Myomatous erythrocytosis syndrome: a uterine fibroid associated with polycythaemia.

Myomatous erythrocytosis syndrome (MES) is a rare form of secondary erythrocytosis seen with myomas. Here, we present a case of a postmenopausal, nulliparous woman in her 50s incidentally found to have asymptomatic erythrocytosis on routine laboratory work. She was found to have an 18.5 cm myoma and after surgical resection, the patient's haematological values returned to normal ranges after a few weeks. This established the diagnosis as MES. The aetiology of MES continues to remain unknown but is most likely caused by an autonomous production of erythropoietin from the myomatous tissue. This case highlights obtaining a detailed history and physical examination to differentiate between the different causes of erythrocytosis, considering MES as a rare cause of secondary erythrocytosis and to prevent unnecessary procedures such as phlebotomy as surgery is the mainstay of treatment.

The impact of expanding gynecologic oncology care to ovarian cancer patients in small cities and rural communities.

OBJECTIVE: Patients with ovarian cancer from smaller cities and rural communities face unique challenges in accessing comprehensive care. This study compares management strategies, outcomes, and access to care for patients in a small city and surrounding rural communities before and after establishing a full-time gynecologic oncology (GO) office. METHODS: A local tumor registry was used to identify patients diagnosed with ovarian cancer before and after a full-time GO office was established. Quantitative analyses were used to compare disease characteristics, management strategies, overall survival, and distance traveled for care between cohorts. RESULTS: Out of 381 patients, 171 women were diagnosed prior to establishing a full-time GO office (pre-GO) and 210 after (post-GO). Post-GO patients were more likely to undergo surgery by a GO specialist (97.1% versus 53.2%, p < 0.01), receive surgery locally (79.0% versus 43.3%, p < 0.01), and undergo complete lymph node dissection (63.3% versus 38.6%, p < 0.01). Patients treated with chemotherapy by GO increased from 10.3% pre-GO to 76.9% post-GO. 5-year survival rates were 33.8% versus 49.5% in the pre-GO and post-GO groups, respectively (p < 0.01). Median survival time increased from 30.8 months to 52.5 months from pre-GO to post-GO time periods. Distance patients traveled for surgery decreased from a mean of 47.9 miles pre-GO to 26.8 miles post-GO. CONCLUSION: After establishing a full-time GO office within a small city, local patients had significantly improved overall survival and access to care. These results highlight the benefit of expanding GO care into small cities with surrounding rural communities and may be used to address public health discrepancies for women across the country.

Surgery and Platinum/Etoposide-Based Chemotherapy for the Treatment of Epithelioid Trophoblastic Tumor.

OBJECTIVE: Epithelioid trophoblastic tumor (ETT) is a rare variant of gestational trophoblastic neoplasia that develops from chorionic-type intermediate trophoblast, simulates carcinoma, presents years after a pregnancy event, is associated with low or normal human chorionic gonadotropin levels, and is relatively resistant to chemotherapy. Our aim was to identify the role of surgery in combination with platinum/etoposide-based chemotherapy in the management of both localized and metastatic ETT. METHODS: A retrospective review was performed of women with ETT treated at a gestational trophoblastic disease center from 2010 to 2016. RESULTS: Five patients were identified who had complete records. Mean age was 38.0 years. Three women presented with abnormal uterine bleeding, 2 women presented with respiratory complaints, and 1 woman was asymptomatic. Two women had no identifiable antecedent pregnancy, 2 women had spontaneous abortions, and 1 woman had a normal term delivery before diagnosis. Four (80%) of 5 women had metastatic pulmonary disease. All 5 women underwent hysterectomy, and 3 women had resection of metastatic pulmonary disease. The 4 women with metastatic disease were also treated with chemotherapy. All 5 women are currently without evidence of disease. CONCLUSIONS: Surgery, including hysterectomy and resection of metastatic disease, is an important component in the treatment of women with ETT. Adjuvant chemotherapy with a platinum/etoposide-containing regimen should be used in women with metastatic disease. All 5 women with ETT in this series were cured using this approach, including the 4 who had metastatic disease.

Actinomycin D for methotrexate-failed low-risk gestational trophoblastic neoplasia.

