Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated advanced gastric cancer: an exploratory analysis of the phase III ABSOLUTE trial.

BACKGROUND: In the ABSOLUTE trial, weekly nanoparticle albumin-bound paclitaxel (w-nab-PTX) showed non-inferiority to weekly solvent-based paclitaxel (w-sb-PTX) for overall survival (OS). Thus, w-nab-PTX might be an option for second-line chemotherapy in advanced gastric cancer (AGC). However, predictive factors for efficacies of these agents have not been evaluated. METHODS: Patients previously enrolled in the ABSOLUTE trial were divided into apparent peritoneal metastasis group (PM group) and no apparent peritoneal metastasis group (no PM group) based on baseline imaging evaluated by RECIST ver. 1.1 criteria and amount of ascites. OS, progression-free survival, and overall response rate were compared between two arms in each group. RESULTS: This study included 240 and 243 patients in the w-nab-PTX and w-sb-PTX arms, respectively. In the PM group, the w-nab-PTX arm (n = 88) had longer OS than the w-sb-PTX arm (n = 103), and median survival time (MST) of 9.9 and 8.7 months [hazard ratio (HR) 0.63; 95% CI 0.45-0.88; P = 0.0060], respectively. In the no PM group, the w-nab-PTX arm (n = 140) had shorter OS than the w-sb-PTX arm (n = 152), and MST of 11.6 and 15.7 months (HR 1.40; 95% CI 1.06-1.86; P = 0.0180), respectively. After adjusting for prognostic factors, the HR for OS in the w-nab-PTX arm versus the w-sb-PTX arm was 0.59 (95% CI 0.42-0.83; P = 0.0023; PM group) and 1.34 (95% CI 1.01-1.78; P = 0.0414; no PM group), with significant interaction between treatment efficacy and presence of peritoneal metastasis (P = 0.0003). CONCLUSIONS: The presence of apparent peritoneal metastasis might be a predictive factor for selecting w-nab-PTX for pretreated AGC patients. TRIAL REGISTRATION NUMBER: JapicCTI-132059.

Tenascin C in colorectal cancer stroma is a predictive marker for liver metastasis and is a potent target of miR-198 as identified by microRNA analysis.

BACKGROUND: Tumour stroma has important roles in the development of colorectal cancer (CRC) metastasis. We aimed to clarify the roles of microRNAs (miRNAs) and their target genes in CRC stroma in the development of liver metastasis. METHODS: Tumour stroma was isolated from formalin-fixed, paraffin-embedded tissues of primary CRCs with or without liver metastasis by laser capture microdissection, and miRNA expression was analysed using TaqMan miRNA arrays. RESULTS: Hierarchical clustering classified 16 CRCs into two groups according to the existence of synchronous liver metastasis. Combinatory target prediction identified tenascin C as a predicted target of miR-198, one of the top 10 miRNAs downregulated in tumour stroma of CRCs with synchronous liver metastasis. Immunohistochemical analysis of tenascin C in 139 primary CRCs revealed that a high staining intensity was correlated with synchronous liver metastasis (P<0.001). Univariate and multivariate analyses revealed that the tenascin C staining intensity was an independent prognostic factor to predict postoperative overall survival (P=0.005; n=139) and liver metastasis-free survival (P=0.001; n=128). CONCLUSIONS: Alterations of miRNAs in CRC stroma appear to form a metastasis-permissive environment that can elevate tenascin C to promote liver metastasis. Tenascin C in primary CRC stroma has the potential to be a novel biomarker to predict postoperative prognosis.

Overexpression of Lysophosphatidylcholine Acyltransferase 1 and Concomitant Lipid Alterations in Gastric Cancer.

