Challenges of pelvic imaging in obese women.

Obesity is a major global health concern affecting all ages, socioeconomic groups, and countries. Although men have higher rates of overweight, women have higher rates of obesity. In the United States, more than 60% of women are overweight or obese, with slightly more than one-third considered frankly obese. Obesity is a major risk factor for noncommunicable diseases such as diabetes mellitus, cardiovascular disease, hypertension, stroke, and specific cancers. Obesity is associated with increased mortality for all cancers, with the highest death rates occurring in the heaviest women. Obesity can contribute to missed diagnoses, nondiagnostic results of imaging studies, imaging examination cancellation because of weight or girth restrictions, scheduling of inappropriate examinations, and increased radiation dose exposure. The utility of the clinical examination is often limited in the obese woman, which results in an even greater reliance on imaging; however, the obese woman may experience a lowered quality of and less access to medical imaging. Recognition of equipment limitations, imaging artifacts, optimization techniques, and appropriateness of modality choices is critical to providing good patient care to this health-challenged group. The clinical indication, the patient's weight, and the body diameters are three key factors to consider when choosing the most appropriate examination. Familiarity with the optimization of imaging techniques across all modalities is important to convert potentially suboptimal examinations into diagnostic-quality studies. The aim of this review is to identify key areas in which obesity affects the imaging care of women with pelvic conditions and to outline strategies to address these areas.

What is integrative oncology and can it help my patients?

Integrative oncology lends itself to the comprehensive practice of gynecologic oncology with multiple tools and interventions that can impact on QoL and survival. However, there remains a paucity of well-designed, well-powered randomized control trials on various CAM modalities for gynecologic cancer patients. The reasons for the lack of level 1 evidence include the nascent state of integrative medicine as a science, the limitations on CAM funding, the relative lack of integration of CAM practitioners into the oncology community, and absence of strict regulation of herbs and supplements by the US FDA. The use of CAM as adjunctive therapies will likely continue given the patient-driven trends to date, and given the evidence for at least safety and potentially efficacy, our patients deserve our willingness to use all possible approaches to improving their outcomes. Continued evolution of our ability to specifically measure and describe QoL will further our ability to hone in on domains most important to patients and their survival and allow practitioners to make patient-specific recommendations. Multimodal programs that include physical activity, stress management, and diet have the potential to address demonstrated deficits in PWB and FWB in ovarian cancer patients which suggests a model of collaborative gynecologic oncology care). Integrative oncology represents a holistic approach to patient care whose goal is maximization of patient quantity and quality of life. Patients can achieve this optimal outcome through the synergy of conventional care, integrative modalities, lifestyle modifications, and supportive care. Refer to Table 4 for a listing of integrated medicine Internet resources.

Intraoperative neuraxial anesthesia but not postoperative neuraxial analgesia is associated with increased relapse-free survival in ovarian cancer patients after primary cytoreductive surgery.

OBJECTIVES: Regional anesthesia has been shown to blunt the response to surgical stress and decrease the use of volatile anesthetics and the consumption of opioids, which may reduce immune compromise and potentially delay tumor recurrence. The goal of this study was to find a possible association between intraoperative regional anesthesia and decreased cancer recurrence. METHODS: Patients who underwent surgery for ovarian cancer between January 1, 2000, and October 1, 2006, were included. Subjects who had optimal surgical debulking (<1.0 cm of remaining tumor) were evaluated for time to tumor recurrence (carcinoantigen 125 >21 U/mL or computed tomography evidence of disease progression) and/or death. RESULTS: One hundred eighty-two patients were evaluated; 127 did not receive epidural anesthesia/analgesia. Among the 55 who had epidural catheters placed, 26 were used intraoperatively and postoperatively; 29 were used only postoperatively. Cancer recurrence was documented in 121 patients. The median (interquartile range) time to recurrence was 40 (25-52) months. The intraoperative use epidural group had a mean (95% confidence interval) time to recurrence of 73 (56-91) months, which was longer than either the epidural postoperative group 33 (21-45) months (P = 0.002) or the no-epidural group 38 (30-47) months (P = 0.001). The postoperative-only and no-epidural groups were not different (P = 0.92). Intraoperative epidural significantly reduced (hazard ratio, 0.37 [95% confidence interval, 0.19-0.73]) tumor recurrence risk. CONCLUSIONS: Intraoperative use of epidural anesthesia was associated with an increased time to tumor recurrence after surgery in ovarian cancer patients. This may be a result of preservation of the immune system function.

