Uterine smooth muscle tumor of uncertain malignant potential: A review of current knowledge.

Uterine smooth muscle tumor of uncertain malignant potential is a subtype of uterine smooth muscle neoplasms. It is characterized by distinct pathologic findings with morphologic features intermediate between those of benign leiomyoma and malignant leiomyosarcoma. Clinically, STUMP is rare and its clinical picture is comparable to that of leiomyoma, with diagnosis typically being made postoperatively. Most patients with STUMP are uneventful after tumor resection. However, a small portion of patients may experience recurrence that may even lead to mortality. Given the uncommon occurrence of STUMP and the low frequency of malignant potential, currently there is still no standard guideline in treating patients with this disease and this can be challenging for physicians. Moreover, because cases are rarely available for study, investigating this tumor is difficult. Thus, matters such as the pathologic diagnostic criteria, strategy of clinical management, identification of prognostic factors, and the pathogenesis of this disease remain to be clarified. We collected and analyzed recently published case series studies of STUMP to obtain up-to-date clinical information. The current status of research in various basic and clinical aspects of this tumor was also reviewed.

Antrodia camphorata induces apoptosis and enhances the cytotoxic effect of paclitaxel in human ovarian cancer cells.

INTRODUCTION: Antrodia camphorata is a Chinese herb. Recently, several reports demonstrated that it had growth-inhibiting effects on some cancer cells. In this study, we investigated whether the crude extract of A. camphorata could inhibit the growth of ovarian cancer cells and examined the possible mechanisms involved. We also examined whether the cytotoxic effect of paclitaxel on ovarian cancer cells would be affected by A. camphorata. MATERIALS AND METHODS: Two human ovarian cancer cell lines, SKOV-3 and TOV-21G, were treated with A. camphorata (3-300 µg/mL). An MTT assay was used to test its cytotoxic effect. The apoptosis-related factors including the activity of caspase-3, -8, and -9 and the cytochrome c level released from mitochondria were analyzed. The expression of Bcl-2 family proteins (Bcl-2, Bcl-xL, Bax, Bim, Bad, and Bak) was examined by Western blot analysis. Cell lines were further treated with paclitaxel or paclitaxel plus A. camphorata to examine the cytotoxic efficiency. RESULTS: The MTT assay revealed that A. camphorata was cytotoxic to both the ovarian cancer cells in a dose- and time-dependent manner. Activities of caspase-3, -8, and -9 and release of mitochondrial cytochrome c increased in both ovarian cancer cell lines with increased dose of A. camphorata. Western blot analysis of Bcl-2 family proteins revealed an increased expression of Bad in SKOV-3 cells, whereas increased expression of Bim and Bak and decreased expression of Bcl-xL were noted in TOV-21G cells. In addition, the cytotoxic effect of paclitaxel on SKOV-3 and TOV-21G cells was increased significantly with the addition of A. camphorata (P < 0.01) by MTT assay. CONCLUSIONS: These in vitro results suggest that A. camphorata causes a cytotoxic effect on ovarian cancer cells through the induction of apoptosis. It may also enhance the antitumor effect of paclitaxel. Further studies with the ultimate goal of conducting clinical trials are warranted.

Prognostic and predictive values of E-cadherin for patients of ovarian clear cell adenocarcinoma.

OBJECTIVES: The purpose of the study was to analyze negative versus positive immunoexpression of epithelial cadherin (E-cadherin) and p53 in patients with primary advanced ovarian clear cell adenocarcinoma (OCCA) and its significance in relation to clinical features, progression-free survival and overall survival (OS). METHODS AND MATERIALS: Protein expression of E-cadherin and p53 was immunohistochemically evaluated in 61 OCCA patients with stages IIC to IV. The clinical factors studied included stage, age, CA-125, residual tumors, and chemotherapy regimens. RESULTS: Positive p53 immunoexpression was 44.8% (26/58) of OCCAs; in contrast, E-cadherin immunoexpression was observed in 75.9% (44/58) of OCCAs. The expected 5-year OS rate of OCCA treated with paclitaxel-based chemotherapy was significantly better than non-paclitaxel-based chemotherapy (40% vs 0%, P = 0.001). The expected 5-year OS rate of OCCA patients with positive E-cadherin immunoexpression (>10%) was also significantly better than patients with negative E-cadherin immunoexpression (≤10%) (35% vs 0%, P = 0.02). The expected 5-year OS rate of those receiving paclitaxel-platinum chemotherapy was not significantly different from platinum-based chemotherapy for those with negative E-cadherin immunoexpression (P = 0.11). The expected 5-year OS rate of those receiving paclitaxel-based chemotherapy was better than non-paclitaxel-based chemotherapy for those with positive E-cadherin immunoexpression (43% vs 0%, P = 0.01). Paclitaxel-based chemotherapy and positive E-cadherin immunoexpression were 2 independent prognostic factors in OS of patients with OCCA (P = 0.01 and 0.04, respectively). CONCLUSIONS: E-cadherin is a useful prognostic marker for OCCA patients, and paclitaxel-based chemotherapy can improve survival among patients with positive E-cadherin immunoreactivity.

