David M. Kushner

Terpenoids from Zingiber officinale (Ginger) Induce Apoptosis in Endometrial Cancer Cells through the Activation of p53

Novel strategies are necessary to improve chemotherapy response in advanced and recurrent endometrial cancer. Here, we demonstrate that terpenoids present in the Steam Distilled Extract of Ginger (SDGE) are potent inhibitors of proliferation of endometrial cancer cells. SDGE, isolated from six different batches of ginger rhizomes, consistently inhibited proliferation of the endometrial cancer cell lines Ishikawa and ECC-1 at IC50 of 1.25 µg/ml. SDGE also enhanced the anti-proliferative effect of radiation and cisplatin. Decreased proliferation of Ishikawa and ECC-1 cells was a direct result of SDGE-induced apoptosis as demonstrated by FITC-Annexin V staining and expression of cleaved caspase 3. GC/MS analysis identified a total of 22 different terpenoid compounds in SDGE, with the isomers neral and geranial constituting 30–40%. Citral, a mixture of neral and geranial inhibited the proliferation of Ishikawa and ECC-1 cells at an IC50 10 µM (2.3 µg/ml). Phenolic compounds such as gingerol and shogaol were not detected in SDGE and 6-gingerol was a weaker inhibitor of the proliferation of the endometrial cancer cells. SDGE was more effective in inducing cancer cell death than citral, suggesting that other terpenes present in SDGE were also contributing to endometrial cancer cell death. SDGE treatment resulted in a rapid and strong increase in intracellular calcium and a 20–40% decrease in the mitochondrial membrane potential. Ser-15 of p53 was phosphorylated after 15 min treatment of the cancer cells with SDGE. This increase in p53 was associated with 90% decrease in Bcl2 whereas no effect was observed on Bax. Inhibitor of p53, pifithrin-α, attenuated the anti-cancer effects of SDGE and apoptosis was also not observed in the p53neg SKOV-3 cells. Our studies demonstrate that terpenoids from SDGE mediate apoptosis by activating p53 and should be therefore be investigated as agents for the treatment of endometrial cancer.

Survivors of endometrial cancer: Who is at risk for sexual dysfunction?

OBJECTIVE Our goal was to determine the prevalence of sexual dysfunction and identify risk factors associated with sexual morbidity in patients with early stage endometrial cancer. METHODS This prospective trial included patients with stage I-IIIa endometrial cancer, without evidence of disease, and one to five years out from primary surgical treatment. Patients who received chemotherapy were excluded. The Female Sexual Function Index (FSFI) was used to measure our primary endpoint of sexual function. Other patient reported outcome indices included: Functional Assessment of Cancer Therapy-Endometrial (FACT-En), Center for Epidemiology Studies Depression scale (CES-D), and Menopausal Rating Scale (MRS). RESULTS Of the 72 women treated for early stage endometrial cancer, 65% were married, 69% had a sexual partner, the mean age was 60, 86% had stage I disease, and 18% received radiation therapy. The median score for the FSFI was 16.6 (0-32.8; scores below 26 are diagnostic for sexual dysfunction). Eighty nine percent of the patients had a score below 26. There was a moderate correlation between the total FSFI score and FACT-En scores but not with CES-D or MRS. Histologic grade, relationship status, mental health, and diabetes significantly correlated with total FSFI scores in multivariate analysis. CONCLUSION This patient population commonly thought to be at low risk actually suffers from severe sexual dysfunction. The four risk factors revealed by multivariate analysis need to be studied in greater detail in order to appropriately target patients and develop meaningful interventions.

Uterine rupture disguised by urinary retention following a second trimester induced abortion: a case report

BackgroundUterine rupture classically presents with severe abdominal pain, loss of fetal station, vaginal bleeding, and shock.Case presentationWe present a case of uterine rupture presenting as significant urinary retention that occurred following a second trimester abortion induced with mifepristone and misoprostol. Uterine rupture was discovered unexpectedly on diagnostic laparoscopy. The uterine rupture was contained by dense adhesions between the omentum and bladder with the previous uterine cesarean hysterotomy scar.ConclusionThis case highlights the difficulties in diagnosis of abnormal placentation and an unusual presentation of uterine rupture. This case was managed successfully laparoscopically.

