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Cord blood (CB) is used increasingly in transplant patients lacking sibling or unrelated donors. A major hurdle to the use of CB is low cell dose which is largely responsible for elevated risk of graft failure and significantly delayed neutrophil and platelet engraftment. Since a positive correlation has been demonstrated between the total nucleated cell (TNC) and CD34+ cell dose transplanted and time to neutrophil and platelet engraftment, strategies to increase these measures are under development. One strategy includes the ex vivo expansion of CB mononuclear cells (MNC) with mesenchymal stem cells (MSC) in a cytokine cocktail. We demonstrate that this strategy can be further improved if CD3+ and/or CD14+ cells are first depleted from the CB MNC prior to ex vivo expansion. Ready translation of this depletion strategy to improve ex vivo CB expansion in the clinic is feasible since clinical-grade devices and reagents are available. Ultimately the goal of improving TNC and CD34+ transplant doses is to further improve the rate of neutrophil and platelet engraftment in CB recipients.

Objective Pegylated liposomal doxorubicin (PLD) was introduced to reduce the adverse effect of doxorubicin in treating recurrent ovarian cancer. We sought to characterize the efficacy and adverse-effect profile of PLD in different doses and to evaluate predictive factors of palmar-plantar erythrodysesthesia (PPE). Methods Patients with recurrent ovarian, primary peritoneal, and fallopian tube carcinoma treated with single-agent PLD between 1996 and 2006 at The University of Texas M. D. Anderson Cancer Center were retrospectively identified, and charts were reviewed for patient demographics, PLD data, adverse effects, use of cooling mechanisms, and survival. Results Three hundred-thirty patients were included and PPE of any grade occurred in 30.9%. Patients received a median of 3 (mean 4.32) cycles of PLD treatment. The different PLD doses ( 50 mg/m 2 ) were not associated with differences in overall survival (OS), progression-free survival (PFS), or time to progression (TTP). The incidences of mucositis, neutropenia, peripheral neuropathy, and vomiting were significantly higher at doses >50 mg/m 2 than at doses 2 . More patients who used cooling mechanisms (39%) had PPE than those who did not (26%). There was an association between mucositis, neutropenia, and peripheral neuropathy and PPE. More cycles of PLD (>6) also increased the incidence of PPE. In our study, only 7% of women discontinued PLD for toxicity while 74% discontinued for progression. Conclusion There was no association between different doses of PLD and OS, PFS, or TTP. A higher dose and more cycles increased the incidence of several toxicities, including PPE. The use of cooling mechanisms, higher number of PLD cycles, and occurrence of mucositis, neutropenia, and peripheral neuropathy are possible predictors of PPE.

The purpose of this study was to evaluate the impact of increasing the magnesium (Mg(2+)) supplementation in the pre- and posthydration of patients receiving cisplatin plus radiation (CisXRT) to prevent chemotherapy-induced hypomagnesemia (CIH) events.The study was conducted on newly diagnosed cervical cancer patients receiving CisXRT. The first prospective intervention to prevent CIH was to increase the pre- and posthydration Mg(2+) from 1 to 2 g. After completion of the first intervention, the analysis demonstrated the persistent occurrence of CIH on cycle 3, and later, a second intervention was implemented to increase Mg(2+) to 3 g in the pre- and posthydration. Patients that failed to complete at least five cycles or received cisplatin in combination with another chemotherapy regimen were excluded from the study. Baseline group included 70 patients that had received CisXRT prior to any changes in magnesium supplementation.There were 62.8% (44/70) and 32.6% (22/70) of patients with episodes of CIH in the baseline and first intervention groups, respectively (P = 0.007). In the second intervention group, a 49.6% decrease in the total number of episodes compared to control group was observed. Patients in the second intervention group showed a 100% improvement incidence of persistent CIH over the two other cohorts (P = 0.001).The increase of Mg(2+) to 2 g for the initial two cycles and then to 3 g with the third cycle of CisXRT therapy prevented episodes of CIH and decreased associated treatment delays.

Objectives Persistent nodal disease in the surgical specimen (pN+) after preoperative chemotherapy for urothelial carcinoma is associated with a poor prognosis. To improve our understanding regarding the outcomes of such patients, we performed a retrospective review of our experience. Methods From 1993 to 2003, 857 patients underwent radical cystectomy for urothelial carcinoma of the bladder, and 150 were found to have pN+ disease. Of these 150 patients, 37 had pN+ disease despite preoperative chemotherapy and formed the basis of this report. The survival data were analyzed using the Kaplan-Meier method and Cox regression analysis. Results The median patient age was 66 years (range 39-85), and the median follow-up was 50 months (range 13.0-58.7). The clinical stage at the initiation of preoperative chemotherapy was cT2 with lymphovascular invasion in 7, cT3b in 6, cT4a in 4, cT4b in 2, and cN+ in 18. The 2-year overall, disease-specific, and recurrence-free survival rate was 20%, 29.2%, and 13.5%, respectively. Of the 37 patients, 11 (30%) received adjuvant chemotherapy after surgery, most (73%) were platinum-based regimens. On Kaplan-Meier analysis, adjuvant chemotherapy was associated with improved recurrence-free and disease-specific survival. On multivariate analysis, surgical margin status, sex, and histologic type were significantly associated with overall survival, and the histologic type and use of adjuvant chemotherapy were significantly associated with recurrence-free survival. Conclusions Patients with persistent nodal disease despite preoperative chemotherapy have a poor prognosis. A cohort of such patients might do well with adjuvant chemotherapy. The lymph node density and pT category were not prognostic in patients with nodal metastasis after preoperative chemotherapy.

Purpose: The involvement of phosphatase and tensin homologue deleted on chromosome ten (PTEN) in endometrial carcinoma has implicated phosphatidylinositol 3-kinase signaling and mammalian target of rapamycin (mTOR) activation in this disease. Understanding the extent of mTOR involvement and the mechanism responsible for activation is important, as mTOR inhibitors are currently being evaluated in clinical trials for endometrial carcinoma. Although tuberous sclerosis complex 2 (TSC2) is the “gatekeeper” for mTOR activation, little is known about defects in the TSC2 tumor suppressor or signaling pathways that regulate TSC2, such as LKB1/AMP-activated protein kinase, in the development of endometrial carcinoma. Experimental Design: We determined the frequency of mTOR activation in endometrial carcinoma (primary tumors and cell lines) and investigated PTEN, LKB1, and TSC2 defects as underlying cause(s) of mTOR activation, and determined the ability of rapamycin to reverse these signaling defects in endometrial carcinoma cells. Results: Activation of mTOR was a consistent feature in endometrial carcinomas and cell lines. In addition to PTEN, loss of TSC2 and LKB1 expression occurred in a significant fraction of primary tumors (13% and 21%, respectively). In tumors that retained TSC2 expression, phosphorylation of tuberin at S939 was observed with a high frequency, indicating that mTOR repression by TSC2 had been relieved via AKT phosphorylation of this tumor suppressor. In PTEN-null and LKB1-null endometrial carcinoma cell lines with functional inactivation of TSC2, phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 were able to inhibit AKT and mTOR signaling and reverse TSC2 phosphorylation. In contrast, although rapamycin inhibited mTOR signaling, it did not relieve phosphorylation of TSC2 at S939. Conclusions: Inactivation of TSC2 via loss of expression or phosphorylation occurred frequently in endometrial carcinoma to activate mTOR signaling. High-frequency mTOR activation supports mTOR as a rational therapeutic target for endometrial carcinoma. However, whereas rapamycin and its analogues may be efficacious at inhibiting mTOR activity, these drugs do not reverse the functional inactivation of TSC2 that occurs in these tumors.