Fertility-preserving treatment of stage IA, well-differentiated endometrial carcinoma in young women with hysteroscopic resection and high-dose progesterone therapy.

OBJECTIVE: The standard treatment for endometrial cancer is surgery with hysterectomy. However, this procedure will cause infertility in young women who desire to preserve pregnant ability. Conservative management with hormone therapy has been shown to be satisfactory in both tumor control and fertility preservation. Recently, hysteroscopic tumor resection followed by progestin therapy has been reported to be an alternative strategy. In this study we present our experience with this approach. MATERIALS AND METHODS: Six young patients (30-36 years old) diagnosed with grade 1 stage IA endometrial cancer who wished to preserve fertility were enrolled for this treatment procedure. The patients underwent hysteroscopic tumor resection followed by oral progestin therapy with either megestrol acetate or medroxyprogesterone acetate for at least 6 months. Interval hysteroscopy with biopsy was performed during the treatment course to evaluate disease response. RESULTS: All of the six patients had complete tumor remission after hysteroscopic resection and progestin therapy (five in 6 months, one in 9 months). In a median follow-up of 32 months (range 4-49months), one patient became pregnant spontaneously and delivered a full-term healthy baby via cesarean section. She received a definite surgery 3 months later, and the pathology confirmed no tumor existence. The other five patients were also free of disease at the last follow-up. CONCLUSION: Hysteroscopic tumor resection followed by progestin therapy for early-stage and well-differentiated endometrial cancer is a safe conservative treatment strategy. It could be an option for young patients who wish to preserve fertility.

Expression analysis of apoptosis-related markers TP53, BCL-2, BAX and c-MYC in female genital tract sarcomas.

BACKGROUND: Most female genital tract sarcomas are highly malignant and fatal. Their aggressive growth pattern and poor response to chemotherapy are the major causes of death. Deregulation of the apoptosis pathway is related to tumorigenesis and chemodrug resistance. The purpose of this study was to investigate the expression status and relationship of the apoptosis-related markers TP53, BCL-2, BAX and c-MYC in this group of tumors. In addition, correlations of these markers with clinicopathologic findings and their prognostic significance were also examined. METHODS: Paraffin blocks of female genital tract sarcoma tissue from 54 patients were obtained after pathology review. Protein expression of TP53, BCL-2, BAX and c-MYC was examined using immunohistochemical staining with standard procedures. A semiquantitative method was used to assess the staining result where scoring 1-3 was negative and 4-9 was positive for expression. The mutual relationships between TP53, BCL-2, BAX and c-MYC were examined. Associations between expression of the apoptotic markers and tumor stage as well as outcome were also analyzed. RESULTS: We found that all 4 of the apoptosis-related markers were frequently expressed in female genital tract sarcomas. Of the 54 cases, 24 (44%) were positive for TP53, 23 (43%) for BCL-2, 25 (46%) for BAX, and 30 (56%) for c-MYC. A significant positive association was observed between BAX and c-MYC (p < 0.001). There was no significant difference for the expression status of the 4 markers in early and late stage tumors. In prognostic analysis, overexpression of TP53, late stage, and age were significant prognostic factors in both univariate and multivariate analyses. CONCLUSION: Since changes in TP53, BCL-2, BAX and c-MYC frequently occur in female genital tract sarcomas, deregulation of apoptosis appears to be involved in the pathogenesis of this group of tumors. This mechanism may occur early in tumorigenesis and include the c-MYC/BAX apoptotic pathway or BCL-2. However, TP53 mutation may play a crucial role in this process, and clinically, it could be used as a prognostic indicator.

