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Background. Uterine papillary serous carcinoma is an aggressive tumor with a high propensity for distant spread. Metastases to the heart or pericardium are rare in gynecologic malignancies and usually fatal. Case. A 64-year-old African American woman was diagnosed with recurrent uterine papillary serous carcinoma metastatic to the pericardium. Her case at presentation was significant for an elevated serum CA-125, evidence of metastatic disease to the liver, and massive cardiomegaly. Cytologic analysis of fluid obtained by pericardiocentesis confirmed recurrence. Despite treatment with paclitaxel and a pleuropericardial window, the patient succumbed to her disease. Conclusion. The prognosis for patients whose recurrent uterine papillary serous carcinoma has metastasized to the heart or pericardium is extremely poor. Effective adjuvant and salvage therapies are essential.

In March 2010, President Obama signed into law the Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act. This legislation attempts to address cost control and improve the quality of healthcare in the United States. Cancer is a major health problem in the United States and the leading cause of death for Americans under the age of 80. Therefore, cancer care providers need to be fully engaged in ongoing discussions regarding quality measurement and care delivery. With the optimum level of collaboration and support, the proposals in the legislation can be properly structured to deliver improved access to care via better delivery systems, as well as more appropriate reimbursement to advance the prevention and treatment of cancer.

Background. Patients with Stage I Grade 1 endometrial carcinoma have an excellent prognosis and a 10-year survival rate of more than 90%. In every clinical series, however, a few patients in this group have recurrence and die of their disease. Methods. The authors reviewed 80 patients with Stage I Grade 1 endometrial carcinoma treated at their institution from 1955–1980. Eight patients died of recurrent disease within 4 years of diagnosis. The authors studied multiple clinical and histopathologic features, estrogen receptor (ER) and progesterone receptor (PR) status, DNA flow cytometric characteristics, and the expression of c-myb, H-ras, and neu oncogenes. Results were compared with those for a control group of 11 patients who survived more than 10 years free of disease. Results. The authors identified the following four statistically significant adverse prognostic factors: myo-metrial invasion, vascular invasion, 8 or more mitoses per 10 high-power fields, and an absence of PR. Residual tumor, aneuploidy, and high proliferative activity were associated with a more aggressive behavior, although the relationship did not reach statistical significance. Conclusions. All patients who died of disease within 4 years had tumors with two or more of the significant adverse prognostic factors. Cancer 1992; 70:790–798.

Among the different types of variability (interindividual, intra-individual, analytical, and preanalytical) that can influence the results of any biological assay, preanalytical variations are the most difficult to manage. Preanalytical variations are defined as any variation taking place between

B72.3 is a murine monoclonal antibody that recognizes a high-molecular-weight tumor-associated glycoprotein (TAG-72). Nine patients with TAG-72-positive ovarian carcinoma or papillary serous carcinoma of the peritoneum received an intraperitoneal infusion of 2, 4, or 10 mg B72.3 labeled with 0.5-1.2 (mean, 0.8) mCi 90Y. All patients had laparotomy, with multiple tissue and tumor samples removed 3-7 days later. The concentration of the total 90Y label in peritoneal fluid cleared with an extrapolated half-life of 68.6 +/- 4.5 hours. A low-molecular-weight 90Y-labeled species of metabolite was identified by high-performance liquid chromatography. The concentration of this low-molecular-weight species initially increased in the peritoneal fluid, with a half-life of 0.9 hour, and was rapidly cleared from the peritoneal cavity, with a half-life of 23.1 hours. Both the 90Y-labeled metabolite and the 90Y-labeled B72.3 were absorbed into the plasma, with half-lives of 16 +/- 2.2 hours and 25 +/- 5 hours, respectively. The clearance half-lives for these agents in plasma were 25 +/- 3 hours for the metabolite and 42 +/- 17 hours for B72.3. Approximately 8%-11% of the total injected 90Y label appeared in urine over 72 hours. Most of the label (about 70%) was present as the 90Y-labeled metabolite, but about 30% of the 90Y label in urine appeared identical to the authentic 90Y-labeled B72.3 standard when assayed by chromatography. Tissue distribution studies showed that normal tumor tissue and omentum contained the highest content of 90Y (about 0.017% of the injected dose per gram), followed in descending order by liver, normal lymph nodes, peritoneum, bone, and fascia. The lowest concentrations of 90Y were found in rectus abdominis muscle, bone marrow, and fat. There was substantial heterogeneity in the uptake of the 90Y label into tumor sites among patients and among different sites within the same patient. No correlation could be demonstrated between the TAG-72 content and the amount of 90Y label found in tumor sites. Preliminary radiation dosimetry estimates suggest that the tumor sites received about 82.8 cGy for each millicurie of 90Y administered. Thus, if an adequate total radiation dose can be achieved, 90Y-labeled B72.3 should be therapeutically useful for treating diffuse intraperitoneal disease.

Although uncommonly performed in this setting, splenectomy is sometimes indicated in patients with gynecologic malignancies. From January 1970 through March 1989, 45 patients at The University of Texas M.D. Anderson Cancer Center underwent splenectomy during the course of gynecologic laparotomies. All procedures were performed by the gynecology staff and trainees. Twenty-seven patients (60%) had ovarian cancer; endometrial and cervical cancers were present in three patients each. The remaining 11 patients had other diseases. Splenectomy was planned preoperatively in only 9 patients (20%). Thirteen patients (29%) underwent splenectopmy because of injury to the spleen. Injury was most commonly due to traction during omentectomy, resulting in capsular laceration. The injury was immediately recognized in 12 patients; 1 patient required reexploration for hemoperitoneum. In 24 patients (53%), splenectomy was performed for tumor reduction. Pathologic examination showed that 11 of 24 patients had capsular involvement by tumor, 7 had parenchymal metastases, and 6 had no direct splenic involvement. Residual tumor following cytoreduction was smaller than 2 cm in 62.5% of patients. Splenectomy is a well-tolerated procedure and the operative approach can be tailored to the clinical situation and distribution of tumor. An attempt should be made to repair splenic injury when tumor involvement is not present.

Between 1965 and 1985, 160 patients had initial treatment at the M. D. Anderson Cancer Center for Stage I adenocarcinoma of the uterine cervix less than or equal to 4 cm in diameter. Of these patients, 84 were treated with radiation therapy (RT) alone, 20 were treated with external and intracavitary radiation followed by total hysterectomy (R + S), and 56 were treated with radical hysterectomy (RH). Survival rate was strongly correlated with tumor volume (P = 0.0008), lymphangiogram findings (P = 0.01), and tumor grade (P = 0.0018). Patients with a normal-appearing cervix or a small visible or palpable tumor that did not expand the cervix more than 3 cm had survival and pelvic-control rates of more than 90% after treatment with RH or RT. However, after 5 years, 45% of patients treated with RH for tumors 3-4 cm in diameter had disease recurrence in the pelvis, compared with 11% of patients treated with either RT or R + S (P = 0.025). For patients treated with RH, recurrence was also strongly correlated with findings of lymph/vascular space invasion (P = 0.0004) and poorly differentiated tumor (P = 0.018). Major complication rates were comparable for the three treatment groups. The high rate of pelvic recurrence following treatment with radical hysterectomy alone for patients with tumors greater than 3 cm in diameter, particularly in the presence of lymph/vascular space invasion, poorly differentiated features, and/or positive nodes, should be considered in planning the primary management of patients with Stage I adenocarcinoma of the cervix.

