About the Huang Lab

ABSTRACT

Hypothesis:
Serum CA125 is a potential biomarker for metastatic disease and recurrence in patients with uterine papillary serous carcinoma (UPSC).

Methods:
All patients with UPSC who had preoperative CA125 measurement and surgical staging between 1998 and 2008 at the participating institutions were included in this analysis (N = 52). Data were extracted from patients' records. Fisher exact and χ² tests were used to assess the association of CA125 levels with clinical and pathological variables. The correlation between CA125 levels (high/low) and lymph node metastases (positive/negative) was evaluated using Spearman correlation coefficients. The association of CA125 elevation with recurrence-free survival was assessed using Cox proportional hazards regression modeling.

Results:
Preoperative CA125 elevation (>30 U/mL) was observed in 9 (17%) patients and was associated with advanced International Federation of Gynecologists and Obstetricians (FIGO) stage III/IV disease (P = 0.002), lymph node involvement (P = 0.007), and presence of omental metastases (P = 0.001). Disease recurrence and survival data were available for 51 of the 52 patients. During a mean follow-up time of 36 months, 15 (29%) patients experienced disease recurrence and 10 (19%) patients died. There was a moderate positive correlation between CA125 levels and lymph node metastases (r² = 0.39). On multivariate survival analysis, an elevated CA125 level compared to nonelevated CA-125 was not associated with disease recurrence (hazard ratio, 1.61; 95% confidence interval, 0.55-4.77).

Conclusion:
Preoperative CA125 levels were significantly associated with metastatic disease in patients with UPSC. However, in this study of surgically staged UPSC patients, preoperative CA125 elevation was not an independent predictor of disease recurrence.

ABSTRACT

Objective:
We sought to evaluate the expression of G protein-coupled receptor 30 (GPR30) and estrogen receptor (ER)beta in uterine carcinosarcoma (CS).

Study Design:
Immunohistochemistry was performed using antibodies to GPR30, ERbeta, ERalpha, and progesterone receptor (PR). The staining intensity and percentage of positive cells were scored for each tissue section. Expression levels were compared using the Wilcoxon rank sum test. Correlation was evaluated by Spearman rho and logistic regression.

Results:
Compared with normal endometrium, CS had lower ERalpha and PR expression (both P < .01) but higher GPR30 epithelial expression (P = .03). Advanced-stage CS had higher GPR30 (P < .01) and ERbeta (P = .02) epithelial expression compared with early-stage CS. Expression of GPR30 and ERbeta correlated with each other (P < .01), and not with ERalpha or PR.

Conclusion:
In uterine CS, GPR30 and ERbeta are coordinately overexpressed and expression levels increase in advanced-stage disease, supporting the involvement of alternative ERs in disease progression.

Copyright 2010 Mosby, Inc. All rights reserved.

ABSTRACT

Purpose:
This study was undertaken to examine the role of the insulin-like growth factor (IGF) signaling pathway in the response of ovarian cancer cells to Taxol and to evaluate the significance of this pathway in human epithelial ovarian tumors.

Experimental Design:
The effect of Taxol treatment on AKT activation in A2780 ovarian carcinoma cells was evaluated using antibodies specific for phospho-AKT. To study the drug-resistant phenotype, we developed a Taxol-resistant cell line, HEY-T30, derived from HEY ovarian carcinoma cells. IGF2 expression was measured by real-time PCR. A type 1 IGF receptor (IGF1R) inhibitor, NVP-AEW541, and IGF2 small interfering RNA were used to evaluate the effect of IGF pathway inhibition on proliferation and Taxol sensitivity. IGF2 protein expression was evaluated by immunohistochemistry in 115 epithelial ovarian tumors and analyzed in relation to clinical/pathologic factors using the chi(2) or Fisher's exact tests. The influence of IGF2 expression on survival was studied with Cox regression.

Results:
Taxol-induced AKT phosphorylation required IGF1R tyrosine kinase activity and was associated with upregulation of IGF2. Resistant cells had higher IGF2 expression compared with sensitive cells, and IGF pathway inhibition restored sensitivity to Taxol. High IGF2 tumor expression correlated with advanced stage (P < 0.001) and tumor grade (P < 0.01) and reduced disease-free survival (P < 0.05).

