Water only fasting and its effect on chemotherapy administration in gynecologic malignancies.

OBJECTIVE: As a protective response, during starvation organisms withdraw energy from growth and reproduction to focus on cellular maintenance. Cancer cells cannot undergo this differential response which has been theorized as an adjunct to improve both the effect of chemotherapy treatment and reduce treatment side effects. We sought to investigate the feasibility and effect of short-term fasting in patients receiving chemotherapy for gynecologic malignancy. METHODS: A randomized control trial was conducted of women with gynecologic malignancies receiving at least 6 planned chemotherapy cycles. Fasting patients maintaining a water-only fast for 24 h before and 24 h following each chemotherapy cycle were compared to nonfasting patients. Treatment related side effects and quality of life (QOL) was assessed using NCCN-FACT FOSI-18 questionnaire. RESULTS: Analysis included data from 120 cycles of chemotherapy. The majority of patients had stage 3 and 4 malignancy requiring multi-agent chemotherapy. Eleven patients had ovarian, 8 had uterine, and 1 had cervical cancer. Ninety percent received taxane and platinum-based doublet therapy. Weight loss and unanticipated hospitalizations were similar between treatment groups. Fewer dose reductions or delays were seen in the fasting group. There was no significant difference in mean QOL scores, but fasting group QOL scores improved over the course of treatment to a level that reached the minimal clinically important difference. CONCLUSION: A 48-h fast is well tolerated without increasing weight loss, hospital admissions, or chemotherapy dose reduction/delays. Fasting resulted in fewer treatment modifications and improved quality of life scores over the course of treatment.

Loop electrosurgical excision procedure: an effective, inexpensive, and durable teaching model.

The effectiveness of simulation training for enhancing operative skills is well established. Here we describe the construction of a simple, low-cost model for teaching the loop electrosurgical excision procedure. Composed of common materials such as polyvinyl chloride pipe and sausages, the simulation model, shown in the accompanying figure, can be easily reproduced by other training programs. In addition, we also present an instructional video that utilizes this model to review loop electrosurgical excision procedure techniques, highlighting important steps in the procedure and briefly addressing challenging situations and common mistakes as well as strategies to prevent them. The video and model can be used in conjunction with a simulation skills laboratory to teach the procedure to students, residents, and new practitioners.

High grade primitive neuroectodermal tumor of the uterus: A case report.

•Primitive neuroectodermal tumor of the uterus is extremely rare.•Diagnosis requires timely evaluation with molecular analysis.•Different combinations of adjuvant chemotherapy have been reported.

A tumor-stroma targeted oncolytic adenovirus replicated in human ovary cancer samples and inhibited growth of disseminated solid tumors in mice.

Targeting the tumor stroma in addition to the malignant cell compartment is of paramount importance to achieve complete tumor regression. In this work, we modified a previously designed tumor stroma-targeted conditionally replicative adenovirus (CRAd) based on the SPARC promoter by introducing a mutated E1A unable to bind pRB and pseudotyped with a chimeric Ad5/3 fiber (Ad F512v1), and assessed its replication/lytic capacity in ovary cancer in vitro and in vivo. AdF512v1 was able to replicate in fresh samples obtained from patients: (i) with primary human ovary cancer; (ii) that underwent neoadjuvant treatment; (iii) with metastatic disease. In addition, we show that four intraperitoneal (i.p.) injections of 5 × 10(10) v.p. eliminated 50% of xenografted human ovary tumors disseminated in nude mice. Moreover, AdF512v1 replication in tumor models was enhanced 15-40-fold when the tumor contained a mix of malignant and SPARC-expressing stromal cells (fibroblasts and endothelial cells). Contrary to the wild-type virus, AdF512v1 was unable to replicate in normal human ovary samples while the wild-type virus can replicate. This study provides evidence on the lytic capacity of this CRAd and highlights the importance of targeting the stromal tissue in addition to the malignant cell compartment to achieve tumor regression.

Incidence of mechanical malfunction in low-profile subcutaneous implantable venous access devices in patients receiving chemotherapy for gynecologic malignancies.