About one-half of cervical cancer patients whose tumors recur after radical surgery have negative lymph nodes and clear resection margins. We evaluated 95 patients with squamous cell tumors who underwent radical hysterectomy and pelvic lymphadenectomy between January 1975 and December 1985 and who were thought to be at low risk for recurrence to see whether other clinical or histopathologic factors were predictive of tumor recurrence. Detailed retrospective record review and complete pathology review were accomplished for each case. The 5-year actuarial survival rate was 89%. Nine patients developed recurrent disease (9.5%), of whom eight died. Several clinical features were evaluated as possible prognostic factors: patient age (P = .26), patient race (P = .60), cervical diameter (P = .24), extent of gross cervical involvement (P = .36), and presence of contact bleeding (P = .82). Histopathologic features were examined: depth of invasion (P = .31), number of mitoses (P = .42), character of the tumor-stromal border (P = .15), histologic differentiation (P = .02), lymph-vascular space invasion (P = .56), and width of tumor (P = .23). Depth of invasion did correlate with increasing tumor width (P less than .001). Once node- and margin-positive patients are excluded, differentiation may be the only feature useful in identifying patients at risk for recurrence. Because almost one-half of our patients had poorly differentiated tumors, sole use of this feature as a criterion for adjuvant therapy would have resulted in overtreatment of low-risk patients.

From 1967 through December 1987, 145 patients with endometrioid carcinoma of the ovary were treated at the University of Texas M. D. Anderson Cancer Center. Thirty-eight patients (26.2%) had stage I disease, 28 (19.3%) stage II, 60 (41.4%) stage III, and 11 (7.6%) stage IV; 8 patients (5.5%) were unstaged. Grade 2 or 3 histology was seen in 119 patients (82.1%). In addition to surgical therapy, 128 patients underwent chemotherapy, including single-agent therapy, noncisplatin combination therapy, and cisplatin-based therapy. No statistically significant improvement in median survival was noted among these three chemotherapy groups for stages II, III, and IV (P = 0.22). A significant improvement in median survival was noted for those patients who achieved a complete clinical response, regardless of type of chemotherapy (96 or more months for single-agent therapy, P = 0.001; 31.5 months for noncisplatin combination therapy, P = 0.016; and 85 months for cisplatin-based therapy, P = 0.0001). Synchronous ovarian and uterine malignancies were seen in 18 patients (12.4%). No difference in survival was seen for patients with endometriosis (P = 0.13) or endometrial cancer (P = 0.09) when compared with those who did not have these histologic findings.

Between October 1985 and January 1989, 33 patients with stage I (31) or clinically occult stage II (2) endometrial cancer at a high risk for recurrence were entered in a prospective study evaluating adjuvant cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy. Eligibility criteria included grade 2 tumors with middle- or outer-third myometrial invasion (16), grade 3 tumors with any degree of myometrial invasion (17), presence of extrauterine disease with no gross residual (17), or a high-risk histologic subtype including papillary serous (4), adenosquamous (5), or clear cell (1) tumors. Patients received PAC (50/50/500 mg/m 2 ) at 4-week intervals for six cycles. Thirty patients (90%) completed therapy. Toxicity included severe neutropenia in 14 patients, neutropenic sepsis in 2 patients, and doxorubicin-related cardiomyopathy in 1 patient. There were no treatment deaths. Current median follow-up is 25 months. Nine patients (27%) have developed a recurrence, 7 of whom died, after a median interval of 14 months. Eight of the 9 with recurrence initially had extrauterine disease ( P = 0.02). The resulting 2-year actuarial progression-free and overall survival rates were 79 and 83%, respectively. The median progression-free interval was 29 months for patients with extrauterine disease and 45 + months for those with no extrauterine disease ( P = 0.02). These results suggest that a phase 3 randomized trial comparing adjuvant PAC with radiation therapy is warranted.

To determine the growth inhibitory effects of mifepristone on endometrial cancer cell growth and evaluate its effect on apoptosis using HEC-1-A and Ishikawa human endometrial cancer cell lines.The human endometrial cancer cell lines, HEC-1-A and Ishikawa, were cultured in vitro. MTT assays were completed in order to estimate the IC(50) of mifepristone. Both cell lines were then treated with the respective IC(50) values. Immunohistochemistry assays were performed to investigate the expression of estrogen receptors alpha and beta (ERalpha/beta), progesterone receptor alpha and beta (PR alpha/beta), cyclooxygenase-2 (COX-2), bax, p53, and bcl-2. Flow cytometry analysis was performed to study cell cycle arrest and apoptosis.The estimated IC(50) of mifepristone for HEC-1-A and Ishikawa was found to be 16 and 19 mug/ml respectively. At this concentration, there was no change in either ERalpha/beta or PR alpha/beta in Ishikawa. However, PR beta expression increased with time of treatment in HEC-1-A. Expression of p53 was increased with duration of treatment in both cell lines. Consequently a decrease in bcl-2 and an increase in COX-2 expression were seen in HEC-1-A and Ishikawa cells, respectively. Lastly, flow cytometry analysis confirmed an accumulation of cells in G0 phase after 72 h of treatment in both cell lines.Mifepristone demonstrates activity in both HEC-1-A and Ishikawa cells at clinically relevant concentrations based on an oral human dose of about 200 mg/day. While its mechanism of action remains unknown, this data supports an increase in apoptosis that may be due to p53 activation rather than hormone receptor mediation. Additional studies are needed to help further identify mifepristone mechanism of action.

Objective. To evaluate fundal injection of blue dye and radiocolloid for lymphatic mapping and sentinel node identification in women with high-risk endometrial cancer. Methods. At laparotomy, 18 women with high-risk endometrial cancer had isosulfan blue and technitium-99 radiocolloid injected into the uterine fundus subserosally. Sentinel nodes were then identified either by direct observation of blue dye, by radioactive counts using a handheld gamma counter, or by a combination of both methods. The number and location of sentinel node(s) were recorded and compared with the final lymph node specimens after hysterectomy and selective lymphadenectomy. Results. A sentinel node was identified in only 8 (45%) of the cases. Four patients had sentinel nodes only in the pelvis, 2 had sentinel nodes in the pelvis and above the bifurcation of the aorta, and 2 patients had sentinel nodes above the bifurcation of the aorta only. Seven (88%) patients had unilateral drainage of dye and the radiocolloid; the other patient had bilateral drainage. No patients had metastatic disease to sentinel or nonsentinel lymph nodes. Conclusions. Subserosal fundal injection of blue dye and the radiocolloid is a poor technique for identifying sentinel lymph nodes in patients with high-risk endometrial cancer.

Objectives. To evaluate the efficacy and tolerability of imatinib mesylate (Gleevec; Novartis Pharmaceuticals, Basel, Switzerland) in patients with recurrent ovarian and primary peritoneal cancer. Methods. This was an open-label, single-institution phase II trial. Patients were eligible if they had measurable platinum/taxane-resistant disease, received 2–4 prior treatment regimens, and over-expressed at least one imatinib target (c-Kit, PDGFR-β, or c-Abl) by immunohistochemistry. Imatinib was administered orally at 600 mg daily for 6 weeks (one course) and was repeated in the absence of measurable progression. Results. Sixteen enrolled patients were evaluable for toxicity and 12 for response. The median number of prior treatments was 4. A total of 29 courses were initiated. No complete or partial responses were documented during a median follow-up of 6.6 months. However, 4 (33%) of the 12 evaluable patients had stable disease lasting 3.8, 6.4, 7.5, and 8+ months. Expression of PDGFR-β and c-Abl was seen in 15 (94%) and c-Kit in 8 (50%) patients' tumors. There was no relationship between best response (stable disease) and target expression. Adverse events were uncommon, with fatigue and nausea/vomiting being reported in 34% and 31% of cycles, respectively. Two patients underwent dose reduction for rash and edema ( n = 1) and grade 3 neutropenia ( n = 1). No grade 4 toxicity was observed. Conclusion. Imatinib mesylate was well tolerated but did not produce clinical responses in patients with previously treated metastatic ovarian and primary peritoneal carcinoma.

