariate regression analysis revealed that time to relapse after initial treatment, cancer antigen-125 level at recurrence, and the number of recurrent lesions were independent predictors of OSr. Incorporating these factors, we stratified patients into low-risk (n = 19), intermediate-risk (n = 43), and high-risk (n = 46) groups. The likelihood of cancer-specific death was higher in both the high-risk (HR = 8.948, 95% confidence interval [CI] = 3.498–22.893, P

OBJECTIVE This study aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) with or without carboplatin in Korean patients with recurrent ovarian cancer (ROC), fallopian tube, or primary peritoneal cancer. METHODS This retrospective study included 52 patients with ROC, fallopian tube, or primary peritoneal cancer who received PLD (50 mg/m2) between 1st December 2014 and 31th July 2016. RESULTS The mean number of chemotherapy cycles was 3.8 (range, 2 to 9) in the PLD monotherapy group and 7 (range, 2 to 13) in the PLD combined with carboplatin (PLD-C) group. In overall response rates and clinical beneficial rates, PLD monotherapy group shows 5.0% and 17.5%, and PLD-C group shows 33.3% and 75.0%. The mean progression-free survival (PFS) was 5 and 13 months in the PLD monotherapy and PLD-C groups, respectively. At 6 months after treatment initiation, absence of disease progression was confirmed in 6 (15%) and 10 (83.3%) patients in the PLD monotherapy and PLD-C groups. Hematological adverse events (e.g., neutropenia and thrombocytopenia) were more common in the PLD-C group (P

Transient receptor potential vanilloid 3 (TRPV3) is a non-selective cation channel with modest permeability to calcium ions. It is involved in intracellular calcium signaling and is therefore important in processes such as thermal sensation, skin barrier formation, and wound healing. TRPV3 was initially proposed as a warm temperature sensor. It is activated by synthetic small-molecule chemicals and plant-derived natural compounds such as camphor and eugenol. Schisandra chinensis (Turcz.) Baill (SC) has diverse pharmacological properties including antiallergic, anti-inflammatory, and wound healing activities. It is extensively used as an oriental herbal medicine for the treatment of various diseases. In this study, we investigated whether SC fruit extracts and seed oil, as well as four compounds isolated from the fruit can activate the TRPV3 channel. By performing whole-cell patch clamp recording in HEK293T cells overexpressing TRPV3, we found that the methanolic extract of SC fruit has an agonistic effect on the TRPV3 channel. Furthermore, electrophysiological analysis revealed that γ-schisandrin, one of the isolated compounds, activated TRPV3 at a concentration of 30 µM. In addition, γ-schisandrin (~100 µM) increased cytoplasmic Ca2+ concentrations by approximately 20% in response to TRPV3 activation. This is the first report to indicate that SC extract and γ-schisandrin can modulate the TRPV3 channel. This report also suggests a mechanism by which γ-schisandrin acts as a therapeutic agent against TRPV3-related diseases.

To demonstrate the survival impact of intraoperative tumor rupture in women with stage I clear cell carcinoma (CCC) of the ovary.A total of 193 patients with stage I CCC of the ovary who had undergone a complete staging operation followed by ≥three cycles of adjuvant platinum-based chemotherapy, were retrospectively reviewed. Survival analysis was performed and compared between three stage groups: IA/IB, IC1, and IC2/IC3.There were 70, 51, and 72 women with ovarian CCC in stages IA/IB, IC1, and IC2/IC3, respectively. Intraoperative tumor rupture occurred in 69 (35.8%) patients. Gross endometriosis (p=0.020) and significant peritumoral adhesion (p0.001) were associated with intraoperative tumor rupture. However, neither laparoscopic approach nor large tumor size10cm were associated with intraoperative tumor rupture. Patients with stage IC2/IC3 compared to those with stage IC1, had poorer progression-free survival (PFS) (5-year PFS, 68.5% versus 91.7%; p=0.010) and overall survival (OS) (5-year OS, 81.1% versus 95.4%; p=0.027). However, there was no significant difference between patients with stages IA/IB and IC1 CCC in PFS (5-year PFS 88.8% versus 91.7%; p=0.291) and OS (5-year OS 94.6% versus 95.4%; p=0.444). Stage IC2/IC3 was the only independent poor prognostic factor for OS (hazard ratio, 3.50; 95% confidence interval, 1.31 to 9.36).Surgical spillage of tumor cells does not appear to have a negative impact on survival outcomes of women with stage I ovarian CCC who received ≥three cycles of adjuvant platinum-based chemotherapy.