Phase II study of treatment of advanced ovarian cancer with folate-receptor-targeted therapeutic (vintafolide) and companion SPECT-based imaging agent (99mTc-etarfolatide).

BACKGROUND: This report examines (99m)Tc-etarfolatide imaging to identify the presence of folate receptor (FR) on tumors of women with recurrent/refractory ovarian or endometrial cancer and correlates expression with response to FR-targeted therapy (vintafolide). PATIENTS AND METHODS: In this phase II, single-arm, multicenter study, patients with advanced ovarian cancer were imaged with (99m)Tc-etarfolatide before vintafolide treatment. Up to 10 target lesions (TLs) were selected based on Response Evaluation Criteria In Solid Tumors criteria using computed tomography scans. Single-photon emission computed tomography images of TLs were assessed for (99m)Tc-etarfolatide uptake as either FR positive or negative. Patients were categorized by percentage of TLs positive and grouped as FR(100%), FR(10%-90%), and FR(0%). Lesion and patient response were correlated with etarfolatide uptake. RESULTS: Forty-nine patients were enrolled; 43 were available for analysis. One hundred thirty-nine lesions were (99m)Tc-etarfolatide evaluable: 110 FR positive and 29 FR negative. Lesion disease control rate (DCR = stable or response) was observed in 56.4% of FR-positive lesions versus 20.7% of FR-negative lesions (P < 0.001). Patient DCR was 57%, 36%, and 33% in FR(100%), FR(10%-90%), and FR(0%) patients, respectively. Median overall survival was 14.6, 9.6, and 3.0 months in FR(100%), FR(10%-90%), and FR(0%) patients, respectively. CONCLUSIONS: Overall response to FR-targeted therapy and DCR correlate with FR positivity demonstrated by (99m)Tc-etarfolatide imaging. CLINICAL TRIAL NUMBER: NCT00507741.

Prognostic impact of lymphadenectomy in clinically early stage malignant germ cell tumour of the ovary.

BACKGROUND: The aim of this study was to determine the impact of lymphadenectomy and nodal metastasis on survival in clinical stage I malignant ovarian germ cell tumour (OGCT). METHODS: Data were obtained from the National Cancer Institute registry from 1988 to 2006. Analyses were performed using Student's t-test, Kaplan-Meier and Cox proportional hazard methods. RESULTS: In all, 1083 patients with OGCT who have undergone surgical treatment and deemed at time of the surgery to have disease clinically confined to the ovary were included 590 (54.48%) had no lymphadenectomy (LND-1) and 493 (45.52%) had lymphadenectomy. Of the 493 patients who had lymphadenectomy, 441 (89.5%) were FIGO surgical stage I (LND+1) and 52 (10.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND+3C). The 5-year survival was 96.9% for LND-1, 97.7% for LND+1 and 93.4% for LND+3C (P=0.5). On multivariate analysis, lymphadenectomy was not an independent predictor of survival when controlling for age, histology and race (HR: 1.26, 95% CI: 0.62-2.58, P=0.5). Moreover, the presence of lymph node metastasis had no significant effect on survival (HR: 2.7, 95% CI: 0.67-10.96, P=0.16). CONCLUSION: Neither lymphadenectomy nor lymph node metastasis was an independent predictor of survival in patients with OGCT confined to the ovary. This probably reflects the highly chemosensitive nature of these tumours.

Stage IA vs. IB endometrial stromal sarcoma: does the new staging system predict survival?