Butein induces apoptotic cell death of human cervical cancer cells.

Butein is a chalcone, a flavonoid that is widely biosynthesized in plants. Butein has been identified to possess varied pharmacological activity and is extractable from traditional Chinese medicinal herbs, therefore applicable for disease treatment. Recently, in vitro and in vivo studies have shown that butein may induce apoptotic cell death in various human cancer cells. In this study we investigated the apoptotic effect of butein and the underlying mechanisms in human cervical cancer cells. Two cell lines, C-33A and SiHa cells, were treated with butein at different dosages for different durations. The effect of butein on cell viability was assessed by MTT assay, which revealed that butein exerted cytotoxicity in both cervical cancer cells in a dose- and time-dependent fashion. Apoptotic pathway-related factors in the butein-treated cervical cancer cells were then examined. JC-1 flow cytometry, cytochrome c assay, and caspase activity assays demonstrated that butein disturbed mitochondrial transmembrane potential, and increased cytosolic cytochrome c levels and caspase activities in both cervical cancer cells. Western blot analysis revealed that butein downregulated anti-apoptotic protein Bcl-xL and led to proteolytic cleavage of poly (ADP-ribose) polymerase. In addition, butein decreased expressions of the inhibitor of apoptosis (IAP) proteins, including X-linked IAP, survivin, and cellular IAP-1. The findings of this study suggest that butein can decrease cervical cancer cell viability via a pro-apoptotic effect, which involves inhibition of the IAP proteins and activation of both extrinsic and intrinsic pro-apoptotic pathways. Therefore, butein may be applicable for cervical cancer treatment.

Clinicopathologic Features and Treatment Outcomes in Patients with Stage I, High-Risk Histology or High-Grade Endometrial Cancer after Primary Staging Surgery: A Taiwanese Gynecologic Oncology Group Study.

To investigate the clinicopathological features and treatment outcomes in patients with stage I, high-risk endometrial cancer. Patients with International Federation of Gynecology and Obstetrics stage I, papillary serous, clear cell, or grade 3 endometrioid carcinoma treated between 2000 and 2012 were analyzed for the clinical and pathological factors in relation to prognosis. A total of 267 patients (stage IA; n = 175, stage IB; n = 92) were included. Among the clinicopathological features, stage and age were significant prognostic factors. The recurrence rate and overall survival for stage IB versus IA were 22.8% versus 9.1% (p = 0.003) and 149.7 months versus 201.8 months (p < 0.001), respectively. The patients >60 years of age also had a higher recurrence rate (21.7% versus 9.7%, p = 0.008) and poorer survival (102.0 months versus 196.8 months, p = 0.001) than those ≤60 years of age. Distant recurrence (64.9%) occurred more frequently than local recurrence (24.3%) and local combined with distant recurrence (10.8%) (p < 0.001). The postoperative treatment modality had no impact on tumor recurrence rate, recurrence site, or overall survival. Distant recurrence is a major cause of treatment failure in patients with stage I, high-risk endometrial cancer. However, current adjuvant treatment appeared to have little effect in preventing its occurrence.

Continuous oral cyclophosphamide as salvage or maintenance therapy in ovarian, primary peritoneal, and fallopian tube cancers: A retrospective, single institute study.

OBJECTIVE: Most patients with recurrent ovarian cancer are treated with multiple regimens of intravenous salvage chemotherapy. These anticancer agents often cause severe toxicities and offset their therapeutic effects. The present study assessed the experience of a single institute regarding the safety and treatment outcomes of continuous oral cyclophosphamide in patients with ovarian, primary peritoneal, and fallopian tube cancers. MATERIALS AND METHODS: A retrospective review was conducted on patients who received oral cyclophosphamide as salvage or maintenance therapy. All the patients had received platinum plus paclitaxel as the front line chemotherapy before being enrolled in the study. Oral cyclophosphamide 50 or 100 mg daily was administered. The response rate, progression-free survival, and side effects were evaluated. RESULTS: Twenty patients were eligible for analysis, and 18 patients (90%) initially had FIGO stage IIIC disease. Most patients were heavily pretreated with the median number of previous chemotherapy regimens being 4 (range 1-8). Seventeen patients received oral cyclophosphamide as salvage therapy. Complete and partial responses were obtained in 3 and 2 patients, respectively. Five patients were classified as having stable disease. The median progression-free survival was 15 weeks (range 5-60 weeks). Three patients received oral cyclophosphamide as maintenance therapy in the remission status. The remission duration was maintained for 18, 28, and 67 weeks. Grade 2-3 myelosuppression was the only side effect. CONCLUSION: Continuous oral cyclophosphamide can be used as an alternative salvage therapy in recurrent ovarian cancer with an acceptable response rate and toxicity. Additional clinical trials are required to evaluate its efficacy as maintenance therapy.

