Lymph Node Micrometastases in Early-Stage Cervical Cancer are Not Predictive of Survival.

Although patients with early-stage cervical cancer have in general a favorable prognosis, 10% to 40% patients still recur depending on pathologic risk factors. The objective of this study was to evaluate if the presence of lymph node micrometastasis (LNmM) had an impact on patient's survival. We performed a multi-institutional retrospective review on patients with early-stage cervical cancer, with histologically negative lymph nodes, treated with radical hysterectomy and pelvic lymphadenectomy for the study period 1994 to 2004. Tissue blocks of lymph nodes from the patient's original surgery were recut and then evaluated for the presence of micrometastases. One hundred twenty-nine patients were identified who met inclusion criteria. LNmM were found in 26 patients (20%). In an average follow-up time of 70 mo, there were 11 recurrences (8.5%). Of the 11 recurrences, 2 (18%) patients had LNmM. Patients with LNmM were more likely to have received adjuvant radiation and chemotherapy. In stratified log-rank analysis, LNmM were not associated with any other high-risk clinical or pathologic variables. Survival data analysis did not demonstrate an association between the presence of LNmM and recurrence or overall survival. The presence of LNmM was not associated with an unfavorable prognosis nor was it associated with other high-risk clinical or pathologic variables predicting recurrence. Further study is warranted to understand the role of micrometastases in cervical cancer.

Modulation of p38 MAPK signaling enhances dendritic cell activation of human CD4+ Th17 responses to ovarian tumor antigen.

The recent finding that Th17 infiltration of ovarian tumors positively predicts patient outcomes suggests that Th17 responses play a protective role in ovarian tumor immunity. This observation has led to the question of whether Th17 cells could be induced or expanded to therapeutic advantage by tumor vaccination. In this study, we show that treatment of ovarian tumor antigen-loaded, cytokine-matured human dendritic cells (DC) with a combination of IL-15 and a p38 MAP kinase inhibitor offers potent synergy in antagonism of CD4(+) Treg induction and redirection toward CD4(+) Th17 responses that correlate with strong CD8(+) cytotoxic T lymphocyte (CTL) activation. Ovarian tumor antigen-specific CD4(+) T cells secrete high levels of IL-17 and show reduced expression of CTLA-4, PD-1, and Foxp3 following activation with IL-15/p38 inhibitor-treated DC. We further show that modulation of p38 MAPK signaling in DC is associated with reduced expression of B7-H1 (PD-L1), loss of indoleamine 2,3-dioxygenase activity, and increased phosphorylation of ERK 1/2 MAPK. These observations may allow the development of innovative DC vaccination strategies to boost Th17 immunity in ovarian cancer patients.

Lower extremity glandography (LEG): a new concept to identify and enhance lymphatic preservation.

BACKGROUND: Lower extremity edema remains a major postoperative complication after inguinal lymphadenectomy for vulvar cancer. This study documents the lymphatic drainage of the vulva versus the lymphatic drainage of the lower extremity coming through the femoral triangle. METHODS: Seven patients underwent either unilateral or bilateral inguinal lymphadenectomy in conjunction with a radical vulvar resection. Preoperatively, patients had technetium-99 injected into the vulvar cancer. Isosulfan blue was injected into the medioanterior thigh 10 cm below the inguinal ligament. The femoral triangle was opened, and a neoprobe was used to locate the "hot" node bearing the technetium-99. Gentle dissection located the blue lymphatic channel and any blue lymph nodes. The blue and hot nodes were resected and submitted separately. The patients then underwent a complete inguinal lymphadenectomy. RESULTS: A total of 11 groin dissections were performed. In 9 of the 11 groins, the hot node was identified, and in 8 of the 11 groins, blue node or lymphatic channel was identified. The hot nodes were uniformly located on the superior medial aspect of the femoral triangle. The blue nodes were uniformly located on the lateral aspect of the femoral triangle just anterior to the femoral artery or vein. Three patients had hot lymph nodes containing cancer. Of those 3 patients, one had an additional node positive. None of the blue lymph nodes contained cancer. CONCLUSIONS: This procedure demonstrates the alternative lymphatic drainage of the leg versus the vulva. Larger studies are necessary to document the exclusivity of these 2 drainage systems. Preservation of the lymphatic drainage of the leg may result in decreased lymphedema.

Recurrent endometrial carcinoma regression with the use of the aromatase inhibitor anastrozole.

Recurrent/metastatic endometrial adenocarcinoma that is not amenable to cure with local or regional therapy and/or chemotherapy represents a discouraging clinical entity for the clinician. We report the case of 58-year-old woman with recurrent endometrial carcinoma that was resistant to chemotherapy that was treated successfully with the aromatase inhibitor anastrozole.

Ovarian tumor ascites CD14+ cells suppress dendritic cell-activated CD4+ T-cell responses through IL-10 secretion and indoleamine 2,3-dioxygenase.