OBJECTIVE: To determine outcomes and factors associated with failure of 5-day actinomycin D for treatment of methotrexate-failed low-risk gestational trophoblastic neoplasia (GTN). STUDY DESIGN: We reviewed the records of 358 patients treated with methotrexate 0.4 mg/kg (max 25 mg) IV push q.d. x 5 d every 14 d for FIGO-defined, low-risk GTN between 1979 and 2009. Actinomycin D 0.5 mg IV push q.d. x 5 d every 14 d was given to 64 of 68 patients (18%) who failed methotrexate: 48 (75%) for resistance and 16 (25%) for toxicity. Adjuvant surgery was used in selected patients. Clinical response and survival as well as factors affecting outcomes were analyzed retrospectively. RESULTS: The complete response rate to secondary chemotherapy with actinomycin D for failed methotrexate treatment of low-risk GTN was 75% (48/64), including 71% (34/48) for methotrexate resistance and 88% (14/16) for methotrexate toxicity. All 20 patients (6%) who failed sequential single-agent chemotherapy with methotrexate and actinomycin D were placed into permanent remission with the use of multiagent chemotherapy with or without surgery. The only factor significantly associated with resistance to secondary actinomycin D chemotherapy was clinicopathologic diagnosis of choriocarcinoma versus postmolar GTN (56% versus 20%, p = 0.025). CONCLUSION: Actinomycin D 0.5 mg IV q.d. x 5 d every 14 d used as secondary therapy in methotrexate-failed low-risk GTN resulted in a 75% complete response rate and eventual 100% cure with subsequent multiagent chemotherapy with or without surgery. Resistance to sequential methotrexate and actinomycin D chemotherapy was significantly associated with original FIGO score > or = 3 and clinicopathologic diagnosis of choriocarcinoma.

Treatment of nonmetastatic and metastatic low-risk gestational trophoblastic neoplasia: factors associated with resistance to single-agent methotrexate chemotherapy.

OBJECTIVE: To determine factors associated with resistance to methotrexate treatment of low-risk gestational trophoblastic neoplasia (GTN). METHODS: We reviewed the records of 358 patients with low-risk GTN (FIGO stage I and stages II-III, score<7) treated initially with methotrexate 0.4 mg/kg (max 25mg) IV push daily × 5 days every 14 days between 1979 and 2009. Actinomycin D 0.5mg IV push daily × 5 days every 14 days was used in 64 patients who developed resistance or toxicity to initial methotrexate chemotherapy, and combination drug regimens were used in 20 patients who failed single-agent chemotherapy. Adjuvant surgery was used in 34 selected patients. Clinical response and survival as well as factors affecting outcomes were analyzed retrospectively. RESULTS: The complete response rate to initial methotrexate chemotherapy was 81% (290/358) and the complete response rate to actinomycin D as secondary therapy was 75% (48/64), for an overall complete response rate to sequential single-agent chemotherapy of 94% (338/358). The remaining 20 patients (6%) were all placed into permanent remission with the use of multiagent chemotherapy with or without surgery. Resistance to initial methotrexate chemotherapy was associated with increasing FIGO score (p<.0001), clinicopathologic diagnosis of choriocarcinoma (p=.028), higher pretreatment hCG (p=0.001) and presence of metastatic, disease (p=.018). CONCLUSIONS: Sequential single-agent chemotherapy with methotrexate (0.4 mg/kg-max 25mg) followed by actinomycin D (0.5mg) each given IV push for 5 consecutive days every other week for treatment of low-risk GTN resulted in only 6% of patients requiring multiagent chemotherapy and a 100% survival rate.

Cardiac metastasis from poorly differentiated carcinoma of the cervix: a case report.

BACKGROUND: Disease metastatic to the heart from cervical carcinoma is rare and associated with a poor prognosis. Multimodality treatment has been shown to provide palliative benefit. CASE: A woman presented with stage Ib2 cervical cancer metastatic to the tricuspid valve. She presented with small bowel obstruction from a small bowel metastasis 4 years after initial treatment with chemoradiation. Computed tomographic imaging revealed a small bowel mass as well as a pericardial effusion. Cardiac magnetic resonance imaging showed a tricuspid mass. Endomyocardial biopsy confirmed metastatic disease consistent with a cervical primary. The patient was treated with bowel resection, systemic chemotherapy and cardiac radiation. She died of cardiac failure 8 months after diagnosis of the cardiac lesion. CONCLUSION: Cervical cancer metastatic to the heart is rare and associated with a poor prognosis. Selected patients may benefit from multimodality treatment.