Conclusion:
IGF2 modulates Taxol resistance, and tumor IGF2 expression is a candidate prognostic biomarker in epithelial ovarian tumors. IGF pathway inhibition sensitizes drug-resistant ovarian carcinoma cells to Taxol. Such novel findings suggest that IGF2 represents a therapeutic target in ovarian cancer, particularly in the setting of Taxol resistance.

Copyright 2010 AACR.

ABSTRACT

Background:
Müllerian adenosarcoma is a rare mixed epithelial-mesenchymal tumor. An extragenital site of origin and sarcomatous overgrowth are associated with aggressive clinical behavior.

Case:
We present a rare case of extragenital adenosarcoma with sarcomatous overgrowth and coexistent endometriosis. She was treated with initial cytoreductive surgery and chemotherapy. She underwent a second surgery for management of a high-grade bowel obstruction, due to pathologically confirmed recurrent intraperitoneal adenosarcoma. A complete clinical response was achieved with liposomal doxorubicin, and the patient remains disease-free eighteen months after completion of chemotherapy.

Conclusion:
Liposomal doxorubicin appears to be an active agent for the treatment of adenosarcoma with sarcomatous overgrowth. In addition, we conclude from our review of all reported cases of extragenital adenosarcoma that concurrent endometriosis may represent a favorable prognostic factor.

ABSTRACT

Objectives:
A phase II trial designed to evaluate the safety and efficacy of weekly topotecan and docetaxel in heavily treated patients with recurrent uterine or epithelial ovarian cancers.

Methods:
Eligible patients with recurrent epithelial ovarian or uterine cancers were treated with weekly topotecan 3.5 mg/m(2) and docetaxel 30 mg/m(2) for 3 consecutive weeks. Cycles were repeated every 4 weeks for 6 cycles or until evidence of disease progression, unacceptable toxicity, or death. Response was assessed as per RECIST or Rustin's criteria. Time to best response and overall survival were calculated using Kaplan-Meier statistical methods.

Results:
Twenty-seven patients registered, of which 24 were evaluable for response. The majority of patients had received 2 prior chemotherapy regimens. Of the total 86 cycles of chemotherapy that were administered, there were three grade 4 (all neutropenia) and ten grade 3 toxicities. Six of the grade 3 non-hematologic toxicities were unrelated to treatment. There were 8 dose delays and 4 dose reductions. The overall response rate was 25% (95% CI: 7.7%-42.3%, 8% CR, 17% PR), and 38% of the patients had clinical benefit (95% CI: 18.1%-56.9%; CR+PR+13% SD). The median duration of response was 8.5 months (range 3-19 months). The median overall survival was 18.5 months (range 1.8-50.7 months).

Conclusion:
The combination of weekly topotecan and docetaxel has clinical benefit and is well tolerated in this heavily treated patient population. Patients with platinum-resistant tumors had clinical benefit and should be considered for further study with this regimen.

ABSTRACT

Objectives:
To evaluate the relationship of hormone (estrogen receptor alpha, estrogen receptor beta, progesterone receptor) and growth factor receptor (insulin-like growth factor receptor, human epidermal growth factor receptor 2) expression with disease progression in uterine carcinosarcoma.

Study Design:
Immunohistochemistry was performed on tissue arrays using standard methodology. Differences between groups were evaluated by the Wilcoxon rank-sum test. Interactions between tumor stage and receptor expression were determined by linear trend analysis.

Results:
Compared with normal endometrium, carcinosarcomas exhibited low estrogen receptor alpha and progesterone receptor expression (all P < .01), but overexpressed estrogen receptor beta (P = .02). Estrogen receptor beta expression increased in advanced stage disease (P = .02). Insulin-like growth factor receptor expression was lower in carcinosarcoma compared with normal endometrium (P = .01). Human epidermal growth factor receptor 2 expression was elevated and increased with disease progression (P < .01).

Conclusion:
In uterine carcinosarcoma, estrogen receptor beta expression is elevated and increases with disease progression, whereas estrogen receptor alpha and progesterone receptor are suppressed. Human epidermal growth factor receptor 2 expression is increased, whereas insulin-like growth factor receptor is lower than in normal endometrium. These data support a potential role for estrogen receptor beta in disease progression via crosstalk with human epidermal growth factor receptor 2.

