Christina S. Chu

Cutting Edge: Regulatory T Cells from Lung Cancer Patients Directly Inhibit Autologous T Cell Proliferation

Active suppression by T regulatory cells plays an important role in the down-regulation of T cell responses to foreign and self-Ags. Thus far, the potential role of CD4+CD25+ T cells in human tumors has not been reported. In this work we show that lung tumors contain large numbers of these cells and that they have constitutive high-level expression of CD152 (CTLA-4). Furthermore, the CD4+CD25+ T cells mediate potent inhibition of autologous T cell proliferation. Finally, regulatory T cells from patient tumors failed to inhibit the proliferation of allogeneic T cells. Together these results suggest that the CD4+CD25+ T cells found in lung tumors selectively inhibit the host immune response and therefore could contribute to the progression of lung cancer.

Peritumoral Lymphatic Vessel Density and Vascular Endothelial Growth Factor C Expression in Early-Stage Squamous Cell Carcinoma of the Uterine Cervix

Purpose: Lymphatic invasion and nodal metastasis plays a major role in the spread of cervical cancer; however, little is known about the mechanisms whereby tumor cells enter the lymphatic system. Experimental Design: We examined the intra- and peritumoral lymphatic vessel density (LVD) using D2-40 immunohistochemistry in 111 cervical squamous cell carcinomas and correlated them with vascular endothelial growth factor (VEGF)-C expression, clinicopathologic tumor features, and outcome. Results: Compared with benign cervix, intratumoral and peritumoral LVD was significantly increased (P < 0.0001). Peritumoral LVD was significantly higher than intratumoral LVD (P = 0.009). High peritumoral, but not intratumoral, LVD showed significant correlation with high tumor stage, lymphatic invasion, and nodal metastasis. VEGF-C showed increased expression at the invasive edge compared with the center of tumors (P < 0.0001) and correlated with high peritumoral LVD, lymphatic invasion, and nodal metastasis. High peritumoral LVD and VEGF-C expression at the invasive edge of tumors were associated with poor overall and recurrence-free survival in univariate analysis. In multivariate analysis, peritumoral LVD was the only independent term predictive of overall survival. Conclusions: Our findings suggest a potential role for VEGF-C in tumor-induced lymphangiogenesis represented by high peritumoral LVD, which may be one of the mechanisms leading to lymphatic invasion and metastatic spread. High peritumoral LVD may be an independent prognostic factor in early-stage cervical cancer.

Low D2-40 immunoreactivity correlates with lymphatic invasion and nodal metastasis in early-stage squamous cell carcinoma of the uterine cervix

Lymphatic invasion and nodal metastasis are predictors of shorter disease-free and overall survival in carcinoma of the uterine cervix. The monoclonal antibody D2-40, which reacts with the oncofetal membrane antigen M2A, is a new selective marker for lymphatic endothelium, and has been shown to be useful in identifying the presence of lymphatic invasion in various malignant neoplasms, including cervical carcinoma. However, the reactivity of the tumor cells with D2-40 has not yet been evaluated. In this study, we examined the pattern of D2-40 immunoreactivity in a series of 138 invasive squamous cell carcinomas of the uterine cervix. We correlated the presence and extent of D2-40 immunoreactivity in the tumor cells with various clinicopathologic features, the presence of lymphatic invasion, lymph node metastasis and outcome. Diffuse or focal D2-40 immunoreactivity was present in 17 (12%) and 81 (59%) tumors, respectively, while 40 (29%) tumors showed no immunoreactivity. Lymphatic invasion and nodal metastasis were present in 56 and 29% of tumors, respectively. Tumor emboli within lymphatic spaces and metastatic tumor foci in lymph nodes showed no immunoreactivity in 86 and 80% of the cases, respectively. Lymphatic invasion and nodal metastasis were significantly more common in tumors showing low D2-40 immunoreactivity (P<0.0001 and 0.022, respectively). D2-40 immunoreactivity showed no correlation with any other clinicopathologic features examined, including tumor size, grade and FIGO stage. In univariate analysis low D2-40 immunoreactivity was significantly associated with shorter recurrence-free, but not with overall survival. Our studies suggest that D2-40 immunostaining may serve as a marker for increased risk of lymphatic invasion and tumor recurrence in cervical biopsy material. Further study of the biological function of the M2A antigen may shed some light on the interaction of tumor cells with lymphatics.