The purpose of this study was to evaluate overall survival (OS) and determine prognostic subclassifications for stage IIIA endometrial cancer. Stage IIIA endometrial cancer patients treated at M.D. Anderson Cancer Center from 1989 to 2002 were reviewed. Clinical information was obtained from the medical record. Cox regression analyses were performed to evaluate the association of pathologic criteria and OS. Patients were divided into four groups based on this analysis: E1, endometrioid/pelvic cytology only; E2, endometrioid/adnexa +/- serosal spread; NE1, nonendometrioid/pelvic cytology only; and NE2, nonendometrioid/adenexa +/- serosal spread. Forty-nine patients were identified. By multivariate analysis, histology and extent of disease were the only factors associated with OS. Five-year OS in the four subgroups based on histology and extent of disease were: E1, 79%, E2, 65%, NE1, 64%, and NE2, 13%. Histologic subtype and extent of pelvic disease are the only prognostic factors associated with OS. Patients with endometrioid tumors and extent of pelvic disease limited to positive cytology had a favorable outcome, with or without adjuvant therapy. Future prospective clinical trials should consider subclassifying patients with stage IIIA disease to better evaluate the role of adjuvant therapy.

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40 - 60% lifetime risk for colon cancer, a 40 - 60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number ofwomen with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their sentinel cancer. METHODS: Women whose families fulfilled Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained. RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40. CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the sentinel cancer, preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome.

The purpose of this study was to identify characteristics significant to survival and progression-free survival in patients with advanced ovarian cancer receiving high-dose chemotherapy. In all, 96 patients received autologous stem cell transplantation. Regimens included paclitaxel with carboplatin (PC), topotecan, melphalan, cyclophosphamide (TMC) and cyclophosphamide, BCNU, thiotepa (CBT). At the time of transplantation, 43% of patients were in clinical CR, 34% were in clinical PR, 18% had progressive disease and 5% had stable disease. There were no treatment-related deaths. The 6-year survival by Kaplan-Meier was 38%. For patients who received transplantation for remission consolidation, the 6-year survival was 53% with a PFS of 29%. On univariate analysis, the CBT regimen, clear cell histology and disease status other than CR prior to treatment were statistically significant adverse prognostic factors. This analysis has demonstrated that patients in clinical remission are most likely to benefit from autologous transplantation, with the exception of patients with clear cell histology. The TMC combination appeared to be superior to the PC and CBT combinations. Comparative studies of different consolidation approaches will be necessary to determine if autologous transplantation is the preferred treatment for this patient population.

Objective The aim of this study was to identify clinical and pathologic characteristics of patients with uterine papillary serous carcinoma (UPSC) who were all surgically managed at a single institution. The identified characteristics were then correlated with overall survival (OS). Methods One hundred twenty-nine patients with FIGO stage I–IV UPSC who were surgically staged at the University of Texas M. D. Anderson Cancer Center between 1989 and 2002 were identified. For each patient, medical records and pathology reports were reviewed. The Kaplan–Meier method was used to generate OS data. Factors predictive of outcome were compared using the log-rank test and Cox regression analysis. Results There were 52 patients with stage I disease, 5 with stage II, 41 with stage III, and 31 with stage IV. The median age at the time of diagnosis was 68 years (range, 44–93 years). A personal history of breast cancer was reported by 12.4% of the patients, and a family history of breast cancer was reported by 16%. The 5-year OS among all patients was 45.9%. Among the stage I patients (IA, n = 19; IB, n = 26; and IC, n = 7), the 5-year OS was 62.9% (IA, 81.5%; IB, 58.6%; and IC, 34.3%). The 5-year OS for patients with stage III and IV disease was 37.3 and 19.9%, respectively. Pathologic features predictive of OS included lymph node status ( P ≤ 0.01), lymph vascular invasion ( P ≤ 0.05), and depth of uterine invasion ( P ≤ 0.05). Among patients with no uterine invasion ( n = 32), surgical staging revealed that 37% had stage III or IV disease. Among stage III patients, those who received chemotherapy had a longer OS than those who did not receive chemotherapy ( P = 0.03). Conclusion In this population of nonselected patients with UPSC, approximately 20% had a personal or family history of breast cancer. Stage, lymph node status, lymph vascular invasion, and depth of myometrial invasion were all risk factors for a worse prognosis. Traditional risk factors, however, did not predict the presence or the absence of metastasis. Among patients with noninvasive uterine disease, there was a high proportion with abdominal metastasis. Therefore, complete surgical staging of these patients is vital in determining their prognosis.

Purpose. Imatinib mesylate is a tyrosine kinase inhibitor that specifically targets c-Kit, Abl, and platelet-derived growth factor receptor (PDGFR). It has been shown to be an effective treatment for patients with chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). These cancers are characterized by activating mutations of the Abl and c-Kit tyrosine kinases, respectively. To determine whether imatinib mesylate could be a potentially useful agent in the treatment of endometrial cancer, we assessed the expressions of Abl, c-Kit, and PDGFR in both primary and recurrent endometrial carcinoma. Experimental design. We performed immunohistochemical analysis on formalin-fixed, paraffin-embedded sections from 63 patients: 33 with endometrioid endometrial carcinoma (EEC), 11 with uterine papillary serous carcinoma (UPSC), 12 with recurrent EEC, and seven with recurrent UPSC. The sections were stained with commercially available antibodies for Abl, PDGFR, and c-Kit. The sections were also stained for phosphorylated Abl and phosphorylated PDGFR. Results. Among the primary EEC, 28/33 (85%) stained positively for Abl and 30/33 (91%) were positive for PDGFR. Of the primary UPSC, 8/11 (73%) were positive for Abl. In addition, 8/11 (73%) of the primary UPSC tumors were positive for PDGFR. Neither the primary EEC (0/33) nor the primary UPSC (0/11) expressed c-Kit. Of the recurrent EEC tumors, 11/12 (92%) were positive for Abl expression, 12/12 (100%) were positive for PDGFR, and 2/8 (25%) were positive for c-Kit. Of the recurrent UPSC, 6/7 (86%) were positive for Abl, 7/7 (100%) were positive for PDGFR, and 2/4 (50%) for c-Kit. In addition, the majority of primary and recurrent tumors were positive for phosphorylated Abl (primary EEC, 91%; primary UPSC, 64%; recurrent EEC, 83%; recurrent UPSC, 86%), and phosphorylated PDGFR (primary EEC, 46%; primary UPSC, 40%; recurrent EEC, 58%; recurrent UPSC, 100%). Within the EEC primary tumors, the differences in kinase expression by grade of tumor were not significant except for PDGFR kinase; the lower grade tumors (1 and 2) had more PDGFR expression than the grade 3 tumors ( P Conclusions. The majority of primary and recurrent EEC, as well as primary and recurrent UPSC express Abl and PDGFR. This preclinical data suggest that imatinib mesylate may be useful in the treatment of patients with endometrial carcinoma.