Prediction of persistence or recurrence after conization for cervical intraepithelial neoplasia III.

OBJECTIVE: To estimate the predictive factors for persistent/recurrent disease before and after conization for cervical intraepithelial neoplasia III. METHODS: Patients who received conization due to histologic diagnosis of cervical intraepithelial neoplasia III from 1998 to 2000 and who had at least one cytologic/histologic follow-up within one year of conization (n = 449) were enrolled in our study. All available demographic and pathologic parameters were analyzed. RESULTS: We performed multivariable logistic regression analysis to identify predictive factors for cervical intraepithelial neoplasia III persistence/recurrence. Age (greater than 50 years) was the only preoperative predictor and had an odds ratio equaling 3.070 (95% confidence interval [CI] 1.421-6.630, P = .004). Post-cone endocervical curettage was found to be the most statistically significant factor for predicting persistent disease (odds ratio 7.940, 95% CI 3.428-18.390, P < .001). Positive endocervical curettage was associated with 65.5% (36/55) of persistent disease, whereas negative endocervical curettage was associated with only 7.6% (26/342). Positive endocervical resection margins and multiple-quadrant disease also had predictive values with odds ratios equaling 2.972 (95% CI 1.401-6.281, P = .004) and 2.180 (95% CI 1.014-4.689, P = .046), respectively. The positive predictive values for age (> 50 years), positive endocervical curettage, positive endocervical resection margin, and multiple quadrant disease were 31.7%, 65.5%, 40.0%, and 21.9%, respectively. CONCLUSION: We found that age is the only preoperative predictive factor. Pathologic parameters, including endocervical curettage, endocervical resection margins, and multiple-quadrant disease are the only postoperative predictive factors for cervical intraepithelial neoplasia persistence or recurrence found in our study. These factors should be considered in patient management before and after therapeutic conization for cervical intraepithelial neoplasia III. LEVEL OF EVIDENCE: II-3.

Prognostic factors and adjuvant therapy on survival in early-stage cervical adenocarcinoma/adenosquamous carcinoma after primary radical surgery: A Taiwanese Gynecologic Oncology Group (TGOG) study.

OBJECTIVE: We aimed to identify prognostic factors of early-stage cervical adenocarcinoma (AC) and adenosquamous carcinoma (ASC) treated with primary radical surgery, and to evaluate the impact of postoperative adjuvant therapy on outcome. METHODS: The clinical-pathological data of all patients (n = 1132) with stages I-II cervical AC/ASC treated with primary radical surgery at the member hospitals of the Taiwanese Gynecologic Oncology Group were retrospectively reviewed. RESULTS: In multivariate analysis, stage II, deep stromal invasion (DSI), lymphovascular space invasion (LVSI), positive pelvic lymph node (PLN), and parametrial involvement (PI) were significant factors for recurrence-free survival (RFS), while only DSI, PI, and positive PLN were independent factors for cancer-specific survival (CSS). Low- and high-risk groups were defined by prognostic scores derived from the four factors (DSI, LVSI, positive PLN, PI) selected by internal validation. Postoperative adjuvant therapy significantly improved outcome for PLN-positive patients (RFS, p = 0.014; CSS, p = 0.016), but not for PLN-negative high-risk group because of higher mean prognostic score (p = 0.028) of adjuvant+ than adjuvant- patients. CONCLUSIONS: PLN metastasis, PI, DSI, and LVSI were independent prognostic factors. Prospective studies of postoperative adjuvant therapy with prognostic score and nodal status stratification for cervical AC/ASC are necessary.

KAI1 metastasis suppressor protein is down-regulated during the progression of human endometrial cancer.

