Jonathan D. Boone

The utilization of palliative care in gynecologic oncology patients near the end of life

BACKGROUND Palliative and supportive care services provide excellent care to patients near the end of life. It is estimated that enrollment in such services can reduce end-of-life costs; however, there is limited data available regarding the impact of palliative services in end-of-life care in gynecologic oncology patients. We examined the use of palliative services in gynecologic oncology patients during the last six months of life. METHODS After IRB approval, a retrospective chart review of patients with a diagnosis of a gynecologic malignancy who died between June 2007 and June 2010 was performed. Abstracted data included demographics, admission and procedural history, use of anti-cancer therapy, and palliative care utilization during the last six months of life. RESULTS 268 patients were identified. Most patients were white (76.9%) and had ovarian cancer (56.7%). During the last six months of life, 155 (57.8%) patients underwent anti-cancer therapy with chemotherapy, 19 (7.1%) patients were treated with radiation therapy, and 17 patients (6.3%) underwent treatment with both. 218 patients (81.3%) had at least one admission during this time (range 0-14). The most common reason for admission was gastrointestinal complaints (37.1%), followed by admissions for procedures (18.3%). The median time between the last admission and death was 32 days. 157 patients (58.6%) underwent at least one procedure during the last six months of life (range 0-11). The most common procedure performed was paracentesis (22.6%). 198 (73.9%) patients died at home or in a palliative care unit. 189 (70.5%) patients were referred to hospice or palliative care. 3.2% underwent a procedure or treatment with chemotherapy or radiation after hospice enrollment. The median time between hospice enrollment and death was 22 days. 55% of patients were enrolled in hospice less than 30 days before death. Of the 79 patients not referred to hospice, only 16.5% had documentation of refusing hospice services. CONCLUSIONS During the last six months of life, the majority of gynecologic oncology patients receive anticancer therapy and many have repeated hospital admissions. While the majority of patients are referred for palliative care, it appears that most patients spend less than 30 days on hospice. Earlier referral could decrease the number of hospital admissions and procedures while providing invaluable support during this end of life transition.

New insights into cervical cancer screening

Worldwide, cervical cancer is a leading cause of cancer related morbidity and mortality. For over 50 years, cervical cytology has been the gold standard for cervical cancer screening. Because of its profound effect on cervical cancer mortality in nations that have adopted screening programs, the Pap smear is widely accepted as the model screening test. Since its introduction, many studies have analyzed the Pap smear and found that it is not without its shortcomings including low sensitivity for detection of cervical intraepithelial neoplasia 2/3. Additionally, the discovery of infection with the human papillomavirus (HPV) as a necessary step in the development of cervical cancer has led to the development of HPV testing as an adjunct to cytology screening. More recently, researchers have compared HPV testing and cytology in the primary screening of cervical cancer. In this review, we will discuss cytologic testing limitations, the role of HPV DNA testing as an alternative screening tool, the impact of the HPV vaccine on screening, and future directions in cervical cancer screening.

Laparoscopic Fluorescent Visualization of the Ureter With Intravenous IRDye800CW

OBJECTIVES Ureter injury is a serious complication of laparoscopic surgery. Current strategies to identify the ureters, such as placement of a ureteral stent, carry additional risks for patients. We hypothesize that the systemically injected near-infrared (NIR) dye IRDye800CW-CA can be used to visualize ureters intraoperatively. METHODS Adult female mixed-breed pigs weighing 24 to 41 kg (n = 2 per dose) were given a 30, 60, or 120 μg/kg systemic injection of IRDye800CW-CA. Using the Food and Drug Administration-cleared Pinpoint laparoscopic NIR system, images of the ureter and bladder were captured every 10 minutes for 60 minutes after injection. To determine the biodistribution of the dye, tissues were collected for ex vivo analysis with the Pearl Impulse system. ImageJ software was used to quantify fluorescence signal and signal-to-background ratio (SBR) for the intraoperative images. RESULTS The ureter was identified in all pigs at each dose, with peak intensity reached by 30 minutes and remaining elevated throughout the duration of imaging (60 minutes). The 60 μg/kg dose was determined to be optimal for differentiating ureters according to absolute fluorescence (>60 counts/pixel) and SBR (3.1). Urine fluorescence was inversely related to plasma fluorescence (R(2) = -0.82). Ex vivo imaging of kidney, ureter, bladder, and abdominal wall tissues revealed low fluorescence. CONCLUSION Systemic administration of IRDye800CW-CA shows promise in providing ureteral identification with high specificity during laparoscopic surgery. The low dose required, rapid time to visualization, and absence of invasive ureteral instrumentation inherent to this technique may reduce complications related to pelvic surgery.