The combination of monthly carboplatin and weekly paclitaxel is highly active for the treatment of recurrent ovarian cancer.

OBJECTIVES: To evaluate the response rate and toxicity of a regimen comprised of monthly carboplatin and weekly paclitaxel for recurrent ovarian cancer. METHODS: We performed a retrospective chart review of patients with recurrent ovarian cancer treated between 2001 and 2006 at a single institution with carboplatin AUC 5 (day 1), and paclitaxel 80 mg/m(2) (days 1, 8, 15) of a 28-day cycle. Primary endpoints were response rate, progression-free survival and overall survival. RESULTS: Twenty patients were treated with this regimen from 2001 to 2006. Stage ranged from stages IC to IV. All received intravenous platinum and taxane as their initial therapy. Histologic subtypes included papillary serous (17), carcinosarcoma (1), and clear cell (2). The median number of prior regimens was 1 (range 1-3). The overall response rate was 85.0% (15 complete responses, 2 partial responses). Patients with tumors categorized as platinum sensitive had a response rate of 93.3% (14/15) and those with tumors deemed platinum resistant had a response rate of 60.0% (3/5). The median survival has not yet been reached after a median follow-up of 28 months. Neutropenia was the only grade 3/4 toxicity, occurring in 7 patients (35.0%). Platinum hypersensitivity reactions occurred in 5 patients (25.0%) who all successfully continued treatment using a carboplatin desensitization protocol. CONCLUSIONS: A monthly carboplatin and weekly paclitaxel regimen is highly active for women with recurrent platinum-sensitive and platinum-resistant epithelial ovarian cancer. The regimen is well tolerated. This pilot series demonstrates the potential for this regimen as treatment of choice among doublet first salvage regimens for patients with recurrent epithelial ovarian cancer, thus warranting multi-institutional study.

FIGO stage IIIC endometrial carcinoma: prognostic factors and outcomes.

OBJECTIVES: Investigate the clinicopathologic characteristics, nodal distribution, and postoperative treatment of patients with FIGO stage IIIC endometrial carcinoma and determine patterns of recurrence and survival. METHODS: A retrospective review of 85 patients who underwent surgical staging with lymph node dissection at a single institution between 1979 and 2005 was performed. Data collected from patient charts included demographics, treatment, recurrence and survival. Variables were compared using the log-rank and X2 tests, and multivariate analysis was performed. RESULTS: Of 1487 patients who underwent surgical staging for endometrial cancer, 104 (7.0%) were diagnosed with stage IIIC disease and 85 of these were analyzed. Stage was determined by positive pelvic lymph nodes (PLN) in 54 patients, and positive para-aortic lymph nodes (PaLN)+/-PLN in 31 patients. With a median follow up of 50 months, 5-year overall survival (OS) was 61.3%, recurrence-free survival (RFS) was 58.0%, and disease-specific survival (DSS) was 71.9%. Median OS, RFS and DSS were 131 months, 131 months, and not attained, respectively. Five-year OS and RFS with positive PaLN were 48.8% and 44.4% respectively, compared to 69.7% and 65.6% with positive PLN only. On multivariate analysis, age, non-endometrioid histology, and >50% invasion were significantly associated with OS; age and non-endometrioid histology were associated with RFS. Disease recurred in 21 patients (24.7%): 15 distant, 4 abdominal, 1 para-aortic, and 1 pelvic. Disease recurred outside the field of radiation in all patients. CONCLUSIONS: Endometrial cancer patients with FIGO stage IIIC had a 5-year OS of 61.3%, a RFS of 58.0% and a DSS of 71.9% in this series. Because of the high proportion of distant sites of recurrence (71.4%), recurrence outside the radiation field (100%), and mortality after recurrence (86.3%), multimodality therapy should be considered.

Synuclein-gamma (SNCG) may be a novel prognostic biomarker in uterine papillary serous carcinoma.