PURPOSE: KAI1 is a metastasis suppressor gene located on human chromosome 11p11.2. It is a member of the structurally distinct family of cell surface glycoprotein, transmembrane 4 protein superfamily. KAI1 was initially isolated as a gene that suppressed metastasis of rat prostate tumor cells. Decreased KAI1 expression has been observed recently in various human cancers, including pancreatic, lung, hepatic, colorectal, breast, ovarian, esophageal, and cervical cancers. Frequent down-regulation of the KAI1 protein was also observed in endometrial cancer cell lines. The aim of this study was to determine whether this gene is altered in human endometrial carcinoma. In addition, its prognostic significance in this tumor was also evaluated. EXPERIMENTAL DESIGN: Tumor specimens from 18 cases with various degrees of endometrial hyperplasia, 97 primary endometrial carcinomas with various stages, and 28 metastatic lesions of this cancer were examined in this study. Using the method of immunohistochemistry, we characterized the KAI1 protein expression in the 143 endometrial tumors. Expression of KAI1 at RNA level was also examined in 35 of the 143 samples using a real-time quantitative PCR method. The data from immunohistochemical analysis were correlated with various clinicopathological factors. RESULTS: High levels of KAI1 protein expression were detected in almost all of the specimens with endometrial hyperplasia (17 of 18). In contrast, loss of KAI1 expression occurred in an increasing frequency (27.8-71.4%) from early stages of primary endometrial carcinomas to metastatic tumors (P < 0.001). In addition, more poorly differentiated tumors demonstrated significantly lower KAI1 expression as compared with the well-differentiated tumors (P < 0.001). It was also found that patients with KAI1-negative tumors had a lower survival rate than those with KAI1-decreased or positive tumors (P = 0.0042 and 0.0286, respectively). However, in multivariate analysis, the prognostic significance of KAI1 expression was inferior to tumor stage. CONCLUSION: These data suggest that KAI1 expression is down-regulated in advanced endometrial cancer. Clinically it may be a useful indicator of the tumor progression and may provide prognostic information on the outcome of this disease.

Butein Shows Cytotoxic Effects and Induces Apoptosis in Human Ovarian Cancer Cells.

Butein is a polyphenol, one of the compounds of chalcones, which are flavonoids that are widely biosynthesized in plants, and exhibits different pharmacological activities. Plants containing butein have been used in Chinese traditional medicine. Recently, it has been reported that butein suppresses proliferation and triggers apoptosis in various human cancer cells in vitro and in vivo. The aim of this study was to investigate its pro-apoptotic effect and mechanisms in two cultured human ovarian cancer cells (ES-2 and TOV-21G). The effects of butein on cell viability were assessed by a MTT assay at 3, 10, 30, and 100 µ/M. The apoptotic pathway related factors, including the mitochondrial transmembrane potential (MTP), cytochrome c, caspase cascade, and Bcl-2 family proteins, were examined. MTT assay revealed that butein was cytotoxic to both ovarian cancer cells in a dose- and time-dependent manner. JC-1 flow cytometry, cytochrome c, and caspase activity assays revealed that butein damaged the MTP, increased the level of cytosol cytochrome c and the activities of caspase-3, -8, and -9 in the two ovarian cancer cells. Western blot analysis revealed that butein down-regulated the anti-apoptotic proteins Bcl-2 and Bcl-xL and increased the pro-apoptotic proteins Bax and Bad. These findings suggest that butein-induced apoptosis in ovarian cancer cells via the activation of both extrinsic and intrinsic pathways. In addition, butein also down-regulated the expressions of the inhibitor of apoptosis (IAP) proteins, XIAP, survivin, CIAP-1, and CIAP-2. This indicates that the inhibition of IAP proteins was also involved in butein-induced apoptosis. The results of our study suggest that butein may be a promising anticancer agent in treating ovarian cancer.

Cytotoxic effect and induction of apoptosis in human cervical cancer cells by Antrodia camphorata.

Antrodia camphorata is a Chinese herb indigenous to Taiwan. Previous reports demonstrated that it could induce apoptosis in some cancer cells. The purpose of this study was to investigate the apoptotic effect of the crude extract of A. camphorata in cervical cancer cells. Two human cervical cancer cell lines, HeLa and C-33A, were treated with extract of A. camphorata (10-1000 µg/mL). We found that A. camphorata extract was cytotoxic to both cervical cancer cells in a dose- and time-dependent manner as examined by MTT assay. Treatment with A. camphorata extract at 400 µg/mL induced a 2.3- and 4.4-fold increase in oligonucleosome formation from the cleaved chromosomal DNA in HeLa and C-33A cells, respectively. A. camphorata extract also activated caspase-3, -8, and -9 activities and increased the cytosolic level of cytochrome c in both cell lines as the dosage increased. Furthermore, A. camphorata extract increased expressions of Bak, Bad and Bim, while decreasing expressions of Bcl-2 and Bcl-xL of the Bcl-2 family proteins in HeLa and C-33A cells. The expression of IAP proteins, XIAP and survivin, was also decreased in both cervical cancer cells after treatment with A. camphorata. Our in vitro study suggests that A. camphorata is cytotoxic to cervical cancer cells through both extrinsic and intrinsic apoptotic mechanisms. It could be used as a novel phytotherapeutic agent or auxiliary therapy in the treatment of cervical cancer.

