Association between recurrent metastasis from stage II and III primary colorectal tumors and moderate microsatellite instability

Colorectal cancer cells frequently have low levels of microsatellite instability (MSI-L) and elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), but little is known about the clinicopathologic significance of these features. We observed that patients with stage II or III colorectal cancer with MSI-L and/or EMAST had shorter times of recurrence-free survival than patients with high levels of MSI (P = .0084) or with highly stable microsatellites P = .0415), based on Kaplan-Meier analysis. MSI-L and/or EMAST were independent predictors of recurrent distant metastasis from primary stage II or III colorectal tumors (Cox proportional hazard analysis: hazard ratio, 1.83; 95% confidence interval, 1.06-3.15; P = .0301).     

TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma

Although the role of TGF-β in tumor progression has been studied extensively, its impact on drug delivery in tumors remains far from understood. In this study, we examined the effect of TGF-β blockade on the delivery and efficacy of conventional therapeutics and nanotherapeutics in orthotopic mammary carcinoma mouse models. We used both genetic (overexpression of sTβRII, a soluble TGF-β type II receptor) and pharmacologic (1D11, a TGF-β neutralizing antibody) approaches to block TGF-β signaling. In two orthotopic mammary carcinoma models (human MDA-MB-231 and murine 4T1 cell lines), TGF-β blockade significantly decreased tumor growth and metastasis. TGF-β blockade also increased the recruitment and incorporation of perivascular cells into tumor blood vessels and increased the fraction of perfused vessels. Moreover, TGF-β blockade normalized the tumor interstitial matrix by decreasing collagen I content. As a result of this vessel and interstitial matrix normalization, TGF-β blockade improved the intratumoral penetration of both a low-molecular-weight conventional chemotherapeutic drug and a nanotherapeutic agent, leading to better control of tumor growth.     

Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases

Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)–amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti–VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.     

The Role of Noninvasive Imaging in Early Diagnosis of Clinically Masked Prepulseless Inflammatory Phase of Takayasu's Arteritis

Diagnosis of early-phase Takayasu's arteritis (TA) is extremely difficult and overlooked as most often presentation is nonspecific and mimics various other diseases. Early diagnosis and initiation of proper therapy could alter the natural course of the disease. We describe an adolescent male presenting with pyrexia of unknown origin and clinical features simulating idiopathic dilated cardiomyopathy. Transthoracic echocardiography was suggestive of dilated cardiomyopathy with severe left ventricular dysfunction. Later vascular ultrasonography and CT aortography showed extensive thickening of intima-media of aorta and its major branches suggestive of inflammatory phase of TA. We discuss the role of noninvasive imaging in diagnosis of clinically masked prepulseless inflammatory phase of TA. (Echocardiography 2012;29:59-63)).