Jenny M. Whitworth

Lynch Syndrome in Women Less Than 50 Years of Age With Endometrial Cancer

OBJECTIVE: To estimate the frequency of mismatch repair deficiencies associated with hereditary nonpolyposis colorectal cancer, or Lynch syndrome, in women less than age 50 with endometrial cancer. METHODS: Consecutive patients less than age 50 diagnosed with endometrial adenocarcinoma were identified. Available pathologic specimens were freshly sliced, and protein expression for MLH1, MSH2, MSH6, and PMS2 was evaluated by immunohistochemistry. Slides were scored on a semiquantitative method with complete absence of any of the four proteins suggesting a deficiency. All results were confirmed by microsatellite instability testing. RESULTS: Sixty-one pathology specimens were analyzed. Twenty-one (34%) of the tumors had absence of staining of at least one of the four mismatch repair proteins determined by immunohistochemistry and confirmed by microsatellite instability testing. Obese patients were less likely than nonobese patients to have a mismatch repair deficiency (21% versus 59%, respectively). Non-obese patients had a relative risk for a mismatch repair deficiency of 5.5 (95% confidence interval 1.6–19.1; P=.01). CONCLUSION: Many women diagnosed with endometrial cancer before age 50 will have a mismatch repair deficiency discovered by immunohistochemistry and microsatellite instability testing. A number of young women diagnosed with endometrial cancer will require further genetic testing for mismatch repair mutations. LEVEL OF EVIDENCE: III

Clinical and pathologic correlates in surgical stage II endometrial carcinoma.

OBJECTIVE: To identify the surgical, pathologic, and therapeutic factors that influence outcome in patients with surgical stage II endometrial adenocarcinoma. METHODS: All patients with comprehensively staged stage II endometrial adenocarcinoma were identified. Data regarding preoperative, surgical, pathologic, adjuvant therapy, and outcomes were collected. Factors were compared with the &khgr;2 test, and survival curves were generated and compared with the log rank test. RESULTS: Of 162 patients with surgical stage II endometrial cancer, the median age was 65 years, and the median body mass index was 31.2 kg/m2. An extrafascial hysterectomy was performed in 75% of cases, whereas 25% of patients underwent radical hysterectomy. At least 10 nodes were recovered in more than 90% of cases. Stage IIA disease was present in 52% of cases, whereas stage IIB accounted for the remaining 48%. After staging, 48% of patients had adjuvant radiation therapy (16% with brachytherapy alone). The remainder received no adjuvant therapy. At a median follow-up of 26 months, 17% experienced disease recurrence. Five-year overall survival rate was 88% and disease-free survival rate was 81%. A significantly better 5-year disease-free survival rate was seen in patients undergoing radical hysterectomy compared with extrafascial hysterectomy (94% compared with 76%, P=.05). Adjuvant radiation did not lead to improved survival. CONCLUSION: In this large series of surgical stage II endometrial cancer cases, improved survival was noted relative to historical controls and in particular with radical compared with extrafascial hysterectomy. LEVEL OF EVIDENCE: II

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.

The safety and efficacy of day 1 versus day 2 administration of pegfilgrastim in patients receiving myelosuppressive chemotherapy for gynecologic malignancies

OBJECTIVE Pegfilgrastim is indicated to decrease the incidence of febrile neutropenia in patients with gynecologic malignancies who are receiving myelosuppressive chemotherapy. We sought to compare the safety and efficacy of day 1 pegfilgrastim administration to day 2 administration in patients with gynecologic malignancies. METHODS We retrospectively evaluated patients receiving both chemotherapy and pegfilgrastim from June 1, 2006 to August 31, 2007 for a gynecologic malignancy. Abstracted data included patient demographics, pathology, blood counts, toxicity, and chemotherapy. After administration of chemotherapy, all patients either received 6 mg of pegfilgrastim subcutaneously on day 1 or day 2. RESULTS 1226 administrations of pegfilgrastim in 230 patients were identified. 490 administrations of pegfilgrastim were given on day 1 compared to 736 on day 2. 70% of patients had ovarian cancer with a median age of 64 years (range 15-88). 79% of patients had stage III, IV, or recurrent disease and 67% were undergoing primary chemotherapy. The most common chemotherapy was docetaxel/carboplatin (53%) followed by paclitaxel/carboplatin (19%). The mean absolute neutrophil count (ANC) nadir was 4810/mm(3) in the day 1 cohort compared to 4212/mm(3) in the day 2 cohort (p=.004). The incidence of Grade 3/4 neutropenia was similar in both groups (4.9% in day 1 vs. 5.7% in day 2; p=.63). Grade 3/4 febrile neutropenia was uncommon in both cohorts (0 episodes vs. 3 episodes; p=.41). Treatment delays were similar in both cohorts (5.9% vs. 7.5%; p=.35). Dose modifications were also similar in both cohorts (2.8% vs. 5.3%; p=.06). CONCLUSION Day 1 administration of pegfilgrastim is as effective as day 2 administration in the prevention of neutropenia in patients with gynecologic malignancies. Treatment delays and dose modifications were not increased after day 1 administration of pegfilgrastim. Administering pegfilgrastim on day 1 appears to be safe, effective, and convenient in selected patients receiving myelopsuppressive chemotherapy for gynecologic malignancies.