ABSTRACT

Objective:
The purpose of this study was to determine the clinical utility of CA125 measurement in patients with uterine carcinosarcoma (CS).

Methods:
Ninety-five consecutive patients treated for CS at a single institution were identified. All 54 patients who underwent preoperative CA125 measurement were included in the study. Data were abstracted from the medical records. Tests of association between preoperative CA125 and previously identified clinicopathologic prognostic factors were performed using Fisher's exact test and Pearson chi-square test. To evaluate the relationship of CA125 elevation and survival, a Cox proportional hazard model was used for multivariate analysis, incorporating all of the prognostic factors identified by univariate analysis.

Results:
Preoperative CA125 was significantly associated with the presence of extrauterine disease (P<0.001), deep myometrial invasion (P<0.001), and serous histology of the epithelial component (P=0.005). Using univariate survival analysis, stage (HR=1.808, P=0.004), postoperative CA125 level (HR=9.855, P<0.001), and estrogen receptor positivity (HR=0.314, P=0.029) were significantly associated with survival. In the multivariate model, only postoperative CA125 level remained significantly associated with poor survival (HR=5.725, P=0.009).

Conclusion:
Preoperative CA125 elevation is a marker of extrauterine disease and deep myometrial invasion in patients with uterine CS. Postoperative CA125 elevation is an independent prognostic factor for poor survival. These findings indicate that CA125 may be a clinically useful serum marker in the management of patients with CS.

ABSTRACT

Objective:
This study was undertaken to evaluate the ability of preoperative endometrial sampling to accurately diagnose high-grade endometrial tumors.

Study Design:
Three hundred sixty endometrial cancer patients had preoperative endometrial sampling and hysterectomy specimens that underwent pathologic review at a single institution from 1995 to 2005. The sensitivity of Pipelle and curettage to diagnose high-grade endometrial tumors (grade 3 endometrioid adenocarcinoma, serous carcinoma, carcinosarcoma, clear cell carcinoma) was determined. Agreement between preoperative and hysterectomy diagnoses was measured by the Kappa statistic.

Results:
Sensitivity of Pipelle and curettage was 93.8% and 97% in patients with low-grade cancer and 99.2% and 100% in patients with high-grade cancer. Good agreement was observed between the preoperative and the hysterectomy histologic diagnoses (Kappa = 0.69), and between the preoperative and hysterectomy tumor grade (Kappa=0.78).

Conclusion:
Preoperative endometrial sampling with Pipelle or curettage is sensitive and accurate for the diagnosis of high-grade endometrial tumors, including tumors with nonendometrioid histology.

ABSTRACT

Background:
Cisplatin (CDDP) administration concomitant with radiotherapy (RT) for the treatment of locally advanced cervical cancer has evolved from an inpatient 5-day every 21-day regimen to a weekly outpatient regimen. This study was designed to test for differences in progression-free survival (PFS) and toxicity between the 2 regimens.

Methods:
In all, 77 consecutive patients at a single institution with stage IB2-IV cervical cancer were included in this analysis (using the International Federation of Gynecologists and Obstetricians staging system). All patients were treated with CDDP, external beam RT, and 2 9-Gy high-dose-rate brachytherapy treatments. Two cohorts were compared: 1) 5-day, patients treated from 1995 to 2001 with CDDP 20 mg/m(2) x 5 days every 21 days concomitant with RT; 2) weekly, treated after May 2001 with CDDP 40 mg/m(2) weekly concomitant with RT.

Results:
In all, 50 patients were treated with the 5-day regimen and 27 patients with the weekly regimen. There were no significant demographic differences between the groups. Overall 3-year PFS, controlling for stage, was 90% and 76% for 5-day and weekly groups, respectively (P = .01). Adjusting for stage, age, and completion of treatment, the risk of treatment failure among the weekly group was 3.46 times higher than the 5-day group (P = .02). The weekly group had a 3.43 times higher risk of developing acute toxicities than the 5-day group (P = .02) in advanced-stage patients.

Conclusions:
Patients who received weekly CDDP have a shorter 3-year PFS. Patients with advanced-stage cervical cancer who received weekly CDDP had significantly more acute toxicities. These data should be confirmed in a multi-institutional, randomized, controlled study.

