Eugene P. Toy

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.

Brain metastases in epithelial ovarian and primary peritoneal carcinoma.

Objectives: Central nervous system metastases are believed to be becoming more clinically evident as long-term survival for epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC) has improved. Our objective was to report our experience with managing brain metastatic disease (BMD) in patients with EOC and PPC. Methods: A retrospective review was performed on patients with EOC and PPC diagnosed with BMD from 1983 to 2007 at our institution. Results: Twenty-four patients were identified. Patients with multiple brain lesions (n = 16) had a shorter median time to diagnosis of BMD than patients with single lesions (n = 8; 22.5 vs 39 months). Radiation therapy was included in the treatment of BMD for 19 patients (78%). Fourteen patients received whole-brain radiation therapy (WBRT) only (survival, 6 months [range, 1-51 months]). Three patients received a combination of gamma knife radiosurgery and WBRT (survival, 20 months [range, 17-67 months]), and 1 patient received gamma knife radiosurgery alone (survival, 10 months). Four patients underwent craniotomy with 3 receiving postoperative WBRT (survival, 8.5 months [range, 2-97 months]). Two patients elected for palliative care only. The median survival from the diagnosis of BMD was 8.5 months (range, 1-97 months) with a 42% 1-year survival and 16% 2-year survival. Patients with single lesions had a significantly longer survival than patients with multiple lesions (17 months [range, 3-97 months] vs 6 months [range, 3-67 months], respectively). Conclusions: Our report provides the largest single-institution experience of brain metastasis from EOC and PPC in patients receiving predominantly platinum and paclitaxel therapy. Patients with BMD from EOC and PPC have a poor prognosis overall; however, prolonged survival is possible in a small subset of patients.

Correlation of tumor phenotype with c-fms proto-oncogene expression in an in vivo intraperitoneal model for experimental human breast cancer metastasis

Although proto-oncogene expression has been shown to correlate with clinical outcome in breast carcinoma, an experimental model has not been proposed to study this phenomenon in vivo. In addition, the ability to modulate this proto-oncogene in vivo to correlate with phenotypic behavior has not been determined. Utilizing an intraperitoneal model for metastatic spread with BT20 human breast carcinoma cells, clonally expanded cells expressing five fold higher c-fms protein were compared with parent BT20 cells as well as an underexpressing clone using intrasplenic injection following left flank cut-down in female nude and Severe combined immunodeficient (SCID) mice. Athymic BALB/c nude and SCID animals were observed for clinical evidence of tumorigenicity with necropsy performed at either 50 or 80 days unless compromised earlier. Immunohistochemistry (IHC) of the harvested tumors was performed to correlate c-fms expression from its original in vitro culture to the in vivo model. At day 50, differences in primary tumor take and spread to the pelvis were already evident favoring the c-fms over-expression group with IHC of these tumors revealing significantly higher intensity of staining for c-fms, (mean H score of 205 vs. 43 in the over-expression and parent groups, respectively). At day 80, tumor take and spread was comparable; however, tumor size in the over-expression group was significantly larger than the parent and under-expressing group in both the BALB/c and SCID experiments. Modulation of c-fms proto-oncogene expression was also achieved using the anti-glucocorticoid, RU-486, via oral administration to SCID mice with subsequent correlation to IHC staining. This model thus provides tumors of significant size and organ diversity which retain their phenotype early in tumorigenesis allowing an early endpoint to assess efficacy of novel treatments.

Evaluating the significance of location of lymph node metastasis and extranodal disease in women with stage IIIC endometrial cancer

OBJECTIVE To determine the prognostic significance of location of lymph node metastasis and extranodal disease for women with stage IIIC endometrial cancer. METHODS Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Statistical analysis used Chi-square test, Kaplan-Meier method, and Cox proportional hazards model. RESULTS A total of 2559 women were identified; 1453 stage IIIC1, and with 906 stage IIIC2 tumors. Compared to stage IIIC1; more stage IIIC2 patients demonstrated high-risk factors such as grade III disease (p<0.001), unfavorable histologic types (p=0.01), concurrent disease at other extrauterine sites (p<0.001), and greater than two positive lymph nodes (p<0.001). While the 5-year disease specific survival was comparable (p>0.05) among node positive patients found to have positive peritoneal cytology (44.0%), adnexal/serosal metastasis (42.9%), and vaginal/parametrial involvement (41.8%); it differed individually in all three categories from those with nodal metastasis alone (67.0%, p<0.001). Among women with extranodal disease, the location of nodal metastasis had no effect on survival (HR=0.92; 95% CI, 0.74-1.14). For women with node only stage IIIC tumors, those patients with positive para-aortic nodes were more likely to die from their tumors (HR=1.40; 95% CI, 1.12-1.75). CONCLUSION(S) Location of lymph node metastasis is prognostic in patients with nodal disease alone, and not in those with extranodal disease. Extranodal disease is associated with a poor prognosis and should be regarded in conjunction with location of lymph node metastasis for risk-stratification in stage IIIC endometrial cancer.

