Venous thromboembolism in advanced ovarian cancer patients undergoing frontline adjuvant chemotherapy.

OBJECTIVE: The aim of this study was to define the incidence and prognostic significance of venous thromboembolism (VTE) in patients with advanced, epithelial ovarian cancer undergoing frontline adjuvant chemotherapy after an extended period (28 days) of postoperative prophylaxis. METHODS: A retrospective analysis of patients with advanced, epithelial ovarian cancer who underwent surgery and chemotherapy at a single institution from January 2008 through December 2011 was performed. Exclusion criteria were history of VTE, VTE during the postoperative period, clear cell histology, use of anticoagulation for a different indication, and lack of compliance with 28 days of postoperative prophylaxis with a low-molecular-weight heparin. Baseline patient demographics and oncologic outcomes were analyzed. Clinically symptomatic VTE was identified and confirmed with imaging studies. Otherwise, VTE was identified on imaging studies done to assess disease status at the conclusion of adjuvant chemotherapy. RESULTS: One hundred twenty-eight patients met criteria for inclusion. Sixteen patients had a reported VTE during the time they were on frontline chemotherapy (12.5%). Nine patients (7%) had a pulmonary embolus, and 8 (6.3%) had a deep vein thrombus. The mean BMI in the group that developed VTE was 28, and in the group without VTE, it was 26.5 (P = 0.23). Three (23%) of the 16 patients who developed VTE had undergone a suboptimal cytoreduction compared with 12 (11%) of the 112 in the group with no VTE (P = 0.4). Six (37%) of the 16 patients who developed VTE during chemotherapy underwent a bowel resection and/or splenectomy during their cytoreductive surgery compared with 18 (16%) of the 112 patients who did not develop VTE (P = 0.079). Eight of the patients in the VTE group had indwelling venous catheters during chemotherapy (50%) compared with 39 (35%) in the group with no VTE (P = 0.27). In the group that developed VTE, there was a trend toward increased preoperative CA-125, higher rates of bowel resection and/or splenectomy during surgery, decreased use of aspirin, and inferior survival. On multivariate analysis, patients who developed VTE had significantly longer postoperative hospital stays (7 vs 5 days [P = 0.009]) and lower rates of complete response (P = 0.01). CONCLUSIONS: A 12.5% risk for VTE merits consideration of prophylaxis during chemotherapy in this cohort. A randomized, controlled trial is needed to clarify whether the benefits of long-term prophylaxis outweigh the risks and costs of such therapy.

Non-small cell lung cancer presenting as back cyst.

Cutaneous metastasis as the presenting sign of lung cancer is rare, with a poor prognosis and a life expectancy of 3 to 5 months. We present the complicated course of a 60-year-old woman with extensive metastatic non-small cell lung cancer that presented as a back cyst. Due to the benign appearance of the cyst and the difficulty discovering the location of the primary malignancy, diagnosis and treatment were delayed. Unfortunately, once aggressive treatment was initiated at the request of the patient, she died 2 weeks later. This case highlights the importance of recognizing cutaneous lesions as a sign of internal malignancy and emphasizes multidisciplinary discussion that focuses on the patient's quality of life.

Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer.

BackgroundImmune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study.MethodsEligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens. The treatment included guadecitabine (30 mg/m2) on days 1-4, and pembrolizumab (200 mg i.v.) on day 5, every 21 days. The primary endpoint was the response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment.ResultsAmong 35 evaluable patients, 3 patients had partial responses (8.6%), and 8 (22.9%) patients had stable disease, resulting in a clinical benefit rate of 31.4% (95% CI: 16.9%-49.3%). The median duration of clinical benefit was 6.8 months. Long-interspersed element 1 (LINE1) was hypomethylated in post-treatment PBMCs, and methylomic and transcriptomic analyses showed activation of antitumor immunity in post-treatment biopsies. High-dimensional immune profiling of PBMCs showed a higher frequency of naive and/or central memory CD4+ T cells and of classical monocytes in patients with a durable clinical benefit or response (CBR). A higher baseline density of CD8+ T cells and CD20+ B cells and the presence of tertiary lymphoid structures in tumors were associated with a durable CBR.ConclusionEpigenetic priming using a hypomethylating agent with an ICI was feasible and resulted in a durable clinical benefit associated with immune responses in selected patients with recurrent OC.Trial registrationClinicalTrials.gov NCT02901899.FundingUS Army Medical Research and Material Command/Congressionally Directed Medical Research Programs (USAMRMC/CDMRP) grant W81XWH-17-0141; the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center; Walter S. and Lucienne Driskill Immunotherapy Research funds; Astex Pharmaceuticals; Merck & Co.; National Cancer Institute (NCI), NIH grants CCSG P30 CA060553, CCSG P30 CA060553, and CA060553.

In vivo analysis of human multidrug resistance protein 1 (MRP1) activity using transient expression of fluorescently tagged MRP1.

The multidrug resistance protein 1 (MRP1) contributes cellular resistance to a wide array of physiological toxins and chemotherapeutic agents. Its in vivo activity has been studied primarily in cells that have been continuously drug selected, culture conditions that might confound the effects of MRP1 expression with the effects of a cell's detoxification machinery. Transient transfection with a MRP1-green fluorescent protein (EGFP) fusion protein allowed us to measure the activity of MRP1 in cells that had insufficient time to induce other chemoprotective proteins. Furthermore, separate transfections with MRP1-yellow fluorescent protein and a fluorescently tagged P-glycoprotein (MDR1-cyan fluorescent protein) permitted the drug-resistant properties of MRP1-expressing cells to be compared with those of MDR1-expressing cells. Our data showed that the expression of MRP1-EGFP results in significantly decreased cellular accumulation of tetramethylrhodamine ethyl ester (TMRE) and daunorubicin, mildly decreased cellular accumulation of mitoxantrone, and decreased nuclear accumulation of doxorubicin. Additionally, MRP1-EGFP expression protected cells from the microtubule depolymerization caused by vincristine and colchicine, but not by vinblastine.