BACKGROUND: The involvement of lipids in carcinogenic and developmental processes has been reported in some malignancies, but their roles in gastric cancer remain to be analyzed. In this study, we compared the lipid content of gastric cancer tissue and adjacent nonneoplastic mucosa using imaging mass spectrometry. METHODS: Mass spectra were acquired from 12 sections of human gastric cancer tissue and adjacent nonneoplastic mucosa using a matrix-assisted laser desorption-ionization time-of-flight tandem mass spectrometry type mass spectrometer equipped with a 355 nm Nd:YAG laser. Protein expression of lysophosphatidylcholine acyltransferase 1 (LPCAT1), which converts lysophosphatidylcholine (LPC) to phosphatidylcholine (PC) in the presence of acyl-CoA in Lands' cycle, was immunohistochemically analyzed in 182 gastric cancer specimens. RESULTS: The averaged mass spectra from the cancer tissue and nonneoplastic mucosa were identical. Most of the signals that differed between cancer tissue and nonneoplastic mucosa corresponded to phospholipids, the majority of which were PC and LPC. Two signals, m/z 798.5 and 496.3, were higher and lower, respectively, in cancer tissues, predominantly in differentiated adenocarcinoma. A database search enabled identification of the ions at m/z 798.5 and m/z 496.3 as potassium-adducted PC (16:0/18:1) and proton-adducted LPC (16:0), respectively. Immunohistochemical analysis revealed that LPCAT1 was highly expressed in cancer lesions compared to nonneoplastic mucosa, predominantly in differentiated adenocarcinoma. LPCAT1 expression levels correlated positively with tumor differentiation and negatively with tumor depth, lymph node metastasis, and tumor stage. CONCLUSIONS: Overexpressed LPCAT1 protein in gastric mucosa appears to play important roles in the tumorigenic process of gastric cancer by converting LPC to PC.

Microarray analysis reveals distinct gene set profiles for gastric and intestinal gastrointestinal stromal tumors.

AIM: We sought to address the mechanisms by which intestinal gastrointestinal stromal tumors (GIST) have a markedly higher risk of recurrence than gastric GISTs. MATERIALS AND METHODS: Gene expression levels were compared among six primary gastric, three intestinal and six metastatic liver GISTs using cDNA microarray. Protein levels of Slit homolog 2 (SLIT2) were analyzed by immunohistochemistry in 25 primary gastric and 10 intestinal GIST. RESULTS: Intestinal GIST had gene expression profiles similar to clinically malignant and metastatic GIST. In gene set-enrichment analysis, the gene sets MITOTIC_CELL CYCLE and NEURON_DIFFERENTIATION were up-regulated and down-regulated, respectively, in intestinal GIST compared to gastric GIST. High-risk gastric GISTs and intestinal GIST, expressed similar levels of SLIT2 protein, which were lower than those of low-risk gastric GISTs. CONCLUSION: The gene-expression profile of intestinal GISTs was similar to that of metastatic liver GISTs. Besides higher proliferative activity, down-regulation of SLIT2 might be involved in clinically malignant phenotypes of intestinal GIST.

Collateral thermal damage to the pancreas by ultrasonic instruments during lymph node dissection in laparoscopic gastrectomy.

INTRODUCTION: Laparoscopic gastrectomy (LG) with D2 or more extended lymphadenectomy for advanced gastric cancer is technically demanding. Collateral thermal damage to the pancreas secondary to energized dissection during lymphadenectomy has been reported. We retrospectively compared the pancreatic damage between LG and open gastrectomy (OG) by measuring the amylase concentration of the drainage fluid and analyzing heat conductance to the pancreas with a porcine model. METHODS: We evaluated the data of 105 consecutive patients with gastric adenocarcinoma who underwent LG or OG with lymph node dissection. Digital thermography was used to evaluate the extent of heat conductance to the pancreas during suprapancreatic lymph node dissection by either an ultrasonically activated device or electric cautery in a porcine model. RESULTS: The incidence of clinically relevant pancreatic fistula formation was not statistically significant between the LG and OG groups (3/57 vs 0/48 cases; P = 0.306). However, the median amylase concentrations of the drainage fluid on postoperative days 1 and 3 were 1355.7 and 308.8 IU/L, respectively, in the LG group and 369.0 and 125.8 IU/L, respectively, in the OG group (P < 0.001). In the experimental model, more time was required to cool the surface of the pancreas to < 40°C in the ultrasonically activated device group than in the electric cautery group (10.1 ± 5.2 vs 5.2 ± 3.0 s; P = 0.013). CONCLUSIONS: Unavoidable collateral thermal damage to the pancreas associated with electrosurgical devices might exist during LG. Heat conductance must be given more consideration in extended lymph node dissection.