Chronic myelogenous leukemia (CML) invariably progresses to blast crisis, which represents the most proliferative phase of the disease. The BCR-ABL1 oncogene stimulates growth and survival pathways by phosphorylating numerous substrates, including various Src family members. Here we describe up-regulation, in contrast to activation, of the ubiquitously expressed Src kinase, Fyn, by BCR-ABL1. In a tissue microarray, Fyn expression was significantly increased in CML blast crisis compared with chronic phase. Cells overexpressing BCR-ABL1 in vitro and in vivo display an up-regulation of Fyn protein and mRNA. Knockdown of Fyn with shRNA slows leukemia cell growth, inhibits clonogenicity, and leads to increased sensitivity to imatinib, indicating that Fyn mediates CML cell proliferation. In severe combined immunodeficient (SCID) mice injected with Fyn shRNA–expressing cells, myeloid-derived cell numbers dropped by 50% and death from leukemia was delayed. Taken together, these results encourage the development of therapies targeting Fyn expression.

Purpose: Epidermal growth factor receptor (EGFR) is an attractive target for the treatment of urothelial carcinoma, but a clinical response can be expected in only a small proportion of patients. The aim of this study was to define molecular markers of response to cetuximab therapy in a panel of urothelial carcinoma cell lines.Experimental Design: Eleven cell lines were investigated for antiproliferative response to cetuximab based on [3H]thymidine incorporation. A variety of markers, including EGFR expression, phosphorylation, and gene amplification, as well as the expression of other growth factor receptors, their ligands, and markers of epithelial-to-mesenchymal transition were investigated. Cohen's κ statistic was used to estimate the agreement between response and expression of these markers. E-cadherin was silenced by small interfering RNA in two sensitive cell lines, and the effect on the response to cetuximab was measured.Results: We were able to identify a panel of relevant markers pertaining especially to alternate growth factor receptor expression and epithelial-to-mesenchymal transition that predicted response to cetuximab. The data suggested that expression of intact HER-4 (κ, 1.00; P = 0.008), E-cadherin (κ, 0.81; P = 0.015), and β-catenin (κ, 0.81; P = 0.015) and loss of expression of platelet-derived growth factor receptor β (κ, 0.57; P = 0.167) were associated with response to cetuximab therapy. Silencing E-cadherin in two sensitive cell lines reduced responsiveness to cetuximab in both (P < 0.001).Conclusions: A panel of predictive markers for cetuximab response has been established in vitro and is currently being evaluated in a prospective clinical trial of neoadjuvant EGFR-targeted therapy. Most importantly, E-cadherin seems to play a central role in modulation of EGFR response in urothelial carcinoma.

OBJECTIVES To evaluate whether the clinical grade predicts the final pathologic stage in upper urinary tract transitional cell carcinoma. METHODS We retrospectively reviewed the records of 184 consecutive patients undergoing nephroureterectomy for upper urinary tract transitional cell carcinoma at our institution from 1986 to 2004. Their clinical, surgical, and pathologic data were reviewed to determine the positive and negative predictive values of the clinical biopsy grade with respect to the final pathologic disease stage. RESULTS Of the 184 patients, 119 (64.7%) had information available regarding the clinical grade of disease from the preoperative endoscopic biopsy. The distribution was grade 1 in 2 (1.6%), grade 2 in 46 (38.7%), and grade 3 in 71 (59.7%) patients. Of the 71 patients with grade 3 disease, 47 had Stage pT2 disease or higher (66% positive predictive value). Of the 48 patients with less than grade 3 disease, 35 had less than pT2 disease (72% negative predictive value). Of the 71 patients with grade 3 disease, 30 had pT3 disease or greater (42% positive predictive value), and of the 48 patients with less than grade 3 disease, 44 had less than pT3 disease (92% negative predictive value). CONCLUSIONS The histologic grade obtained from the diagnostic biopsy for upper urinary tract transitional cell carcinoma can be used to predict the pathologic disease stage. This information can be used to counsel patients before surgery and to identify patients for whom neoadjuvant chemotherapy would be most beneficial.

Although grading has been demonstrated to be an important prognostic factor in ovarian serous carcinoma, there is no system universally used to perform this task. A few years ago, we proposed a two-tier system for grading ovarian serous carcinoma that is based primarily on the assessment of nuclear atypia (uniformity vs. pleomorphism) in the worst area of the tumor. Tumor grade in this two-tier system is correlated with survival. After being used by numerous pathologists and trainees at The University of Texas M.D. Anderson Cancer Center (MDACC) for 15 years, we have observed that this system is user-friendly and reproducible. We undertook this study to evaluate the interobserver and intraobserver variability among a group of 7 gynecologic pathologists and 2 general surgical pathologists using this grading system. A total of 80 cases of ovarian serous carcinoma, 40 low-grade and 40 high-grade, were circulated twice among these pathologists. Slides with examples of low-grade and high-grade serous carcinoma were sent with the unknowns. A website was used to provide diagnostic criteria, images of examples of ovarian low-grade and high-grade carcinoma, and a log form to facilitate data entry. Statistical analysis demonstrated an overall kappa statistic among the different observers of 0.909. The intergrader kappa's ranged from 0.717 to 1.000 in the first round of the review and from 0.701 to 1.000 in the second round. Eight of the participants had an intragrader kappa ranging from 0.775 to 1.000 (excellent agreement), whereas a single participant had an intragrader kappa of 0.725 (good agreement). This study demonstrates that the two-tier grading system (the MDACC grading system) for ovarian serous carcinoma on the basis of the assessment of nuclear atypia is easy to learn and is highly reproducible. These findings would support its universal use, which would be beneficial for the standardization of clinical trials and protocols, thus facilitating the understanding of this disease and investigation into the treatment of patients affected by these tumors.

BACKGROUND. Nonbilharzial squamous cell carcinoma (SCC) of the bladder is a rare entity in the Western hemisphere. To further understanding of its natural history, a contemporary experience with management and outcome of this disease was reviewed. METHODS. Between 1988 and 2003, 27 patients with pure SCC were treated at the center. Charts were reviewed to assess impact of therapy on survival and patterns of recurrence in those that died of disease. RESULTS. The 2-year overall survival and recurrence-free survival (RFS) rates were 47.6% and 32.8%, respectively, with a median follow-up of 15.3 months in survivors. Eight patients received initial chemotherapy and/or radiation therapy with the intent of performing surgical consolidation. In 5 of these patients surgical consolidation was not performed due to rapid progression of disease and death. Of the 3 patients who were treated with neoadjuvant therapy (1 with chemotherapy, 1 with radiation, and 1 with chemoradiation) and had surgical consolidation, 2 (67%) were downstaged at cystectomy and remain disease-free. In 10 of 20 patients who underwent radical cystectomy the disease recurred after a median duration of 5.1 months and 7 died: 3 of local recurrence, 1 of distant recurrence, and 3 of both. History of superficial transitional cell carcinoma that differentiated into pure SCC (P 5 .035; hazards ratio [HR] of 3.73) and treatment by radical cystectomy (P 5 .002; HR of 0.19) were associated with RFS. CONCLUSIONS. In select patients with resectable disease, radical cystectomy remains the mainstay of therapy for pure SCC of the bladder. Locoregional recurrence is the primary cause of death in the majority of patients. The role for neoadjuvant therapy is unclear. Cancer 2007;110:764–9. � 2007 American Cancer Society.

ObjectiveThe prognostic significance of lymphovascular space invasion (LVSI) in patients with early-stage endometrial cancer is not established. We sought to determine if LVSI status in patients with early-stage low-risk endometrial cancer correlates with recurrence and survival.MethodsThe records of all women who underwent hysterectomy for primary treatment of endometrial cancer from January 2006 through January 2011 at 1 academic institution were reviewed. Patients with grade 1 or 2 endometrioid histology, myometrial invasion less than 50%, and disease confined to the uterus (clinical International Federation of Obstetrics and Gynecology stage IA) were analyzed. Fisher exact test and the Wilcoxon rank-sum test were applied to compare patients with and without LVSI. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method.ResultsTwo hundred forty patients met the inclusion criteria. Forty (16.7%) had LVSI. Ninety-one patients (37.9%) underwent lymphadenectomy. Median tumor size was 30 mm in patients with and 26 mm in patients without LVSI (P = 0.150). Thirty patients (12.5%) received adjuvant therapy. Site of recurrence did not differ between patients with and without LVSI. Patients with LVSI were more likely to have myometrial invasion (P < 0.001), postoperative pathologic grade 2 disease (P < 0.001), to undergo lymphadenectomy (P = 0.049) and receive adjuvant therapy (P < 0.001). The 5-year cumulative incidence of recurrence was 3.8% in the no-LVSI group and 14.2% in the LVSI group (P = 0.053). The presence of LVSI was significantly associated with worse RFS (P = 0.002) and OS (P = 0.013).ConclusionsPatients with low-risk endometrial cancer and LVSI have worse RFS and OS despite being more likely to undergo lymphadenectomy and adjuvant therapy.