Objective Arzoxifene, an orally active third-generation selective estrogen-receptor modulator (SERM), opposes the action of estrogen on the breast and endometrium but exerts an estrogen-agonist effect on bone and the lipid profile. Since this is an appealing combination for hormonal therapy of estrogen-related cancers, we initiated testing the potential of arzoxifene in women with treatment-refractory endometrial cancer. Methods Two phase I studies were conducted to evaluate the safety and pharmacokinetics of single and multiple doses of arzoxifene. In addition, two multi-institutional phase II trials have been completed on 100 women with metastatic or recurrent endometrial cancer. Results No serious adverse events were observed in the single-dose phase I study, the principal side effect being hot flashes in 5/15 healthy volunteers. In the second phase I study, conducted in 32 women with metastatic breast cancer, one patient had a serious, possibly drug-related adverse reaction (pulmonary embolism). The two multi-institutional trials demonstrated significant activity at 20 mg/day in patients with metastatic or recurrent endometrial cancer. Observed clinical response rates were 25 and 31%, with a median response duration of 19.3 and 13.9 months, respectively. Progression of the disease was stabilized in a substantial number of women. Toxicity was mild, except for two cases of pulmonary embolism that might have been drug related. Conclusions Further investigation is warranted to verify these preliminary response rates and the clinical significance of the stable disease cases, to compare clinical outcomes with those in progestin-treated women, and to elucidate the mechanisms of SERM action in this disease.

Objectives To characterize clinical and pathologic characteristics of sarcomatoid carcinoma of the cervix. Methods We retrospectively reviewed the charts of women with sarcomatoid carcinoma of the cervix identified by query of the Snomed pathologic diagnostic retrieval system and by direct physician query. Data were extracted from available charts, and pathology review was performed on all cases. SPSS was used for statistical analysis. Results Nine of 12 identified patients had complete clinical information and pathologic material available. The mean age at diagnosis was 48 (range, 29–76) years. Stage at diagnosis was I (4 patients), II (2 patients), and IV (3 patients). Patients younger than 40 years of age presented with stage I disease. All patients had visible tumor; 8 of 9 had vaginal bleeding or discharge at presentation. Microscopic evaluation revealed areas of spindle-cell sarcomatous tumor confluent with areas of poorly differentiated squamous cell carcinoma. Immunohistochemistry demonstrated coexpression of cytokeratin and vimentin in tumor cells. Tumors with a prominent spindle-cell component also expressed smooth muscle actin. Initial treatment varied, but all patients had a complete response to initial treatment. Five patients recurred with a median disease-free interval of 4.9 (range, 2–9.5) months, and none responded to second-line therapy. Four patients remained disease-free at 5, 18, 30, and 40 months, respectively, after completing initial therapy. Conclusions Sarcomatoid carcinoma of the cervix is an aggressive neoplasm. Primary treatment offers the best chance for cure in women with early-stage disease. Patients with advanced disease at presentation or recurrence succumb to their disease.

Objective The goal of this study was to determine response rate and evaluate toxicity of LY353381 (arzoxifene) in patients with recurrent or advanced endometrial cancer (EC). Methods A phase II, open-labeled study with arzoxifene was performed at 13 centers. Patients with measurable recurrent/advanced EC not amenable to curative therapies were eligible if either the primary tumor or recurrent tumor was ER+ and/or PR+. If receptor status could not be determined, patients with well or moderately well-differentiated EC were also permitted. Prior use of salvage chemotherapy was not allowed; however, prior use of progestagens was permitted and patients were stratified by prior exposure to progestagen. Patients received 20 mg/day PO, and were treated for at least 8 weeks in the absence of disease progression or unacceptable toxicity. Efficacy was based on the frequency of complete (CR) and partial (PR) responses, and a 95% confidence interval (CI) was calculated. The Kaplan–Meier method was used to analyze time to progression and duration of response. Results From February 1999 through April 2001, 37 patients were entered of whom 34 received treatment. Efficacy was evaluated for the 29 patients who received at least 4 weeks of therapy and at least one tumor response assessment. Safety was assessed in all 34 patients who received any drug. Thirty patients were defined as progestagen sensitive, and 4 patients were defined as progestagen failures. Twenty-six patients were ER+, and 22 were PR+. Nine (1 CR + 8 PR) of 29 patients responded (31%, CI 25–51%), with a median duration of response of 13.9 months. All 9 responses occurred in progestagen-sensitive patients. Two additional patients (one from each progestagen cohort) had stable disease for ≥6 months. The median progression-free interval was 3.7 months (CI 1.9–6.6 months) for all 29 patients. Toxicity was minimal with no grade 3–4 toxic effects, and 9 patients had only grade 1–2 toxic effects (7 grade 1, 2 grade 2). Hot flashes were the most common toxic effect and, in all 3 reported cases, were grade 1. Conclusions Arzoxifene has demonstrated a high response rate with the longest median duration of response reported in a phase II trial of this patient population. The ease of administration and extremely favorable toxicity profile make this an agent warranting further evaluation.

Tamoxifen is associated with increased rates of endometrial hyperplasia and adenocarcinoma. Our previous work suggested tamoxifen-associated endometrial cancers might be associated with p53 mutations. PTEN, a tumor suppressor gene, is altered in low-grade endometrial carcinoma. This study evaluates PTEN immunohistochemical (IHC) expression in tamoxifen-associated endometrial cancers.Twenty-eight endometrial carcinoma specimens were examined from patients with a history of breast cancer. Patients who had taken Tamoxifen (15) were compared to non-users (13). IHC staining was performed for PTEN; overexpression was defined as greater than 70% positivity.The mean duration of tamoxifen use was 3.3 years (3-171 months). Four out of 15 (27%) tamoxifen users expressed PTEN compared with 2 out of 13 (15%) of non-users.In this study, it appears that tamoxifen-associated endometrial cancers are not significantly different from sporadic endometrial cancer with regards to PTEN IHC expression, although there is a trend towards retained PTEN expression.

Gestational trophoblastic disease rarely presents in patients beyond the reproductive years. To our knowledge, this is the first case of mixed trophoblastic disease in a postmenopausal woman. We present here a case of a 60-year-old woman with evidence of a pelvic mass and pulmonary metastasis. Surgery revealed an 8 x 6 x 6 cm multinodular uterine tumor involving the right adnexa. Histologic review was consistent with choriocarcinoma with intermediate trophoblastic features. Postoperative beta-hCG was 381 561 mIU/ml. We conclude that maintaining a high index of suspicion facilitates the identification of postmenopausal patients with metastatic gestational trophoblastic disease. This case reconfirms the deceptive presentation of the "great masquerader".

Early cervical cancer includes a broad range of disease, from clinically undetectable microinvasive cancer to large, bulky tumors that replace the entire cervix. Further subgrouping of this category is therefore necessary to define the optimal treatment approach for individual cases. The International Federation of Gynecology and Obstetrics (FIGO) staging system stratifies stage I tumors into two broad categories, stage IA (microinvasive) and stage IB (gross tumor). Management of women with stage IA disease is controversial. In the United States, patients with stromal invasion of less than 3 mm and no lymphvascular involvement are usually treated conservatively with simple hysterectomy. In selected patients who desire fertility, cone biopsy with negative surgical margins is also considered. Patients with invasion of more than 3 mm or lymphvascular space involvement are at risk for pelvic lymph node metastasis and are most often treated with radical hysterectomy and pelvic lymphadenectomy. Stage IB1 cervical cancer is managed by either radical surgery or radiotherapy with equivalent recurrence and survival rates. In patients with tumors less than 4 cm in diameter, the decision between radical surgery and radiotherapy is guided by patients’ overall health and treatment preferences. For younger women, radical surgery is preferred because ovarian function can be preserved and vaginal stenosis secondary to radiation can be avoided. Radiation therapy is preferred for women who may not tolerate radical surgery. We always prefer primary radiation therapy for patients with tumors larger than 4 cm in diameter. Recent data convincingly demonstrate that the addition of cisplatin-based chemotherapy significantly improves overall survival rates in cervical cancer patients who undergo radiation therapy.