Survival and reproductive outcomes in women treated for malignant ovarian germ cell tumors.

OBJECTIVE: The objective of this study is to review all malignant germ-cell tumors (MOGCTs) treated at our institution, focusing on reproductive outcomes and menstrual function of patients treated with fertility-sparing surgery and adjuvant chemotherapy. METHODS: We performed a retrospective chart review of patients treated for MOGCTs between January 1, 1979 and March 31, 2008. Charts of identified patients were abstracted and data were collected. Patients who had fertility-sparing surgery were contacted and a telephone questionnaire was performed to gather reproductive and menstrual history. RESULTS: Forty patients were treated for MOGCTs at our institution. Mean age at the time of diagnosis was 26.5years (range, 10-48years). Histologic subtypes were: immature teratoma (52.5%), dysgerminoma (27.5%), yolk sac tumor (10.0%), mixed germ cell tumor (7.5%), and choriocarcinoma (2.5%). Thirty-five percent of tumors were FIGO stages II-IV. Twenty-seven patients (67.5%) were treated with chemotherapy postoperatively, 23 (85%) of whom received bleomycin, etoposide and cisplatin (BEP). There were three recurrences, but no deaths. Fertility-sparing surgery was performed in 22 patients (55%), 16 of whom received adjuvant chemotherapy. Fourteen of these patients were contacted. Of the 10 remaining patients desiring pregnancy, 8 (80%) had 11 successful spontaneous pregnancies, one required in-vitro fertilization, and the other required donor egg in-vitro fertilization, resulting in 14 live births. All 14 patients had normal menstrual cycles within one year of completing chemotherapy. CONCLUSIONS: Overall survival was 100% among patients with both local and advanced MOGCTs, including those who underwent fertility-sparing surgery. Fertility-sparing surgery plus adjuvant chemotherapy appeared to have little or no effect on fertility or menstrual cycles.

Risk factors for cervical precancer and cancer in HIV-infected, HPV-positive Rwandan women.

BACKGROUND: Although cervical cancer is an AIDS-defining condition, infection with human immunodeficiency virus (HIV) may only modestly increase the risk of cervical cancer. There is a paucity of information regarding factors that influence the natural history of human papillomavirus (HPV) in HIV-infected women. We examined factors associated with cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in Rwandan women infected with both HIV and HPV (HIV+/HPV+). METHODS: In 2005, 710 HIV+ Rwandan women ≥25 years enrolled in an observational cohort study; 476 (67%) tested HPV+. Each woman provided sociodemographic data, CD4 count, a cervical cytology specimen and cervicovaginal lavage (CVL), which was tested for >40 HPV genotypes by MY09/MY11 PCR assay. Logistic regression models calculated odds ratios (OR) and 95% confidence intervals (CI) of associations of potential risk factors for CIN3+ among HIV+/HPV+ women. RESULTS: Of the 476 HIV+/HPV+ women 42 (8.8%) were diagnosed with CIN3+. Factors associated with CIN3+ included ≥7 (vs. 0-2) pregnancies, malarial infection in the previous six months (vs. never), and ≥7 (vs. 0-2) lifetime sexual partners. Compared to women infected by non-HPV16 carcinogenic HPV genotypes, HPV16 infection was positively associated and non-carcinogenic HPV infection was inversely associated with CIN3+. CD4 count was significantly associated with CIN3+ only in analyses of women with non-HPV16 carcinogenic HPV (OR = 0.62 per 100 cells/mm(3), CI = 0.40-0.97). CONCLUSIONS: In this HIV+/HPV+ population, lower CD4 was significantly associated with CIN3+ only in women infected with carcinogenic non-HPV16. We found a trend for higher risk of CIN3+ in HIV+ women reporting recent malarial infection; this association should be investigated in a larger group of HIV+/HPV+ women.

Management of metastatic high-risk gestational trophoblastic neoplasia: FIGO stages II-IV: risk factor score > or = 7.