Mechanisms of chemotherapeutic drug resistance in cancer therapy--a quick review.

Chemotherapy is one of the principal modes of treatment for cancer patients. Clinically, many tumors present a satisfactory response when they are first exposed to the chemotherapeutic drugs. However, drug resistance occurs sooner or later in these tumors, and the majority of the patients develop progressive disease. The mechanisms of treatment failure of chemotherapeutic drugs have been well studied. Via a unique protection system, i.e. multidrug resistance (MDR), the cancer cells can escape the toxic effect of most commonly used cancer drugs in spite of their different chemical structures and different mechanisms of intracellular activity. There are two classes of transporter proteins at the cellular surface which are responsible for MDR in tumors. One is the adenosine triphosphate-binding cassette transporter superfamily, which is an energy-requiring efflux pump with the function of extruding toxic chemotherapeutic drugs from the cancer cells. The other is the solute carrier transporter superfamily, which mediates the cellular uptake of anticancer drugs, and drug resistance may result from decreased activity of these transporters. Although transporters of MDR are responsible for the tumor resistance to many chemotherapeutic drugs currently used in cancer therapy, the mechanisms of resistance to platinum-based antitumor agents are through different pathways. In this article, the mechanisms of MDR transporters mediating resistance to the commonly used chemotherapeutic drugs and to platinum-based agents are reviewed. Finally, with the finding of cancer stem cells in more and more solid tumors, it is recognized that the cancer stem cell is spared along with its normal tissue stem cell counterparts with very subtle differences. One characteristic of the normal tissue stem cell is the self-protection ability through innate MDR transporters. Therefore, the essential self-protection property is also present in the cancer stem cells. The quiescent tumor stem cell with constitutive MDR is the main barrier to therapy. Successful cancer therapy will depend on the ability to discern the subtle differences between the tumor and normal stem cells so that approaches can be developed to eliminate the tumor stem cells without excessive toxicity to normal stem cells.

Molecular carcinogenesis of endometrial cancer.

In 1983, Bokhman proposed a dualistic model of endometrial tumorigenesis based on the clinical observations and clinicopathologic correlations. The majority of endometrial cancers (approximately 70-80%), designated as type I carcinomas, follow the estrogen-related pathway. Histologically, most of the type I tumors seem to arise in the background of hyperplastic endometrium, show an endometrioid differentiation, and are of low grade. Clinically, they are overall characterized by a favorable behavior. Another 10-20% of endometrial cancers, designated as type II carcinomas, follow the estrogen-unrelated pathway and arise in the background of atrophic endometrium. Type II tumors usually occur at an older age, approximately 5-10 years later than type I tumors. They are typically high-grade carcinomas of nonendometrioid differentiation, most frequently serous, less frequently clear cell. Type II carcinomas behave as an aggressive clinical course and poor prognosis. This dualistic model was subsequently supported by the molecular studies, approximately a decade later. At present, endometrioid and serous carcinoma, which represent the major phenotypes of types I and II endometrial carcinomas, respectively, are characterized by distinctive types of genetic instability and molecular alterations. In endometrioid (type I) carcinoma, four major genetic changes are responsible for the tumorigenesis, i.e. silencing of PTEN tumor suppressor gene, presence of microsatellite instability due to alterations of the mismatch repair genes, mutation of K-ras protooncogene, and alteration of beta-catenin gene. On the other hand, p53 mutation and overexpression of Her2/neu oncogene are two major genetic alterations in serous and clear cell (type II) carcinomas. However, like in any model, there is evidence for exceptions. Many endometrial carcinomas are in the gray zone with overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II endometrial cancers. Finally, a small group of endometrial carcinoma is noted to be hereditary. It is known as the most common extracolonic malignancy in hereditary nonpolyposis colorectal cancer (Lynch syndrome), an autosomal dominantly inherited disorder of cancer susceptibility. Inactivation of the mismatch repair genes MSH2 and MSH6 seems to play a central role in the tumorigenesis.