OBJECTIVE: To determine the correlation of the new FIGO staging system with survival in stage I patients with low-grade and high-grade endometrial stromal sarcomas. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Kaplan-Meier log rank and Cox proportional hazards models were used for survival analysis and to identify possible predictors for survival. RESULTS: The identified cohort included 464 women, 310 (67%) low-grade endometrial stromal sarcoma, 96 (21%) high-grade endometrial stromal sarcoma, and 58 (12%) unclassified endometrial stromal sarcoma. Among low-grade and high-grade endometrial stromal sarcomas, there was no significant demographic or clinico-pathologic difference between stages IA and IB. The 5-year overall survival was worse in high-grade endometrial stromal sarcoma than low-grade endometrial stromal sarcoma (45.4% vs. 97.2%, p<0.001). The difference in 5-year overall survival among women with low-grade endometrial stromal sarcoma between stages IA and IB was significant (100% vs. 93.5%, p=0.003), but not among women with high-grade endometrial stromal sarcoma (51.4% vs. 43.5%, p=0.27). Although age (p=0.001), race (p=0.005), and stage (p=0.004) were all significant prognostic factors in low-grade endometrial stromal sarcoma, only cervical involvement (p=0.02) was a significant predictor in high-grade endometrial stromal sarcoma. CONCLUSION: The new staging system is appropriate for risk stratification in low-grade endometrial stromal sarcoma. The prognosis in high-grade endometrial stromal sarcoma seems to be most influenced by the presence of cervical involvement and not by tumor size as the staging criteria would suggest.

The racial disparity in outcomes in endometrial cancer: could this be explained on a molecular level?

OBJECTIVE: The racial disparities among patients with endometrial carcinoma have been previously reported. The objective of this study is to analyze and compare the molecular profiles in endometrial cancer in Caucasian and African American patients using a number of known molecular markers. MATERIALS AND METHODS: 147 patients diagnosed with endometrial cancer between 1995 and 2001 were included in the study. Patients' demographics, clinical and pathological data were reviewed. Immunohistochemical staining for p53, VEGF, Ki-67 and HIF-1alpha was performed on tissue micro array sections. Tumors' expression of p53, VEGF, Ki-67, and HIF-1alpha was compared based on ethnicity and tumor type (Type I = endometrioid carcinomas and Type II = non-endometrioid carcinomas). Spearman's correlation and Fisher's Exact Tests were used for statistical analysis and Kaplan-Meier, log-rank and Cox regression were used for survival analysis. RESULTS: 97 patients were Caucasian and 50 patients were African American. The mean age was 62 (33-91) years for Caucasian patients and 63.5 (24-89) years for the African American patients. African American patients had more Type II carcinoma than Caucasian patients (P = 0.055). High p53 expression was statistically significant among the African American patients (49% vs. 30%, P = 0.035) versus Caucasian patients. There was no significant difference demonstrated when comparing the VEGF, Ki-67, and HIF-1alpha expression between the racial groups. Survival analysis showed a trend toward a shorter survival in the African American patients compared to the Caucasian patients; median survival 62 versus 77 months (P = 0.061). On the other hand, we did not find a significant difference in survival by ethnicity when we adjusted for tumor histology. CONCLUSION: While African American patients with endometrial cancer seem to show a trend toward a shorter survival, this seems to be mainly due to the fact that they have a higher proportion of Type II tumors. The molecular profiles for p53, Ki-67, VEGF and HIF-1alpha expression of histologically matched tumors were similar between the two ethnic groups.

Maspin expression and localization impact on angiogenesis and prognosis in ovarian cancer.

INTRODUCTION: The goal of this study is to evaluate the relation of maspin expression and its cellular localization to markers of angiogenesis in epithelial ovarian serous carcinoma (OSC). MATERIALS AND METHODS: We identified 118 patients with high-grade advanced stage OSC who were treated at our institution. Clinical data were collected, and immunohistochemistry (IHC) with antibodies to VEGF, CD34, COX-2, and maspin was performed on paraffin-embedded tumor blocks. CD34 immunostaining was used to determine microvessel density. The correlation between the various molecular markers was assessed using the Chi-square test. Survival analysis was computed using the Kaplan-Meier model, and various prognostic variables were compared using Cox regression analysis. RESULTS: Maspin expression was noted in 81.4% (96/118) of tumors. Expression was localized to the nuclear compartment in 21.2% of cases, whereas 60.2% of cases showed evidence of cytoplasmic +/- nuclear expression. Tumors that exhibited nuclear maspin expression had lower VEGF and COX-2 expression than tumors with negative or cytoplasmic expression. Tumors with high nuclear maspin expression had lower mean MVD than those with low or negative expression. The median survival based on localization of maspin was 1146 days for those with negative tumors, 1803 days for those with nuclear maspin, and 637 days for those with cytoplasmic maspin (P < 0.001). In a Cox regression analysis, maspin localization was an independent prognostic factor. CONCLUSION: Maspin expression and localization seem to play a role in ovarian cancer angiogenesis and progression. High nuclear expression was associated with reduced markers of angiogenesis and prolonged survival.