OBJECTIVES: SNCG in breast cancer is a marker for advanced and aggressive disease thereby correlating with a poor prognosis in patients. We set out to determine if SNCG expression in UPSC correlates with aggressive cellular properties, poor prognosis, and chemoresistance, and if silencing SNCG can reverse these attributes in vitro. METHODS: A focused, real time PCR array was performed comparing a papillary serous (SPEC2) and an endometrioid (Ishikawa) endometrial cancer cell line. SNCG was the most differentially expressed gene. SNCG expression was confirmed by real time PCR, Western blot, and immunohistochemistry (IHC) and correlated with outcomes in a pilot set of 20 UPSC patients. A stably transfected SPEC2 cell line was created using shSNCG oligonucleotides. The effect of SNCG knockdown in SPEC2 cells on cell proliferation and sensitivity to paclitaxel-induced apoptosis was measured using a cell viability assay, BrdU incorporation assay, as well as cleaved PARP analyses. RESULTS: SNCG mRNA as well as protein was highly expressed in SPEC2 cells while minimally to undetectable in several endometrioid endometrial cancer and normal endometrial cell lines. IHC also confirmed unique SNCG expression in UPSC tumors compared to low grade endometrial cancers. In UPSC patients, SNCG expression by IHC correlated with advanced stage and decreased progression-free survival. Knockdown of SNCG in SPEC2 cells caused a significant decrease in cell proliferation and increased sensitivity to paclitaxel-induced apoptosis. CONCLUSIONS: SNCG is a novel biomarker for aggressive disease and chemoresistance in UPSC and merits further investigation both as a prognostic tool and as a therapeutic target.

The impact of robotics on practice management of endometrial cancer: transitioning from traditional surgery.

BACKGROUND: Evaluation of the impact of a new robotic surgery programme on perioperative outcomes for endometrial cancer METHODS: A prospective database of all patients undergoing staging for endometrial cancer during July 2007-July 2008 was collected and analysed. Demographic data and perioperative outcomes were compared between cases performed via laparotomy, laparoscopy and robotics. RESULTS: Sixty-five patients underwent staging during the time of data collection (LAP-26, LSC-7, ROB-32). No difference in surgical volume in the year before vs. after robotics was identified. Median operative time for robotics and laparotomy was significantly less than for laparoscopy (p = 0.023). There was no significant difference in lymph node yields between the three groups (p = 0.92). Robotics was associated with significantly less blood loss (p < 0.0001). Complication rates were significantly lower in the robotic group compared to the laparotomy group (p = 0.05). Median hospital stay was 1 day for the minimally invasive groups. Total number of perioperative inpatient days decreased from 331 to 150 in one year. Practice management of endometrial cancer transitioned from a predominantly open approach (5.6% LSC) to robotics (11% LSC, 49% ROB) within 12 months. CONCLUSIONS: Robotic surgery dramatically altered our management of endometrial cancer and was associated with a significant improvement in several perioperative outcomes when compared to laparotomy and laparoscopy.

Robotic surgery in gynecologic oncology: impact on fellowship training.

OBJECTIVES: To report the impact of a new robotic surgery program on the surgical training of gynecologic oncology fellows over a 12 month period of time. METHODS: A robotic surgery program was introduced into the gynecologic oncology fellowship program at Northwestern University Feinberg School of Medicine in June 2007. A database of patients undergoing surgical management of endometrial and cervical cancer between July 2007 and July 2008 was collected and analyzed. Changes in fellow surgical training were measured and analyzed. RESULTS: Fellow surgical training for endometrial and cervical cancer underwent a dramatic transition in 12 months. The proportion of patients undergoing minimally invasive surgery increased from 3.3% (4/110 patients) to 43.5% (47/108 patients). Fellow training transitioned from primarily an open approach (94.4%) to a minimally invasive approach (11% laparoscopic, 49% robotic, 40% open) for endometrial cancer stagings, and from an open approach (100%) to an open (50%) and robotic (50%) approach for radical hysterectomies. Fellow participation in robotic procedures increased from 45% in the first 3 months to 72% within 6 months, and 92% by 12 months. The role of the fellow in robotic cases transitioned from bedside assistant to console operator within 3 months. CONCLUSIONS: Fellow surgical training underwent a dramatic change with the introduction of a robotic surgery program. The management of endometrial and cervical cancer was impacted the most by robotics. Robotic surgery broadened fellowship surgical training, but balanced surgical training and standardized fellow training modules remain challenges for fellowship programs.

Progestins activate the AKT pathway in leiomyoma cells and promote survival.