Background The application of next-generation sequencing technology to gene expression quantification analysis, namely, RNA-Sequencing, has transformed the way in which gene expression studies are conducted and analyzed. These advances are of particular interest to researchers studying organisms with missing or incomplete genomes, as the need for knowledge of sequence information is overcome. De novo assembly methods have gained widespread acceptance in the RNA-Seq community for organisms with no true reference genome or transcriptome. While such methods have tremendous utility, computational cost is still a significant challenge for organisms with large and complex genomes. Results In this manuscript, we present a comparison of four reference-based mapping methods for non-human primate data. We utilize TopHat2 and GSNAP for mapping to the human genome, and Bowtie2 and Stampy for mapping to the human genome and transcriptome for a total of six mapping approaches. For each of these methods, we explore mapping rates and locations, number of detected genes, correlations between computed expression values, and the utility of the resulting data for differential expression analysis. Conclusions We show that reference-based mapping methods indeed have utility in RNA-Seq analysis of mammalian data with no true reference, and the details of mapping methods should be carefully considered when doing so. Critical algorithm features include short seed sequences, the allowance of mismatches, and the allowance of gapped alignments in addition to splice junction gaps. Such features facilitate sensitive alignment of non-human primate RNA-Seq data to a human reference. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-570) contains supplementary material, which is available to authorized users.

Objective. The goal of this study was to determine the optimal dose of topotecan when used in combination with high-dose melphalan and cyclophosphamide (TMC), and to assess the toxicity and efficacy of the regimen in patients with advanced ovarian cancer. Methods. Fifty-three patients with persistent or recurrent ovarian cancer were treated. Disease status at study entry included: platinum-sensitive recurrent disease (15 patients), platinum-resistant or refractory recurrent disease (15 patients), positive second-look surgery (16 patients), failure to achieve a primary clinical complete response (CR) (7 patients). Following stem cell mobilization and collection, patients were given cyclophosphamide 1 g/m 2 /day on Days −6, −5, −4; melphalan 70 mg/m 2 /day on Days −3, −2; and topotecan at escalating doses from 1.25 to 4.0 mg/m 2 /day on Days −6 to −2. Peripheral blood stem cells were infused on Day 0. Results. The optimal topotecan dose selected for future trials was 4.0 mg/m 2 /day × 5 days. The regimen had acceptable toxicity with no regimen-related death. Toxicity (Bearman toxicity criteria) was limited mostly to grade 1–2 mucositis and diarrhea. The overall response rate of patients with measurable or evaluable disease was 93%. Median survival has not yet been reached, but with a median follow up of 18 months (range: 11–37) 77% of patients are alive. Conclusion. With a topotecan dose of 4.0 mg/m 2 /day × 5 days, the TMC regimen has acceptable toxicity and produces high response rates. In the setting of ovarian cancer, high-dose chemotherapy should be administered only as part of well-designed clinical trials. TMC should be considered a potential regimen for future randomized trials in patients with advanced ovarian cancer.

9539 Background: Quality performance measures for cancer care, including use of chemotherapy in the last two-weeks of life, will be required for reporting. In this study, we evaluated the pattern and frequency of chemotherapy use for ST patients in the last two-weeks of life, and whether such treatment included standard or investigational drugs. Methods: We conducted a retrospective study of 5,607 adult cancer patients (≥18 years) who received their care at The University of Texas MD Anderson Cancer Center and died between December 01, 2010 through May 31, 2012. Data on patients’ demographics, and chemotherapy agents dispensed (excluded: hormones) were obtained from the institution’s administrative databases. Type of treatment (research versus standard) was obtained from our chemotherapy dispensed database. Chi-square test and Fisher's exact test were used to determine the association between categorical variables.All statistically significant levels were determined with P values < 0.05. Results: Only 3.9% (216/5,607) of ST patients who died had received chemotherapy within 14 days EOL. For those 216 patients who received chemothapy: median age 64 years; 48% female; 89% metastatic disease. The distribution by chemotherapy treatment route: intravenous (IV) 85%; IV plus oral 6%; oral 6%; other 3%. The distribution of patients by number of chemotherapy agents: one 56%; two 31%, and three or more 13%. Among those who received chemotherapy, 98.6% (213/216) of the chemotherapy administered were standard agents. There were no differences in frequency distribution for chemotherapy treatment route (p>0.05), number of chemotherapy agents (p>0.05) between patients with metastatic and non-metastatic disease, or between men and women (p>0.05). Conclusions: Our results indicate EOL chemotherapy use was infrequent in our patients with STs, and most of those treated received standard chemotherapy, with simple one or two drug regimens. We need more research to determine factors that influence chemotherapy use at EOL, and if it palliates physical symptoms and/or emotional distress in advanced stages of disease.

Identification of histopathologic factors that predict the risk of tumor recurrence allows for selection of women with endometrial cancer who might benefit from adjuvant therapy. Most studies of adjuvant treatment have focused on external-beam irradiation or oral progestational agents and have failed to document a survival advantage for treated patients. Although recurrent or metastatic endometrial tumors often respond to salvage treatment with cytotoxic agents, there is relatively little experience with postoperative systemic chemotherapy used in an adjuvant setting. A few nonrandomized trials—using doxorubicin/platinum-based regimens—have suggested that adjuvant chemotherapy may be beneficial in some patients subsets. Data from largerscale, randomized trials do not exist. Additional clinical experience is needed before a definite role for adjuvant chemotherapy can be established.

Because granulosa cell tumors of the ovary are rare, the optimal treatment for women with gross residual disease after primary surgery or recurrence is not known. Our objective was to review the results of radiotherapy for advanced or recurrent granulosa cell tumor of the ovary.This retrospective review identified 34 patients with ovarian granulosa cell tumors treated with radiation at the University of Texas M. D. Anderson Cancer Center between 1949 and 1988. Fourteen received treatment for clinically measurable disease; 20 received adjuvant radiotherapy after surgery for minimal residual (1 cm) or microscopic residual disease. The 14 patients with measurable disease formed the basis for this review.Ten of 14 patients were treated with moving-strip whole-abdomen radiation (27-28 Gy), 9 with 60Co, and 1 with 6-MeV photons and a pelvic boost of 28 Gy with 22-25 MeV photons. The other 4 patients were treated with pelvic radiotherapy (45-61 Gy) with 22-25 MeV photons. Six of 14 patients (43%) had a clinical complete response to radiotherapy, with a median follow-up of 13 years (range, 5-21 years). Three of 6 who responded to radiation had relapse 4-5 years later; 2 of these 3 died of disease and 1 was alive with disease at last follow-up. Three responders remain alive without evidence of disease 10-21 years after treatment. The 8 nonresponders had a median survival of 12.3 months (range, 1-60 months).Radiotherapy can induce a clinical response with occasional long-term remission in patients with persistent or recurrent granulosa cell tumor of the ovary.