Low podoplanin expression in pretreatment biopsy material predicts poor prognosis in advanced-stage squamous cell carcinoma of the uterine cervix treated by primary radiation

Lymphatic invasion and nodal metastasis are predictors of poor outcome in cervix carcinoma. We have recently found that low podoplanin immunoreactivity in cervix carcinoma correlated with the presence of lymphatic invasion and nodal metastasis. In the current study, we examined whether podoplanin expression in pretreatment cervical biopsies can predict the presence lymphatic invasion, nodal metastasis, and outcome in advanced-stage tumors treated by nonsurgical means. Podoplanin expression was analyzed by immunohistochemistry in 48 cervical biopsies and corresponding hysterectomy specimens of early-stage invasive squamous cell carcinoma and in 74 pretreatment biopsies from advanced-stage tumors treated with primary radiation. We found a highly significant correlation between podoplanin expression obtained in biopsy and corresponding hysterectomy materials (r=0.8962, P<0.0001). Low podoplanin expression showed a significant correlation with lymphatic invasion (P<0.0001) and nodal metastasis (P=0.0058). Low podoplanin expression in pretreatment biopsy material showed a significant correlation with poor disease-free (P=0.0009) and overall (P=0.0002) survival in advanced-stage tumors. Our results suggest that in advanced-stage cervix carcinomas treated by radiation, when traditional prognostic indicators are not available and treatment decisions are based on biopsy material and clinical staging parameters, examination of podoplanin expression in pretreatment biopsy material may be a useful marker to predict lymphatic metastasis and patient outcome. Prospective studies involving larger numbers of patients are needed to further evaluate the clinical utility of examination of podoplanin expression in patients with cervix carcinoma.

Immunotherapy opportunities in ovarian cancer

Ovarian cancer is responsible for the majority of gynecologic cancer deaths and despite the highest standard of multimodality therapy with surgery and cytotoxic chemotherapy, long-term survival remains low. With compelling evidence that epithelial ovarian cancer is an immunogenic tumor capable of stimulating an antitumor immune response, renewed efforts to develop immune therapies to augment the efficacy of traditional therapies are underway. Current immunotherapies focus on varied modes of antitumor vaccine development, particularly with the use of dendritic cell vaccines, effective methods for adoptive T-cell transfer and combinatorial approaches with immune modulatory therapy subverting natural tolerance mechanisms or boosting effector mechanisms. Additional combinatorial approaches include the use of cytokines and/or chemotherapy with immune therapy.

Primary peritoneal carcinoma: a review of the literature.

Target AudienceObstetricians & Gynecologists, Family PhysiciansLearning ObjectivesAfter completion of this article, the reader will be able to understand the similarities and differences between primary peritoneal carcinoma and epithelial ovarian cancer, the criteria used to define peritoneal carcin

Vaginal cuff recurrence of endometrial cancer treated by laparoscopic-assisted vaginal hysterectomy.

BACKGROUND Laparoscopic-assisted vaginal hysterectomy (LAVH) has been suggested as an alternative to total abdominal hysterectomy (TAH) for the treatment of early endometrial cancer. Although studies have reported good results with equivalent rates of recurrence and survival, the need for use of intrauterine manipulators during the LAVH raises the concern for operative dissemination of tumor cells. CASES We report three patients with stage I, noninvasive or superficially invasive endometrial cancer with vaginal cuff recurrence within 9 months of treatment by LAVH. CONCLUSION While LAVH may be a technically acceptable alternative to TAH for the management of early-stage endometrial cancer, its routine use should be undertaken with caution, as the long-term risks for recurrence and survival have yet to be defined in a randomized, controlled fashion.

Risk of occult malignancy in morcellated hysterectomy: a case series.