Three-dimensional fusion images combining CT gastrography and CT angiography for early gastric cancer: pilot experiences of preoperative simulation prior to totally laparoscopic gastrectomy.

We herein report two cases of gastric cancer in which preoperative 3-D CT gastrography and CT angiography fusion images enabled totally laparoscopic gastrectomy. Case 1 involved a 60-year-old woman with a superficial depressed lesion on the greater curvature of the middle gastric body. Case 2 involved a 64-year-old woman with a superficial depressed lesion on the posterior wall of the upper gastric body. In both cases, 3-D fusion images were prepared from enhanced CT scans after the area near the lesions was clipped under preoperative gastroendoscopy. Based on the relative position between the clips and nearby vessels, a resection line was preoperatively determined in each case. Totally laparoscopic distal gastrectomy and totally laparoscopic proximal gastrectomy were performed in cases 1 and 2, respectively, with safe surgical margins. Three-dimensional fusion images can help in preoperative simulation of totally laparoscopic gastrectomy.

Quantitative assessment of the free jejunal graft perfusion.

BACKGROUND: Reconstruction with free jejunal graft (FJG) is often performed for patients with hypopharyngeal or cervical esophageal cancer. During reconstruction with an FJG after pharyngoesophagectomy, it is critical to intraoperatively detect venous anastomotic failure and subsequent venous malperfusion to avoid postoperative FJG necrosis. This study introduces a novel method for assessing blood perfusion in FJGs by using indocyanine green (ICG) fluorescence angiography. METHODS: We used ICG fluorescence angiography to quantitatively assess FJG blood perfusion in archived fluorescence video files from 26 patients who had undergone FJG transfer. A software program "ROIs", was used to create a time-fluorescence intensity curve. We retrospectively measured the maximum fluorescence intensity at the terminal ileum and the duration (T1/2max) between when the intensity began rising and when it reached half of the maximum. RESULTS: Among the 26 patients, 5 patients suffered venous anastomotic failure. In three of these cases, anastomosis was corrected intraoperatively; the other two patients underwent a second FJG transfer. Retrospective assessment showed that the mean T1/2max at the FJG serosae was significantly longer in these five patients than that in FJGs with good blood perfusion. Our analysis revealed that a T1/2max >9.6 s may be a good indicator of FJG venous malperfusion. CONCLUSIONS: Quantitative analysis of ICG fluorescence angiography proved useful for detecting venous anastomotic failure of FJG, and may help to reduce vascular problems in FJG reconstruction.

Laparoscopic narrow-band imaging for the diagnosis of peritoneal metastasis in gastric cancer.