To determine the toxicity and activity of intravenous vinorelbine given daily for 3 consecutive days every 3 weeks in patients with platinum-resistant epithelial ovarian cancer.Between September 1994 and October 1995, 23 women with refractory epithelial ovarian cancer were entered onto this phase I study. All patients had measurable disease and platinum-resistant tumor, and prior therapy was limited to a maximum of two prior regimens. Nineteen (83%) were assessable for toxicity and 20 (87%) were assessable for response. Vinorelbine was administered intravenously daily for 3 consecutive days; this was repeated every 21 days. The starting dose was 20 mg/m2 daily x3, with dose escalation by 5 mg/m2 daily x3. Dose-limiting toxicity (DLT) was defined as grade 4 granulocytopenia for3 days, grade 4 thrombocytopenia, neutropenic fever, or grade 3 or greater nonhematologic toxicity. The maximal tolerated dose (MTD) was defined as the highest dose level at which50% of patients developed a DLT. Once the MTD of vinorelbine without granulocyte colony-stimulating factor (filgrastim) support was defined, dosing was begun at the MTD level and administration of 5 microg/kg filgrastim was initiated on day 4 and continued until WBC counts reached10,000/microL. Clinical response, progression-free survival, and survival were also determined.Nineteen patients evaluable for toxicity received a total of 135 cycles of vinorelbine. The major DLT was neutropenia. The MTD of vinorelbine without filgrastim support was established as 20 mg/m2 daily x3. The MTD of vinorelbine with filgrastim support was established as 25 mg/m2 daily x3. Of 20 patients evaluable for response, 2 patients (10%) had a complete response and 4 (20%) had a partial response, for an overall response rate of 30%.These results warrant further study of vinorelbine in patients with platinum-resistant epithelial ovarian cancer. However, further study of the daily x3 schedule may not be warranted because of failure to achieve higher weekly dose intensity and because of nonhematologic toxicity in the form of intense bone pain.

Objective. To evaluate the efficacy and toxicity of prolonged oral etoposide as single agent chemotherapy in patients with advanced or recurrent carcinoma of the cervix. Methods. Between May 1991 and February 1993, 44 patients with advanced or recurrent carcinoma of the cervix were entered onto this study. Patients were eligible if they had received no more than two prior cytotoxic regimens. The initial dose of etoposide was 37.5 mg/m 2 administered orally on a daily basis on days 1–21 of a 28-day cycle. Subsequent doses were unchanged, reduced, escalated, or omitted according to toxicity. Patients were evaluated for response and toxicity using standard Gynecologic Oncology Group criteria. Results. Forty-four patients were evaluable for response and toxicity. The overall response rate was 9.1% (2 CR, 2 PR). In patients with no prior chemotherapy the response rate was 4/25 compared to 0/19 for those who had prior therapy. The mean response duration was 2.7 months and the median survival from treatment for all patients was 7.7 months. The major toxicity was granulocytopenia, with 11% of patients having grade 3 or 4 toxicity. Gastrointestinal toxicity of some degree occurred in 11% of patients, and alopecia was universal. Conclusion. Prolonged oral etoposide has limited activity in advanced or recurrent carcinoma of the cervix. Its use as palliative therapy for this disease is not indicated.

PURPOSE To evaluate the efficacy and toxicity of intravenous vinorelbine as single-agent chemotherapy in patients with advanced or recurrent squamous cell carcinoma of the cervix. PATIENTS AND METHODS Between August 1993 and July 1995, 35 patients with advanced or recurrent squamous cell carcinoma of the cervix were entered onto this study. Patients had received no prior therapeutic chemotherapy. The initial dose of vinorelbine 30 mg/m2 was administered as a weekly intravenous infusion. Subsequent doses were unchanged, reduced, escalated, or omitted according to observed toxicity. Patients were evaluated for response and toxicity using standard Gynecologic Oncology Group (GOG) and World Health Organization criteria, respectively. RESULTS Thirty-three of 35 patients were assessable for response and 35 of 35 for toxicity. The overall response rate was 18% (one complete response [CR], five partial responses [PR]). The mean response duration was 5.2 months and the median survival from treatment for all patients was 11.0 months. The major toxicity was leukopenia, with 61% of patients who had grade 3 or 4. Gastrointestinal and neurotoxicity were infrequent and mild. CONCLUSION Vinorelbine has moderate activity in advanced or recurrent squamous cell carcinoma of the cervix. Further studies of combination regimens with this agent are justified in this patient population.

Transcription is centrally involved in an array of biological processes, which include growth, development, and response to external stimuli. In eukaryotes, protein-coding genes are transcribed by the RNA polymerase II transcriptional machinery, which comprises RNA polymerase II and other factors that are required for basal and regulated transcription. Transcription by RNA polymerase II is directed by cis-acting DNA sequences that typically consist of a core promoter along with regulatory elements, such as enhancers, that contain binding sites for sequence-specific transcriptional activator and/or repressor proteins. Thus, the study of both the trans-acting protein factors and the cis-acting DNA elements is necessary to gain a better understanding of the fundamental mechanisms by which genes are transcribed (for recent reviews, see Bjorkland and Kim 1996; Burley and Roeder 1996; Orphanides et al. 1996; Roeder 1996; Verrijzer and Tjian 1996; Ptashne and Gann 1997; Sauer and Tjian 1997; Smale 1997; Tansey and Herr 1997). The key DNA element that is essential for transcription by RNA polymerase II is the core promoter—the DNA sequences, which encompass the transcription start site (within about −40 to +40 relative to the +1 start site) and are sufficient to direct the accurate initiation of transcription. Two important core promoter motifs are the TATA box and the initiator (Inr) (Fig. ​(Fig.1).1). The TATA box is an A/T-rich sequence that is located ∼25–30 nucleotides upstream of the RNA start site of many, but not all, promoters. It is recognized by the TATA box-binding polypeptide (TBP), which is a component of the multisubunit TFIID complex. The Inr encompasses the RNA start site, and like the TATA box, it is also present in many, but not all, core promoters (Smale and Baltimore 1989; Smale 1994, 1997). Inr elements have been characterized in various TATA-less and TATA-containing promoters, and the Inr consensus sequence is Py-Py-A+1-N-T/A-Py-Py (where A+1 is the transcription start site) in mammalian genes (Smale and Baltimore 1989; Bucher 1990; Javahery et al. 1994) and T-C-A+1-G/T-T-T/C in Drosophila genes (Hultmark et al. 1986; Purnell et al. 1994; Arkhipova 1995). Figure 1 The TATA box, Inr, and DPE are core promoter elements. The consensus sequences and locations of the TATA box, Inr, and DPE motifs are indicated. The TATA box and DPE appear to be functionally redundant, and promoters generally do not contain ... Many promoters contain functionally important sequences that are downstream of the transcription start site. Such downstream promoter sequences have been found in TATA-containing promoters (see, e.g., Lewis and Manley 1985; Nakatani et al. 1990; Lee et al. 1992; Emanuel and Gilmour 1993; Purnell and Gilmour 1993), as well as in TATA-less promoters (see, e.g., Biggin and Tjian 1988; Perkins et al. 1988; Soeller et al. 1988; Smale and Baltimore 1989; Jarrell and Meselson 1991; Contursi et al. 1995; Minchiotti et al. 1997). It appears that many of these downstream promoter sequences are involved in basal transcription, but it is also important to consider that some downstream promoter sequences might be binding sites for sequence-specific transcriptional activators. In the analysis of the interaction of purified TFIID with TATA-less promoters, a conserved downstream core promoter element was found to be required for the sequence-specific binding of TFIID to a subset of TATA-less promoters (Burke and Kadonaga 1996). This motif was termed the downstream promoter element (DPE). The DPE is a distinct 7-nucleotide element that is located at about +30 (typically, from +28 to +34) relative to the transcription start site (Fig. ​(Fig.1).1). It is present in many, but not all, promoters and is bound by TFIID but not by TBP. In addition, nearly all of the promoters that have been found to contain DPE-like sequences are TATA-less promoters. Modification of the DPE by clustered point mutagenesis was found to cause a decrease in the binding of purified TFIID to the promoter as well as an 8- to 100-fold reduction in basal transcriptional activity in vitro. Mutational analysis of the Inr and DPE motifs revealed that the DPE acts in conjunction with the Inr to provide a binding site for TFIID in the absence of a TATA box. Interestingly, the loss of transcriptional activity upon disruption of the TATA box in a TATA-containing promoter could be recovered by the insertion of a DPE at a downstream position (+28 to +34) in the defective promoter. Thus, the DPE appears to be a functionally important, conserved downstream core promoter element. We are, however, still in the early stages of understanding the DPE. In this work we have investigated several fundamental questions regarding the role of the DPE in the transcription process. These experiments provide evidence for the function of TBP-associated factors (TAFs) in DPE-driven basal transcription and reveal that the DPE has many properties that are analogous to those of the TATA box.