ObjectivesTo evaluate the current patterns of use of minimally invasive surgical procedures, including traditional, robotic-assisted, and single-port laparoscopy, by Society of Gynecologic Oncology (SGO) members and to compare the results to those of our 2004 and 2007 surveys.MethodsThe Society of Gynecologic Oncology members were surveyed through an online or mailed-paper survey. Data were analyzed and compared with results of our prior surveys.ResultsFour hundred six (32%) of 1279 SGO members responded. Eighty-three percent of respondents (n = 337) performed traditional laparoscopic surgery (compared with 84% in 2004 and 91% in 2007). Ninety-seven percent of respondents performed robotic surgery (compared with 27% in 2007). When respondents were asked to indicate procedures that they performed with the robot but not with traditional laparoscopy, 75% indicated radical hysterectomy and pelvic lymphadenectomy for cervical cancer. Overall, 70% of respondents indicated that hysterectomy and staging for uterine cancer was the procedure they most commonly performed with a minimally invasive approach. Only 17% of respondents who performed minimally invasive surgery performed single-port laparoscopy, and only 5% of respondents indicated that single-port laparoscopy has an important or very important role in the field.ConclusionsSince our prior surveys, we found a significant increase in the overall use and indications for robotic surgery. Radical hysterectomy or trachelectomy and pelvic lymphadenectomy for cervical cancer and total hysterectomy and staging for endometrial cancer were procedures found to be significantly more appropriate for the robotic platform in comparison to traditional laparoscopy. The indications for laparoscopy have expanded beyond endometrial cancer staging to include surgical management of early-stage cervical and ovarian cancers, but the use of single-port laparoscopy remains limited.

Purpose The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregulated in endometrial cancer (EC). Hormonal manipulation leads to response in some patients with EC, but resistance derived from PI3K pathway activation has been documented. Targeting mammalian target of rapamycin (mTOR) may overcome endocrine resistance. We conducted a two-institution phase II trial of everolimus and letrozole in women with recurrent EC. Patients and Methods Patients were considered incurable, had measurable disease, and were treated with up to two prior cytotoxic regimens. Everolimus was administered orally at 10 mg daily and letrozole was administered orally at 2.5 mg daily. Each cycle consisted of 4 weeks of therapy. Patients were treated until progression, toxicity, or complete response (CR). The primary end point was the clinical benefit rate (CBR), which was defined as CR, partial response, or stable disease (≥ 16 weeks) by RECIST 1.0 criteria. Translational studies were performed to correlate biomarkers with response. Results Thirty-eight patients were enrolled (median age, 62 years; range, 24 to 82 years). Thirty-five patients were evaluable for response. The CBR was 40% (14 of 35 patients); the median number of cycles among responders was 15 (range, seven to 29 cycles). The confirmed objective response rate (RR) was 32% (11 of 35 patients; nine CRs and two partial responses; median, 15 cycles; range, eight to 29 cycles). Twenty percent of patients (seven of 35 patients) were taken off treatment after a prolonged CR and at the discretion of the treating clinician. None of the patients discontinued treatment as a result of toxicity. Serous histology was the best predictor of lack of response. Patients with endometrioid histology and CTNNB1 mutations responded well to everolimus and letrozole. Conclusion Everolimus plus letrozole results in a high CBR and RR in patients with recurrent EC. Further development of this combination in recurrent endometrioid EC is under way.

The mTOR complex 2 (mTORC2) containing mTOR and rictor is thought to be rapamycin insensitive and was recently shown to regulate the prosurvival kinase AKT by phosphorylation on Ser473. We investigated the molecular effects of mTOR inhibition by the rapamycin derivatives (RDs) temsirolimus (CCI-779) and everolimus (RAD001) in acute myeloid leukemia (AML) cells. Unexpectedly, RDs not only inhibited the mTOR complex 1 (mTORC1) containing mTOR and raptor with decreased p70S6K, 4EPB1 phosphorylation, and GLUT1 mRNA, but also blocked AKT activation via inhibition of mTORC2 formation. This resulted in suppression of phosphorylation of the direct AKT substrate FKHR and decreased transcription of D-cyclins in AML cells. Similar observations were made in samples from patients with hematologic malignancies who received RDs in clinical studies. Our study provides the first evidence that rapamycin derivatives inhibit AKT signaling in primary AML cells both in vitro and in vivo, and supports the therapeutic potential of mTOR inhibition strategies in leukemias.

The chemokine receptor CXCR4 mediates the migration of hematopoietic cells to the stroma-derived factor 1α (SDF-1α)–producing bone marrow microenvironment. Using peptide-based CXCR4 inhibitors derived from the chemokine viral macrophage inflammatory protein II, we tested the hypothesis that the inhibition of CXCR4 increases sensitivity to chemotherapy by interfering with stromal/leukemia cell interactions. First, leukemic cells expressing varying amounts of surface CXCR4 were examined for their chemotactic response to SDF-1α or stromal cells, alone or in the presence of different CXCR4 inhibitors. Results showed that the polypeptide RCP168 had the strongest antagonistic effect on the SDF-1α– or stromal cell–induced chemotaxis of leukemic cells. Furthermore, RCP168 blocked the binding of anti-CXCR4 monoclonal antibody 12G5 to surface CXCR4 in a concentration-dependent manner and inhibited SDF-1α–induced AKT and extracellular signal-regulated kinase phosphorylation. Finally, RCP168 significantly enhanced chemotherapy-induced apoptosis in stroma-cocultured Jurkat, primary chronic lymphocytic leukemia, and in a subset of acute myelogenous leukemia cells harboring Flt3 mutation. Equivalent results were obtained with the small-molecule CXCR4 inhibitor AMD3465. Our data therefore suggest that the SDF-1α/CXCR4 interaction contributes to the resistance of leukemia cells to chemotherapy-induced apoptosis. Disruption of these interactions by the peptide CXCR4 inhibitor RCP168 represents a novel strategy for targeting leukemic cells within the bone marrow microenvironment. [Mol Cancer Ther 2006;5(12):3113–21]

Background: Breast cancer mortality (BCM) in the United States declined from 33.1 per 100 000 women in 1990 to 26.6 per 100 000 women in 2000, yielding a 19.6% relative decline in BCM since 1990. Our goal is to apportion this decline between screening and therapy and to be able to state with some certainty that these interventions affected this decline. Methods: We started with an age-appropriate population of 2 000 000 women in 1975 and monitored these women through 2000. On the basis of population data each year, we assigned screening and breast cancer to women. If a woman was diagnosed with breast cancer, we simulated a lifetime for her with death from breast cancer, and we modifi ed this lifetime depending on the use of adjuvant therapy and whether the cancer was screen-detected. A woman’s lifetime was taken as the minimum of her lifetime with death from breast cancer and her simulated natural lifetime. We used Bayesian simulation modeling, which allows for asso ciating probability distributions with our estimates. Results: We calculated the probabilities that screening mammography and adjuvant therapy contributed to the observed decline in BCM to be 90% and 99%, respectively. The posterior mean reduction in BCM due to screening is 10.6% ± 5.7% and due to therapy is 19.5% ± 5.4%. The decrease in the hazard of BCM due to tamoxifen use for ER-positive tumors is 37% ± 14% and that due to adjuvant (nontaxane) chemotherapy is 15% ± 14%. Discussion: The spread in our posterior distributions refl ect the uncertainty present in the data sources available to us. However, despite this uncertainty we conclude a high probability that both screening and impro vements in therapy contributed to the reduction in BCM observed in the United States from 1990 to 2000. [J Natl Cancer Inst Monogr 2006;36:30 – 6]

Purpose: Partial cystectomy is a surgical option for select patients diagnosed with urothelial carcinoma. We review our experience with partial cystectomy for muscle invasive urothelial carcinoma to assess local control and survival rates.Material and Methods: From 1982 to 2003 a total of 37 patients with muscle invasive urothelial carcinoma underwent partial cystectomy with curative intent. Reviewed data included history of superficial tumors, presence of variant histology, tumor location, clinical stage, pathological stage, presence of carcinoma in situ, adjuvant therapy and disease status.Results: The 5-year overall, disease specific and recurrence-free survival rates were 67%, 87% and 39%, respectively. Mean followup was 72.6 months (range 6 to 217). Of the 37 patients 19 (51%) did not have tumor recurrence, 9 (24%) had superficial recurrence in the bladder that was treated successfully and 9 (24%) had recurrence with advanced disease. A total of 24 patients (65%) had an intact bladder with no evidenc...

