Diljeet K. Singh

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.

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

Evaluation of the impact of a new robotic surgery programme on perioperative outcomes for endometrial cancer

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.

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.

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.

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.

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/mm3, 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.

A comparison of 2 methods of vaginal cuff closure during robotic hysterectomy

To compare 2 methods of vaginal cuff closure with regard to safety, ease of use, and postoperative outcome.

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.