Secondary cytoreductive surgery for localized intra-abdominal recurrences in epithelial ovarian cancer.

OBJECTIVE: The aim of this study was to evaluate the role of secondary cytoreductive surgery in patients with recurrent epithelial ovarian cancer with an apparent solitary intra-abdominal focus. METHODS: We conducted a retrospective review of patients with epithelial ovarian cancer who underwent secondary cytoreduction for recurrence at the University of Texas M. D. Anderson Cancer Center between 1985 and 1994. Eligible patients included those who had a laparotomy to resect a tumor that was apparently solitary. Cytoreductive surgery was defined as optimal if the diameter of the largest residual tumor was < or =2 cm and suboptimal if >2 cm. RESULTS: Twenty-five patients met our eligibility criteria. Their mean age was 55 years (range, 35-73 years). The median time from primary diagnosis to recurrence was 37.6 months. Tumor was found to be confined to a solitary site in 15 patients (60%), to two sites in 6 (24%), and to three or more sites in 4 (16%). Surgical procedures included cytoreduction in 10 patients, intestinal resection in 8, splenectomy in 3, and limited biopsies in 4. Secondary cytoreduction was optimal in 18 of 25 patients (72%). The median postsecondary cytoreduction survival was 25.1 months for patients who had suboptimal secondary cytoreduction compared with 56.9 months for those who had optimal cytoreduction (P = 0.08). CONCLUSIONS: Secondary cytoreductive surgery for recurrent ovarian cancer at an apparently solitary intra-abdominal site resulted in optimal residual tumor in a high proportion of patients. Although there was no survival advantage for patients whose tumor was optimally debulked, there was a trend toward improved survival. A large prospective randomized trial of secondary cytoreduction for recurrence is recommended.

Outcome and reproductive function after conservative surgery for borderline ovarian tumors.

OBJECTIVE: To study reproductive function and disease outcome in women with borderline ovarian tumors who were treated with conservative surgery. METHODS: Patients with borderline ovarian tumors were identified from institutional databases. Patients were eligible if they had pathologically confirmed borderline ovarian tumors, no prior sterilization, no history of radiation therapy, retained their uterus and ovarian tissue, and were younger than age 45. Information was acquired by retrospective medical record review and patient interview. RESULTS: Forty-three patients met the eligibility criteria. The median age was 25 years, with a range of 15-39 years. Twenty-six patients had serous tumors, and 17 had mucinous tumors. Fifteen had stage I disease, three had stage III, and 25 were unstaged. Follow-up was available for all patients (median, 5.7 years). Twenty-nine remained disease-free, and 14 developed a new primary lesion/recurrence, with a median time to recurrence of 39.3 months. Recurrence was more frequent in patients treated with ovarian cystectomy than in those treated with oophorectomy alone (58% compared with 23%) (P <.04). After treatment, 29 of 36 patients (81%) retained normal menstrual cycles, and 12 of 24 patients attempting pregnancy conceived 25 pregnancies. Most patients were highly satisfied with conservative surgery. CONCLUSION: Conservative surgery remains a therapeutic option in selected patients with borderline ovarian tumors. Although the rate of new lesion/recurrence is relatively high, especially in those treated with ovarian cystectomy, mortality from cancer remains low. Many patients who desire pregnancy are able to conceive and deliver healthy offspring after conservative surgery.

Immature teratomas of the genital tract in older women.