HER2 overexpression is one of the most recognizable molecular alterations in breast tumors known to be associated with a poor prognosis. In the study described here, we explored the effect of HER2 overexpression on the sensitivity of breast cancer cells to the growth-inhibitory effects of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), a synthetic triterpenoid, both in vitro and in vivo in a xenograft model of breast cancer. Both cell growth and colony formation in the soft agar assay, a hallmark of the transformation phenotype, were preferentially suppressed in HER2-overexpressing cell lines at low concentrations of CDDO, whereas growth-inhibitory effects at high concentrations did not correlate with the expression level of HER2. CDDO dose-dependently inhibited phosphorylation of HER2 in HER2-overexpressing cells and diminished HER2 kinase activity in vitro. CDDO induced the transactivation of the nuclear receptor peroxisome proliferator-activated receptor-γ in both vector control and HER2-transfected MCF7 cells. Dose-response studies showed that the growth inhibition seen at lower concentrations of CDDO correlated with induction of the tumor suppressor gene caveolin-1, which is known to inhibit breast cancer cell growth. CDDO also reduced cyclin D1 mRNA and protein expression. In vivo studies with liposomally encapsulated CDDO showed complete abrogation of the growth of the highly tumorigenic MCF7/HER2 cells in a xenograft model of breast cancer. These findings provide the first in vitro and in vivo evidence that CDDO effectively inhibits HER2 tyrosine kinase activity and potently suppresses the growth of HER2-overexpressing breast cancer cells and suggest that CDDO has a therapeutic potential in advanced breast cancer. [Mol Cancer Ther 2006;5(2):317–28]

BACKGROUND Endometrial carcinoma is a common malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC). Like colon carcinoma, endometrial carcinoma is diagnosed at an earlier age in women with HNPCC. In contrast to colon carcinoma, the pathologic features of endometrial carcinoma in HNPCC have not been studied in detail. It was the purpose of this study to pathologically characterize a series of HNPCC associated endometrial carcinomas. METHODS Fifty women with HNPCC and endometrial carcinoma were analyzed from four different hereditary cancer registries. H&E stained slides and pathology reports were reviewed for clinically important pathologic features of endometrial carcinoma. These results were compared with those for two different groups of sporadic endometrial carcinoma – women younger than age 50 years (n = 42) and women of all ages with tumors demonstrating microsatellite instability (MSI-high) secondary to methylation of MLH1 (n = 26). RESULTS Nearly one-fourth of HNPCC patients in this study had endometrial tumors with pathologic features that would require adjuvant therapy after hysterectomy. There was a trend toward the HNPCC patients having more nonendometrioid tumors; all of these patients were carriers of MSH2 mutations. Such nonendometrioid tumors were extremely rare in the MLH1 methylated group. A subset of MLH1 methylated sporadic tumors demonstrated a unique, ‘undifferentiated’ histology that was not observed in HNPCC or the young group. CONCLUSION Data suggest a genotype–phenotype relation in which microsatellite instability resulting from MLH1 methylation is almost exclusively associated with classical or ‘undifferentiated’ endometrioid tumors, whereas microsatellite instability secondary to MSH2 mutation can result in a more variable histologic spectrum of endometrial carcinoma. Cancer 2006. © 2005 American Cancer Society.

To use a large-scale multi-institutional dataset to quantify the prevalence of packed red blood cell transfusions and examine the associations between transfusion and perioperative outcomes in gynecologic cancer surgery.The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) participant use file was queried for all gynecologic cancer cases between 2010 and 2012. Demographic, preoperative and intraoperative variables were compared between transfusion and non-transfusion groups using chi-squared, Fisher's exact and Wilcoxon rank-sum tests. The primary endpoint was 30-day composite morbidity. Secondary endpoints included composite surgical site infections, mortality and length of stay.A total of 8519 patients were analyzed, and 13.8% received a packed red blood cell transfusion. In the multivariate analysis, after adjusting for key clinical and perioperative factors, including preoperative anemia and case magnitude, transfusion was associated with higher composite morbidity (OR = 1.85, 95% CI 1.5-2.24), surgical site infections (OR 1.80, 95% CI 1.39-2.35), mortality (OR 3.38, 95% CI 1.80-6.36) and length of hospital stay (3.02 days v. 7.17 days, P0.001).Blood transfusions are associated with increased surgical wound infections, composite morbidity and mortality. Based on our analysis of the NSQIP database, transfusion practices in gynecologic cancer should be scrutinized. Examination of institutional practices and creation of transfusion guidelines for gynecologic malignancies could potentially result in better utilization of blood bank resources and clinical outcomes among patients.

Purpose To compare quality of life and sexual functioning in cervical cancer survivors treated with either radical hysterectomy and lymph node dissection or radiotherapy. Methods Women were interviewed at least 5 years after initial treatment for cervical cancer. Eligible women had squamous cell tumors smaller than 6 cm at diagnosis, were currently disease-free, and had either undergone surgery or radiotherapy, but not both. The two treatment groups were then compared using univariate analysis and multivariate linear regression with a control group of age- and race-matched women with no history of cancer. Results One hundred fourteen patients (37 surgery, 37 radiotherapy, 40 controls) were included for analysis. When compared with surgery patients and controls using univariate analysis, radiation patients had significantly poorer scores on standardized questionnaires measuring health-related quality of life (physical and mental health), psychosocial distress and sexual functioning. The disparity in sexual function remained significant in a multivariate analysis. Univariate and multivariate analyses did not show significant differences between radical hysterectomy patients and controls on any of the outcome measures. Conclusion Cervical cancer survivors treated with radiotherapy had worse sexual functioning than did those treated with radical hysterectomy and lymph node dissection. In contrast, these data suggest that cervical cancer survivors treated with surgery alone can expect overall quality of life and sexual function not unlike that of peers without a history of cancer.

With the aging of the world's population, cancer pain will become an increasingly important health issue. The purpose of this study was to describe the cancer pain experience of Americans (n = 60) and Israelis (n = 39) 65 years and older. Outpatients in teaching hospitals in the U.S. and in Israel completed study questionnaires. Thirty percent of the total variance of worst pain was explained by age, symptom severity, and cancer stage, and 40% of the total variance of pain interference was explained by whether they were American or Israeli, symptom severity, and sense of coherence. Israeli patients had significantly higher scores on worst pain and pain interference, and significantly lower pain management index (PMI) and knowledge and attitudes toward pain and pain control scores. Studies with larger samples and across different cultures are needed to confirm these findings in order to develop culturally appropriate interventions.