Copyright 2006 American Cancer Society.

ABSTRACT

Purpose:
To evaluate the drug combination of discodermolide and Taxol in human ovarian cancer cells and in an in vivo model of ovarian carcinoma.

Experimental Design:
The combination index method was used to evaluate the interaction of Taxol and discodermolide in human ovarian SKOV-3 carcinoma cells. Data were correlated with alterations in cell cycle distribution and caspase activation. In addition, SKOV-3 xenograft-bearing mice were treated with either Taxol, discodermolide, or a combination of both drugs given concurrently to evaluate the antitumor efficacy and toxicity of this combination. The Matrigel plug assay and CD31 immunohistochemistry were done to assess antiangiogenic effects.

Results:
Taxol and discodermolide interact synergistically over a range of concentrations and molar ratios that cause drug-induced aneuploidy in ovarian carcinoma cells. In SKOV-3 xenograft-bearing mice, the combination is significantly superior to either single agent, and induces tumor regressions without notable toxicities. Immunohistochemical analysis of CD31 and Matrigel plug analysis show decreased vessel formation in mice treated with the combination relative to either drug alone.

Conclusions:
The synergistic activity of Taxol and discodermolide in cells is most potent at drug concentrations that result in drug-induced aneuploidy rather than mitotic arrest. Moreover, in an animal model of ovarian carcinoma, this is a well-tolerated combination that induces tumor regressions and suppresses angiogenesis. These data confirm the potency of this combination and support the use of concurrent low doses of Taxol and discodermolide for potential use in cancer therapeutics.

ABSTRACT

Background:
Cisplatin (CDDP) administration concomitant with radiotherapy (RT) for the treatment of locally advanced cervical cancer has evolved from an inpatient 5-day every 21-day regimen to a weekly outpatient regimen. This study was designed to test for differences in progression-free survival (PFS) and toxicity between the 2 regimens.

Methods:
In all, 77 consecutive patients at a single institution with stage IB2-IV cervical cancer were included in this analysis (using the International Federation of Gynecologists and Obstetricians staging system). All patients were treated with CDDP, external beam RT, and 2 9-Gy high-dose-rate brachytherapy treatments. Two cohorts were compared: 1) 5-day, patients treated from 1995 to 2001 with CDDP 20 mg/m(2) x 5 days every 21 days concomitant with RT; 2) weekly, treated after May 2001 with CDDP 40 mg/m(2) weekly concomitant with RT.

Results:
In all, 50 patients were treated with the 5-day regimen and 27 patients with the weekly regimen. There were no significant demographic differences between the groups. Overall 3-year PFS, controlling for stage, was 90% and 76% for 5-day and weekly groups, respectively (P = .01). Adjusting for stage, age, and completion of treatment, the risk of treatment failure among the weekly group was 3.46 times higher than the 5-day group (P = .02). The weekly group had a 3.43 times higher risk of developing acute toxicities than the 5-day group (P = .02) in advanced-stage patients.

Conclusions:
Patients who received weekly CDDP have a shorter 3-year PFS. Patients with advanced-stage cervical cancer who received weekly CDDP had significantly more acute toxicities. These data should be confirmed in a multi-institutional, randomized, controlled study.

Copyright 2006 American Cancer Society.

ABSTRACT

Ovarian cancer is the most lethal gynecologic malignancy with a five-year survival rate below 25% for patients with stages III and IV disease. Identifying key mediators of ovarian cancer invasion and metastasis is critical to the development of more effective therapeutic interventions. We previously identified Filamin A interacting protein 1-like (FILIP1L) as an important mediator of cell proliferation and migration. In addition, targeted expression of FILIP1L in tumors inhibited tumor growth in vivo. In our present study, we confirmed that both mRNA and protein expression of FILIP1L were downregulated in ovarian cancer cells compared with normal ovarian epithelial cells. FILIP1L expression was inversely correlated with the invasive potential of ovarian cancer cell lines and clinical ovarian cancer specimens. We also provide evidence that DNA methylation is a mechanism by which FILIP1L is downregulated in ovarian cancer. The CpG island in the FILIP1L promoter was heavily methylated in ovarian cancer cells. Methylation status of the FILIP1L promoter was inversely correlated with FILIP1L expression in ovarian cell lines and clinical ovarian specimens. Reduced methylation in the FILIP1L promoter following treatment with a DNA demethylating agent was associated with restoration of FILIP1L expression in ovarian cancer cells. A transcription activator, cAMP-responsive element binding protein (CREB) was shown to bind to the CREB/ATF site in the CpG island of the FILIP1L promoter. Overall, these findings suggest that downregulation of FILIP1L associated with DNA methylation is related with the invasive phenotype in ovarian cancer and that modulation of FILIP1L expression has the potential to be a target for ovarian cancer therapy.

