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author:("oleni, balewa")
1.  Experimental Treatment of Estrogen Receptor (ER) Positive Breast Cancer with Tamoxifen and Brivanib Alaninate, a VEGFR-2/FGFR-1 Kinase Inhibitor: a potential clinical application of angiogenesis inhibitors 
Tamoxifen, a selective estrogen receptor modulator (SERM), and brivanib alaninate, a VEGFR-2 inhibitor, are two target specific agents that result in a substantial decrease in tumor growth when given alone. Tamoxifen activates SERM stimulated breast and endometrial tumor growth. Tamoxifen and brivanib alaninate have side effects that can affect therapeutic outcomes. The primary goal of the current study was to evaluate the therapeutic effects of lower doses of both agents when given in combination to mice with SERM sensitive, estrogen stimulated tumor xenografts (MCF-7 E2 tumors). Experiments were conducted to evaluate the response of SERM stimulated breast (MCF-7 Tam, MCF-7 Ral) and endometrial tumors (EnCa 101) to demonstrate the activity of brivanib alaninate in SERM resistant models.
Experimental Design
In the current study, tumor xenografts were minced and bi-transplanted into the mammary fat pads of athymic, ovariectomized mice. Preliminary experiments were conducted to determine an effective oral dose of tamoxifen and brivanib alaninate that had minimal effect on tumor growth. Doses of 125 µg of tamoxifen and 0.05 mg/g of brivanib alaninate were evaluated. An experiment was designed to evaluate the effect of the two agents together when started at the time of tumor implantation. An additional experiment was done in which tumors were already established and then treated, to obtain enough tumor tissue for molecular analysis.
Brivanib alaninate was effective at inhibiting tumor growth in SERM sensitive (MCF-7 E2) and SERM stimulated (EnCa 101, MCF-7 Ral, MCF-7 Tam) models. The effect of the low dose drug combination as an antitumor strategy for SERM sensitive (MCF-7 E2) in early treatment was as effective as higher doses of either drug used alone. In established tumors, the combination is successful at decreasing tumor growth, while neither agent alone is effective. Molecular analysis revealed a decreased phosphorylation of VEGFR-2 in tumors that were treated with brivanib alaninate and an increase in VEGFA transcription to compensate for the blockade of VEGFR-2 by increasing the transcription of VEGFA. Tamoxifen increases the phosphorylation of VEGFR-2 and this effect is abrogated by brivanib alaninate. There was also increased necrosis in tumors treated with brivanib alaninate.
Historically, tamoxifen has a role in blocking angiogenesis as well as the blockade of the ER. Tamoxifen and a low dose of an angiogenesis inhibitor, brivanib alaninate, can potentially be combined not only to maximize therapeutic efficacy but also to retard SERM resistant tumor growth.
PMCID: PMC2927957  PMID: 20303261
2.  A comparison of perioperative outcomes of Video-Assisted Thoracic Surgical (VATS) Lobectomy with open thoracotomy and lobectomy: Results of an analysis using propensity score based weighting 
Randomized trials comparing VATS lobectomy to open lobectomy are of small size. We analyzed a case-control series using propensity score-weighting to adjust for important covariates in order to compare the clinical outcomes of the two techniques.
We compared patients undergoing lobectomy for clinical stage I lung cancer (NSCLC) by either VATS or open (THOR) methods. Inverse probability of treatment weighted estimators, with weights derived from propensity scores, were used to adjust cohorts for determinants of perioperative morbidity and mortality including age, gender, preop FEV1, ASA class, and Charlson Comorbidity Index (CCI). Bootstrap methods provided standard errors. Endpoints were postoperative stay (LOS), chest tube duration, complications, and lymph node retrieval.
We analyzed 136 consecutive lobectomy patients. Operative mortality was 1/62 (1.6%) for THOR and 1/74 (1.4%) for VATS, P = 1.00. 5/74 (6.7%) VATS were converted to open procedures. Adjusted median LOS was 7 days (THOR) versus 4 days (VATS), P < 0.0001, HR = 0.33. Adjusted median chest tube duration (days) was 5 (THOR) versus 3 (VATS), P < 0.0001, HR = 0.42. Complication rates were 39% (THOR) versus 34% (VATS), P = 0.61. Adjusted mean number of lymph nodes dissected per patient was 18.1 (THOR) versus 14.8 (VATS), p = 0.17.
After balancing covariates that affect morbidity, mortality and LOS in this case-control series using propensity-weighting, the results confirm that VATS lobectomy is associated with a statistically significant shorter LOS, similar mortality and complication rates and similar rates of lymph node removal in patients with clinical stage I NSCLC.
PMCID: PMC2848683  PMID: 20307297

Results 1-2 (2)