OBJECTIVE: The purpose of this study was to investigate the incidence of mechanical complications associated with low-profile subcutaneous implantable venous access devices in gynecologic oncology patients. METHODS: Gynecologic oncology patients with low-profile Port-a-Caths implanted between March 2005 and July 2006 were identified into a computerized database. Patient demographics, operative complications, number of chemotherapy cycles, duration of implantation, and mechanical complications were collected. Primary outcomes included port leakage, catheter fracture, and catheter embolization. RESULTS: 112 patients underwent 115 Port-a-Cath placements with low profile single-lumen plastic ports with Groshong-valved catheters. Mean Port-a-Cath indwelling duration was 197 days (range: 4-395) with a mean number of 12 chemotherapy cycles (range 0-64). The cumulative complication rate necessitating removal or replacement was 15%. Of the 14 Port-a-Caths removed, ten (8.7%) were secondary to mechanical malfunction: one for leakage at the port site, two for catheter fracture, and seven for fracture with catheter embolization to the heart or pulmonary vasculature-most commonly the right ventricle. Patients with embolization were asymptomatic and all embolized catheters were successfully retrieved by interventional radiology without complications. CONCLUSIONS: The rates of catheter fracture and embolization have previously been reported to be low in patients with subcutaneous Port-a-Caths, and have not been studied in patients receiving low-profile subcutaneous Port-a-Caths. This study suggests that catheter fracture may be more common (8.7%) and must be considered in patients with malfunctioning low-profile Port-a-Caths. Embolized catheters can be removed by interventional radiology without significant adverse affects.

A cohort study evaluating robotic versus laparotomy surgical outcomes of obese women with endometrial carcinoma.

OBJECTIVE: Minimally invasive surgery offers advantages for management of obese patients, but technical difficulty often deters its utilization. Compared to laparotomy, robotic surgery should allow comparable staging and improved surgical outcomes. Therefore, we evaluated outcomes in robotic and laparotomy cohorts of obese women with endometrial cancer at our institution. METHODS: Retrospective robotic and laparotomy cohorts of obese women (BMI ≥ 30 kg/m(2)) undergoing surgical management of primary endometrial cancer from March 2006 to March 2009 were formulated utilizing a computerized database. Patient demographics, operative statistics, peri-operative complications, and pathologic details were collected in an intent to treat analysis. Chi-square or Fisher's exact test and t-test were used for statistical analysis. RESULTS: 73 women underwent robotic surgical management, 11% converted to laparotomy. Mean BMI (39.8 vs. 41.9, p=0.152), number of co-morbidities (2.49 vs. 2.62, p=0.690), number of previous surgeries (0.97 vs. 0.94, p=0.841), and lymphadenectomies performed (65.8% vs. 56.7%, p=0.227) were similar between cohorts. Total lymph nodes obtained were not statistically different between cohorts (8.01 vs. 7.24, p=0.505). Total operative time and room time was significantly longer for robotic surgery; however, estimated blood loss, the percentage of patients receiving transfusion, hospital length of stay, wound complications (4.1% vs. 20.2%, p=0.002) and other complications (9.6% vs. 29.8%, p=0.001) were improved for the robotic cohort. CONCLUSIONS: Robotic management of obese women with endometrial cancer yields acceptable staging results and improved surgical outcomes. Although operating time is longer, hospital time is shorter. Robotic surgery may be an ideal approach for these patients.

Conditionally replicating adenovirus expressing TIMP2 for ovarian cancer therapy.