ABSTRACT

Upregulation of IGF2 occurs in both childhood and adult malignancies. Its overexpresssion is associated with resistance to chemotherapy and worse prognosis. IGF2 promoter usage is developmentally regulated; however, malignant tissues are characterized by re-activation of the fetal IGF2 promoters, especially P3. In this review, we describe the mechanisms of IGF2 signaling and regulation in normal and malignant tissues and their clinical implications.

Copyright ©2015 Elsevier Ltd. All rights reserved.

ABSTRACT

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting.

Copyright ©2015 Elsevier Ltd. All rights reserved.

ABSTRACT

Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone.

ABSTRACT

Objective:
Uterine carcinosarcoma (CS) is a rare uterine tumor with an extremely poor prognosis. In the adjuvant setting, efficacy has been shown with radiotherapy (RT), systemic chemotherapy, or both. This is the first report describing the efficacy and toxicity of adjuvant ifosfamide or ifosfamide plus cisplatin "sandwiched" with RT in patients with surgically staged and completely resected uterine carcinosarcoma.

Methods:
Women with surgically staged CS with no gross residual disease were initially administered ifosfamide (1.2 g/m(2)/day×5 days) with cisplatin (20 mg/m(2)/day×5 days) every 3 weeks for 3 cycles followed by pelvic external beam RT and brachytherapy followed by 3 additional cycles of ifosfamide (1.0 g/m2/day) with cisplatin (20 mg/m(2)/day×5 days) every 3 weeks. Similar to the GOG trial in recurrent CS (Sutton et al., 2000), the addition of cisplatin added toxicity without additional efficacy, so mid-study, the cisplatin was eliminated from the regimen. Toxicities were recorded and disease-free survival (DFS) was calculated with Kaplan-Meier statistical methods.

Results:
In total, 12 patients received ifosfamide and cisplatin and 15 patients received ifosfamide alone, both 'sandwiched' with RT. The median follow up was 35.9 months (range 6-88). The 2 year DFS was similar in both the ifosfamide/cisplatin and ifosfamide groups (log-rank p=0.16), so they were combined for analysis. 19 patients (70%) completed the protocol. As expected, stage 1 patients had a better 2-year DFS (18.75 ± 1.12 months; log-rank p=0.008 when compared to stages 2, 3, 4). Also, in stages 2, 3 and 4 patients, the DFS was 15.81 ± 1.73 months. Grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 18%, 4% and 4% of cycles, respectively.

Conclusions:
Ifosfamide "sandwiched" with RT appears to be an efficacious regimen for surgically staged CS patients with no residual disease, even in patients with advanced stage. The addition of cisplatin to the regimen added toxicity without improving efficacy. Even with ifosfamide alone, the efficacy of this 'sandwich' regimen comes with a moderate but tolerable toxicity profile.

Copyright ©2011. Published by Elsevier Inc.

ABSTRACT

Purpose:
Although overall there is a positive association between obesity and risk of prostate cancer (PrCa) recurrence, results of individual studies are somewhat inconsistent. We investigated whether the failure to exclude diabetics in prior studies could have increased the likelihood of conflicting results.

Methods:
A total of 610 PrCa patients who underwent radical prostatectomy between 2005 and 2012 were followed for recurrence, defined as a rise in serum PSA ≥ 0.2 ng/ml following surgery. Body mass index (BMI) and history of type 2 diabetes were documented prior to PrCa surgery. The analysis was conducted using Cox proportional hazard models.