BACKGROUND Screening mammography detects breast cancers earlier than those detected symptomatically, and so mammographically detected breast cancers tend to have better prognoses. The so-called stage shift that results from screen detection is subject to lead-time and length biases, and so earlier detection may not translate into longer survival. We used data from three large breast cancer screening trials--Health Insurance Plan (HIP) of New York and two Canadian National Breast Cancer Screening Studies (CNBSS)--to investigate survival benefits of breast cancer screening beyond stage shift. We also address whether method of detection is an independent prognostic factor in breast cancer. METHODS The HIP trial randomly assigned approximately 62,000 women to screening and control groups. The two CNBSS trial cohorts CNBSS-1 and CNBSS-2 included a total of 44,970 women in the screening group and 44,961 in the control group. After adjusting for stage and other tumor characteristics in a Cox proportional hazards model, survival distributions were compared by method of breast cancer detection with both univariate and multivariable analyses. All P values are two-sided. RESULTS Breast cancers detected by screening mammography had a shift in stage distribution to earlier stages (for HIP, P < .001; for CNBSS-1, P = .03; and for CNBSS-2, P < .001). After adjusting for tumor size, lymph node status, and disease stage in a Cox proportional hazards model, method of detection was a statistically significant independent predictor of disease-specific survival. Patients with interval cancers had a 53% (95% confidence interval [CI] = 17% to 100%) greater hazard of death from breast cancer than patients with screen-detected cancers, and patients with cancer in the control groups had a 36% (95% CI = 10% to 68%) greater hazard of death than patients with screen-detected cancer. CONCLUSION There was an apparent survival benefit beyond stage shift for patients with screen-detected breast cancers compared with patients with breast cancers detected otherwise. Method of detection appears to be an important prognostic factor, even after adjusting for known tumor characteristics. This finding suggests that clinical trialists should routinely collect information about method of detection.

Objective We compared the efficacy and side effects of taxanes, with or without platinum, to bleomycin, etoposide, and cisplatin (BEP) in treating sex cord-stromal ovarian tumors. Methods We conducted a retrospective review of all patients with sex cord-stromal ovarian tumors seen at our institution from 1985 to 2002. Eligible patients were those who underwent pathologic confirmation, clinical evaluation, and treatment with a taxane or BEP for initial or recurrent disease. Results Of 222 patients identified, 21 received BEP for new ( n = 11) or recurrent disease ( n = 10); 44 received a taxane during 48 treatment episodes (four patients on two occasions each) for new ( n = 11) or recurrent disease ( n = 37). Newly diagnosed patients treated with BEP vs. taxanes had no significant difference in response rate (Fisher's exact test, P = 1), progression-free survival (PFS) (log-rank test, P = 0.213), or overall survival (log-rank test, P = 0.994). Among patients treated for recurrent measurable disease, the response rate was higher for BEP-treated (71%) than for taxane-treated patients (37%), but this was not statistically significant. In all patients treated for recurrent disease, there was no significant difference in failure to progress at chemotherapy completion between BEP- (70%) and taxane-treated patients (62%) or in median PFS (11.2 vs. 7.2 months). The presence of platinum in taxane-containing regimens correlated with response. Taxane-related side effects included neutropenia ( n = 6), anemia ( n = 1), thrombocytopenia ( n = 1), myelodysplasia ( n = 1), and hypersensitivity ( n = 1). BEP-related side effects included pulmonary fibrosis ( n = 3) and neutropenia ( n = 2). Conclusions Taxanes demonstrated activity against sex cord-stromal tumors of the ovary and may be less toxic than BEP. Taxane and platinum combination chemotherapy warrants further investigation in this disease.

Little is known about Israeli elders' cancer pain experience. The purpose of this study was to explore the cancer pain experience, including pain intensity, pain management index, pain interference, symptom severity, and knowledge and attitudes toward pain and pain control.Descriptive cross-sectional methods were used to obtain data with four instruments. The patients were 39 Israelis 65 years and older who were receiving outpatient treatment for cancer in a major hospital center in Israel.Results showed that over half (56.7%) reported severe worst pain and had negative pain management indexes (56.4%). In addition, knowledge and attitudes toward pain and pain control were poor (54.55%). There were no significant relationships between pain intensity and other variables. However, pain interference demonstrated a significant positive relationship with symptom severity. Post hoc analysis revealed that Ashkenazi Jewish and more educated patients reported significantly less pain interference than Sephardic Jewish patients.Larger samples representative of the cultural differences in Israel are needed to more definitively identify elements of the cancer pain experience in Israeli elders that can be addressed to improve pain management.

In acute myeloid leukemia (AML), resistance to chemotherapy is associated with defects in both the extrinsic and intrinsic pathways of apoptosis. Novel agents that activate endogenous apoptosis-inducing mechanisms directly may be potentially useful to overcome chemoresistance in AML. We examined the mechanisms of apoptosis induction by the novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) in AML cells. CDDO-induced apoptosis was associated with the loss of mitochondrial inner transmembrane potential, caspases activation, the translocation of apoptosis-inducing factor to the nucleus, and DNA fragmentation in AML cells. Apoptosis was equally evident in cells deficient in caspase-9 or caspase-8 after exposure to CDDO, suggesting caspase-independent cell death. The use of small interfering RNA to reduce the expression of apoptosis-inducing factor partially inhibited CDDO-induced apoptosis in AML cells. Cells overexpressing Bcl-2 were markedly resistant to CDDO-induced apoptosis. Moreover, CDDO promoted the release of cytochrome c from isolated mitochondria, suggesting that CDDO targets the mitochondria directly to trigger the intrinsic pathway of cell death in intact cells. Together, these results suggest that CDDO functions by activating the intrinsic pathway of apoptosis and initiates caspase-dependent and independent cell death. The direct modulation of mitochondrial-mediated, caspase-independent apoptosis by CDDO may be advantageous for overcoming chemoresistance in AML.

Purpose To determine the efficacy and side effects of taxanes, with or without platinum, for the treatment of sex cord-stromal tumors of the ovary. Patients and Methods We conducted a retrospective review of all patients seen from 1985 to 2002 at The University of Texas M.D. Anderson Cancer Center with ovarian sex cord-stromal tumors. Eligible patients underwent pathology confirmation and clinical evaluation at M.D. Anderson and received a taxane for initial or recurrent disease. Results Of 222 patients identified, 44 were eligible for analysis. For nine patients treated in the first-line adjuvant setting, median progression-free survival (PFS) was not reached at 51 months. Of two patients treated for measurable disease in the first-line setting, one had a complete response. Median PFS was 34.3 months; median overall survival (OS) was not reached. Median follow-up was 90.3 months (range, 39.4 to 140.5 months). Response rate for 30 patients treated with a taxane ± platinum for recurrent, measurable disease was 42%. Median PFS was 19.6 months; median OS was not reached. Median follow-up was 100.7 months (range, 8.1 to 361.3 months). The presence of platinum correlated with response in the recurrent, measurable disease setting. The number of patients was insufficient to detect relative efficacy of paclitaxel and docetaxel. Adverse effects of paclitaxel included neutropenia (n = 6), anemia (n = 1), thrombocytopenia (n = 1), myelodysplasia (n = 1), and hypersensitivity (n = 1). Conclusion Taxanes seem to be active agents in the treatment of patients with sex cord-stromal tumors of the ovary. The combination of taxanes with platinum in the treatment of this disease deserves additional investigation.

Purpose/objectives To identify oncology nurses priorities for topics and issues to be addressed by developing a clinical nursing research program at a large comprehensive cancer center. Design Delphi survey, completed in two rounds. Setting A large comprehensive cancer center in the southern United States. Sample All 1,500 RNs employed at the cancer center. Round I asked nurses to identify topics they believed needed to be studied, and 642 nurses responded. In round II, 567 nurses ranked these priorities. Methods Surveys were distributed to all nurses who work in a variety of settings at the cancer center. Open-ended responses from round I were content analyzed, round II rankings of importance were described, and factor analysis was performed. Main research variables 120 topics were identified from a content analysis of research areas described by nurses in the cancer center. Findings 120 research priorities were identified. Factor analysis revealed three factors: clinical care, nurses and skills, and administrative aspects. Conclusions The top five research priorities identified at the cancer center were, in rank order, acute and chronic pain, infection rates and control, job satisfaction, nurse-patient ratios and staffing, and nurse retention. This study's survey included items similar to those on the recently conducted Oncology Nursing Society research priority survey. Pain and issues with infection were among the top five priorities in both surveys. Implications for nursing Conducting a survey to identify nurses perceptions of research was useful in involving nurses in the conduct of research, and the results were useful guides to beginning a coordinated program of nursing research.