BACKGROUND: Staging laparoscopy (SL) is often used to diagnose peritoneal metastasis in patients with advanced gastric cancer, but accurate detection of metastasis can be difficult. We evaluated the usefulness of laparoscopic narrow-band imaging (NBI) versus conventional laparoscopic white-light imaging (WLI) for the diagnosis of peritoneal metastasis. METHODS: We excised 37 white nodules from the parietal peritoneum of 26 patients with gastric cancer and suspected peritoneal metastasis. The WLI and NBI findings were compared with the pathological findings. All the peritoneal lesions examined were observed as white nodules on WLI. Intranodular vessels were evaluated by WLI and NBI for (1) vessel dilatation, (2) vessel tortuousness, (3) vessel heterogeneity, and (4) brown spots. RESULTS: Each individual abnormal finding had a diagnostic accuracy of less than 79 % with or without NBI. Detection of any one abnormal finding had a sensitivity, specificity, and accuracy of 47.8, 85.7, and 62.2 %, respectively, on WLI and 91.3, 71.4, and 83.8 %, respectively, on NBI, for detection of peritoneal metastasis. Detection of any one abnormal finding on NBI plus clear demarcation of the nodule on WLI had a sensitivity of 91.3 %, specificity of 92.9 %, and accuracy of 91.9 % for detection of peritoneal metastasis. Pathological examination showed that a brown spot detected on NBI correlated with dilated vessels around cancer cells. Vascular endothelial growth factor was expressed in 76.2 % of peritoneal metastases. CONCLUSIONS: NBI was more sensitive for the detection of dilated vessels than WLI. NBI could be a useful tool for the diagnosis of peritoneal metastasis during SL.

Anti-VEGF antibody therapy induces tumor hypoxia and stanniocalcin 2 expression and potentiates growth of human colon cancer xenografts.

Tumor angiogenesis plays a critical role in colorectal cancer progression. Recent randomized clinical trials have revealed the additive effect of bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF)-A, to conventional chemotherapy in the improved survival of patients with metastatic colorectal cancer. However, a number of preclinical reports indicate the development of resistance to anti-angiogenic therapy. In this study, we addressed the effects of anti-VEGF antibodies on the growth and malignant behavior of colorectal cancer cells. TK-4, a solid tumor strain derived from a colon cancer patient, was subcutaneously or orthotopically implanted into nude mice. Short-term administration of anti-VEGF antibodies inhibited the growth of cecal tumors at day 14 by suppressing mitosis, but prolonged treatment resulted in the recovery of cellular proliferation and suppression of apoptosis at day 35. Intratumoral hypoxia induced by anti-VEGF antibody treatment resulted in activation of hypoxia inducible factor-1α protein and an increased number of aldehyde dehydrogenase 1-positive tumor cells. In microarray analysis, stanniocalcin 2 (STC2) was the most highly upregulated gene in anti-VEGF antibody-treated tumors. In vitro analyses showed that the growth and migration of SW480 colon cancer cells under hypoxic conditions were significantly inhibited by knockdown of STC2. In vivo serial transplantation of TK-4 revealed that long-term administration of anti-VEGF antibodies increased the tumorigenicity of colon cancers and accelerated tumor growth when transplanted into secondary recipient mice. Our data provide a potential molecular explanation for the limited clinical effectiveness of anti-VEGF antibodies.

Mesenteric paraganglioma: Report of a case.

We report a rare case of paraganglioma that developed in the mesentery of terminal ileum. A 78-year-old woman complained of right-sided abdominal pain. Abdominal computed tomography revealed a solid heterogeneously enhanced mass in the right lower abdomen. The tumor was laparoscopically excised. The mesenteric tumor was well circumscribed, ovoid, and encapsulated and measured 3 cm × 1.5 cm × 1.5 cm. Histological examination showed a cellular neoplasm comprised of nests and groups of tumor cells separated by fibrovascular connective tissue, giving a characteristic nested Zellballen pattern. Immunohistochemically, the tumor cells were positive for chromogranin, synaptophysin, CD56, and vimentin and negative for cytokeratins, SMA, CD34, CD117/c-kit and S100. On the basis of histologic and immunohistochemical features, a diagnosis of mesenteric paraganglioma was made. The operative and postoperative courses were unremarkable, and the patient was discharged on postoperative day 7. She was doing well 1 year after the surgery with no signs of recurrence. Extra-adrenal paragangliomas most commonly develop adjacent to the aorta, particularly the area corresponding to the organ of Zuckerkandl. Mesenteric paraganglioma, as in our case, is extremely rare; only 11 cases have been reported in the literature. We herein discuss the clinical findings of these cases.