PURPOSE: Current treatments for ovarian cancer have limited therapeutic outcomes due to advanced stage of the disease at diagnosis. Among new therapies, conditionally replicating adenoviruses (CRAds), designed to selectively lyse cancer cells, hold promise. In clinical trials, CRAds exhibited limited efficacy thus far. Second-generation CRAds are being developed to express a therapeutic protein to enhance antitumor efficacy. One attractive target in the tumor microenvironment is the matrix metalloproteinases (MMPs) that degrade the extracellular matrix, and are upregulated in ovarian cancer. Tissue inhibitor of metalloproteinase 2 (TIMP2) is an endogenous inhibitor of MMPs. The present study developed and evaluated a novel CRAd (Ad5/3-CXCR4-TIMP2) for ovarian cancer therapy. EXPERIMENTAL DESIGN: A targeted CRAd, Ad5/3-CXCR4-TIMP2 was developed using the CXCR4 promoter for enhanced replication, and expressing the TIMP2 transgene. The efficacy of this armed CRAd was determined in both established human ovarian cancer cell lines and in primary ovarian tumor samples. RESULTS: Ad5/3-CXCR4-TIMP2 mediated expression of functional TIMP2, as demonstrated by the inhibition of MMP activity. In addition, arming with TIMP2 did not inhibit viral replication or oncolytic potency, as the TIMP2-armed viruses showed enhanced killing of cancer cells when compared to the unarmed viruses. We also examined viral replication in primary ovarian cancer tissues obtained from patients with stage III and IV ovarian cancer. In four of the five tumor samples, Ad5/3-CXCR4-TIMP2 revealed a 21- to 89-fold increase in replication when compared to the Ad5/3 virus. CONCLUSION: Results support the translational potential of Ad5/3-CXCR4-TIMP2 for treatment of patients with advanced ovarian cancer.

Impact of a weekly multidisciplinary tumor board conference on the management of women with gynecologic malignancies.

BACKGROUND: The objective of this study was to evaluate the impact of a weekly tumor board conference on the management of patients with gynecologic malignancies. METHODS: The medical records of consecutive patients referred to a multidisciplinary gynecologic oncology tumor board were reviewed. Patient demographics were abstracted from medical records and tumor board minutes. An evaluation was made whether the pathological or radiological findings were changed by the tumor board consultants. If a discrepancy existed, it was determined whether the change impacted clinical management. RESULTS: From January 2004 to December 2006, 741 patients presented at the tumor board were evaluable. Seventy-one percent of the patients were presented for pathology review and 29% for radiology review. The most common diagnoses were ovarian cancer (29%), endometrial cancer (26%), and cervical cancer (12%). Of the 526 pathology reviews, 27% had a change in diagnosis; this discrepancy altered clinical management 74% of the time (20% of all reviews). Of the 215 radiology presentations, 89% were reviewed to confirm recurrent or persistent disease; malignant disease was confirmed 74% of the time. Review of imaging studies resulted in a new diagnosis or upstaging 10% of the time. CONCLUSIONS: A multidisciplinary tumor board allows a wide range of gynecologic diagnoses and clinical scenarios to be discussed. Careful review of pathology results in a change in the clinical management of 20% of patients presented at the tumor board. The majority of radiology reviews are presented to confirm persistent or recurrent cancer before recommending further therapy.

A phase I study of a tropism-modified conditionally replicative adenovirus for recurrent malignant gynecologic diseases.

PURPOSE: To determine the maximum tolerated dose (MTD), toxicity spectrum, clinical activity, and biological effects of the tropism-modified, infectivity-enhanced conditionally replicative adenovirus (CRAd), Ad5-Δ24-Arg-Gly-Asp (RGD), in patients with malignant gynecologic diseases. EXPERIMENTAL DESIGN: Cohorts of eligible patients were treated daily for 3 days through an i.p. catheter. Vector doses ranged from 1 × 10(9) to 1 × 10(12) viral particles per day. Toxicity was evaluated using CTCv3.0. CA-125 and Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to determine clinical efficacy. Corollary biological studies included assessment of CRAd replication, wild-type virus generation, viral shedding, and neutralizing antibody response. RESULTS: Twenty-one patients were treated. Adverse clinical effects were limited to grade 1/2 fever, fatigue, or abdominal pain. No vector-related grade 3/4 toxicities were noted. No clinically significant laboratory abnormalities were noted. The maximum tolerated dose was not reached. Over a 1 month follow-up, 15 (71%) patients had stable disease and six (29%) had progressive disease. No partial or complete responses were noted. Seven patients had a decrease in CA-125; four had a >20% drop. RGD-specific PCR showed the presence of study vector in ascites of 16 patients. Seven revealed an increase in virus after day 3, suggesting replication of Ad5-Δ24-RGD. Minimal wild-type virus generation was detected. Viral shedding studies showed insignificant shedding in the serum, saliva, and urine. Anti-adenoviral neutralizing antibody effects were prevalent. CONCLUSIONS: This study, the first to evaluate an infectivity-enhanced CRAd in human cancer, shows the feasibility, safety, potential antitumor response, and biological activity of this approach in ovarian cancer. Further evaluation of infectivity enhanced virotherapy approaches for malignant gynecologic diseases is warranted.