Purpose Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer characterized by early metastasis, resistance to therapy, and a high mortality rate. Little is known about the biology of these tumors. Smaller studies suggest that Her-2/neu may be involved in the tumorigenesis of this disease. The purpose of this study was to evaluate the protein expression and gene amplification of Her-2/neu in UPSC and to determine its prognostic value. Patients and Methods Tumor tissue from 68 patients with UPSC treated at The University of Texas M.D. Anderson Cancer Center from 1989 to 2002 was available. Her-2/neu expression was evaluated by immunohistochemistry (IHC). Overexpression was defined as complete membrane staining in greater than 10% of the cells. In tumors with overexpression of Her-2/neu by IHC, fluorescence in situ hybridization (FISH) was performed to assess gene amplification. Clinical and pathologic information was obtained from medical records. Results Twelve (18%) of 68 tumors demonstrated Her-2/neu overexpression. Of these, only two showed gene amplification. When evaluating all 68 patients, Her-2/neu overexpression was associated with a poorer overall survival (OS; P = .008). In our multivariate Cox proportional hazards models, Her-2/neu IHC overexpression, lymph node status, and stage were each associated with OS (P ≤ .05). Conclusion Positive IHC overexpression of Her-2/neu was seen in 18% of UPSCs but was rarely correlated with Her-2/neu gene amplification. Overexpression of Her-2/neu was associated with a worse overall prognosis. The use of trastuzumab (Herceptin; Genentech, South San Francisco, CA) in women with UPSC should be further evaluated in a clinical trial setting.

Intensity of the preparative regimen is an important component of allogeneic transplantations for myelodysplasia (MDS) or acute myelogenous leukemia (AML). We compared outcomes after a truly nonablative regimen (120 mg/m2 fludarabine, 4 g/m2 cytarabine, and 36 mg/m2 idarubicin [FAI]) and a more myelosuppressive, reduced-intensity regimen (100 to 150 mg/m2 fludarabine and 140 or 180 mg/m2 melphalan [FM]). We performed a retrospective analysis of 94 patients with MDS (n = 26) and AML (n = 68) treated with FM (n = 62) and FAI (n = 32). The FAI group had a higher proportion of patients in complete remission (CR) at transplantation (44% versus 16%, P = .006), patients in first CR (28% versus 3%, P = .008), and HLA-matched sibling donors (81% versus 40%, P = .001). Median follow-up is 40 months. FM was significantly associated with a higher degree of donor cell engraftment, higher cumulative incidence of treatment-related mortality (TRM; P = .036), and lower cumulative incidence of relapse-related mortality (P = .029). Relapse rate after FAI and FM was 61% and 30%, respectively. Actuarial 3-year survival rate was 30% after FAI and 35% following FM. In a multivariate analysis of patient- and treatment-related prognostic factors, progression-free survival was improved after FM, for patients in CR at transplantation, and for those with intermediate-risk cytogenetics. Survival was improved for patients in CR at transplantation. In conclusion, FM provided better disease control though at a cost of increased TRM and morbidity.

Purpose To evaluate the efficacy of long-term nontunneled silicone catheters impregnated with minocycline and rifampin (M-R) in reducing catheter-related bloodstream infections. Patients and Methods This prospective, randomized, double-blind clinical trial was conducted at M.D. Anderson Cancer Center, a tertiary care hospital in Houston, TX. All patients in the trial had a malignancy. Results Between September 1999 and May 2002, 356 assessable catheters were used: 182 M-R and 174 nonimpregnated. The patients' characteristics were comparable between the two study groups. The mean (± standard deviation) duration of catheterization with M-R catheters was comparable to that of nonimpregnated catheters (66.21 ± 30.88 v 63.01 ± 30.80 days). A total of 17 catheter-related bloodstream infections occurred during the course of the study. Three were associated with the use of M-R catheters and 14 were associated with the nonimpregnated catheters, with a rate of catheter-related bloodstream infection of 0.25 and 1.28/1,000 catheter-days, respectively (P = .003). Gram-positive cocci accounted for the majority of the organisms causing the infections. There were no allergic reactions associated with M-R catheters. Conclusion Long-term nontunneled central venous catheters impregnated with minocycline and rifampin are efficacious and safe in reducing catheter-related bloodstream infections in cancer patients.

Leptin is secreted by bone marrow (BM) adipocytes and stromal cells and was shown to stimulate myeloid proliferation. We here report that primary acute promyelocytic leukemia (APL) cells express high levels of the leptin-receptor (OB-R) long isoform. In cells with regulated promyelocytic leukemia–retinoic acid receptor (PML-RARα) expression, inducing PML-RARα was found to increase OB-R levels. We then investigated the effects of leptin produced by BM adipocytes on APL cells using a coculture system with mesenchymal stem cell (MSC)–derived adipocytes. In PML-RARα–expressing cells, all-trans retinoic acid (ATRA)– and doxorubicin-induced apoptosis were significantly reduced by coculture with adipocyte-differentiated MSCs. This antiapoptotic effect required direct cell-to-cell interactions, was associated with phosphorylation of signal transducer and activator of transcription-3 (STAT3) and mitogen-activated protein kinase (MAPK), and was reduced by blocking OB-R. This report provides a mechanistic basis for the BM adipocyte–leukemia cell interaction and suggests that OB-R receptor blockade may have therapeutic use in APL.

Purpose: To identify prognostic factors related to outcome in 219 children and adolescents with synovial sarcoma. Patients and Methods: We combined the experiences of the four following research groups: Cooperative Weichteilsarkomastudie Group, Germany (n = 95); St. Jude Children’s Research Hospital, Memphis, TN (n = 49); Istituto Nazionale dei Tumori, Milan, Italy (n = 33); and The University of Texas M.D. Anderson Cancer Center, Houston, TX (n = 42). Kaplan-Meier and Cox proportional hazard analyses were performed. Results: The median age at diagnosis was 13 years (range, 1 to 20 years), and the median follow-up was 6.6 years (range, 0.5 to 30.7 years). The estimated 5-year overall survival and event-free survival rates for the entire group were 80% ± 3% (SE) and 72% ± 3%, respectively. A previously unreported interaction between tumor size and invasiveness was observed that statistically significantly related to outcome. In multivarible analysis, patients with T1B and T2B disease (hazard ratio [HR] = 5.6, 95% confidence interval (CI), 1.9 to 16.2; and HR = 5.9, 95% CI, 2.1 to 16.4, respectively) or Intergroup Rhabdomyosarcoma Study (IRS) Clinical Group III and IV disease (HR = 2.7, 95% CI, 1.2 to 6.5; and HR = 14.1, 95% CI, 4.3 to 31.3, respectively) had poor overall survival. Treatment with radiotherapy was related to improved overall survival (HR = 0.4; 95% CI, 0.2 to 0.7). In IRS Group III patients, objective response to chemotherapy (18 of 30, 60%) correlated with improved survival. Conclusion: Clinical group, tumor size, and invasiveness are important prognostic factors. Multicenter randomized clinical trials are needed to determine both the effect of chemotherapy on survival and the necessity of local radiotherapy in patients with completely resected tumors.

We retrospectively analyzed the effect of maintenance endocrine therapy (MET) after high-dose chemotherapy with hematopoietic progenitor cell transplant (HDCT) on the progression-free survival (PFS) of patients with hormone-dependent metastatic breast cancer (MBC). One hundred and nine consecutive patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive MBC, who were progression free for at least 4 months after HDCT with cyclophosphamide, carmustine and thiotepa (CBT), were analyzed. Of these, 55 were non-randomly submitted to MET. After a median follow-up of 34.4 months (17.1-91.0), univariate analysis showed that MET was significantly associated with improved median PFS (31.1 vs 19.2 months, P = 0.022). Complete response to HDCT, pattern of metastatic spread, extent of the disease, single vs multiple metastatic sites, prior endocrine therapy for metastatic disease and prior exposure to any hormonal therapy (adjuvant and/or for the advanced disease) were also associated with PFS at univariate analysis. A multivariate Cox proportional hazard model was fitted to the data in order to correct the effect of MET for the other significant covariates. After correcting for these covariates, MET was still significant, predicting improved PFS (hazard ratio (HR) 0.580, 95% CI; 0.362-0.931). Administration of MET after optimal cytoreduction might result in increased efficacy of HDCT in hormone-dependent metastatic breast cancer.

