Ketao Jin

Differential response to EGFR- and VEGF-targeted therapies in patient-derived tumor tissue xenograft models of colon carcinoma and related metastases

Heterogeneity in primary tumors and related metastases may result in failure of antitumor therapies, particularly in targeted therapies for the treatment of cancer. In this study, patient-derived tumor tissue (PDTT) xenograft models of colon carcinoma with lymphatic and hepatic metastases were used to evaluate the response to EGFR- and VEGF-targeted therapies. Our results showed that primary colon carcinoma and its corresponding lymphatic and hepatic metastases have a different response rate to anti-EGFR (cetuximab) and anti-VEGF (bevacizumab) therapies. However, the underlying mechanism of these types of phenomenon is still unclear. To investigate whether such phenomena may result from the heterogeneity in primary colon carcinoma and related metastases, we compared the expression levels of cell signaling pathway proteins using immunohistochemical staining and western blotting, and the gene status of KRAS using pyrosequencing in the same primary colon carcinoma and its corresponding lymphatic and hepatic metastatic tissues which were used for establishing the PDTT xenograft models. Our results showed that the expression levels of EGFR, VEGF, Akt/pAkt, ERK/pERK, MAPK/pMAPK, and mTOR/pmTOR were different in primary colon carcinoma and matched lymphatic and hepatic metastases although the KRAS gene status in all cases was wild-type. Our results indicate that the heterogeneity in primary colon carcinoma and its corresponding lymphatic and hepatic metastases may result in differences in the response to dual-inhibition of EGFR and VEGF.

Surgical treatment of retrorectal tumors: a retrospective study of a ten-year experience in three institutions.

BACKGROUND/AIMS The relative rarity and anatomical position of retrorectal tumors may lead to difficulty in diagnosis and surgical management. METHODOLOGY This was a retrospective review of 93 patients who had resection of retrorectal tumors between 2002 and 2011. RESULTS All patients in this study were treated with excision of the retrorectal tumors. Surgical approach included transsacral approach (78 cases), transabdominal approach (12 cases) and combined approach (3 cases). Seventy-two benign lesions (77.4%) and 21 malignant (22.6%) were confirmed by histological examination. The 72 benign cases included dermoid cysts (26 cases), simple cysts (12 cases), teratomas (12 cases), neurofibromas (12 cases), fibrolipomas (6 cases), neurilemmomas (3 cases) and synovioma (1 case). The twenty-one malignant cases included lymphomas (6 cases), malignant teratomas (5 cases), fibrosarcomas (3 cases), interstitialomas (6 cases) and malignant mesothelioma (1 case). Complications occurred in 16.1% of patients including intra-operative bleedings (6 cases), rectal injury (6 cases) and presacral infection (3 cases). CONCLUSIONS Primary retrorectal tumors are very rare. Successful treatment of these tumors requires extensive knowledge of pelvic anatomy and expertise in pelvic surgery.

Mammotome® biopsy system for the resection of breast lesions: Clinical experience in two high‑volume teaching hospitals

Ultrasound-guided vacuum-assisted breast biopsy (VABB) is regarded as a feasible, effective, minimally invasive and safe method for the removal of benign breast lesions, without the occurrence of serious complications. The aim of this study was to evaluate the feasibility, efficacy and safety of ultrasound-guided VABB using the Mammotome® biopsy system in the treatment of breast lesions. The clinical outcomes of 3,681 patients with breast lesions were evaluated following excisions by ultrasound-guided VABB in two high-volume teaching hospitals. From January 2008 to December 2012, a total of 4,867 ultrasound-guided VABB procedures were performed in the 3,681 patients, who had a mean age of 37.8 years (range, 16–73 years). The parameters examined in this analysis included lesion size, lesion location in the inner breast, Breast Imaging Reporting and Data System (BI-RADS) ultrasound category and histopathological diagnosis. Ultrasonography follow-up was performed at 3–6 month intervals in order to assess recurrence. The size of the investigated lesions ranged between 6 and 62 mm and a histopathological diagnosis was made in 100% of cases. The results indicated that the majority of specimens (98.89%) were benign. On average, the ultrasound-guided VABB was performed in 10.3 min (range, 7.5–43 min) and the mean number of cores removed in the procedure was 8.1 (range, 3–32). A complete excision was achieved in the majority of cases (99.7%). The presence of a hematoma was the most common complication following the biopsy, and was observed in 27.5% of patients. The mean follow-up period was 25.5 months (range, 1–60 months), during which the rate of recurrence was 4.4%. The results indicated that ultrasound-guided VABB using the Mammotome biopsy system is an effective and safe procedure that is able to rapidly remove the majority of benign breast lesions using a small incision and without the occurrence of scarring or complications.

Antitumor effect of FP3 in combination with cetuximab on patient-derived tumor tissue xenograft models of primary colon carcinoma and related lymphatic and hepatic metastases

