Calcification of the extracellular matrix (ECM) can be physiological or pathological. Physiological calcification occurs in bone when the soft ECM is converted into a rigid material capable of sustaining mechanical force; pathological calcification can occur in arteries and cartilage and other soft tissues. No molecular determinant regulating ECM calcification has yet been identified. A candidate molecule is matrix GLA protein (Mgp), a mineral-binding ECM protein synthesized by vascular smooth-muscle cells and chondrocytes, two cell types that produce an uncalcified ECM. Mice that lack Mgp develop to term but die within two months as a result of arterial calcification which leads to blood-vessel rupture. Chondrocytes that elaborate a typical cartilage matrix can be seen in the affected arteries. Mgp-deficient mice additionally exhibit inappropriate calcification of various cartilages, including the growth plate, which eventually leads to short stature, osteopenia and fractures. These results indicate that ECM calcification must be actively inhibited in soft tissues. To our knowledge, Mgp is the first inhibitor of calcification of arteries and cartilage to be characterized in vivo.

Objective:To evaluate the influence of surgical margin status on survival and site of recurrence in patients treated with hepatic resection for colorectal metastases. Methods: Using a multicenter database, 557 patients who underwent hepatic resection for colorectal metastases were identified. Demographics, operative data, pathologic margin status, site of recurrence (margin, other intrahepatic site, extrahepatic), and longterm survival data were collected and analyzed. Results: On final pathologic analysis, margin status was positive in 45 patients, and negative by 1 to 4 mm in 129, 5 to 9 mm in 85, and Ն1 cm in 298. At a median follow-up of 29 months, the 1-, 3-, and 5-year actuarial survival rates were 97%, 74%, and 58%; median survival was 74 months. Tumor size Ն5 cm, Ͼ3 tumor nodules, and carcinoembryonic antigen level Ͼ200 ng/mL predicted poor survival (all P Ͻ 0.05). Median survival was 49 months in patients with positive margins and not yet reached in patients with negative margins (P ϭ 0.01). After hepatic resection, 225 (40.4%) patients had recurrence: 21 at the surgical margin, 56 at another intrahepatic site, 82 at an extrahepatic site, and 66 at both intrahepatic and extrahepatic sites. Patients with negative margins of 1 to 4 mm, 5 to 9 mm, and Ն1 cm had similar overall recurrence rates (P Ͼ 0.05). Patients with positive margins were more likely to have surgical margin recurrence (P ϭ 0.003). Adverse preoperative biologic factors including tumor number greater than 3 (P ϭ 0.01) and a preoperative CEA level greater than 200 ng/mL (P ϭ 0.04) were associated with an increased risk of positive surgical margin. Conclusions:A positive margin after resection of hepatic colorectal metastases is associated with adverse biologic factors and increased risk of surgical-margin recurrence. The width of a negative surgical margin does not affect survival, recurrence risk, or site of recurrence. A predicted margin of Ͻ1 cm after resection of hepatic colorectal metastases should not be used as an exclusion criterion for resection. L iver resection currently represents the only potentially curative therapeutic option for hepatic colorectal metastasis (CRM), and 5-year survival rates of 25% to 58% have been reported. [1][2][3][4][5][6] Traditionally, primary tumor stage, preoperative carcinoembryonic antigen (CEA) level, hepatic tumor size, number of hepatic metastases, time from primary tumor treatment to diagnosis of hepatic metastases, and presence of extrahepatic disease have been reported to be independent predictors of survival after resection. 7,8 Surgical margin status is an additional factor that has been evaluated for its influence on long-term survival after resection of CRM, but its significance remains controversial. Several series concerning liver resection for colorectal liver metastasis have reported that surgical margins of less than 1 cm are an absolute 9,10 or relative contraindication to surgery.11 Cady et al 10 have reported that a surgical margin less than 1 cm was associated on univariate analys...

The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of inducing angiogenesis, some cancers vascularize by the non-angiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option prevails in human breast cancer liver metastases, a setting where results with anti-angiogenic therapy have been disappointing. In our preclinical mechanistic studies, we show that cancer cell motility mediated by the Arp2/3 complex is required for vessel co-option in liver metastases in vivo and that combined inhibition of angiogenesis and vessel co-option is more effective than inhibiting angiogenesis alone in this setting. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option may be a warranted therapeutic strategy.

a b s t r a c tAn international panel of multidisciplinary experts convened to develop recommendations for managing patients with colorectal cancer (CRC) and synchronous liver metastases (CRCLM). A modified Delphi method was used. CRCLM is defined as liver metastases detected at or before diagnosis of the primary CRC. Early and late metachronous metastases are defined as those detected 612 months and >12 months after surgery, respectively. To provide information on potential curability, use of high-quality contrast-enhanced computed tomography (CT) before chemotherapy is recommended. Magnetic resonance imaging is increasingly being used preoperatively to aid detection of subcentimetric metastases, Contents lists available at ScienceDirectCancer Treatment Reviews j o u r n a l h o m e p a g e : w w w . e l s e v i e r h e a l t h . c o m / j o u r n a l s / c t r v and alongside CT in difficult situations. To evaluate operability, radiology should provide information on: nodule size and number, segmental localization and relationship with major vessels, response after neoadjuvant chemotherapy, non-tumoral liver condition and anticipated remnant liver volume. Pathological evaluation should assess response to preoperative chemotherapy for both the primary tumour and metastases, and provide information on the tumour, margin size and micrometastases. Although the treatment strategy depends on the clinical scenario, the consensus was for chemotherapy before surgery in most cases. When the primary CRC is asymptomatic, liver surgery may be performed first (reverse approach). When CRCLM are unresectable, the goal of preoperative chemotherapy is to downsize tumours to allow resection. Hepatic resection should not be denied to patients with stable disease after optimal chemotherapy, provided an adequate liver remnant with inflow and outflow preservation remains. All patients with synchronous CRCLM should be evaluated by a hepatobiliary multidisciplinary team.

HE ADDITION OF BEVACIZUMAB, a monoclonal antibody against vascular endothelial growth factor, to cytotoxic chemotherapy is associated with improved survival in patients with stage IV colorectal cancer and higher pathologic response rates in patients undergoing resection of colorectal liver metastases. 1,2 Response to bevacizumab, which exerts an antiangiogenic mechanism of action, may be inadequately assessed by traditional size-based radiologic criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), which were designed for assessing tumor volume reduction following cytotoxic chemotherapy. [3][4][5] In support of this, a recent phase 3 trial showed that the addition of bevacizumab to oxaliplatin-based chemotherapy for metastatic colorectal cancer improved progression-free survival without affecting RECIST-defined response rates. 6 Recently, pathologic response to preoperative chemotherapy has been shown to correlate with improved sur-Author Affiliations are listed at the end of this article.