5511 Background: Recent studies show that germline or somatic BRCA1/2 mutations and homologous recombination (HR) defects can be used to predict response to PARP inhibitors in recurrent ovarian cancer. However, the impact of defects in BRCA1/2 and HR genes on overall clinical outcomes are not yet defined for patients undergoing neoadjuvant chemotherapy (NACT) versus upfront surgical debulking (USD). Methods: Previously untreated ovarian cancer patients were prospectively enrolled under approved IRB protocol. Germline and tumor BRCA1/2 mutation testing and methylation were analyzed when sufficient tumor and blood was available. Mutation in 21 additional hereditary cancer genes (including HR genes) was also evaluated. Tumor HR defects were scored on LOH, telomeric allelic imbalance, and large-scale state transitions (as previously described). Presence of germline or somatic BRCA1/2 mutations, BRCA1 methylation, HR score ≥42, or germline mutation in other HR genes were defined together as HRD positive. Results: Of 299 enrolled patients, 129 (43%) received USD and 170 (57%) received NACT. Patients receiving USD had better outcomes compared to NACT, including overall survival (OS, 65.8 vs 45.2 months, p = 0.0003) and event free survival (EFS, 24.8 vs 15.6 months, p < 0.0001). In the overall cohort, EFS was significantly longer for HRD positive patients vs HRD negative (20.5 vs 16.3 months, p = 0.0268). Patients with somatic and germline BRCA1/2 mutations had longer OS vs BRCA1/2 negative (65.3 vs 46.1 months, p = 0.0403). Overall outcomes were worse in NACT compared to USD, but impact of BRCA1/2 mutations and HR defects was stronger in this group. NACT patients with any HR defect had longer EFS (19.7 vs 14.5 months, p = 0.0247). NACT patients with BRCA1/2 germline mutations had longer OS (65.3 vs 38.3 months, p = 0.0230). NACT patients with BRCA1/2 germline mutation had longer EFS (22.6 vs 14.6 months, p = 0.0047). OS and EFS in USD patients were significantly changed based on only debulking status; mutation or HR status did not have a statistically significant effect. Conclusions: While HR defects and BRCA1/2 mutations influence overall outcomes for ovarian cancer patients, the impact is stronger in NACT compared to USD.

Objective: To compare cone specimen size between loop electrosurgical excision procedure (LEEP) and cold knife cone (CKC), and evaluate the association between specimen size and margin status. Methods/materials: A retrospective review was performed of women with adenocarcinoma in situ (AIS) who underwent CKC or LEEP between 1998 and 2013. Specimen size, including length (distance from the external cervical os to the endocervical margin) and volume were compared between LEEP and CKC, and correlated with margin status. Results: Eighty-five patients underwent a total of 136 procedures, including 91 CKCs (67%) and 45 LEEPs (33%), with 27 removed as a single specimen (one-piece LEEP) and 18 as two specimens with an ectocervical specimen and a deeper endocervical top-hat specimen (two-piece LEEP). The two-piece LEEP specimen median length was significantly longer (2.1 cm) versus CKC (1.4 cm, p3) versus CKC (3.4 cm3, p3, pConclusion: Our results suggest that a two-piece LEEP produces a larger specimen size with similar rates of positive margins compared with CKC. Given the decreased cost and morbidity compared with CKC, a two-piece LEEP should be considered in the management of women with AIS.

Background and objectives Data showing the impact of the robotic simulator on fellowship training are limited. This study was conducted to determine whether simulator scores reflect the experience of the robotic gynecologic surgeon and to develop a simulator curriculum for trainees in gynecologic oncology. Methods All faculty and fellows in the Department of Gynecologic Oncology and Reproductive Medicine were asked to participate. For phase 1, all participants were divided into 2 groups based on robotic surgical experience: beginner (0-50 cases) and experienced (>50 cases). Each participant completed 9 modules 3 times each to establish baseline data. Median module scores for the experienced group defined the benchmarks scores. In phase 2, all trainees who did not meet the benchmark score on a module were asked to repeat the module until they reached the score twice. Results Twenty-four participants were included: 18 beginners and 6 experienced surgeons. For all modules, experienced surgeons received higher median scores than beginners. There was a significant difference between the scores of the 2 groups in the Energy Switching 1 (87.5 vs 92.5; P = .002) and Suture Sponge 2 (75.0 vs 87.3; P = .011) modules. Thirteen trainees participated in phase 2. For 8 of 9 of the modules, >75% of trainees met proficiency, with a median of 3 to 6 attempts (range, 2-24). Conclusion Based on the findings, scores reflected each surgeon's experience. With repetition, most of the trainees were able to reach the benchmark scores. Further study is needed to determine the impact of surgical simulation on true intraoperative performance.

Uterine adenosarcoma is a rare malignancy with little data on optimal management. We aimed to clarify the impact of adjuvant therapy in patients with uterine adenosarcoma and identify risk factors for recurrence and death.We performed a retrospective review of patients undergoing primary evaluation and treatment for uterine adenosarcoma at a single institution from July 1982 through December 2011. Univariate and multivariate analyses were used to identify prognostic factors for progression-free survival (PFS) and overall survival (OS).We identified 100 patients with uterine adenosarcoma, and 74 patients met the inclusion criteria. On multivariate analysis, sarcomatous overgrowth (SO) and lymphovascular space invasion (LVSI) were predictors of worse PFS and OS. Median PFS and OS were 29.4 and 55.4 months for patients with SO, compared to 105.9 and 112.4 months for patients without SO (PFS HR 2.58, 95% CI 1.37-4.84, p=0.003; OS HR 2.45, 95% CI 1.26-4.76, p=0.008). Among patients with stage I disease, 17 of 22 patients (77%) with SO and 8 of 37 patients (22%) without SO had a recurrence (p0.001). Among patients with stage I disease with SO, adjuvant therapy appeared to be associated with longer PFS and OS, but these differences were not statistically significant (PFS, 46.7 vs. 29.4 months, p=0.28; OS, 97.3 vs. 55.4 months, p=0.18).In patients with uterine adenosarcoma, the presence of SO or LVSI confers a higher risk of recurrence. We did not identify an optimal treatment strategy for patients with SO, but adjuvant therapy may be associated with prolonged PFS.

Purpose To prospectively determine sexual function, bother, and potency preservation in men treated with prostate brachytherapy and twice-weekly tadalafil. Methods and Materials From 2005 to 2011, men treated with low-dose-rate prostate brachytherapy were treated on a prospective registration study. All patients were prescribed tadalafil 10 mg twice weekly. The expanded prostate cancer index composite questionnaire was administered before treatment and at each followup. A subgroup analysis of men with sexual potency at baseline was performed. Results A total of 237 men were analyzed. Median age was 64 years (range, 44–86). Median followup was 24.8 months (range, 1–60). At baseline, 175 men (74%) reported erections firm enough for sexual activity and 148 (62%) were potent (erections firm enough for intercourse). Statistically significant changes in sexual function/bother were appreciated from baseline throughout the analysis period, although absolute changes were relatively small and did not meet criteria for clinical significance. At 24-months followup, 72% reported erections firm enough for sexual activity and 56% were potent. Of men with potency at baseline, 89% had erections firm enough for sexual activity and 76% remained potent 24 months after treatment. Conclusions Peri-procedural tadalafil and prostate brachytherapy resulted in high rates of sexual potency preservation and no clinically significant effect on sexual quality of life.