Ovarian and cervical cancer patient derived xenografts: The past, present, and future

Preclinical research in gynecologic malignancies has largely relied upon cloned cancer-derived cell lines and tumor xenografts derived from these cell lines. Unfortunately, the use of cell lines for translational research has disadvantages because genetic and phenotypic alterations from serial passaging have resulted in expression profiles that are different from the original patient tumors. The patient-derived xenograft (PDX) model derived from human tumor not previously cultured has shown better representation of the heterogeneity of gynecologic malignancies and the human tumor microenvironment with preservation of cytogenetics, cellular complexity, and vascular and stromal tumor architecture. Studies have shown promise with these models to analyze tumor development and adaptation, test drug efficacy, and predict clinical outcomes. Their ultimate value may be seen with preclinical drug screening including novel targeted therapies, biomarker identification, and the development of individualized treatment plans. This article reviews PDX model development, current studies testing chemotherapeutics and targeted therapies, and limitations of the PDX model in gynecologic malignancies.

Targeting the Wnt/ β -catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974

Preclinical studies in ovarian cancer have demonstrated upregulation of the Wnt/β-catenin pathway promoting tumor proliferation and chemoresistance. Our objective was to evaluate the effect of the Wnt/β-catenin pathway inhibitor, WNT974, in primary ovarian cancer ascites cells. Ascites cells from patients with papillary serous ovarian cancer were isolated and treated with 1 μM WNT974±100 μM carboplatin. Viability was evaluated with the ATPlite assay. The IC50 was calculated using a dose–response analysis. Immunohistochemistry (IHC) was performed on ascites cells and tumor. Expression of R-spondin 2 (RSPO2), RSPO3, PORCN, WLS, AXIN2, and three previously characterized RSPO fusion transcripts were assessed using Taqman assays. Sixty ascites samples were analyzed for response to WNT974. The ascites samples that showed a decrease in ATP concentration after treatment demonstrated no difference from the untreated cells in percent viability with trypan blue staining. Flow cytometry demonstrated fewer cells in the G2 phase and more in the G1 and S phases after treatment with WNT974. Combination therapy with WNT974 and carboplatin resulted in a higher percentage of samples that showed ≥30% reduction in ATP concentration than either single drug treatment. IHC analysis of Wnt pathway proteins suggests cell cycle arrest rather than cytotoxicity after WNT974 treatment. QPCR indicated that RSPO fusions are not prevalent in ovarian cancer tissues or ascites. However, higher PORCN expression correlated to sensitivity to WNT974 (P=0.0073). In conclusion, WNT974 produces cytostatic effects in patient ascites cells with primary ovarian cancer through inhibition of the Wnt/β-catenin pathway. The combination of WNT974 and carboplatin induces cytotoxicity plus cell cycle arrest in a higher percentage of ascites samples than with single drug treatment. RSPO fusions do not contribute to WNT974 sensitivity; however, higher PORCN expression indicates increased WNT974 sensitivity.

Incidence of port site hernias and/or dehiscence in robotic-assisted procedures in gynecologic oncology patients.

OBJECTIVES The incidence of port site hernia and/or dehiscence using bladeless trocars is 0-1.2%. Robotic surgery uses additional port sites and increases manipulation of instruments, raising the concern for more complications. We sought to characterize the incidence of port site complications following robotic surgery when fascia was not routinely closed. METHODS Robotically-assisted (RA) procedures performed for suspected gynecologic malignancy between 1/2006 and 12/2011 were retrospectively reviewed. Bladeless 12 mm and 8mm robotic trocars were used. Fascial closure was not routinely performed except after specimen removal through the port site. The decision to close the fascia remained at the discretion of the surgeon. RESULTS Data from 842 procedures were included. Mean patient age was 55.6 years. Mean Body Mass Index was 33.6 kg/m(2). RA-total laparoscopic hysterectomy (TLH)± unilateral or bilateral salpingo-oophorectomy (BSO)± lymphadenectomy (LND) accounted for 91.6% of procedures. Final pathology confirmed malignancy in 58.6% of cases, primarily endometrial cancer. In 35 cases, the specimen was removed through the port site; fascia was closed in 54.3% of them and no port site hernias or dehiscences occurred. Only one patient underwent a RA-TLH/BSO/LND for endometrial adenocarcinoma and had a port site dehiscence of the 8mm trocar site. No port site hernias occurred. CONCLUSION Port site hernias and dehiscences are rare in RA gynecologic oncology procedures. When bladeless dilating trocars are used, routine closure of even up to a 12 mm port site is unnecessary, even in cases requiring removal of the specimen through the trocar sites.