Induction of cell-cycle arrest in cervical cancer cells by the human immunodeficiency virus type 1 viral protein R

Objective To determine the ability of the human immunodeficiency virus type 1 (HIV-1) gene vpr to induce cell-cycle arrest in cervical cancer cells with or without human papillomavirus (HPV) type 16 E6 or E7 expression. Methods High- and low-level expression vectors for vpr (designated pVPRHIGH and pVPRLOW, respectively) were used in conjunction with HPV-16 E6 or E7 vectors to transfect HPV-negative C33A cervical cancer cells. Vpr expression vectors encode a cell surface marker gene, murine Thy-1, for specific detection of transfected cells. Dual staining for the surface molecule Thy-1 and DNA content was used to determine cell-cycle profile and G2-phase arrest. Results C33A cells not expressing HPV-16 E6 showed some but not maximal G2-phase arrest when transfected with pVPRHIGH alone (43.2% of cells in the phase). Addition of HPV-16 E6 or E6 plus E7 to pVPRHIGH substantially increased the percentages of cells in the G2 phase (51.3% and 53.0%, respectively). Cotransfection with pVPRHIGH and HPV-16 E7 did not increase significantly the percentage of cells in the G2 phase compared with pVPRHIGH alone (40.6% versus 43.2%). In transfections involving pVPRLOW, a slight degree of G2-phase arrest was observed when Vpr was expressed alone (29.0% of cells in the G2 phase) or in cotransfection with HPV-16 E7 (33.2% of cells), and G2-phase arrest was augmented with the addition of HPV-16 E6 (41.7%) or E6 plus E7 (45.7%). Conclusion Cervical cancer cells are susceptible to cell-cycle arrest induced by HIV-1 vpr. This effect is exacerbated by coexpression of HPV-16 E6, although E6 alone is incapable of inducing any detectable G2-phase arrest, suggesting that E6 and VPR share links in cell-cycle signaling pathways.

Stage IIA1 versus stage IIA2 cervical cancer: does the new staging criteria predict survival?

Objective: (1) To determine the correlation of 2008 International Federation of Gynecology and Obstetrics staging system with survival in patients with stage IIA cervical cancer, (2) to elucidate the treatment patterns in stage IIA1 and stage IIA2 cervical cancer, and (3) to investigate whether radical hysterectomy or radiation influenced overall survival. Methods: Data were extracted from the Surveillance, Epidemiology and End Results database between 1988 and 2005. Statistical analysis used χ2 test, Kaplan-Meier method, Cox regression, and logistic regression. Results: Of the 560 women, 271 (48.4%) had stage IIA1, and 289 (51.6%) had stage IIA2 cervical cancer. Stage IIA2 patients were younger than stage IIA1 patients (mean age, 49 years vs 54 years; P = 0.01). Stage IIA1, compared with stage IIA2, differed significantly regarding the administration of primary radiation (47.2% vs 64.7%, P < 0.001) and adjuvant radiation (60.5% vs 77.5%, P = 0.006). The following variables were significantly associated with the performance of radical hysterectomy: patient age, 65 years or younger, tumor size, ≤2 cm or lesser, high tumor grade, and nonsquamous tumor histology. The incidence of adjuvant radiation after radical hysterectomy was high (48% [tumor size, ≤2 cm] to 86% [tumor size, >6 cm]). The 5-year overall survival was not significantly different between stages IIA1 and IIA2 (65.8% vs 59.5%, P = 0.2). Only patient age (P = 0.01), tumor size (P = 0.02), and lymph node status (P = 0.002) were independent predictors of survival. When controlled for other contributing factors, there was no significant difference in survival between patients treated by radical hysterectomy and primary radiation. Conclusions: The 2008 International Federation of Gynecology and Obstetrics staging criteria is not an independent predictor of survival in stage IIA cervical cancer. Given the equivalent efficacy of radical hysterectomy and radiation, attention should be paid to the high risk of adjuvant radiation in these patients.

Intra-operative detection of nodal metastasis in early stage cervical cancer: A survey of the practice patterns of SGO members

OBJECTIVES To determine the practice patterns of members of Society of Gynecologic Oncologists (SGO) in different clinical situations involving the intra-operative detection of nodal metastasis in early stage cervical cancer. METHODS A study questionnaire was mailed to the current members of SGO (n=874). Data were collected using an internet survey database. Frequency distributions were determined, and non parametric tests were performed. RESULTS Thirty percent SGO members responded (n=274). Only 38.6% routinely performed an intra-operative frozen section evaluation of the lymph nodes. Of these; most (79%) did not abort the radical hysterectomy (RH) for an isolated microscopically positive pelvic lymph node. The likelihood of aborting RH for microscopic nodal involvement increased however with number of positive pelvic lymph nodes (21% with 1, 40% with 2-3, and 61% with >3 positive pelvic lymph nodes), involvement of para-aortic lymph nodes (61%), or bilaterally positive lymph nodes (54%). Similarly, a large number did not complete the RH due to gross involvement of pelvic (45%) or para-aortic lymph node/s (69%). Most (90%) completed the lymphadenectomy before aborting RH. When completing RH, the majority tailored its extent to perform a less radical resection. Variables significantly associated with the likelihood of completing RH in different clinical situations included: location of current practice (West), practice type (private), years in practice (>15 years), and number of cases seen per year (>10/month). CONCLUSION Practice patterns of SGO members are considerably diverse, which is reflective of the conflicting evidence available in the literature. Well designed studies are required to determine the best overall approach.