OBJECTIVE: To evaluate treatment of metastatic high-risk gestational trophoblastic neoplasia (GTN), including durable complete response rates to chemotherapy, factors affecting response to therapy, and overall survival. STUDY DESIGN: Forty women with metastatic high-risk GTN (International Federation of Gynecology and Obstetrics [FIGO] stages II-IV, score > or = 7) completed treatment between 1986 (when EMA-CO became the standard chemotherapy for high-risk disease) and 2009, including 26 who were treated primarily and 14 who were treated secondarily. Patients who had incomplete responses or developed resistance to EMA-CO or other methotrexate-containing regimens were treated with drug combinations employing etoposide and a platinum agent with or without bleomycin or ifosfamide. Adjuvant radiotherapy and surgery were used in selected patients. Clinical response and survival as well as factors affecting outcomes were analyzed retrospectively. RESULTS: The overall survival rate was 90% (36 of 40): 92% (24/26) for primary treatment and 86% (12/14) for secondary treatment. Twenty-one patients (53%) had durable complete clinical responses to initial treatment, 15 patients (37%) developed resistance to initial chemotherapy but were subsequently placed into lasting remission with platinum-based chemotherapy with or without surgery and 4 patients (10%) died of widespread metastatic disease. Durable complete clinical response to initial chemotherapy was significantly influenced by FIGO stage (II and III, 63%, vs. IV, 31%, p = 0.05) and risk factor score (< 12, 71%, vs. > or = 12, 32%, p < 0.02). Survival was also significantly associated with both FIGO stage (II and III, 100%, vs. IV, 69%, p < 0.01) and score (< 12, 100%, vs. > or = 12, 79%, p < 0.05). CONCLUSION: The use of EMA-CO chemotherapy as primary treatment and platinum-based chemotherapy along with surgical excision of resistant disease as secondary treatment for patients with metastatic high-risk GTN resulted in a survival rate of 90%. All patients who died had FIGO stage IV and risk factors scores > or = 12.

A prospective trial comparing lymphangiogram, cross-sectional imaging, and positron emission tomography scan in the detection of lymph node metastasis in locally advanced cervical cancer.

PURPOSE: This study prospectively evaluated the use of lymphangiogram, computed tomography/magnetic resonance imaging, and positron emission tomography (PET) imaging of lymph node metastasis in patients receiving definitive chemoradiotherapy for cervical cancer. MATERIALS AND METHODS: Twenty patients underwent lymphangiogram, computed tomography/magnetic resonance imaging, and PET. There was no histologic verification of metastasis. Four lymph node regions, including the internal, external, and common iliacs, and para-aortic, were scored as positive or negative for metastasis. Agreement between imaging was analyzed using multirater kappa and disease-free survival utilizing Kaplan Meier survival curves and log-rank test. RESULTS: Agreement between imaging was most consistent in the common iliacs (P < 0.001) and least in the para-aortic region (P = 0.41). Disease-free survival (DFS) at one year was statistically associated with positive PET imaging (25%) versus negative PET imaging (86%) (P = 0.033) in the common iliac lymph node region. No other single lymph node region in any modality was statistically associated with DFS. One-year DFS in patients with any positive areas on PET imaging was 50% compared with 90% in patients with negative PET imaging (P = 0.02). Seven patients were noted to have no metastasis in any region by all 3 of the imaging modalities; the 1-year DFS in these 7 patients was 100% compared with 59% in the 13 patients with any positive nodal area (P = 0.05). CONCLUSIONS: Positive lymphadenopathy on PET imaging was associated with reduced DFS.

Human papillomavirus infection and cervical cytology in HIV-infected and HIV-uninfected Rwandan women.

BACKGROUND: Data on human papillomavirus (HPV) prevalence are essential for developing cost-effective cervical cancer prevention programs. METHODS: In 2005, 710 human immunodeficiency virus (HIV)-positive and 226 HIV-negative Rwandan women enrolled in an observational prospective cohort study. Sociodemographic data, CD4+ cell counts, and cervical specimens were obtained. Cervicovaginal lavage specimens were collected from each woman and tested for >40 HPV types by a polymerase chain reaction assay; HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 were considered primary carcinogenic HPV types. RESULTS: The prevalence of HPV was higher in HIV-positive women than in HIV-negative women in all age groups. Among HIV-infected women, 69% were positive for >or=1 HPV type, 46% for a carcinogenic HPV type, and 10% for HPV-16. HPV prevalence peaked at 75% in the HIV-positive women aged 25-34 years and then declined with age to 37.5% in those >or=55 years old (Ptrend<.001). A significant trend of higher prevalence of HPV and carcinogenic HPV with lower CD4+ cell counts and increasing cytologic severity was seen among HIV-positive women. CONCLUSIONS: We found a higher prevalence of HPV infection in HIV-positive than in HIV-negative Rwandan women, and the prevalence of HPV and carcinogenic HPV infection decreased with age.

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.

The role of adjuvant radiation in endometrial cancer.