Novel infectivity-enhanced oncolytic adenovirus with a capsid-incorporated dual-imaging moiety for monitoring virotherapy in ovarian cancer.

We sought to develop a cancer-targeted, infectivity-enhanced oncolytic adenovirus that embodies a capsid-labeling fusion for noninvasive dual-modality imaging of ovarian cancer virotherapy. A functional fusion protein composed of fluorescent and nuclear imaging tags was genetically incorporated into the capsid of an infectivity-enhanced conditionally replicative adenovirus. Incorporation of herpes simplex virus thymidine kinase (HSV-tk) and monomeric red fluorescent protein 1 (mRFP1) into the viral capsid and its genomic stability were verified by molecular analyses. Replication and oncolysis were evaluated in ovarian cancer cells. Fusion functionality was confirmed by in vitro gamma camera and fluorescent microscopy imaging. Comparison of tk-mRFP virus to single-modality controls revealed similar replication efficiency and oncolytic potency. Molecular fusion did not abolish enzymatic activity of HSV-tk as the virus effectively phosphorylated thymidine both ex vivo and in vitro. In vitro fluorescence imaging demonstrated a strong correlation between the intensity of fluorescent signal and cytopathic effect in infected ovarian cancer cells, suggesting that fluorescence can be used to monitor viral replication. We have in vitro validated a new infectivity-enhanced oncolytic adenovirus with a dual-imaging modality-labeled capsid, optimized for ovarian cancer virotherapy. The new agent could provide incremental gains toward climbing the barriers for achieving conditionally replicated adenovirus efficacy in human trials.

Comprehensive surgical staging for endometrial cancer in obese patients: comparing robotics and laparotomy.

OBJECTIVE: To compare adequacy and outcomes of surgical staging for endometrial cancer in obese women by robotics or laparotomy. METHODS: Clinical stage I or occult stage II endometrial cancer patients with body mass indexes (BMIs) of at least 30 (BMI is calculated as weight (kg)/[height (m)]2) were identified undergoing robotic staging and matched 1:2 with laparotomy patients. Patient characteristics, operative times, complications, and pathologic factors were collected. An adequate lymphadenectomy was defined arbitrarily as at least 10 total nodes removed, and adequate pelvic and paraaortic lymphadenectomy was defined as at least six and at least four nodes removed, respectively. RESULTS: A total of 109 patients underwent surgery with the intent of robotic staging and were matched to 191 laparotomy patients. The mean BMI was 40 for each group. The robotic conversion rate was 15.6% (95% confidence interval [CI] 9.5-24.2%). Ninety-two completed robotic patients were compared with 162 matched laparotomy patients. The two groups were comparable regarding total lymph node count (25 +/- compared with 24 +/- 12, P =.45) and the percentage of patients undergoing adequate lymphadenectomy (85% compared with 91%, P=.16) and adequate pelvic (90% compared with 95%, P=.16) and aortic lymphadenectomy (76% compared with 79%, P=.70) for robotic and laparotomy patients, respectively, but there was limited power to detect this difference. The blood transfusion rate (2% compared with 9%, odds ratio [OR] 0.22, 95% CI 0.05-0.97, P=.046), the number of nights in the hospital (1 compared with 3, P<.001), complications (11% compared with 27%, OR 0.29, 95% CI 0.13-0.65 P=.003), and wound problems (2% compared with 17%, OR 0.10, 95% CI 0.02-0.43, P=.002) were reduced for robotic surgery. CONCLUSION: In obese women with endometrial cancer, robotic comprehensive surgical staging is feasible. Importantly, obesity may not compromise the ability to adequately stage patients robotically. LEVEL OF EVIDENCE: II

Conservative management of postoperative Fever in gynecologic patients undergoing major abdominal or vaginal operations.