Effect of miR-122 and its target gene cationic amino acid transporter 1 on colorectal liver metastasis.

Control of liver metastasis is an important issue in the treatment of colorectal cancer (CRC). MicroRNAs have been shown to be involved in the development of many cancers, but little is known about their role in the process of colorectal liver metastasis. We compared miRNA expression between primary colorectal tumors and liver metastasis to identify those involved in the process of metastasis. Cancer cells were isolated from formalin-fixed paraffin-embedded primary CRC samples and their corresponding metastatic liver tumors in six patients using laser capture microdissection, and miRNA expression was analyzed using TaqMan miRNA arrays. The most abundant miRNA in liver metastasis compared with primary tumors was miR-122. Immunohistochemical analysis revealed that the expression levels of cationic amino acid transporter 1 (CAT1), a negative target gene of miR-122, were lower in liver metastases than primary tumors (P < 0.001). Expression levels of CAT1 in 132 primary tumors were negatively correlated with the existence of synchronous liver metastasis (P = 0.0333) and tumor stage (P < 0.0001). In an analysis of 121 colon cancer patients without synchronous liver metastasis, patients with CAT1-low colon cancer had significantly shorter liver metastasis-free survival (P = 0.0258) but not overall survival or disease-free survival. Overexpression of miR-122 and concomitant suppression of CAT1 in the primary tumor appears to play important roles in the development of colorectal liver metastasis. Expression of CAT1 in the primary CRC has the potential to be a novel biomarker to predict the risk of postoperative liver metastasis of CRC patients.

Attenuation of axonal injury and oxidative stress by edaravone protects against cognitive impairments after traumatic brain injury.

Traumatic axonal injury (TAI), a feature of traumatic brain injury (TBI), progressively evolves over hours through impaired axonal transport and is thought to be a major contributor to cognitive dysfunction. In spite of various studies suggesting that pharmacologic or physiologic interventions might reduce TAI, clinical neuroprotective treatments are still unavailable. Edaravone, a free radical scavenger, has been shown to exert neuroprotective effects in animal models of several brain disorders. In this study, to evaluate whether edaravone suppresses TAI following TBI, mice were subjected to weight drop injury and had either edaravone (3.0mg/kg) or saline administered intravenously immediately after impact. Axonal injury and oxidative stress were assessed using immunohistochemistry with antibodies against amyloid precursor protein, a marker of impaired axonal transport, and with 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage. Edaravone significantly suppressed axonal injury and oxidative stress in the cortex, corpus callosum, and hippocampus 24h after injury. The neuroprotective effects of edaravone were observed in mice receiving 1.0, 3.0, or 10mg/kg of edaravone immediately after impact, but not after 0.3mg/kg of edaravone. With treatment 1h after impact, axonal injury was also significantly suppressed and this therapeutic effect persisted up to 6h after impact. Furthermore, behavioral tests performed 9 days after injury showed memory deficits in saline-treated traumatized mice, which were not evident in the edaravone-treated group. These results suggest that edaravone protects against memory deficits following TBI and that this protection is mediated by suppression of TAI and oxidative stress.

Usefulness of three-dimensional angiographic analysis of perigastric vessels before laparoscopic gastrectomy.