CONTEXT: Progesterone has been associated with promoting growth of uterine leiomyomas. The mechanisms involved remain unclear. OBJECTIVE: In this study we investigated the activation of the AKT pathway and its downstream effectors, glycogen synthase kinase-3b and Forkhead box O (FOXO)-1 by progesterone as a mechanism of proliferation and survival of leiomyoma cells. Inhibitors of the AKT pathway were used to demonstrate the role of phosphatidylinositol 3-kinase, AKT, and FOXO1 in contributing to cell proliferation and apoptosis. RESULTS: Treatment of leiomyoma cells with R5020 over a period of 72 h resulted in higher cell numbers compared with untreated cells. When cells were treated with 100 nm R5020 for 1 and 24 h, the levels of phospho(Ser 473)-AKT increased. This increase was inhibited when cells were cotreated with RU486. Treatment of leiomyoma cells with a phosphatidylinositol 3-kinase inhibitor, LY294 dramatically decreased levels of phospho(Ser 473)-AKT, despite R5020 treatment. In addition to increased phospho(Ser 473)-AKT levels, R5020 treatment resulted in an increase in phospho(Ser 256)-FOXO1 and phosphoglycogen synthase kinase-3b. Inhibition of AKT using API-59 decreased proliferation and cell viability even in the presence of R5020. Higher concentrations of API-59-induced apoptosis of leiomyoma cells, even in the presence of R5020. Psammaplysene A increased nuclear FOXO1 levels and did not affect cell proliferation but induced apoptosis of leiomyoma cells. CONCLUSIONS: The progestin, R5020, can rapidly activate the AKT pathway. Inhibition of the AKT pathway inhibits cell proliferation and promotes apoptosis of leiomyoma cells.

A comparison of robot-assisted and traditional radical hysterectomy for early-stage cervical cancer.

A robotics surgery program was introduced into the division of gynecologic oncology at Northwestern University Feinberg School of Medicine in June 2007. A prospective database of all patients undergoing a type III radical hysterectomy for stage IB1 cervical cancer between July 2007 and June 2008 was collected and analyzed. Demographic data and perioperative outcomes were analyzed between a traditional and robot-assisted approach. A total of 14 patients were identified who underwent a type III radical hysterectomy for stage IB1 cervical cancer. Seven patients underwent robotic surgery and seven patients underwent traditional surgery. There were no significant differences in median age or body mass index between the two groups. A significant difference in blood loss between robotic (75 cc) and traditional (700 cc) surgery was detected (P = 0.002). A significant difference in hospital stay between robotic (1 day) and traditional (5 days) surgery was observed (P = 0.0007). No significant difference in operative time (260 vs. 264 min) or lymph node yield (19 and 14) was identified between the robotic and traditional approaches. No major operative complications occurred with robotic radical hysterectomy. Robot-assisted radical hysterectomy was associated with a significant reduction in blood loss and hospital stay. Improved nodal yields, fewer operative complications, and less pain was observed with the robotic approach. Robot-assisted radical hysterectomy appears safe and feasible and further investigation is warranted in a prospective fashion.

Absence of progesterone receptors in a failed case of fertility-sparing treatment in early endometrial cancer: a case report.

BACKGROUND: Fertility-sparing treatment may be offered as an alternative to standard surgical management of early-stage, well-differentiated endometrial cancer in young women. Immunostaining for progesterone receptor (PR) status is not currently part of the standard workup before treatment recommendations are made. CASE: We describe a 29-year-old woman who used oral contraceptive pills on a long-term basis in whom early-stage, well-differentiated endometrial cancer was diagnosed. Progestin therapy failed and the tumor was subsequently found to be PR negative. CONCLUSION: Combination oral contraceptive pills may stimulate clonal expansion of endometrial cells that lack PR, leading to endometrial adenocarcinoma unresponsive to progestin therapy. Consideration should be given to PR immunostaining for confirmation of the receptor status and evaluation of appropriate management options when counseling patients about fertility-sparing therapy.

Results of treatment of patients with gestational trophoblastic neoplasia referred to the Brewer Trophoblastic Disease Center after failure of treatment elsewhere (1979-2006).