The impact of novel retinoids in combination with platinum chemotherapy on ovarian cancer stem cells

OBJECTIVE Retinoids are important modulators of cell growth, differentiation, and proliferation. 9cUAB30, 9cUAB124, and 9cUAB130 are three novel retinoid compounds that show cytotoxic effects in other malignancies. We evaluated these novel retinoids in combination with chemotherapy against ovarian cancer stem cells (CSCs) in vitro and in an ex vivo model. METHODS A2780 cells were plated in 96-well plates and treated with retinoid, carboplatin, or combination therapy. Cell viability was evaluated using ATPLite assay. The A2780 cell line was also analyzed for CSCs by evaluating ALDH activity using flow cytometry. A2780 cells treated ex vivo with retinoids and chemotherapy were injected into the flank of athymic nude mice in order to evaluate subsequent tumor initiating capacity. RESULTS A2780 cells were sensitive to treatment with retinoids and carboplatin. The best treatment resulted from the combination of retinoid 9cUAB130 and carboplatin. Untreated A2780 cells demonstrated ALDH activity in 3.3% of the cell population. Carboplatin treatment enriched ALDH activity to 27.3%, while 9cUAB130±carboplatin maintained the ALDH positive levels similar to untreated controls (2.3% and 6.7%, respectively). Similar results were found in tumorsphere-forming conditions. Flank injections of ex vivo treated A2780 cells resulted in 4/4 mice developing tumors at 40 days in the untreated group, while 0/4 tumors developed in the 9cUAB130 and carboplatin treated group. CONCLUSION Combination treatment with carboplatin and retinoids reduced cell-viability, reduced CSC marker expression, and inhibited tumorigenicity, making it a more effective treatment when compared with carboplatin alone.

The management of cervical intraepithelial neoplasia during pregnancy: is colposcopy necessary?

Objective. The 2006 American Society for Colposcopy and Cervical Pathology Consensus guidelines state that it is acceptable to defer colposcopy until 6 weeks postpartum in pregnant patients with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL) cytology. Therefore, we sought to determine the incidence of cervical intraepithelial neoplasia (CIN) 2,3 in pregnant patients referred to a university colposcopy clinic. Materials and Methods. A retrospective study identified all pregnant women with abnormal cytology referred to the University of Alabama at Birmingham colposcopy clinic between May 2005 and September 2007. After an institutional review board approval was obtained, demographic information, referral cytology, and histologic data were collected. The colposcopic impression was also obtained from the records. Results. Six hundred twenty-five pregnant patients were identified. The mean age was 23 years (range, 14-44 years), the mean parity was 1 (range, 0-7), and the mean gestational age was 24 weeks (range, 4-39 weeks). The most common referral cytology was LSIL (41.0%), followed by ASC-US (34.1%), and high-grade squamous intraepithelial lesion (13.6%). One hundred thirty-eight patients (22%) underwent cervical biopsy at the time of initial colposcopy. Forty-three patients had CIN 1, 28 patients had CIN 2, and 23 patients had CIN 3. Forty-four patients (32%) had no evidence of CIN on biopsy. There were no cases of invasive cervical cancer identified. Of the 469 patients with ASC-US and LSIL cytology, 20 of 78 patients who had a cervical biopsy were diagnosed with CIN 2,3. Of the 128 patients with high-grade intraepithelial lesion or high-grade squamous intraepithelial lesion cytology, 31 of 60 patients who had a cervical biopsy were diagnosed with CIN 2,3. Repeat colposcopy in the third trimester was performed on 47 patients. Only 3 of 13 patients with a repeat biopsy had CIN 2,3. Conclusions. Pregnant patients with ASC-US or LSIL cytology rarely have colposcopically suspected CIN 2,3 at their initial colposcopy that warrants a cervical biopsy; therefore, it is reasonable to defer the initial colposcopy in patients with ASC-US and LSIL until at least 6 weeks postpartum.