We report the clinicopathologic features of three women, 40 years of age or older, with malignant genital tract immature teratomas. All had FIGO stage III, grade II or grade III tumors. One tumor arose from the fallopian tube, the second from the ovary, and the third involved the cortical surfaces of both ovaries with minimal parenchymal involvement. The tumors weighed 1700, 5660, and 330 g and had histologic features similar to those generally seen in younger women. Two of the women died within 1 year of diagnosis. Interval growth of tumor after treatment with chemotherapy was documented in the third patient; she was reexplored and all of the excised tumor was composed of mature tissues. These cases affirm that, although rare, malignant germ cell tumors can occur in older peri- or postmenopausal women.

Organotypic culture of human ovarian surface epithelial cells: a potential model for ovarian carcinogenesis.

The objective of this work was to establish an in vitro multidimensional culture system for human ovarian surface epithelial (HOSE) cells as a model for ovarian carcinogenesis. The epithelial origin of cell outgrowth from cells obtained from the ovarian surface was confirmed by keratin staining. Two cultures from two different patients were established, HOSE-A and HOSE-B. Cultures were infected with a retrovirus expressing human papillomavirus genes E6 and E7 to extend their life span. HOSE cells were seeded onto collagen gels containing NIH3T3-J2 fibroblasts as feeder cells and grown to confluence submerged in growth medium. The collagen bed was then raised to the air-medium interface for 7 d (organotypic culture). Microscopically, fixed cultures revealed a single layer of flat cells growing on the collagen surface, reminiscent of HOSE cells in vivo. Infected HOSE-A and HOSE-B cells exhibited aberrant growth because they stratified. In addition, established ovarian cancer lines grown in this fashion stratified and showed malignant phenotypes. Thus, cells grown in organotypic culture resemble their in vivo counterparts, providing a basis for establishing a system to study growth, proliferation, differential gene expression, and perhaps malignant transformation of HOSE cells.

Neural network control of communications systems.

Neural networks appear well suited to applications in the control of communications systems for two reasons: adaptivity and high speed. This paper describes application of neural networks to two problems, admission control and switch control, which exploit the adaptivity and speed property, respectively. The admission control problem is the selective admission of a set of calls from a number of inhomogeneous call classes, which may have widely differing characteristics as to their rate and variability of traffic, onto a network. It is usually unknown in advance which combinations of calls can be simultaneously accepted so as to ensure satisfactory performance. The approach adopted is that key network performance parameters are observed while carrying various combinations of calls, and their relationship is learned by a neural network structure. The network model chosen has the ability to interpolate or extrapolate from the past results and the ability to adapt to new and changing conditions. The switch control problem is the service policy used by a switch controller in transmitting packets. In a crossbar switch with input queueing, significant loss of throughput can occur when head-of-line service order is employed. A solution can be based on an algorithm which maximizes throughput. However since this solution is typically required in less than one microsecond, software implementation policy is infeasible. We will carry out an analysis of the benefits of such a policy, describe some existing proposed schemes for its implementation, and propose a further scheme that provides this submicrosecond optimization.

Chemical evolution of the citric acid cycle: sunlight photolysis of alpha-ketoglutaric acid.

Sunlight photolysis of alpha-ketoglutaric acid produces succinic acid as a major product. Other higher molecular weight products are identified by GC-MS analysis. These results provide further support for the important role of succinic acid in chemical evolution.

Being there: the effect of the user's presence on MEDLINE search results.

An evaluation was conducted at the University of Iowa Health Sciences Library to determine what effect the user's presence had on MEDLINE search results. One hundred users participated over a four-month period. Three main criteria were used: search precision, search recall, and user satisfaction. Each MEDLINE search was processed twice, once prior to the user's arrival and a second time during the scheduled appointment with the user. The two searches for each user were processed by different searchers, and four searchers alternated processing the user-absent or the user-present search. Users were asked to compare the citations on the two searchers by checking each printout for relevant citations. A short questionnaire was administered to determine general information about users and satisfaction measures for each search. The extensiveness of the interview for the user-absent search was varied in order to determine if the depth of the initial interview would affect the search results. Evaluation of the findings indicated an increase in precision, recall, and user satisfaction for the user-present search. Some difficulties in designing the experiment are discussed and implications of the evaluation results are considered.