BACKGROUND: To develop a standardized protocol for management of postoperative fever in gynecology patients to decrease unnecessary diagnostic workups and empiric use of antibiotics. STUDY DESIGN: A prospective analysis of postoperative gynecology patients identified those who experienced fever (maximum temperature [T(max)] > 100.4 degrees F). Patients were triaged into low- and high-risk groups. High-risk patients were managed independent of the protocol. High-risk criteria included bowel operation, preoperative infection, immunodeficiency, indwelling vascular access, mechanical heart valves, and intensive care unit admissions. Low-risk patients were treated with observation and antipyretics. Patients with persistent or high fever, defined as T(max) > 101 degrees F for > 48 hours, were evaluated and treated based on physical examination findings. RESULTS: We evaluated 292 postoperative patients. Forty-seven percent of patients had a final diagnosis of malignancy. Sixty-four patients were high-risk and 33% of these patients experienced fever. Using the standardized protocol, 228 low-risk patients were managed. Thirty-seven of the 228 patients (16%) had fever postoperatively. Nineteen patients had low-grade fever (100.4 to 101 degrees F); none of these patients required antibiotics. Seventeen patients had fever (101.1 to 102 degrees F) and one patient had fever > 102 degrees F. Using the protocol, 6 of 37 patients (16%) were treated with antibiotics for an infectious diagnosis. CONCLUSIONS: Although postoperative fever is common in gynecologic patients, the incidence of infection is low (3%). A standardized postoperative fever protocol in low-risk gynecology patients decreases use of empiric antibiotics without compromising morbidity.

A phase I study of lapatinib in combination with carboplatin in women with platinum sensitive recurrent ovarian carcinoma.

OBJECTIVES: To determine the maximum tolerated dose (MTD), spectrum of toxicities, clinical activity, and pharmacokinetics of carboplatin given in combination with lapatinib in women with a first recurrence of platinum sensitive epithelial ovarian carcinoma. METHODS: Patients with measurable, platinum sensitive recurrent epithelial ovarian carcinoma were eligible. Cohorts of 3-6 patients were to receive up to 6 cycles of intravenous carboplatin AUC of 6 every 21 days in combination with escalating dosages of oral lapatinib (starting at a dose of 750 mg daily). Toxicity was assessed using NCI CTC for Adverse Events. Clinical response was monitored using RECIST criteria. Pharmacokinetic (PK) analysis was performed for the second cohort of patients. RESULTS: Twelve patients were enrolled. No dose limiting toxicity was noted. Two of 6 patients in the first cohort had unanticipated excessive delays in treatment due to non-dose limiting G3 neutropenia. Therefore, the study was modified to reduce the carboplatin dose in the second cohort. The median number of courses administered to the 11 evaluable patients in these two cohorts was 2.8 (range 1-6). Drug-related grade 3 or 4 toxicities included non-dose limiting G4 thrombocytopenia (n=1), and non-dose limiting G3 neutropenia (n=3). Of the 11 patients who received >or=1 course of therapy, 3 (27%) had a partial response, and 3 (27%) had stable disease. The pharmacokinetics of carboplatin were not significantly altered by concomitant administration of lapatinib. CONCLUSIONS: This regimen of lapatinib and carboplatin was associated with unacceptable non-dose limiting toxicities, excessive treatment delays and limited clinical responses.

Effecting the sixth core competency: a project-based curriculum.

OBJECTIVE: In agreement with the Accreditation Council for Graduate Medical Education guidelines, a systems-based practice (SBP) curriculum was implemented to provide a hands-on, team-based experience, while providing an opportunity to contribute to quality improvement, and to develop a method to assess residents' understanding of SBP. STUDY DESIGN: During departmental conferences, issues affecting our health care operations were identified. Seven teams were formed and the actionable items were investigated. The salient issues and potential solutions were presented to the department. RESULTS: This project resulted in the development of tools designed to assess competency in SBP, communication skills, and professionalism. Completion of a pre- and posttest and annual oral examination questions revealed a significant improvement in the comprehension of SBP. CONCLUSION: This project served as an effective educational forum for the competencies of SBP, communication skills, and professionalism. This initiative also offered improvement of patient care and/or educating peer providers, thereby fulfilling the goal of SBP in the process of education.

Expression of c-kit and platelet-derived growth factor receptors in ovarian granulosa cell tumors.