Despite increasing awareness of physical strain to surgeons associated with minimally invasive surgery (MIS), its use continues to expand. We sought to gather information from gynecologic oncologists regarding physical discomfort due to MIS.Anonymous surveys were e-mailed to 1279 Society of Gynecologic Oncology (SGO) members. Physical symptoms (numbness, pain, stiffness, and fatigue) and surgical and demographic factors were assessed. Univariate and multivariate analyses were performed to determine risk factors for physical symptoms.We analyzed responses of 350 SGO members who completed the survey and currently performed50% of procedures robotically (n=122), laparoscopically (n=67), or abdominally (n=61). Sixty-one percent of members reported physical symptoms related to MIS. The rate of symptoms was higher in the robotic group (72%) than the laparoscopic (57%) or abdominal groups (49%) (p=0.0052). Stiffness (p=0.0373) and fatigue (p=0.0125) were more common in the robotic group. Female sex (p0.0001), higher caseload (p=0.0007), and academic practice (p=0.0186) were associated with increased symptoms. On multivariate analysis, robotic surgery (odds ratio [OR] 2.38, 95% CI 1.20-4.69) and female sex (OR 4.20, 95% CI 2.13-8.29) were significant predictors of symptoms. There was no correlation between seeking treatment and surgical modality (laparotomy 11%, robotic 20%, laparoscopy 25%, p=0.12).Gynecologic oncologists report physical symptoms due to MIS at an alarming rate. Robotic surgery and female sex appear to be risk factors for physical discomfort. As we strive to improve patient outcomes and decrease patient morbidity with MIS, we must also work to improve the ergonomics of MIS for surgeons.

Endometrial cancer remains the most common gynecologic malignancy in the United States and the incidence of new cases has increased over the last three decades. In 2013, the American Cancer Society estimates there will be 49,560 new cases and 8,190 deaths from endometrial cancer1. Although many are cured, the subset of patients with advanced stage endometrial cancer at diagnosis or recurrent disease presents a significant therapeutic challenge. The use of chemotherapy has been extensively evaluated but has shown only modest benefit. The optimal treatment approaches yield response rates from 40–78% in the primary advanced setting and 15–30% in the recurrent setting. Furthermore, among the optimal chemotherapy regimens for this group, median progression-free survival is only 6 months and median overall survival reaches 12 months2,3. This underscores the great need for novel treatment strategies to improve outcomes for this population of women with endometrial cancer. Targeted therapy is a promising strategy as molecular alterations of endometrial cancer are becoming better described and multiple potential targets amenable to biologic therapies are already in development. While single-agent biologic agents may have only a modest clinical impact, augmented results may be anticipated in combination with traditional cytotoxic agents, as well as, other novel biologic agents targeting complementary activated pathways. Targeted therapy carries new and different side effect profiles and toxicities, and patient selection remains one of the largest challenges in effectively incorporating new biologic agents. The use of biologic agents in an unselected patient population has the potential to contribute to morbidity without benefit. Further, this can potentially lead to incorrect classification of a drug as inactive for reasons such as lack of expression of the relevant target or presence of a mutation which confers resistance to the agent 4. At this time, no accurate predictive biomarkers exist for most newly developed targeted agents in endometrial cancer. Endometrial carcinomas exhibit distinct molecular alterations which hold potential druggable targets. The PI3K/AKT/mTOR pathway is the most frequently altered signaling pathway in endometrial carcinoma, including loss of function of the tumor suppressor PTEN, which is seen in up to 83% of endometrioid carcinomas and 55% of precancerous lesions. Loss of function of the tumor suppressor PTEN has been suggested to be an early event in endometrial tumorigenesis.5 This abberation upregulates signaling through the PI3K/AKT/mTOR pathway, leading to uncontrolled cell proliferation and survival. Activation of the PI3K/AKT/mTOR pathway results in elevated levels of downstream markers such as phosphorylated-S6 ribosomal protein (pS6rp) 6,7. In addition, KRAS mutations are found in up to 30% of endometrial cancers 8,9. K-Ras mutations are also seen in 6–16% of endometrial atypical hyperplasia and thus, are considered one of the earliest molecular events in endometrial cancer.10–12 Preliminary analysis in advanced solid tumors indicates that mutations in KRAS may convey resistance to PI3K-directed therapy, especially among endometrial cancer patients. 13. Due to its prominent role in endometrial carcinogenesis, the PI3K/AKT/mTOR pathway has received significant attention for agent development. Several compounds have been discovered that selectively target this pathway, including rapamycin analogs, which directly inhibit mTOR. Many of these compounds –everolimus14, temsirolimus15, and ridaforolimus16 - have completed or are currently being evaluated in clinical trials as monotherapy and/or in combination regimens for the treatment of endometrial carcinoma. The objective of this study was to determine if expression of biomarkers in the mTOR pathway or KRAS mutations would predict response to therapy to everolimus, an oral inhibitor of the mTOR signaling pathway.

Recent literature in ovarian cancer suggests differences in surgical outcomes depending on operative start time. We sought to examine the effects of operative start time on surgical outcomes for patients undergoing minimally invasive surgery for endometrial cancer.A retrospective review was conducted of patients undergoing minimally invasive surgery for endometrial cancer at a single institution between 2000 and 2011. Surgical and oncologic outcomes were compared between patients with an operative start time before noon and those with a surgical start time after noon.A total of 380 patients were included in the study (245 with start times before noon and 135 with start times after noon). There was no difference in age (p=0.57), number of prior surgeries (p=0.28), medical comorbidities (p=0.19), or surgical complexity of the case (p=0.43). Patients with surgery starting before noon had lower median BMI than those beginning after noon, 31.2 vs. 35.3 respectively (p=0.01). No significant differences were observed for intraoperative complications (4.4% of patients after noon vs. 3.7% of patients before noon, p=0.79), estimated blood loss (median 100 cc vs. 100 cc, p=0.75), blood transfusion rates (7.4% vs. 8.2%, p=0.85), and conversion to laparotomy (12.6% vs. 7.4%, p=0.10). There was no difference in operative times between the two groups (198 min vs. 216.5 min, p=0.10). There was no association between operative start time and postoperative non-infectious complications (11.9% vs. 11.0%, p=0.87), or postoperative infections (17.8% vs. 12.3%, p=0.78). Length of hospital stay was longer for surgeries starting after noon (median 2 days vs. 1 day, p=0.005). No differences were observed in rates of cancer recurrence (12.6% vs. 8.8%, p=0.39), recurrence-free survival (p=0.97), or overall survival (p=0.94).Our results indicate equivalent surgical outcomes and no increased risk of postoperative complications regardless of operative start time in minimally invasive endometrial cancer staging, despite longer length of hospital stay for surgeries beginning after noon.

We have previously discovered a synergistically therapeutic combination of two Toll-like receptor ligands, an oligodeoxynucleotide (ODN) and Pam2CSK4. Aerosolization of these ligands stimulates innate immunity within the lungs to prevent pneumonia from bacterial and viral pathogens. Here we examined the safety and tolerability of this treatment in mice, and characterized the expression of biomarkers of innate immune activation. We found that neutrophils appeared in lung lavage fluid 4 h after treatment, reached a peak at 48 h, and resolved by 7 days. The peak of neutrophil influx was accompanied by a small increase in lung permeability. Despite the abundance of neutrophils in lung lavage fluid, only rare neutrophils were visible histopathologically in the interstitium surrounding bronchi and veins and none were visible in alveolar airspaces. The cytokines interleukin 6 (IL-6), tumour necrosis factor, and Chemokine (C-X-C motif) ligand 2 rose several hundred-fold in lung lavage fluid 4 h after treatment in a dose-dependent and synergistic manner, providing useful biomarkers of lung activation. IL-6 rose fivefold in serum with delayed kinetics compared to its rise in lavage fluid, and might serve as a systemic biomarker of immune activation of the lungs. The dose–response relationship of lavage fluid cytokines was preserved in mice that underwent myeloablative treatment with cytosine arabinoside to model the treatment of hematologic malignancy. There were no overt signs of distress in mice treated with ODN/Pam2CSK4 in doses up to eightfold the therapeutic dose, and no changes in temperature, respiratory rate, or behavioral signs of sickness including sugar water preference, food disappearance, cage exploration or social interaction, though there was a small degree of transient weight loss. We conclude that treatment with aerosolized ODN/Pam2CSK4 is well tolerated in mice, and that innate immune activation of the lungs can be monitored by the measurement of inflammatory cytokines in lung lavage fluid and serum.