BACKGROUND: Recognition of perigastric vessel anatomy is important to safely perform gastric surgery, especially in the case of laparoscopic gastrectomy. This study was designed to reevaluate the efficacy of preoperative three-dimensional (3D) angiography reconstructed from enhanced multidetector-row computed tomography (MDCT) data and to classify right gastric artery (RGA) branching patterns. METHODS: Perigastric vessel anatomy was preoperatively analyzed using MDCT-based 3D angiography reconstructed by computer software in patients undergoing laparotomic (n = 75) and laparoscopic (n = 25) gastrectomy. Results were compared with intraoperative findings in all cases, and were also compared with maximum intensity projection (MIP) imaging, which is similar to conventional angiography, in 10 patients. RESULTS: Preoperative diagnoses by 3D angiography were identical to intraoperative findings. The rates of branching patterns of the celiac artery and left gastric vein were comparable with previous reports. The detection rate of the right gastric artery (RGA) was 77.0%. Branching patterns of the hepatic artery were classified into four types: right hepatic artery (RHA) + left hepatic artery (LHA) type, replaced RHA + LHA type, RHA + replaced LHA type, and replaced RHA + replaced LHA type. RGA ramification patterns were classified into three types according to hepatic arterial running patterns: distal (68.8%), proximal (14.3%), and caudal (16.9%). Because of vessel overlapping, RGA ramified points were misdiagnosed under MIP images in two of ten cases (20%). CONCLUSIONS: Preoperative 3D angiography is useful for a new system of classifying RGA ramification patterns into three types. With this system, surgeons can perform laparoscopic gastrectomy with lymph node dissection more safely.

Rapid relapse after resection of a sunitinib-resistant gastrointestinal stromal tumor harboring a secondary mutation in exon 13 of the c-KIT gene.

We describe a case with rapid relapse after resection of a sunitinib-resistant gastrointestinal stromal tumor (GIST). Liver metastases and foci of left retroperitoneal recurrence developed during adjuvant imatinib treatment. The tumors did not shrink after sunitinib treatment, and hepatectomy and retroperitoneal tumorectomy were performed. Histological examination showed a Ki67 labeling index of over 50% in viable tumor cells. Genomic analysis revealed mutations in exons 11 and 13 of the c-KIT gene. Computed-tomographic scan revealed retroperitoneal recurrence at the surgical site five weeks post-operatively. In this case, high proliferative activity of the recurrent foci was associated with resistance to sunitinib and rapid recurrence during the perioperative withdrawal of sunitinib. It is important to consider the possibility of an exon 13 mutation with an aggressive phenotype when treating sunitinib-resistant GISTs. Surgical intervention for sunitinib-resistant GISTs should be carefully considered if R0 resection is not possible.

Near-infrared multichannel Raman spectroscopy with a 1064 nm excitation wavelength for ex vivo diagnosis of gastric cancer.

BACKGROUND: Gastric cancer is one of the major causes of death in Japan. We have previously reported, using biopsy specimens, the usefulness of the 1064 nm near-infrared multichannel Raman spectroscopy (RAS) system as a novel diagnostic modality for gastric cancer. However, our study might not have reflected in vivo use of RAS due to a lack of tissue other than the mucosal layer in the biopsy specimens. Here, we used RAS ex vivo for optical diagnosis of gastric cancer in surgically resected stomach. MATERIALS AND METHODS: A total of 213 Raman spectra were obtained from 12 cancer lesions and their corresponding non-neoplastic areas in 10 stomachs following resection for gastric cancer. To develop optical diagnostic systems for gastric cancer, principal component analysis (PCA) of all the Raman spectra was performed. RESULTS: The averaged Raman spectra of the cancer lesions could be distinguished from those of the non-neoplastic regions. Discrimination analysis of cancer from non-neoplastic regions with 10 principal components revealed that sensitivity, specificity, and accuracy of cancer diagnosis were 73%, 73%, and 72%, respectively. RAS discriminated between differentiated and undifferentiated cancers, early and advanced cancers, as well as T1a (M) and T1b (SM) cancers with high accuracy (98%, 93%, and 98%, respectively). CONCLUSIONS: The 1064 nm near-infrared multichannel RAS system is useful not only for gastric cancer detection, but also for discrimination between differentiated and undifferentiated, as well as early and advanced cancers. RAS could help establish indications for endoscopic treatment by eliminating cancer lesions with an undifferentiated component or submucosal invasion.