Improved outcomes with dose-dense paclitaxel-based neoadjuvant chemotherapy in advanced epithelial ovarian carcinoma

OBJECTIVE We compared tolerability, toxicity, response, and interval debulking surgery (IDS) outcomes between patients who received weekly dose-dense paclitaxel (DDP) and every three-week platinum to standard every three-week taxane plus platinum neoadjuvant chemotherapy (NACT) for advanced epithelial ovarian cancer (EOC). METHODS We conducted a retrospective study of patients receiving NACT at our center between June 1, 2012 and July 31, 2015. Patients with stage III/IV EOC who received at least one cycle of DDP (weekly paclitaxel plus every three-week carboplatin) or standard taxane (every three-week paclitaxel or docetaxel plus carboplatin) therapy were included. Abstracted data included demographics, tolerability, grade 3/4 toxicity, response, and IDS outcomes. Fishers exact and student t-test were used for statistical significance. RESULTS Twenty-one patients received DDP and 40 received standard taxane. Tolerability was comparable. More patients receiving DDP experienced grade 3 or 4 toxicity when considered in aggregate (86% vs. 40%; p=0.001). Pathologic complete response (pCR) was achieved in 14% of DDP patients versus 3% of standard (p=0.11). 48% of patients in the DDP group were debulked to no residual disease (NRD) versus 28% in the standard group (p=0.16). CONCLUSIONS While associated with an increase in severe toxicity compared to standard three-week taxane, DDP appears to facilitate higher rates of pCR and NRD for patients receiving NACT in this preliminary study. These results warrant further investigation of DDP for patients with advanced EOC and assessment of impact on long-term survival outcomes.

The effect of the APPRISE mandate on use of erythropoiesis-stimulating agents and transfusion rates in patients with ovarian cancer receiving chemotherapy.

Objective Erythropoiesis-stimulating agents (ESAs) support chemotherapy-induced anemia in patients with epithelial ovarian cancer (EOC). In response to research demonstrating that ESAs increase tumor growth and shorten survival, the Food and Drug Administration mandated the new APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) guidelines for consenting patients before ESAs administration. We sought to quantify the change in ESA and red blood cell (RBC) transfusion use after the APPRISE mandate was instituted. Methods/Materials After institutional review board approval, a retrospective chart review compared patients with EOC undergoing chemotherapy before and after the APPRISE mandate. Abstracted data included patient demographics, chemotherapy treatment status and regimen, and number of patients requiring ESAs or RBCs. A cost savings analysis was also performed. Results Eighty-four patients who underwent 367 cycles of chemotherapy after the APPRISE guidelines were compared with a matched set of 88 patients receiving 613 cycles of chemotherapy before the APPRISE guidelines. There were no statistically significant differences between the groups. Most patients had advanced stage disease and received primary taxane-/platinum-based chemotherapy. Of 88 patients, 45 (51%) in the pre-APPRISE group received a total of 196 ESA injections compared with 0 patients in the post-APPRISE group. Red blood cell transfusion in the post-APPRISE group was similar to that in the pre-APPRISE group (8.3% vs 14.8%, P = 0.28). Omission of ESAs in the post-APPRISE group resulted in a roughly

Does Obesity Affect Pathologic Agreement of Initial and Final Tumor Grade of Disease in Endometrial Cancer Patients

700,000 savings in billable charges. Conclusions In our institution, the APPRISE guidelines have resulted in complete cessation of the use of ESAs in patients with primary or recurrent EOC, resulting in considerable cost savings. Importantly, RBC transfusion rates did not significantly increase after the guidelines were imposed.

Early warning score: An indicator of adverse outcomes in postoperative patients on a gynecologic oncology service

Objectives The objectives of this study were to compare preoperative and postoperative tumor grade to determine if surgical staging decisions for endometrial cancer based on preoperative biopsy are feasible and whether obesity affects the agreement. Methods A retrospective cohort study of women with endometrial cancer between January 2010 and December 2011 was performed. Demographics, stage of final pathology, biopsy method, preoperative and postoperative tissue grade, and histology were abstracted and stratified by patient body mass index (obese ≥30 kg/m2 and nonobese <30 kg/m2). Patients with incomplete records or uterine sarcoma were excluded. The agreement between preoperative and postoperative tumor grade for all patients and in obese and nonobese patients was determined using weighted κ statistics. Results Four hindered forty-five patients were included: 161 nonobese patients and 284 obese patients. The proportion of preoperative sampling via office biopsy and dilation and curettage was similar in each cohort. Overall, the agreement between preoperative and postoperative pathology was only fair (weighted κ = 0.21). Stratified by body mass index, the agreement between preoperative and postoperative grade remains fair in obese and slight in nonobese patients (weighted κ = 0.21 and 0.19, respectively). Substantial increases in tumor grade from preoperative to postoperative pathologic specimens occurred in both cohorts. Conclusions Obesity does not appear to significantly alter the correlation between preoperative biopsy and final tumor grade. With only fair correlation between preoperative and postoperative pathologic evaluation, utilization of preoperative biopsy pathology results as a triage tool for surgical staging should be avoided. However, the discordance between preoperative and postoperative pathology in favor of a higher grade on final pathology in both groups may cause some surgeons to favor staging.