Uterine morcellation is performed only when significant neoplasia is not anticipated. In this study, we aimed to determine the prevalence of unexpected pathology in a series of low-risk morcellated hysterectomies. We reviewed a series consisting of all patients undergoing hysterectomy with morcellation at a tertiary-care hospital over a 4-yr period (n=101). Patient records were reviewed to retrieve demographics, details of preoperative evaluation (Pap smear, endometrial biopsy, imaging), and surgical pathology diagnoses. The median number of blocks submitted for histology was 6. On final pathology, endometrium was detected in 99% of all cases. No endometrial, myometrial, or cervical neoplasia other than leiomyoma (numerous cases) was present in the morcellated uteri, but in 1 case an atypical trophoblastic nodule with necrosis and myometrial infiltration, suspected to represent epithelioid trophoblastic tumor, was inadvertently morcellated. From this series, the prospective risk of occult malignancy in a low-risk population undergoing morcellation is estimated at 1% (95% confidence interval, <0.01%-5.94%). A subgroup analysis of patients who participated in what we propose as a complete preoperative workup, consisting of nonconcerning Pap smear, endometrial biopsy, and ultrasound or magnetic resonance imaging, showed no significant findings on final histology. Even with a complete workup, however, morcellation of occult uterine malignancy remains a possibility. This risk should be discussed as part of informed consent before morcellation.

Clinical predictors of bevacizumab-associated gastrointestinal perforation.

OBJECTIVES Bevacizumab is a generally well-tolerated drug, but bevacizumab-associated gastrointestinal perforations (BAP) occur in 0 to 15% of patients with ovarian carcinoma. Our goal was to evaluate the clinical predictors of BAP in order to identify factors, which may preclude patients from receiving treatment. METHODS We conducted a review of patients with recurrent epithelial ovarian carcinoma treated with bevacizumab between 2006 and 2009. Demographic and treatment data were collected for statistical analysis. RESULTS Eighty-two patients were identified; perforation occurred in 8 (9.76%). Among patients with perforation, a significantly higher incidence of prior bowel surgeries (p=0.0008) and prior bowel obstruction or ileus (p<0.0001) were found compared to non-perforated patients. The median age at onset of bevacizumab in the perforated group was 3 years younger (60 vs. 63 years, p=0.61). The incidence of thromboembolic events, GI comorbidities, number of prior chemotherapies, and body mass index were similar between the groups. None of the patients in the perforated group developed grade 3 or 4 hypertension, compared to a 32.4% incidence among the non-perforated patients (p=0.09). Upon multivariate analysis, when controlled for age greater or less than 60, prior bowel surgery, obstruction/ileus, and grade 3 or 4 hypertension, only the presence of obstruction/ileus was noted to be a significant predictor of perforation (p=0.04). CONCLUSIONS Predicting BAP remains a challenge. Bowel obstruction or ileus appears to be associated with increased risk of BAP.

Phase I trial of a formulated IL-12 plasmid in combination with carboplatin and docetaxel chemotherapy in the treatment of platinum-sensitive recurrent ovarian cancer

OBJECTIVES The primary objective of this study was to evaluate the safety and tolerability of a formulated IL-12 plasmid administered intraperitoneally (IP) in conjunction with intravenous (IV) carboplatin/docetaxel in platinum-sensitive ovarian cancer patients. METHODS Escalating doses of IL-12 plasmid (phIL-12) formulated with the lipopolymer PEG-PEI-Cholesterol (PPC) were administered IP every 10-11 days for a total of four treatments and the highest dose was expanded to eight treatments. Patients also received IV carboplatin (AUC 5) and docetaxel (75 mg/m(2)) every 21 days. Patients were followed for safety, biological activity and antitumor activity after phIL-12/PPC treatment. RESULTS All 13 patients enrolled in the study received both phIL-12/PPC and chemotherapy treatment. There were 49 plasmid-associated adverse events (AEs). The most common AEs were abdominal pain, transient hypotension, low grade fever, catheter site pain, chills, dysgeusia, infusion-related reaction, and nausea. These AEs appeared to be plasmid dose related. Grade 3 AEs included manageable abdominal pain and cytokine release syndrome. There were no dose limiting toxicities and the plasmid treatment did not augment the chemotherapy-associated AEs. The best overall antitumor response (17% CR, 33% PR, 42% SD and 8% PD) was typical of the patient population enrolled for the study. Translational studies showed rise in IFN-γ and TNF-α concentrations in a dose dependent manner. CONCLUSIONS The escalating doses and cycles of intraperitoneal phIL-12/PPC when combined with carboplatin/docetaxel chemotherapy in recurrent ovarian cancer patients were well tolerated and did not appear to exacerbate the side effects or attenuate the efficacy of the chemotherapy treatment.