9538 Background: Oncologists will be required to report quality measures for cancer care, including use of chemotherapy in the last two-weeks of life. In this study, we evaluated how use of chemotherapy in ST patients (pts) within 14 days of EOL may be influenced by clinical factors. Methods: Adult pts (≥18 years) treated for ST at our institution, deceased December 01, 2010 through May 31, 2012, were retrospectively studied. Data on demographics, chemotherapy (excluded: hormones) within 14 days EOL, comorbidities, and cancer diagnoses were from tumor registry and administrative databases. Logistic regression analysis was performed for association of EOL chemotherapy with age, gender, ethnicity, comorbidities , cancer types, and metastatic status. Results: 5,607 pts met study criteria: median age 64 years; 48% female; 76% metastatic disease. EOL chemotherapy frequency was 3.9% overall, 4.6% in metastatic disease versus 1.7% in non-metastatic disease (p

In other Gynecologic Oncology Group (GOG) studies, ifosfamide demonstrated antineoplastic activity against ovarian epithelial tumors, squamous carcinomas of the cervix, uterine sarcomas, and trophoblastic disease. Responses were also observed in 15% of patients with endometrial adenocarcinoma previously exposed to chemotherapy. This is a phase II trial of ifosfamide in patients with chemotherapy-naive advanced or recurrent endometrial adenocarcinoma. Thirty-seven patients with advanced adenocarcinoma of the endometrium recurrent after surgery and/or radiotherapy were treated with ifosfamide 1.2 g/m 2 intravenously daily for 5 days every 4 weeks and mesna 300 mg/m 2 intravenously every 4 hr for 3 doses daily for 5 days with each course. Three patients were ineligible—one due to a second primary, one did not have an endometrial primary, and the other because of wrong cell type. One patient was inevaluable for response; thus, 33 were evaluable for response. All patients had undergone hysterectomy and 24 had received radiotherapy before entering the trial. Eleven had GOG performance status of 0, 18 had a status of 1, and 4 had performance status of 2. Median age was 68 years (range, 41–86 years). Grade 3 or 4 neutropenia occurred in eight patients each and grade 3 thrombocytopenia was observed in one patient. One patient had a grade 4 neurotoxicity. Complete responses were observed in two patients (6.1%) and partial responses in six (18.2%) for an overall response rate of 24.3%. Ifosfamide in this dose and schedule is an active drug in the treatment of patients with advanced or recurrent adenocarcinoma of the endometrium.

The objective in this paper is to describe the severity and outcome of arterial occlusion complicating treatment of women with gynecologic cancer. A series of six patients who underwent amputation were identified. Acute arterial occlusions were seen in three patients. One patient suffered extensive thrombosis of the hand and wrist resulting in amputation 3 weeks after cytoreductive surgery and chemotherapy for Fallopian tube cancer. She had a history of pulmonary embolism and deep-vein thrombosis. This patient was thought to have thrombophilia. One elderly patient with known arteriosclerosis developed sepsis following radical deep excision and groin dissection for vulvar cancer and lost two digits presumably due to microemboli. One patient developed thrombosis of the femoral artery on the second day following cytoreductive surgery for ovarian cancer. She responded to anticoagulation therapy; however, necrosis remained in portions of the heel and toes. Three patients underwent amputation of a lower extremity when they developed chronic arterial insufficiency after pelvic radiotherapy. The patients were irradiated at the ages of 28, 30, and 35 years for cervix cancer in two patients and a low-grade retroperitoneal sarcoma in one patient. Two received neutron beam therapy and one received conventional photon beam therapy. All three had extensive late radiation morbidity to the bladder and rectum and had multiple prior surgeries. The amputations occurred at the ages of 48, 48, and 55 due to accelerated arteriosclerosis. Two patients died as a result of this complication. Acute and chronic arterial occlusions are rare yet dramatic complications of therapy for gynecologic cancer. This series illustrates the predisposing factors, presentation, and management of these unusual events.

Objective To evaluate the treatment and outcome of patients with adenocarcinoma in situ of the cervix, with special emphasis on cone biopsy margins. Methods Sixty-one women with adenocarcinoma in situ of the cervix treated between April 1984 and December 1993 were identified. Medical records and histologic material were reviewed. Mixed lesions with both adenocarcinoma in situ and squamous cervical intraepithelial neoplasia (CIN) were included. Results The mean age of the patients was 35.9 years. Fifty-five of the 61 (90%) patients had cone biopsies, and 44 of these 55 (80%) subsequently had hysterectomies. Eight women (13%) had associated invasive cancer. Among 50 patients in whom the status of the margins was confirmed, 23 (46%) had positive margins and 27 (54%) had negative margins. Of 23 women with positive margins, 19 had hysterectomies and ten of the 19 (53%) had residual disease in the uterus. Of 27 patients with negative cone margins, 21 had hysterectomies, and seven of the 21 (33%) had residual disease in the uterus. Two women with negative margins who did not have hysterectomies developed recurrent disease. Fifty-five of the total series of 61 patients followed-up for a median of 57 months (range 17–132) had no evidence of disease at last follow-up. Conclusion Women with adenocarcinoma in situ of the cervix often have residual disease in the uterus, regardless of whether the margins on cone biopsy are positive or negative.

Advanced or recurrent uterine leiomyosarcomas have traditionally been resistant to most chemotherapeutic regimens. Preliminary reports suggested the combination of hydroxyurea, dacarbazine (DTIC), and etoposide (VP-16) was sufficiently effective to warrant larger trials. In a Phase II trial undertaken by the Gynecologic Oncology Group, 39 patients with advanced or recurrent leiomyosarcoma were treated with 2 g of hydroxyurea, 700 mg/m2 of DTIC, and 300 mg/m2 of VP-16 in divided doses every 4 weeks. Thirty-eight patients were evaluable for response. Two patients experienced complete responses and five had partial responses for a total objective response rate of 18.4% (95% confidence interval: 7.7-34.3%). In general, therapy was well tolerated with moderate toxicity. Six of the seven responders had disease outside the pelvis. The combination of hydroxyurea, DTIC, and VP-16 exhibits moderate activity against uterine leiomyosarcoma.