A Protocol of Dual Prophylaxis for Venous Thromboembolism Prevention in Gynecologic Cancer Patients

OBJECTIVE: To evaluate a quality improvement protocol for venous thromboembolism prevention in postoperative gynecologic cancer patients. METHODS: On January 1, 2006, we initiated a universal protocol of dual prophylaxis with sequential compression devices and three times daily heparin (or daily low molecular weight heparin) until discharge in gynecologic cancer patients having major surgery. Patients with both malignancy and age over 60 years (or history of prior clot) were discharged on 2 weeks of anticoagulant. Before January 2006, all patients were given sequential compression devices starting before the induction of anesthesia, continuing until discharge from the hospital. Records of gynecologic cancer service patients admitted in 2005 and 2006 were reviewed, excluding patients with a history of heparin-induced thrombocytopenia or those admitted on an anticoagulant. Any pulmonary embolism or deep vein thrombosis diagnosed within 6 weeks of surgery was identified. We performed &khgr;2 and Wilcoxon rank sum tests as well as multivariable regression analysis for confounders. RESULTS: Six of the 311 women meeting inclusion criteria in 2006 (1.9%) and 19 of 294 (6.5%) in 2005 had venous thromboembolism (odds ratio 0.33, 95% confidence interval 0.12–0.88, multivariable analysis adjusting for baseline differences between the groups). Heparin was given to 98.1% of patients in the hospital in 2006, and 91.1% of those meeting high-risk criteria were discharged on an anticoagulant. No differences in major bleeding complications were seen between years. CONCLUSION: A protocol of dual prophylaxis with prolonged prophylaxis in high-risk patients was successfully implemented and was associated with a significant reduction in the rate of venous thromboembolism without increasing bleeding complications. LEVEL OF EVIDENCE: II

Preoperative hypoalbuminemia is an independent predictor of poor perioperative outcomes in women undergoing open surgery for gynecologic malignancies.

OBJECTIVE To quantify the impact of preoperative hypoalbuminemia on 30-day mortality and morbidity after gynecologic cancer surgery. METHODS Patients included in the National Surgical Quality Improvement Program (NSQIP) dataset who underwent any non-emergent surgery for gynecologic malignancy between 1/1/2008 and 12/31/2010 were identified. Analysis was conducted with albumin both as a dichotomous variable (<3.5 g/dl was defined as low albumin) and as a continuous variable to determine a clinically relevant cut-off value. RESULTS Of the total 3171 patients identified, 2110 had preoperative albumin levels available for analysis. In addition, 279 (13.3%) of these patients had low albumin levels. According to multivariate analysis, the low albumin group had significantly higher odds of developing one or more post-operative complications (OR-2,CI: 1.47-2.73, p<0.0001), three or more complications (OR-4.1,CI: 2.31-7.1, p<0.0001), surgical complications (OR-2.39,CI: 1.59-3.58, p<0.0001), thromboembolic complications (OR-2.59,CI: 1.33-5.06, p<0.0001), pulmonary complications (OR-4.06,CI: 2.05-8.03, p<0.0001), or infectious complications (OR-1.84,CI: 1.26-2.69, p<0.0001) and a higher 30-day mortality (OR-6.52,CI: 2.51-16.95, p<0.0001). Upon subgroup analysis, this difference was not found in patients undergoing laparoscopic surgery. In patients undergoing open surgery, the probability of experiencing one or more post-operative complications increased linearly with the decrease in albumin level; however, the probability of patients experiencing three or more complications and 30-day mortality increased sharply as soon as the albumin level decreased below 3g/dl. CONCLUSION Preoperative albumin levels <3g/dL identify a population of patients at a very high-risk of experiencing perioperative morbidity and 30-day mortality after open surgery.

Use of a bupivacaine continuous wound infusion system in gynecologic oncology: a randomized trial.

Objective: The aim of the current study was to evaluate the safety and efficacy of a widely available bupivacaine continuous wound infusion system in gynecologic oncology patients undergoing laparotomy. Methods: A prospective, randomized, double-blind, placebo-controlled trial was performed. After closure of the fascia, flexible soaker catheters were placed in the deep subcutaneous space. The infusion pump was filled with 290 mL of either 0.5% bupivacaine or normal saline, to infuse over 72 hours. Daily assessments of pain scores utilized the Wisconsin Brief Pain Inventory. All patients received intravenous narcotics via patient-controlled devices. Results: Eighty surgeries were evaluated in a total of 79 women (40 per arm). Mean age was 56 years, with 79% having invasive gynecologic pathology. The two groups were not significantly different in terms of type of surgery, length of incision, estimated blood loss, operative time, or medical history. Postoperative outcomes, including wound toxicity, time to flatus, and hospital stay, did not differ. Study patients averaged 75 mg intravenously and 107 mg total narcotic use (morphine equivalent), whereas controls averaged 60 mg intravenously and 86 mg total (P = .40 intravenously; P = .25 total). Acetaminophen and intravenous ketorolac consumption were equal between groups. The Brief Pain Inventory score for “current pain” was 2.84 for bupivacaine patients and 3.14 for controls (P = .46; least = 0, most = 10). There was no individual postoperative day when “current pain” BPI scores differed. “Worst pain” and “least pain” Brief Pain Inventory scores showed similar results. Conclusion: The results suggest that although the continuous infusion system seems safe, it is not efficacious in this patient population. Level of Evidence: I

Sonohysterography: a valuable tool in evaluating the female pelvis.