Stage III uterine carcinosarcoma: 2009 International Federation of Gynecology and Obstetrics Staging System and Prognostic Determinants.

Objectives (1) To determine the significance of positive peritoneal cytology and pelvic versus para-aortic lymph node involvement in uterine carcinosarcoma. (2) To evaluate the impact of isolated retroperitoneal lymph node involvement (IIIC-N) versus retroperitoneal lymph node involvement plus other evidence of extrauterine disease spread (IIIC-N+) on survival in patients with stage IIIC uterine carcinosarcoma. Methods Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Statistical analysis used χ2, Kaplan-Meier method, and Cox proportional hazards model. Results A total of 690 women were identified. When comparing overall survival between patients with disease spread to uterine serosa and/or adnexa and those with positive peritoneal cytology, there was no significant difference (25.4% vs 15.5%, P = 0.2). However, although the 5-year overall survival was comparable between patients with positive pelvic lymph nodes and those with positive para-aortic lymph nodes (22.1% vs 25.4%, P = 1.0), it was significantly worse in stage IIIC-N(+) compared to stage IIIC-N patients (15.0% vs 33.4%, P < 0.001). Only patient’s age (P < 0.001), race (P = 0.03), stage (P < 0.03), and lymphadenectomy (P < 0.001) were independent predictors of survival after adjusting for other contributing factors. In addition, the results of unadjusted analysis concerning the survival difference between different stage groups were confirmed on multivariate analysis. Conclusions Positive peritoneal cytology is associated with poor prognosis in uterine carcinosarcoma, comparable to current International Federation of Gynecology and Obstetrics stage IIIA classification of disease. Although there does not seem to be a significant survival difference between patients with positive pelvic versus those with para-aortic lymph nodes, the prognosis seems to be much worse in patients with stage IIIC uterine carcinosarcoma with other evidence of extrauterine disease spread, suggesting the need for more aggressive therapy.

Inhibition of the c-fms proto-oncogene autocrine loop and tumor phenotype in glucocorticoid stimulated human breast carcinoma cells.

The c-fms proto-oncogene encoded CSF-1 receptor and its ligand represent a feedback loop, which in a paracrine manner, is well known to promote spread of breast cancers. The role of the autocrine feedback loop in promotion of breast tumor behavior, in particular in vitro, is less well understood. The physiologic stimulation of c-fms expression by glucocorticoids (GCs) in vitro and in vivo magnifies the tumor promoting effect seen in these cells from activated c-fms signaling by CSF-1. Targeted molecular therapy against c-fms could therefore abrogate both complementary feedback loops. Using breast cancer cells endogenously co-expressing receptor and ligand, we used complementary approaches to inhibit c-fms expression and function within this autocrine pathway in the context of GC stimulation. Silencing RNA (shRNA), antisense oligonucleotide therapy (AON), and inhibition of c-fms signaling, were all used to quantitate inhibition of GC-stimulated adhesion, motility, and invasion of human breast cancer cells in vitro. shRNA to c-fms downregulated GC-stimulated c-fms mRNA by fourfold over controls, correlating with over twofold reduction in cellular invasiveness. AON therapy was also able to inhibit GC stimulation of c-fms mRNA, and resulted in threefold less invasiveness and 1.5 to 2-fold reductions in adhesion and motility. Finally, the small-molecule c-fms inhibitor Ki20227 was able to decrease in a dose–response manner, breast cancer cell invasion by up to fourfold. Inhibition of this receptor/ligand pair may have clinical utility in inhibition of the autocrine as well as the known paracrine interactions in breast cancer, thus further supporting use of targeted therapies in this disease.

Primary extrauterine endometrial stromal sarcoma: response to hormone therapy

Endometrial stromal sarcomas (ESS) of the uterus are hormone-sensitive tumors. There have been reports in the literature confirming the regression of ESS with progestins, gonadotropin analogues, and aromatase inhibitors. We report a case of primary extrauterine ESS of the rectovaginal septum (RVS), which was poorly responsive and, in fact, progressed on progestin therapy. The question arises: is the evident lack of response to oral progestin in our case an exception or a trend more commonly seen in primary extrauterine, extraovarian ESS? To the best of our knowledge, there has been no report in the literature to address this question. Therefore, we conducted a review of the literature to evaluate the response of these tumors to hormone therapy in relation to their estrogen and progesterone receptor status.