FP3 is an engineered protein which contains the extracellular domain 2 of vascular endothelial growth factor (VEGF) receptor 1 (Flt-1) and the extracellular domain 3 and 4 of VEGF receptor 2 (Flk-1, KDR) fused to the Fc portion of human immunoglobulin G1. Previous studies have demonstrated its antiangiogenic effects in vitro and in vivo, and its antitumor activity in vivo. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combined inhibition of VEGF and EGF signaling may act additively or synergistically. In this study, patient-derived tumor tissue (PDTT) xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3 in combination with cetuximab. Xenografts were treated with FP3 and cetuximab, alone or in combination. After tumor growth was confirmed, volume and microvessel density in tumors were evaluated. Levels of VEGF, EGFR and PCNA in the tumor were examined by immunohistochemical staining, and levels of related cell signaling pathway proteins were examined by western blotting. FP3 in combination with cetuximab showed significant antitumor activity in three xenograft models (primary colon carcinoma, lymphatic metastasis and hepatic metastasis). The microvessel density in tumor tissues treated with FP3 in combination with cetuximab was lower compared to that of the control. Antitumor activity of FP3 in combination with cetuximab was significantly higher than that of each agent alone in two xenograft models (colon carcinoma lymphatic metastasis and hepatic metastasis). This study indicated that addition of FP3 to cetuximab significantly improved tumor growth inhibition in the PDTT xenograft models of colon carcinoma lymphatic and hepatic metastases. Combination anti-VEGF (FP3) and anti-EGFR (cetuximab) therapies may represent a novel therapeutic strategy for the management of metastatic colon carcinoma.

Anti-angiogenic therapy for colorectal cancer: on the way to getting better!

Based on the theory that tumor growth and metastasis depend on vessels to provide oxygen and nutrients, antiangiogenic therapy was thought as a promising approach to cure cancer. Bevacizumab is the first validated angiogenesis inhibitor, when combined with conventional treatments, which can enhance antitumor effects and prolong survival for patients with colorectal cancer. However, recent years, bevacizumab and other angiogenesis inhibitors are more discussed with drug resistance and the diverse test results. Fortunately, antiangiogenic strategy is more than bevacizumab and more than anti-vascular endothelial growth factor. Dozens of compounds that potently inhibit neoplastic blood vessels formation with different mechanisms have been developed, and many of them are being tested clinically for colorectal cancer. This review will numerate the principal antiangiogenic drugs with various mechanisms, recapitulate the information of studying these drugs for colorectal cancer treatment and try to clue better usage of antiangiogenic therapy for patients with colorectal cancer in the future.

Antitumor effects of FP3 in combination with capecitabine on PDTT xenograft models of primary colon carcinoma and related lymphatic and hepatic metastases

FP3 is an engineered protein which contains the extracellular domain 2 of VEGF receptor 1 (Flt-1) and extracellular domain 3 and 4 of VEGF receptor 2 (Flk-1, KDR) fused to the Fc portion of human immunoglobulin G1. Previous studies demonstrated its antiangiogenic effects in vitro and in vivo, and its antitumor activity in vivo. In this study, patient-derived tumor tissue (PDTT) xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3 in combination with capecitabine. Xenografts were treated with FP3, capecitabine, alone or in combination. After tumor growth was confirmed, volume and microvessel density in tumors were evaluated. Levels of VEGF, and PCNA in the tumor were examined by immunohistonchamical staining, level of thymidine phosphorylase (TP) was examined by ELISA, and levels of related cell signaling pathways proteins expression were examined by western blotting. FP3 in combination with capecitabine showed significant antitumor activity in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). The microvessel density in tumor tissues treated with FP3 in combination with capecitabine was lower than that of the control. Antitumor activity of FP3 in combination with capecitabine was significantly higher than that of each agent alone in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). This study indicated that addition of FP3 to capecitabine significantly improved tumor growth inhibition in the PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases.

Antitumor effect of FP3 in a breast cancer xenograft model

FP3 is a novel vascular endothelial growth factor (VEGF) blocker proposed to have antiangiogenic properties. Previous studies revealed that FP3 is a new promising agent for treating human choroidal neovascularization (CNV)-associated age-associated macular degeneration (AMD) and has an inhibitory effect on VEGF-mediated proliferation and migration of human umbilical vein endothelial cells and VEGF-mediated vessel sprouting of the rat aortic ring in vitro. Previous studies have also revealed that FP3 has antitumor effects and antiangiogenic effects in a non-small cell lung cancer cell line (A549), as well as in patient-derived tumor tissue xenograft models of gastric cancer and colon carcinoma with lymphatic and hepatic metastases in nude mice. In the present study, the antitumor effect of FP3 in an MDA-MB-231 breast cancer xenograft model was investigated. Treatment with FP3 for 3 weeks significantly suppressed xenograft growth and this inhibition was associated with a significant decrease in angiogenesis and direct inhibition of tumor cells. The results of the present study indicate that FP3 inhibits breast cancer tumor growth via the indirect inhibition of angiogenesis as well as a direct effect on tumor cells.

Heterogeneity between primary colon carcinoma and paired lymphatic and hepatic metastases

Heterogeneity is one of the recognized characteristics of human tumors, and occurs on multiple levels in a wide range of tumors. A number of studies have focused on the heterogeneity found in primary tumors and related metastases with the consideration that the evaluation of metastatic rather than primary sites could be of clinical relevance. Numerous studies have demonstrated particularly high rates of heterogeneity between primary colorectal tumors and their paired lymphatic and hepatic metastases. It has also been proposed that the heterogeneity between primary colon carcinomas and their paired lymphatic and hepatic metastases may result in different responses to anticancer therapies. The heterogeneity in primary colon carcinoma and corresponding metastases by genome‑wide gene expression analysis has not been extensively studied. In the present study, we investigated the differentially expressed genes between a primary colon carcinoma specimen (obtained from a 40-year-old female colon carcinoma patient with lymphatic and hepatic metastases) and its paired lymphatic and hepatic metastases by genome-wide gene expression analysis using GeneChip HGU133Plus2.0 expression arrays. Our results demonstrate that genome-wide gene expression varies between primary colon carcinoma and its paired lymphatic and hepatic metastases.