Undecylprodigiosin selectively induces apoptosis in human breast carcinoma cells independent of p53.

Undecylprodigiosin (UP) is a bacterial bioactive metabolite produced by Streptomyces and Serratia. In this study, we explored the anticancer effect of UP. Human breast carcinoma cell lines BT-20, MCF-7, MDA-MB-231 and T47D and one nonmalignant human breast epithelial cell line, MCF-10A, were tested in this study. We found that UP exerted a potent cytotoxicity against all breast carcinoma cell lines in a dose- and time-dependent manner. In contrast, UP showed limited toxicity to MCF-10A cells, indicating UP's cytotoxic effect is selective for malignant cells. UP's cytotoxic effect was due to apoptosis, as confirmed by positive TUNEL signals, annexin V-binding, caspase 9 activation and PARP cleavage. Notably, UP-induced apoptosis was blocked by the pan-caspase inhibitor z-VAD.fmk, further indicating the involvement of caspase activity. Moreover, UP caused a marked decrease of the levels of antiapoptotic BCL-X(L), Survivin and XIAP while enhancing the levels of proapoptotic BIK, BIM, MCL-1S and NOXA, consequently favoring induction of apoptosis. Additionally, we found that cells with functional p53 (MCF-7, T47D) or mutant p53 (BT-20, MDA-MB-231) were both susceptible to UP's cytotoxicity. Importantly, UP was able to induce apoptosis in MCF-7 cells with p53 knockdown by RNA interference, confirming the dispensability of p53 in UP-induced apoptosis. Overall, our results establish that UP induces p53-independent apoptosis in breast carcinoma cells with no marked toxicity to nonmalignant cells, raising the possibility of its use as a new chemotherapeutic drug for breast cancer irrespective of p53 status.

Transitional cell carcinoma of the ovary.

OBJECTIVE: Transitional cell carcinoma (TCC) of the ovary is a rare, recently recognized, subtype of ovarian surface epithelial cancer. We present a case of TCC of the ovary, managed by staging operation and followed by postoperative chemotherapy with carboplatin and cyclophosphamide. CASE REPORT: A 67-year-old postmenopausal woman presented with a 2-year history of progressive enlargement of an abdominal mass. Pelvic sonography and abdominal computed tomography showed a pelvic mass measuring 210 x 165 x 203 mm. The serum CA-125 titer was also elevated (65.01 U/mL). A staging operation with total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy and pelvic lymph node dissection was performed. After surgery, the pathologic report of the left ovarian tumor was TCC, grade 2-3, stage IA. The patient then underwent four cycles of postoperative chemotherapy with carboplatin and cyclophosphamide. CA-125 levels declined to within the normal range after the first cycle of chemotherapy. CONCLUSION: TCC of the ovary is a rare subtype of epithelial ovarian cancer. It differs from malignant Brenner tumor by the absence of a benign or borderline Brenner component. Surgical resection is the primary therapeutic approach, and patient outcomes after chemotherapy are better than for other types of common epithelial ovarian cancers.

Management of pelvic lymphocysts by ultrasound-guided aspiration and minocycline sclerotherapy.

OBJECTIVE: The purpose of this study was to describe our experience with ultrasound-guided aspiration of postoperative pelvic lymphocysts followed by intracavitary minocycline injection as sclerotherapy. PATIENTS AND METHODS: From 1997 to 2003, patients who developed either symptomatic or persistent lymphocyst after pelvic lymphadenectomy for gynecological malignancy were recruited in this study. All of the lymphocysts were palpable and were further examined by ultrasonography. Percutaneous ultrasound-guided needle aspiration of the lymphocyst was performed and then immediately followed by a single-dose injection of minocycline into the collapsed cavity. Follow-up was conducted every 4 weeks with pelvic examination and ultrasonography. RESULTS: Nineteen patients with a total of 21 pelvic lymphocysts underwent this procedure. The median size of the lymphocysts was 6 cm in diameter (range, 4-9 cm). Fifteen patients received 1 treatment, 3 received 2, and 1 patient with bilateral lymphocysts received 3 treatments. Complete resolution occurred in 14 patients (74%), and the other 5 patients (26%) had partial resolution with the volume of the lymphocyst decreasing at least 50%. For the 14 patients with complete resolution, the median time from treatment to disappearance of the lymphocyst was 3 months (range, 1-10 months), and none of them developed recurrence during the average follow-up period of 40 months (range, 2-62 months). No significant complication occurred with this procedure except for transient mild to moderate pelvic pain. DISCUSSION: Minocycline sclerotherapy seems to be a simple and safe method with a satisfactory success rate in treating lymphocysts which develop after pelvic lymphadenectomy. It can be performed in an outpatient setting and can be repeated if necessary. This procedure may be considered as the initial treatment modality for patients suffering from symptomatic or persistent lymphocysts after radical gynecological surgery.