OBJECTIVE: To review treatment results of patients with gestational trophoblastic neoplasia (GTN) whose care was transferred to the Brewer Trophoblastic Disease Center after failure of treatment elsewhere from 1979-2006. STUDY DESIGN: Twenty-seven (6.6%) of 408 patients with GTN treated at the Brewer Center from 1979-2006 had received unsuccessful treatment at other institutions prior to transfer to our center. Outcomes were analyzed and compared with 37 patients who received secondary therapy at the Brewer Center from 1962-1978. RESULTS: Overall survival was 93% (25 of 27) in patients treated at the Brewer Center (1979-2006) after failed treatment elsewhere. The most common causes of treatment failure prompting referral to the Brewer Center were (1) use of a single-agent chemotherapy protocol to treat high-risk disease in 11 patients (41%), (2) inappropriate use of weekly methotrexate chemotherapy in 9 patients (33%), (3) failed sequential single-agent chemotherapy in 4 patients (15%), (4) use of the wrong multiagent chemotherapy for high-risk disease in 1 patient (4%) and (5) relapse from remission in 2 patients CONCLUSION: Successful secondary treatment of GTN improved from 59% during 1962-1978 to 93% during 1979-2006 as a result of better chemotherapy protocols and experience treating the disease.

Gestational trophoblastic neoplasia: treatment outcomes.

OBJECTIVE: To report the results of treatment of gestational trophoblastic neoplasia (GTN) at the John I. Brewer Trophoblastic Disease Center over the past 28 years, compare the outcomes to those from the first 16 years, and analyze factors affecting response to treatment and survival. METHODS: We reviewed the records of 408 patients with GTN (excluding placental-site tumors) treated at the Brewer Center from 1979 to 2006. Outcomes and prognostic factors were analyzed and compared with those for the 396 patients treated at the Brewer Center from 1962 to 1978. RESULTS: The overall survival rate in 804 patients with GTN treated from 1962 to 2006 was 93.3% (88.6% from 1962 to 1978 and 97.8% from 1979 to 2006). All 491 patients with nonmetastatic disease treated during both time periods were cured; however, the cure rate for patients with metastatic disease increased from 77.8% (158 of 203) during 1962-1978 to 91.8% (101 of 110) during 1979-2006. Factors determined to significantly influence resistance to initial chemotherapeutic treatment on multivariable analysis from 1979 to 2006 were 1) presence of metastatic compared with nonmetastatic disease (41% compared with 12%; odds ratio [OR] 0.21, 95% confidence interval [CI] 0.13-0.35); 2) metastatic site other than the lung or vagina (76% compared with 31%; OR 0.05, 95% CI 0.02-0.13); 3) prior unsuccessful chemotherapy at another institution compared with primary treatment at our center (63% compared with 17%; OR 0.11, 95% CI 0.05-0.22); and 4) duration of disease greater than 4 months compared with 4 months or less (35% compared with 17%; OR 0.38, 95% CI 0.21-0.66). CONCLUSION: The overall survival rate in patients with GTN treated at the Brewer Center improved from 88.6% in 1962-1978 to 97.8% in 1979-2006.

Chemosensitization of endometrial cancer cells through AKT inhibition involves FOXO1.

OBJECTIVE: Endometrial cancer is the most common type of gynecologic cancer in the United States. In this study, we propose that inhibition of the AKT pathway sensitizes cells to chemotherapeutic agents by increasing FOXO1 expression. METHODS: Ishikawa and RL95 cells were treated with the AKT inhibitor (API-59CJ-OMe) alone and in combination with carboplatin or paclitaxel. Cells were counted using a hemocytometer and cell cycle analysis done with flow cytometry. Apoptosis was measured with TUNEL and Annexin V/DAPI staining. FOXO1 protein expression and localization was done using immunofluorescent staining of cells. Finally, the adenovirus containing triple mutant FOXO1 was used to overexpress the constitutively active FOXO1 in Ishikawa cells and its effects on cell viability were studied. RESULTS: Treatment with 6 microM API-59CJ-OME resulted in preferential cell death in Ishikawa and RL95 cells compared to another endometrial cancer cell line, ECC1 after 48 h of treatment. API-59CJ-OME treatment of Ishikawa cells resulted in cell cycle arrest in the G2/M phase. The addition of API-59CJ-OME to carboplatin resulted in a synergistic increase in cell death by apoptosis compared to the responses to each agent separately. Treatment with API-59CJ-OME, carboplatin, paclitaxel or the combinations for 24 h increased nuclear expression of FOXO1 in Ishikawa cells. Overexpression of FOXO1 caused 37% of the cells to die within 24 h. Addition of carboplatin to the AD-FOXO1 expressing cells further increased cell death to 71%. CONCLUSIONS: Inhibition of AKT signaling potentiates cell death in Ishikawa and RL95 cells when combined with carboplatin through mechanisms involving FOXO1 activation.