Surgical intervention for imatinib and sunitinib-resistant gastrointestinal stromal tumors.

Imatinib mesylate is an effective treatment for recurrent or metastatic gastrointestinal stromal tumors (GISTs), but secondary resistance has been reported. The tyrosine kinase inhibitor sunitinib malate has shown efficacy in imatinib-resistant GISTs, and has been used as second-line therapy for recurrent or metastatic GISTs. However, it is often difficult to treat patients with imatinib- and sunitinib-resistant GISTs. In this report, we describe a case of surgically resected liver and peritoneal recurrences of GISTs that arose polyclonally and were resistant to imatinib and sunitinib. A 67-year-old man was referred to our hospital with multiple recurrent GISTs after failed imatinib treatment. Sunitinib was administered at 50 mg/day for 4 weeks with 2-week intervals between treatments. Some of the recurrent GISTs were sensitive, but others were resistant, and progressive disease was diagnosed. Extended left hepatectomy and peritoneal tumorectomy were performed. Histologically, tumors sensitive to sunitinib showed degenerative changes, while the resistant tumors consisted of KIT-positive, viable GIST cells. The primary mutation in all the tumors consisted of a deletion at nucleotides 555-560 with an E554D point mutation at exon 11 of the c-kit gene. The sunitinib-resistant liver and peritoneal tumors had different point mutations: T to G and T to A, respectively, although both resulted in an N822K amino acid alteration, indicating the polyclonal evolution of recurrent GISTs. Thus, if R0 resection is expected, surgical intervention under the control of imatinib or sunitinib should be considered for the control of metastatic or recurrent GISTs.

Microarray analysis identifies versican and CD9 as potent prognostic markers in gastric gastrointestinal stromal tumors.

Although the main cause of gastrointestinal stromal tumor (GIST) is gain-of-function mutations in the c-kit gene in the interstitial cells of Cajal, concomitant genetic or epigenetic changes other than c-kit appear to occur in the development of metastasis. We sought to identify the genes involved in the metastatic process of gastric GIST. Microarray analysis was performed to compare gene expressions between three gastric GIST and four metastatic liver GIST. Expression levels were higher for 165 genes and lower for 146 genes in metastatic liver GIST. The upregulation of five oncogenes and downregulation of four tumor suppressor genes including versican and CD9 were confirmed by quantitative reverse transcriptional PCR. Immunohistochemistry in 117 GIST revealed that protein levels of versican and CD9 were higher and lower, respectively, in metastatic GIST. High expression of versican and low expression of CD9 in 104 primary gastric GIST correlated with poor disease-free survival (P = 0.0078 and P = 0.0018). In addition to the c-kit gene mutation, genetic or epigenetic changes other than c-kit play important roles in the metastatic process. In particular, versican and CD9 are potential prognostic markers in gastric GIST.

Recent concepts of antiangiogenic therapy.

In 2004, a randomized, controlled phase III clinical trial showed that the addition of bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF)-A, to conventional chemotherapy prolonged the survival of patients with metastatic colorectal cancer. A number of clinical trials are presently underway to test the utility of several angiogenic inhibitors against a variety of malignancies. The original concept of antiangiogenic therapy was the inhibition of outgrowth of new blood vessels; however, it soon became evident that bevacizumab could affect the vasculature through various mechanisms. Recent studies have shown that antiangiogenic agents can normalize the tumor vasculature and prevent the recruitment of endothelial progenitor cells from the bone marrow. Some preclinical studies have also shown that antiangiogenic agents prevent metastasis by modulating the premetastatic niche. Understanding these detailed mechanisms provides the rationale for combination therapy using antiangiogenic agents and cytotoxic chemotherapy, and will lead to more effective treatment strategies. In this review, we summarize the present understanding of the mechanisms of action of antiangiogenic agents and discuss the future prospects of antiangiogenic therapies.