A number of medical conditions, including abnormal uterine bleeding, endometrial cancer, monitoring tamoxifen therapy, infertility, and recurrent abortion, warrant investigation of the female genital tract. Diagnostic studies including hysterosalpingogram, ultrasound, and sonohysterography have proved useful in the investigation of these gynecologic conditions. This article discusses each of these tests with particular emphasis on sonohysterography and their current and potential contributions in both diagnostic and therapeutic applications. The utility of each as well as their comparative value to each other and existing gold standards is reviewed. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to outline the current screening methods for uterine cavity and pelvic abnormalities, to list the advantages of sonohysterography, and to describe the clinical situations where sonohysterography can be used.

Intensive postoperative glucose control reduces the surgical site infection rates in gynecologic oncology patients

OBJECTIVE SSI rates after gynecologic oncology surgery vary from 5% to 35%, but are up to 45% in patients with diabetes mellitus (DM). Strict postoperative glucose control by insulin infusion has been shown to lower morbidity, but not specifically SSI rates. Our project studied continuous postoperative insulin infusion for 24h for gynecologic oncology patients with DM and hyperglycemia with a target blood glucose of <139 mL/dL and a primary outcome of the protocols impact on SSI rates. METHODS We compared SSI rates retrospectively among three groups. Group 1 was composed of patients with DM whose blood glucose was controlled with intermittent subcutaneous insulin injections. Group 2 was composed of patients with DM and postoperative hyperglycemia whose blood glucose was controlled by insulin infusion. Group 3 was composed of patients with neither DM nor hyperglycemia. We controlled for all relevant factors associated with SSI. RESULTS We studied a total of 372 patients. Patients in Group 2 had an SSI rate of 26/135 (19%), similar to patients in Group 3 whose rate was 19/89 (21%). Both were significantly lower than the SSI rate (43/148, 29%) of patients in Group 1. This reduction of 35% is significant (p = 0.02). Multivariate analysis showed an odd ratio = 0.5 (0.28-0.91) in reducing SSI rates after instituting this protocol. CONCLUSIONS Initiating intensive glycemic control for 24h after gynecologic oncology surgery in patients with DM and postoperative hyperglycemia lowers the SSI rate by 35% (OR = 0.5) compared to patients receiving intermittent sliding scale insulin and to a rate equivalent to non-diabetics.

Viral and host determinants of RNA virus vector replication and expression

Abstract Positive-strand RNA viruses have proven to be valuable vectors for delivery and expression of antigens for direct vaccination of animals and vaccine production in plants. However, optimal use of these viruses as vectors for vaccine and other purposes is limited by incomplete understanding of their replication pathways and associated constraints on inserted foreign genes. Further insights into RNA virus vector design and optimization are emerging from recent advances on the function of viral RNA replication factors, the nature of the viral RNA replication complex as a membrane-bounded compartment sequestering replication components from competing processes and host defenses, and identification of surprisingly diverse host genes contributing to many virus replication steps.

Outcomes following surgery and adjuvant radiation in stage II endometrial adenocarcinoma

PURPOSE To evaluate locoregional control, disease free survival, and overall survival in patients treated with surgery and adjuvant radiation for stage II adenocarcinoma of the endometrium. Secondary goals include identification of prognostic factors and the comparison of toxicity profiles after vaginal cuff brachytherapy (VB) alone or combined with pelvic external beam radiation therapy (EXT). MATERIALS AND METHODS All patients receiving adjuvant radiation at the University of Wisconsin following surgery for FIGO stage II adenocarcinoma of the endometrium between January 1991 and December 2006 were retrospectively reviewed. RESULTS Between January 1991 and December 2006, 71 patients with FIGO stage II adenocarcinoma of the endometrium (23 stage IIA, 48 stage IIB) received adjuvant radiation at the University of Wisconsin. Fifty patients were treated with EXT and VB, twenty with VB alone, and one with EXT alone. At a mean follow-up of 5.1 years (range, 0.5-16.8 years), 5-year overall and disease-free survival were both 82%. Factors associated with an increased risk for recurrence include depth of myometrial invasion (p=0.005) and lymphovascular invasion (p=0.02). Receiving EXT was significantly associated with increased depth of myometrial invasion (p=0.007), higher grade (p=0.003), and less extensive surgery (p=0.01). Of the nine recurrences, three were initially local and six were distant recurrences alone. Grade 2 or greater acute and late side effects were significantly greater with EXT therapy compared to VB alone (p<0.0001 and p=0.02, respectively), although severe toxicities (grade 3 or greater) were limited with either modality. DISCUSSION Local recurrence rates remain low after surgery and adjuvant radiation therapy for stage II endometrial cancer using a combination of VB and EXT tailored to the surgical and pathologic features. VB alone resulted in fewer toxicities without an increased recurrence risk compared to the combination of EXT and VB, suggesting that VB without EXT is sufficient for patients with low-risk histopathologic features and comprehensive surgical staging with complete lymphadenectomy.