Triplet combination of gemcitabine, carboplatin, and paclitaxel in previously treated, relapsed ovarian and peritoneal carcinoma: an experience in Taiwan.

OBJECTIVE: The aim of this phase II study was to evaluate the efficacy and toxicity of gemcitabine, carboplatin, and paclitaxel (GCP) combination as salvage therapy in patients with relapsed ovarian or peritoneal cancer who had previously received platinum-based chemotherapy. PATIENTS AND METHODS: Patients with progressive ovarian or peritoneal carcinoma who had previously received platinum-based chemotherapy were enrolled. Gemcitabine was administered at 800 mg/m(2) as a 30-min intravenous infusion on days 1 and 8; carboplatin (AUC of 5) and paclitaxel (175 mg/m(2)) were administered as 60-min and 3-h intravenous infusions, respectively, on day 1. Treatment cycles were repeated every 3 weeks for a maximum of nine cycles. RESULTS: Twenty patients (ovarian carcinoma, 19; peritoneal carcinoma, 1) received this triplet regimen as salvage therapy. All the patients had previously received at least one platinum-based regimen for chemotherapy and 17 of them had received platinum plus paclitaxel. The median number of previous regimens was 2 (range, 1-4), and the median platinum-free interval was 9 months (range, 1-18). A total of 130 cycles were administered with a median of six cycles per patient (range, 3-9). The overall response rate was 75%, including 12 complete responses (60%; 95% confidence interval [CI], 36.1-80.9) and three partial responses (15%; 95% CI, 3.2-37.9). The other five patients showed stable disease (25%; 95% CI, 8.7-49.1). The median duration of the progression-free survival was 6.5 months (range, 3-20). Myelosuppression was the main toxicity, with leukopenia being the most prominent (grade 3/4 toxicity in 35% patients), followed by thrombocytopenia in 20% patients. In addition, 35% patients had grade 3 anemia. All the toxicities were manageable and the patients recovered fully. Among non-hematological toxicities, the only notable one was grades 2 and 3 hepatic toxicity seen in two and one patients, respectively, necessitating a decrease in the paclitaxel dose in two patients. CONCLUSIONS: GCP combination is an effective salvage chemotherapy in patients with heavily pretreated and relapsed ovarian and peritoneal cancer. The significant side effects of myelosuppression and hepatic toxicity were of moderate severity and manageable.

Loss of Smad4 protein expression occurs infrequently in endometrial carcinomas.

Smad4 is a member of the Smad proteins, which are needed for mediating signals of transforming growth factor beta from the cell surface to the nucleus. Smad4 is also a tumor suppressor gene for cancers of the pancreas, colon, and lung. The aim of this study was to investigate the expression and prognostic significance of this gene product in endometrial cancer. Immunohistochemical staining for Smad4 was performed on formalin-fixed, paraffin-embedded specimens of endometrial tumors with an anti-Smad4 monoclonal antibody (clone B8): 97 primary endometrial carcinomas, 20 cases of endometrial hyperplasia, and 26 cases of metastases from endometrial carcinoma. The immunoreactivity of each tumor was correlated with the clinical and histopathologic parameters of the patients. Diffusely positive expression of Smad4 protein was detected in all 20 cases of endometrial hyperplasia and in most of the primary and metastatic endometrial cancers. The frequency of positive expression decreased progressively with tumor grade. Clinically, however, it was not associated with tumor progression, nor did it predict patient outcome. Although loss of heterozygosity at chromosome 18q21 (the location of the Smad4 gene) is frequent in endometrial carcinomas, the authors show in this immunohistochemical study that inactivation of this gene occurs infrequently in this tumor.