The regulation and function of the forkhead transcription factor, Forkhead box O1, is dependent on the progesterone receptor in endometrial carcinoma.

In many type I endometrial cancers, the PTEN gene is inactivated, which ultimately leads to constitutively active Akt and the inhibition of Forkhead box O1 (FOXO1), a member of the FOXO subfamily of Forkhead/winged helix family of transcription factors. The expression, regulation, and function of FOXO1 in endometrial cancer were investigated in this study. Immunohistochemical analysis of 49 endometrial tumor tissues revealed a decrease of FOXO1 expression in 95.9% of the cases compared with the expression in normal endometrium. In four different endometrial cancer cell lines (ECC1, Hec1B, Ishikawa, and RL95), FOXO1 mRNA was expressed at similar levels; however, protein levels were low or undetectable in Ecc1, Ishikawa, and RL95 cells. Using small interfering RNA technology, we demonstrated that the low levels of FOXO1 protein were due to the involvement of Skp2, an oncogenic subunit of the Skp1/Cul1/F-box protein ubiquitin complex, given that silencing Skp2 increased FOXO1 protein expression in Ishikawa cells. Inhibition of Akt in Ishikawa cells also increased nuclear FOXO1 protein levels. Additionally, progestins increased FOXO1 protein levels, specifically through progesterone receptor B (PRB) as determined by using stably transfected PRA-specific and PRB-specific Ishikawa cell lines. Finally, overexpression of triple mutant (Tm) FOXO1 in the PR-specific Ishikawa cell lines caused cell cycle arrest and significantly decreased proliferation in the presence and absence of the progestin, R5020. Furthermore, TmFOXO1 overexpression induced apoptosis in PRB-specific cells in the presence and absence of ligand. Taken together, these data provide insight into the phosphoinositide-3-kinase/Akt/FOXO pathway for the determination of progestin responsiveness and the development of alternate therapies for endometrial cancer.

Hormonal contraception and false-positive cervical cytology: is there an association?

OBJECTIVE: The aim of the study was to determine if use of hormonal contraception influences the false-positive rate of cervical cytology when compared with loop electrosurgical excision procedure or cervical biopsy specimens. MATERIALS AND METHODS: We performed a case-control analysis of 328 women referred for colposcopy after an abnormal Pap test. Patients were divided into cases (true-positive cytology results) and controls (false-positive cytology results). Univariate analysis was performed using the chi and Student t test to identify factors associated with false-positive cytology. Multiple logistic regression analysis was used to estimate odds ratios for the independent association of these factors. RESULTS: The false-positive rate for the entire cohort was 44.8%. Cases were more likely to be pregnant and postmenopausal (odds ratio [OR] = 4.98, 95% CI = 2.16-11.47; OR = 5.48, 95% CI = 1.23-24.36, respectively). Use of hormonal contraception was not significantly different between groups (OR = 0.56, 95% CI = 0.29-1.09 for combination oral contraceptive pills; OR = 0.89, 95% CI = 0.35-2.25 for progestin-containing contraception). Low-grade squamous intraepithelial lesion results were more likely to be false positives (51%) than high-grade squamous intraepithelial lesion (27%) (p <.001). CONCLUSIONS: There remains a substantial lack of correlation between cervical cytology and histology. Use of hormonal contraception was not shown to increase a patient's likelihood of having a false-positive Pap test.

Colouterine fistulas in elderly women: a report of 2 cases.

BACKGROUND: Colouterine fistula is a rare complication of diverticulitis. We report 2 cases of colouterine fistula in elderly women presenting with fever and pyuria and managed with an aggressive workup and surgical treatment. CASES: Two elderly women presented with persistent pyuria, abdominal pain and fever without a vaginal discharge. Imaging revealed diverticulitis and a fistula. One patient, 92 years of age, underwent hysterectomy, sigmoid resection and primary colorectal anastomosis. The second patient, aged 87, was treated with hysterectomy, sigmoid resection and diverting colostomy with delayed colostomy closure. CONCLUSION: Colouterine fistula may present with pyuria, fever and abdominal pain even in the absence of vaginal discharge. Patients who are elderly and fragile are more likely to be treated conservatively and inappropriately. We advocate surgical management, including resection of all involved tissue, early in the course of the disease. In elderly women, aggressive 1- or 2-stage procedures are highly successful and could save the patients' lives.