Results:
Obesity (25.6 %) and diabetes (18.7 %) were common in this cohort. There were 87 (14.3 %) recurrence events during a median follow-up of 30.8 months after surgery among the 610 patients. When analyzed among all PrCa patients, no association was observed between BMI/obesity and PrCa recurrence. However, when analysis was limited to non-diabetics, obese men had a 2.27-fold increased risk (95 % CI 1.17-4.41) of PrCa recurrence relative to normal weight men, after adjusting for age and clinical/pathological tumor characteristics.

Conclusions:
This study found a greater than twofold association between obesity/BMI and PrCa recurrence in non-diabetics. We anticipated these results because the relationship between BMI/obesity and the biologic factors that may underlie the PrCa recurrence-BMI/obesity association, such as insulin, may be altered by the use of anti-diabetes medication or diminished beta-cell insulin production in advanced diabetes. Studies to further assess the molecular factors that explain the BMI/obesity-PrCa recurrence relationship are warranted.

ABSTRACT

Objectives:
This study was undertaken to evaluate the expression of transforming growth factor β1 (TGF-β1) and matrix metalloproteinase 9 (MMP-9), key regulators of the extracellular matrix composition, in the uterosacral ligaments (USLs) of women with pelvic organ prolapse (POP) compared with controls.

Methods:
Under an institutional review board approval, USL samples were obtained from women undergoing vaginal hysterectomy for stage 2 or greater POP (cases, n = 21) and from women without POP undergoing vaginal hysterectomy for benign indications (controls, n = 19). Hematoxylin and eosin and trichrome staining were performed on the USL sections, and the distribution of smooth muscle and fibrous tissue were quantified. Immunohistochemical staining was performed using anti-TGF-β1 and anti-MMP-9 antibodies. The expressions of TGF-β1 and MMP-9 were evaluated by the pathologist, who was blinded to all clinical data.

Results:
Transforming growth factor β1 expression positively correlated with MMP-9 expression (R = 0.4, P = 0.01). The expressions of TGF-β1 and MMP-9 were similar in subjects with POP versus controls. There was a significant increase in fibrous tissue (P = 0.008) and a corresponding decrease in smooth muscle (P = 0.03), associated with increasing age. The TGF-β1 expression, but not MMP-9 expression, also significantly increased with age (P = 0.02).

Discussion:
Although our study uncovered age-related alterations in USL composition and TGF-β1 expression, there was no difference in the expression of TGF-β1 or MMP-9 in the subjects with POP versus controls.

ABSTRACT

Objective:
To evaluate the safety and survival in women treated with adjuvant pelvic radiation "sandwiched" between six cycles of paclitaxel and carboplatin chemotherapy with completely resected UPSC.

Methods:
Surgically staged women with UPSC (FIGO stage 1-4) and no visible residual disease were enrolled. Treatment involved paclitaxel (175 mg/m(2)) and carboplatin (AUC=6.0-7.5) every 21 days for 3 doses, followed by radiation therapy (RT), followed by an additional 3 cycles of paclitaxel and carboplatin (AUC=5-6). Survival analysis, using Kaplan-Meier methods, was performed on patients who completed at least 3 cycles of chemotherapy and RT.

Results:
A total of 81 patients were enrolled, of which 72 patients completed the first 3 cycles of chemotherapy followed by prescribed RT. Median age was 67 years (range: 43-82 years). 59/72 (82%) had disease confined to the uterus and 13/72 (18%) had completely resected extra-uterine disease (stage 3 and 4). 65 (83%) completed the protocol. Overall PFS and OS for combined stage 1 and 2 patients was 65.5 ± 3.6 months and 76.5 ± 4.3 months, respectively. PFS and OS for combined stage 3 and 4 patients was 25.8 ± 3.0 and 35.9 ± 5.3 months, respectively. Three-year % survival probability for stage 1 and 2 patients was 84% and for stage 3 and 4 patients was 50%. Of the 435 chemotherapy cycles administered, there were 11(2.5%) G3/G4 non-hematologic toxicities. 26(6.0%) cycles had dose reductions and 37(8.5%) had dose delays.

Conclusions:
Compared to prior studies of single modality adjuvant therapy, RT "sandwiched" between paclitaxel and carboplatin chemotherapy is well-tolerated and highly efficacious in women with completely resected UPSC.

Copyright ©2011 Elsevier Inc. All rights reserved