The observation that Th17 infiltration in ovarian cancer correlates with markedly improved survival has prompted the question of whether ovarian tumor antigen-specific Th17 responses could be stimulated by tumor vaccination. Dendritic cells (DCs) treated with IL-15 and an inhibitor of p38 MAPK signaling (DC(IL-15/p38inhib)) bias T-cell responses toward a Th1/Th17 phenotype, raising the prospect of therapeutic vaccination; however, significant barriers remain. Tumor vaccines, including DC vaccination, usually stimulate immune responses, but the lack of clinical responses in cancer patients has been disappointing. Possible reasons may include an inability of antitumor T cells to migrate into the tumor microenvironment, and an inability of T cells to retain effector function in the face of tumor-associated immune suppression. We found that ovarian tumor antigen-specific CD4(+) T cells induced by DC(IL-15/p38inhib) migrated in response to CXCL12 and CCL22 (both highly expressed in ovarian cancer) and to ascites CD14(+) myeloid cells. Cocultures showed that ascites CD14(+) cells markedly suppressed antigen-specific CD4(+) T responses, but suppression could be alleviated by treatment with anti-IL-10 or inhibition of indoleamine 2,3-dioxygenase. These results suggest that the efficacy of DC vaccination against ovarian cancer may be boosted by agents that inhibit tumor-associated CD14(+) myeloid cell suppression or indoleamine 2,3-dioxygenase activity.

Dendritic cell vaccination against ovarian cancer--tipping the Treg/TH17 balance to therapeutic advantage?

The pathology of ovarian cancer is characterized by profound immunosuppression in the tumor microenvironment. Mechanisms that contribute to the immunosuppressed state include tumor infiltration by regulatory T cells (Treg), expression of B7-H1 (PDL-1), which can promote T cell anergy and apoptosis through engagement of PD-1 expressed by effector T cells, and expression of indoleamine 2,3-dioxygenase (IDO), which can also contribute to effector T cell anergy. Expression of both B7-H1 and IDO has been associated with differentiation and recruitment of Treg, and clinical studies have shown that each of these mechanisms correlates independently with increased morbidity and mortality in patients with ovarian cancer. In a remarkable counterpoint to these observations, ovarian tumor infiltration with T(H)17 cells correlates with markedly improved clinical outcomes. In this Future Perspectives review, we argue that dendritic cell (DC) vaccination designed to drive tumor-antigen-specific T(H)17 T cell responses, combined with adjuvant treatments that abrogate immunosuppressive mechanisms operative in the tumor microenvironment, offers the potential for clinical benefit in the treatment of ovarian cancer. We also discuss pharmacological approaches to modulation of MAP kinase signaling for manipulation of the functional plasticity of DC, such that they may be directed to promote T(H)17 responses following DC vaccination.

The influence of microvessel density on ovarian carcinogenesis.

OBJECTIVE: Tumor microvessel density, measured by CD31 immunohistochemistry, correlates with survival in patients with ovarian cancer. CA 125 is secreted by most ovarian cancers, and we have previously shown that the rate of decline of CA 125 is also predictive of ovarian cancer survival. Because increased tumor vascularity may allow metastases on one hand, while facilitating the delivery of chemotherapy on the other, we investigated the relationship of tumor microvessel density to preoperative CA 125, residual disease, and the initial response to treatment. METHODS: FIGO stage, grade, age, residual disease, and CD31 microvessel density count were correlated with consecutive patients (n = 202) diagnosed with epithelial ovarian cancer who met entry criteria. The relationship of CD31 staining to preoperative CA 125, and the rate of decline in CA 125 (slope) as a measure of initial response to therapy, was also evaluated based on complete CA 125 data. Spearman correlation and the Wilcoxon rank sum test were used for bivariate analyses. Linear and logistic regression was used for multivariate analysis. RESULTS: There were 21 stage I, 14 stage II, 125 stage III, and 42 stage IV patients diagnosed with epithelial ovarian cancer included in the study. More than half (N = 126) of the patients were optimally cytoreduced. Elevated microvessel density was associated with advanced stage of disease (P = 0.0453), grade (P = 0.0002), and an increased amount of residual disease (P = 0.0144). CA 125 values were higher in patients with residual disease versus patients without residual disease (P = 0.0357), and the decline in the CA 125 (slope) was less steep in patients without residual disease versus patients with residual disease (P = 0.0003). However, the initial response to chemotherapy was unrelated to the microvessel density count as measured by CD31 antibody staining (P = 0.7911). In multivariate analyses, CD31 counts remained significant in relationship to grade. Nonideal slopes, indicating decreased response, were associated with increasing age (P = 0.0008) and residual disease (P = 0.0035). CONCLUSION: Elevated ovarian cancer microvessel density count is related to advanced stage and grade of disease, and compromised potential for cytoreduction. Residual disease is associated with higher CA 125 levels and faster CA 125 decline rates. The rate of decline of CA 125 during the initial response to treatment cannot be predicted based on CD31 counts, confirming a complex relationship between tumor vascularity, metastasis, and response to treatment.