Robotic surgery compared with laparotomy for high-grade endometrial cancer.

High-grade endometrial cancer often presents with occult metastatic disease and this presentation pattern can be considered a contraindication to minimally invasive surgery. We sought to compare the surgical and oncologic outcomes of patients with high-grade endometrial cancer who underwent surgical management/staging via the robotic approach versus the traditional open approach. A retrospective analysis was performed of patients with high-grade endometrial cancer who were treated at a single institution from January 2008 through December 2011. High-grade endometrial histology was defined as FIGO grade 2 or 3 endometrioid, serous, clear cell or uterine carcinosarcoma. Pre-operatively, all patients had clinical stage I disease based on a combination of physical examination and imaging studies. Baseline patient demographics, operative results, complications and oncologic outcomes were analyzed. Eighty consecutive patients were included. Forty-seven patients underwent surgical management using the robotic approach and 33 patients underwent a traditional operation via laparotomy. The groups were well matched in terms of age, body mass index, medical co-morbidities, stage and histology. The average hospital stay for patients who underwent open surgery was significantly longer than for those who underwent a robotic approach [5.6 versus 1.4 days (p = 0.0001)]. Of the patients who underwent robotic surgery, 7/47 (15 %) experienced an operative complication versus 18/33 (55 %) in the open surgery cohort (p = 0.002). The average number of pelvic lymph nodes retrieved in each cohort was 12. The average number of para-aortic lymph nodes retrieved in each group was 4. On final pathologic analysis, 20 patients in the robotic surgery arm were found to have disease that had spread beyond the uterus (43 %), compared to 14 in the traditional surgery group (42 %). There were 11/47 (23 %) recurrences in the robotic surgery group during the study period, compared to 8/33 (24 %) in the laparotomy group. There were no significant differences in progression-free or overall survival between the two cohorts. Robotic surgery is safer than laparotomy for patients with high-grade endometrial cancer. The oncologic outcomes appear similar. Minimizing morbidity in this patient population is important since many are elderly and will require adjuvant therapy.

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

OBJECTIVE: To compare 2 methods of vaginal cuff closure with regard to safety, ease of use, and postoperative outcome. METHODS: All patients undergoing robotic-assisted total hysterectomy by a gynecologic oncologist from July 1, 2010, to July 1, 2011, at Northwestern Memorial Prentice Women's Hospital were included in a retrospective analysis. Providers used either 2-0 monofilament synthetic absorbable suture to close the vaginal cuff in a running fashion, secured with an absorbable suture clip at the angles and then knotted in the middle, or 2-0 absorbable unidirectional barbed suture with a welded-loop closure in a running fashion. RESULTS: A total of 134 patients underwent robotic-assisted total hysterectomy. The 2-0 tied monofilament closure was used in 58 patients, and the 2-0 barbed knotless closure was used in 76 patients. There were no instances of vaginal cuff dehiscence or vaginal cuff cellulitis. Rates of vaginal spotting and bleeding were comparable between the groups (12.0% spotting in the monofilament suture group vs 13.0% spotting in the barbed suture group). All vaginal cuff bleeding resolved on its own without significant intervention. CONCLUSION: The use of either a 2-0 welded-loop unidirectional barbed suture or a 2-0 monofilament absorbable suture to close the vaginal cuff is safe and well tolerated.

Inhibition of AKT with the orally active allosteric AKT inhibitor, MK-2206, sensitizes endometrial cancer cells to progestin.

Progestin resistance is a major obstacle to treating early stage, well-differentiated endometrial cancer as well as recurrent endometrial cancer. The mechanism behind the suboptimal response to progestin is not well understood. The PTEN tumor suppressor gene is frequently mutated in type I endometrial cancers and this mutation results in hyperactivation of the PI3K/AKT pathway. We hypothesized that increased activation of AKT promotes an inadequate response to progestins in endometrial cancer cells. Ishikawa cells stably transfected with progesterone receptor B (PRB23 cells) were treated with the AKT inhibitor, MK-2206, which effectively decreased levels of p(Ser473)-AKT in a dose-dependent (10 nM to 1 uM) and time-dependent manner (0.5 h to 24 h). MK-2206 inhibited levels of p(Thr308)-AKT and a downstream target, p(Thr246)-PRAS40, but did not change levels of p(Thr202/Tyr204)ERK or p(Thr13/Tyr185)SAPK/JNK, demonstrating specificity of MK-2206 for AKT. Additionally, MK-2206 treatment of PRB23 cells resulted in a significant increase in levels of progesterone receptor B (PRB) protein. Microarray analysis of PRB23 cells identified PDK4 as the most highly upregulated gene among 70 upregulated genes in response to R5020. Inhibition of AKT further upregulated progestin-mediated expression of PDK4 but did not affect another progestin-responsive gene, SGK1. Treatment of PRB23 cells with R5020 and MK-2206 independently decreased viability of cells while the combination of R5020 and MK-2206 caused the greatest decrease in cell viability. Furthermore, mice with xenografted tumors treated with MK-2206 alone or with progesterone alone exhibited modest reductions in their tumor volume. The largest decrease in tumor size was observed in the mice treated with both MK-2206 and progesterone; these tumors exhibited the least proliferation (Ki67) and the most apoptosis (cleaved caspase-3) of all the treatment groups. In summary, inhibition of AKT stabilizes the Progesterone Receptor B and augments progesterone response in endometrial cancer cells that have hyperactivated AKT.