Evaluating the role of IL-12 based therapies in ovarian cancer: a review of the literature

Introduction: Immunotherapy, in its entirety, represents a promising field at the forefront of cancer. Treatment with potent cytokine IL-12 has provided science with many challenges, but has also demonstrated promise as therapeutic strategy in ovarian cancer. Areas covered: This review examines the anti-tumor mechanism of action of IL-12 and the development of IL-12 as a potential therapeutic option in a variety of malignancies. It also reviews the immunogenicity of ovarian cancer and covers preclinical and clinical trials that have contributed to the advancement of IL-12 as a potential therapy for ovarian malignancy. The obstacles that researchers have overcome and currently face regarding the use of IL-12 in clinical ovarian cancer trials are also discussed. Expert opinion: IL-12, as a therapeutic modality, is mechanistically logical and shows great promise in preclinical trials. Further clinical studies are warranted to optimize the potential of IL-12 as a treatment strategy for ovarian cancer.

Double prophylaxis for deep venous thrombosis in patients with gynecologic oncology who are undergoing laparotomy: does preoperative anticoagulation matter?

Objective: Double prophylaxis for deep venous thrombosis (DVT) with thromboprophylaxis plus sequential compression devices (SCDs) is recommended for high-risk surgical patients with gynecologic oncology. Despite the use of preoperative thromboprophylaxis in clinical trials, the schedule of perioperative low molecular-weight heparin varies widely. We sought to determine the effectiveness and adverse effects of a preoperative dose of anticoagulation in patients with gynecologic oncology. Methods: A multi-institutional chart review from January 2006 to July 2008 was performed. Patients with gynecologic oncology who received double prophylaxis for laparotomy were eligible. The patients were grouped according to whether they received preoperative anticoagulation (YES PREOP vs NO PREOP). All patients received postoperative low molecular-weight heparin for thromboprophylaxis and SCDs until discharge. Demographic, surgicopathologic, and complication data were collected. Results: A total of 239 patients were identified: YES PREOP (n = 101) and NO PREOP (n = 138). Groups were similar with respect to demographics, diagnosis, and length of hospital stay. There were 2 DVTs in the YES PREOP group compared with 11 in the NO PREOP group (P = 0.04; relative risk, 0.77). There were also fewer DVT-attributable deaths in the YES PREOP group (0 vs 2; P < 0.001). Postoperative hematocrit (30.2% vs 31.4%; P = 0.42) and number of transfusions (26 vs 14; P = 0.31) were similar. Conclusion: The use of preoperative anticoagulation seems to significantly decrease the risk of DVT in this patient population, and complication rates are not increased. Patients receiving double prophylaxis should receive a preoperative dose of anticoagulation for maximum benefit.

Outcomes of patients with gynecologic malignancies undergoing video-assisted thoracoscopic surgery (VATS) and pleurodesis for malignant pleural effusion

OBJECTIVES We evaluated the indications and outcomes of patients with known gynecologic malignancies that underwent video-assisted thoracoscopic surgery (VATS) and pleurodesis for malignant pleural effusion. METHODS After IRB approval was obtained, a retrospective study of patients with gynecologic malignancies who underwent planned VATS/pleurodesis between 1/2000 and 7/2010 was performed. Abstracted data included demographics, diagnosis, disease status, treatment history, indication for VATS, complications, and outcomes. RESULTS Forty-two patients with a gynecologic malignancy underwent VATS/pleurodesis. Median age was 63 years. Twenty-nine patients (69%) had ovarian cancer. Fifty-seven percent had recurrent disease at the time of VATS and 57% were undergoing chemotherapy at the time of VATS. Eight patients (19%) underwent perioperative VATS to improve pulmonary status. Seven patients (17%) underwent a palliative VATS. The median length of stay was 7 days (range 1-53). Sixty-two percent had gross disease noted at the time of VATS. A mean of 1650 cc of fluid was drained at time of surgery (range 300-4500), and the majority (88%) of patients had a talc pleurodesis performed. Seven patients (17%) were readmitted within 30 days; 6 were for complications unrelated to their VATS. One patient was readmitted with hospital-acquired pneumonia and died during readmission. Median time to death after VATS was 104 days (range 4-1062). Patients who underwent a perioperative VATS had the longest survival (845 days). CONCLUSION Patients with gynecologic malignancies may require a VATS/pleurodesis for symptomatic pleural effusions. This procedure appears to be safe and effective in this patient population.

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