We describe the identification and characterization of a conserved downstream basal promoter element that is present in a subset of Drosophila TATA-box-deficient (TATA-less) promoters by using purified, epitope-tagged TFIID complex (eTFIID) from embryos of transgenic Drosophila. DNase I footprinting of the binding of eTFIID to TATA-less promoters revealed that the factor protected a region that extended from the initiation site sequence (about +1) to approximately 35 nucleotides downstream of the RNA start site. In contrast, there was no apparent upstream DNase I protection or hypersensitivity induced by eTFIID in the -25 to -30 region at which TATA motifs are typically located. Further studies revealed a conserved sequence motif, (A/G)G(A/T)CGTG, termed the downstream promoter element (DPE), which is located approximately 30 nucleotides downstream of the RNA start site of many TATA-less promoters. DNase I footprinting and in vitro transcription experiments revealed that a DPE in its normal downstream location is necessary for transcription of DPE-containing TATA-less promoters and can compensate for the disruption of an upstream TATA box of a TATA-containing promoter. Moreover, a systematic mutational analysis of DNA sequences that encompass the DPE confirmed the importance of the consensus DPE sequence motif for basal transcription and further supports the postulate that the DPE is a distinct, downstream basal promoter element. These results suggest that the DPE acts in conjunction with the initiation site sequence to provide a binding site for TFIID in the absence of a TATA box to mediate transcription of TATA-less promoters.

Objective: The purpose of this study was to evaluate the early morbidity, stomal complications, and overall survival rate of gynecologic oncology patients treated with end or loop colostomy for management of colonic fistula. Methods: Seventy-five women with fistulas undergoing fecal diversion procedures from 1983 to 1993 were identified. Information relevant to tumor history, type of fistula, operative procedure, complications, and outcome was extracted from the medical records. Results: A recto- or sigmoid-vaginal fistula was present in 55 patients. The remaining 20 patients had either a colonic fistula involving the bladder, uterus, or skin or multiple fistulas. In 66 (88%) patients, the pelvis had been irradiated. Loop colostomy was performed in 47 (63%) patients and end colostomy in 28 (37%) patients. Cancer was present in 31 (66%) of 47 patients undergoing loop colostomy compared with 12 (43%) of 28 patients undergoing end colostomy ( P = 0.05). No significant differences were detected with regard to age at cancer diagnosis or age at the time of colostomy, body habitus, medical condition, type of cancer, history of pelvic irradiation, or incidence of multiple or complex fistulas. Median operative time was increased by 1 hr and median blood loss from 50 to 200 ml with end colostomy. No significant advantage of loop colostomy over end colostomy was detected in the incidence of acute morbidity or hospital stay. Early stomal complications occurred in 8 patients, 7 of whom had loop colostomy ( P = 0.25). Delayed complications (prolapse, retraction, stool per vagina, or fistula) following loop colostomies occurred more frequently than following end colostomy: 12 (26%) of 47 compared with 2 (7%) of 28 ( P = 0.05), respectively. Five loop stomas were later converted to end stomas. In addition only one of four attempted loop colostomy closures was successful. Overall survival in both groups of patients was similar. Conclusion: There were no statistically significant differences between patients treated with loop or end colostomy with regard to early morbidity or survival. The early and frequent occurrences of stomal complications after loop colostomy overshadow the clinically minor advantages of this method of fecal diversion. Although loop colostomy was performed more often in this setting, these data do not support its routine use for the management of gynecologic oncology patients with fistulas.

Abstract 240 BACKGROUND: Hematologic malignancies (HM) are widely variable in their potential for cure, but most have multiple treatment options that are also increasing due to research. The toxicity profile of the treatments can also be quite variable. Thus, discussing realistic therapeutic goals, and potential serious life threatening toxicities, is critical to planning appropriate end of life medical interventions. We analyzed chemotherapy use within 14 days prior to end of life, and do not resuscitate (DNR) orders, among patients with HM who died at our institution. METHODS: We reviewed all adult patients (age>18 years) with a diagnosis of HM who had received care at M.D. Anderson Cancer Center and died from 12/1/2010 through 5/31/2012 (pts that had a stem cell transplantation within 100 days of end of life were excluded). Data on patients' demographics, chemotherapy within last 14 days, inpatient DNR orders, and co-morbidities were from the institution's administrative databases. HM diagnostic categories were grouped as Leukemia, Lymphoma, Multiple Myeloma and Other. Statistical analysis: odds ratios (OR) with 95% confidence interval (CI) were compared for different groups (chemotherapy use with age, gender, ethnicity, comorbidities, years of disease diagnosis, and HM diagnostic categories); statistical significance was defined as P value < 0.05. RESULTS: 1,179 HM patients died: median age 65 years; 61% female; 472 (40 %) died in hospital, of which 442 (94%) had DNR orders and 294 (26 %) died in ICU. Overall, 272 (23 %) had chemotherapy within 14 days of end of life. 29% of pts with leukemia, 19% of pts with lymphoma, 10% of pts with myeloma, and 25%of pts with other diseases received chemotherapy within the last 14 days of life. Forty-nine% (134/272) of them received chemotherapy as frontline therapy; and (219/272 = 81%) died in hospital. Adjusted by logistical regression, chemotherapy within 14 days of end of life was less common in patients with lymphoma and myeloma than in those with leukemia [odds ratios (ORs), 0.7 and 0.3, respectively; all P0.05). CONCLUSIONS: Nearly a fourth of HM deaths at our hospital occurred within 14 days of treatment, and 60% of these were inpatients receiving second line or later therapy. Most pts (94 %) had DNR orders indicating that an end of life decision was discussed, and 26% died in ICU, suggesting acute events such as sepsis likely led to hospital admission. In addition, some patients with HM can manifest serious disease-related complications, and death may also occur shortly after diagnosis. Patients should be informed of these risks for treatment and end of life planning decisions. Disclosures: No relevant conflicts of interest to declare.

Transitional cell carcinoma (TCC) of the ovary is reportedly more sensitive to first-line chemotherapy and has a better prognosis than the more common serous carcinoma. The purpose of this study was to determine the responsiveness of refractory ovarian TCC to salvage chemotherapy.Thirty-three patients with refractory TCC who received either platinum drugs or taxanes as salvage chemotherapy at our institution were identified through a retrospective review. Clinical information was abstracted from the medical records, and patient characteristics and response rates were determined. Pathologic sections from all cases were reviewed.The median age of the 33 patients was 53 years (range, 39-71 years). FIGO stage distribution among patients included 1 stage II and 32 stage III. Twenty-six tumors (79%) were classified as TCC-predominant (50% of the tumor having the TCC pattern), and seven tumors (21%) were classified as non-TCC predominant (50% of the tumor having the TCC pattern). Twenty-four platinum-sensitive patients received salvage platinum therapy (cisplatin, carboplatin, or other platinum analogs) on 27 separate occasions (three patients were treated twice) either as single agents (n = 20) or in combination (n = 7). In 21 of the 27 instances, patients had measurable disease and were evaluable for response. There were nine (43%) complete responses and six (29%) partial responses; in six instances, no response was observed. The overall response rate was therefore 72%. Thirteen patients, of whom 12 had measurable disease, received taxanes (paclitaxel in 10, docetaxel in 2, and paclitaxel+cisplatin in 1). There were partial responses in six (50%) and no response in six. Only one of the responders received high-dose paclitaxel (250 mg/m2).Our findings suggest that TCC may remain more chemosensitive than more common epithelial tumors in the refractory setting. The relative influences of tumor biology and treatment, however, remain undetermined.