OBJECTIVE: This study aimed at evaluating the expression of tyrosine kinase receptors c-kit, (platelet-derived growth factor receptor-alpha (PDGFR-alpha), and PDGFR-beta in ovarian granulosa cell tumors (GCTs). STUDY DESIGN: Primary ovarian GCT specimens were obtained for immunohistochemical staining.The expressions of c-kit, PDGFR-alpha, and PDGFR-beta were analyzed and scored by a semiquantitative (SQ) method. Normal ovarian tissue from the same patients' specimens served as internal controls. RESULTS: A total of 21 specimens were available for evaluation. C-kit was expressed in only 2 samples, whereas both PDGFR-alpha and PDGFR-beta stained positive in 100% of tumors. PDGFR targets demonstrated strong positive expression in intensity and amount of tissue stained. Normal ovarian tissue demonstrated complete absence of staining for all 3 antibodies evaluated. CONCLUSIONS: The data demonstrated significant expression of PDGFR targets of imatinib mesylate in GCTs, whereas normal ovarian tissues had a complete absence of staining.This expression profile provides the rationale to investigate the role of imatinib mesylate in PDGFR-positive GCTs.

Diffuse endometritis in the setting of umbilical endometriosis: a case report.

BACKGROUND: Umbilical endometriosis is rare and can be a challenging diagnosis in the absence of classic signs and symptoms. CASE: A case of severe, primary, spontaneous umbilical endometriosis with foci of plasma cell endometritis and diffuse stromal lymphovascular presence occurred. CONCLUSION: Despite a lengthy differential, endometriosis must be considered in the evaluation of an umbilical mass. The presence of plasma cell endometritis and stromal lymphovascular elements in the absence of pelvic endometriosis lends evidence to the theory of lymphovascular transport as an etiology of extrapelvic endometriosis.

Cytology versus high-risk HPV testing for follow-up of HPV-positive women without CIN.

Screening for cervical cancer is often considered the success story for cancer screening in the United States. However, much room for improvement still exists. For example, experts have yet to establish the best follow-up strategy for women with an abnormal Papanicolaou test and high-risk human papillomavirus (HPV) followed by a normal colposcopy or biopsy that is negative for cervical intraepithelial neoplasia. The incorporation of HPV testing has allowed the development of a more sensitive and cost-efficient strategy. This article presents a brief overview of related guidelines and current modalities, and reviews selected studies. Finally, future directions and a possible schema for clinical management of these patients are included.

The honeymoon is over.

BACKGROUND: The importance of a broad differential diagnosis is highlighted by a complex patient case. CASE: A young woman returned from her honeymoon complaining of activity-limiting pain. The evaluation revealed multiple constitutional symptoms, a breast mass, a large pelvic mass, pulmonary abnormalities, an external iliac venous thrombosis, and lytic bone lesions. Biopsies from several sites revealed no evidence of neoplasia. CONCLUSION: Consideration of potential etiologies outside of one's practice specialty may be necessary to make a correct diagnosis.

Gene therapy for ovarian cancer.

Ovarian cancer remains the leading cause of death due to gynecologic cancer in women in the United States. Gene and viral-based therapies represent novel therapeutic approaches for cancer. The manipulation of genetic content of tumor cells toward a therapeutic end has been divided into several general strategies, including molecular chemotherapy, mutation compensation, immunopotentiation, and virotherapy. Improvements in delivery vehicles and in evaluation of gene transfer and viral replication remain important areas of investigation. We highlight the most recent advances in these novel therapeutic approaches for ovarian cancer and include a summary of recent clinical trials.

Unilateral cervical cancer in a patient with cervix duplex.

BACKGROUND: Although uterine anomalies are uncommon, gynecologists must be aware of the anatomical challenges that may be encountered from these anomalies. Cervical cancer in the context of a mullerian lateral fusion defect is rare. CASE: A case of a unilateral IB1 squamous cell carcinoma of the cervix in the setting of a complete uterovaginal septum and cervix duplex is described. CONCLUSION: Uterine anomalies compound diagnostic difficulty of routine pathology. Thorough examination and evaluation are crucial for timely diagnosis and treatment. Genital tract duplication, although rare, should always be considered.