Endometrial cancer treatment ideally begins with a staging procedure including abdominopelvic washing, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymph node evaluation. Recommendations for postoperative adjuvant radiotherapy are determined by recurrence risk. Patients who have undergone staging and have early stage I disease and an absence of high-risk features for recurrence generally are treated with surgery alone. Intermediate-risk patients--those with high-risk stage I disease and some stage II patients--may benefit from adjuvant radiation therapy. Several randomized trials show that radiation therapy improves locoregional control among intermediate-risk patients. The optimal type of radiation therapy, whether vaginal brachytherapy or whole-pelvic radiation therapy, remains undetermined, though treatment decision can be guided by risk factors not encompassed by the current staging system. Patients with high-risk stage II disease and stage III disease generally receive external-beam radiotherapy, often in combination with chemotherapy. Chemotherapy alone in advanced-stage patients is a consideration, given the results of the Gynecologic Oncology Group (GOG)-122 trial.

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.

An outpatient intraperitoneal chemotherapy regimen for advanced ovarian cancer.

OBJECTIVES: To assess the feasibility, associated toxicities, and reasons for early cessation of an outpatient intraperitoneal (IP) chemotherapy regimen for treatment of advanced ovarian cancer following optimal cytoreductive surgery. METHODS: Between January 2006 and December 2007, 42 patients with stages IIC-IV epithelial ovarian, tubal, or primary peritoneal cancer who had residual disease <1 cm after cytoreductive surgery were treated with an outpatient IP chemotherapy protocol. Patients received intravenous (IV) docetaxel 75 mg/m(2) and IP cisplatin 75-100 mg/m(2) on day 1, followed by IP paclitaxel 60 mg/m(2) on day 8, with the intent to treat patients every 21 days for 6 cycles of chemotherapy. Charts were abstracted for demographic, chemotherapy, and toxicity-related data. RESULTS: The median age of the 42 patients was 59 years (range 33-70) and the majority of patients had epithelial ovarian cancer (80%), FIGO stage IIIC (83%), and papillary serous histology (74%). Of an intended 252 IP chemotherapy cycles, 172 (68%) were administered. Twenty-nine patients (69%) completed >or=4 cycles and 12 (29%) received all 6 IP cycles. Common grade 3/4 toxicities by patient included neutropenia (43%), infection (21.5%), and gastrointestinal effects (14%). There was one treatment-related death. Reasons for discontinuation were largely chemotherapy (43%) or port (37%) related. CONCLUSIONS: With supportive measures, such as scheduled hydration and granulocyte colony-stimulating factors, outpatient administration of IP chemotherapy was feasible. This regimen resulted in few hospitalizations or treatment delays and demonstrated less toxicity than previously reported IP chemotherapy regimens. Port-related complications were a leading cause of IP chemotherapy discontinuation.

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.

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.

Weekly topotecan for recurrent platinum resistant ovarian cancer.

OBJECTIVE: To evaluate toxicity, response and progression-free survival of weekly topotecan chemotherapy in women with primary and secondary platinum-resistant epithelial ovarian cancer. METHODS: A retrospective analysis of 69 patients who received weekly topotecan with a median dose of 3.75 on days 1, 8 and 15 of a 28-day cycle treated between November 2002 and May 2005. All patients had recurrent epithelial ovarian, primary peritoneal or tubal cancer with primary or secondary resistance to platinum. Disease response was evaluated by CA-125 levels, physical exam, and when appropriate, imaging studies. Toxicity was evaluated using the NCI Common Toxicity Criteria. RESULTS: Response to topotecan therapy was noted in 14 of 69 patients (20.3%); (complete response 7.3%, and partial response 13%). Stable disease was noted in 23 patients (33.3%) and progression of disease occurred in 31 patients (44.9%). Two patients (2.8%) had significant side effects that warranted discontinuation of therapy. There was no significant difference in response to therapy between patients with primary or secondary platinum resistance. A total of 229 cycles was given with a median of 3 (range 1-12) cycles per patient. Grades 3 and 4 myelosuppression was rare: 1 cycle (0.4%) with grade 3 leukopenia, 16 cycles (7%) with grade 3 or 4 neutropenia, 1 cycle (0.4%) with grade 3 anemia, and 2 cycles (0.9%) with grade 3 thrombocytopenia. No patient was admitted with neutropenic fever. The median progression-free survival for responders was 5.7 months (2-16.75). CONCLUSIONS: Weekly topotecan is a well-tolerated and effective regimen for platinum-resistant ovarian cancer with considerable less hematological toxicity when compared with historical data for the 5-day regimen.

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.