Transarterial embolization of hypervascular tumors using trisacryl gelatin microspheres (Embosphere): a prospective multicenter clinical trial in Japan.

PURPOSE: To evaluate the feasibility and safety of transarterial embolization (TAE) using trisacryl gelatin microspheres (TGMs) for hypervascular tumors. MATERIALS AND METHODS: This was a prospective multicenter clinical trial involving five institutions. TAE using TGMs was performed for hypervascular tumors in various locations. The primary endpoint was the technical success. The secondary endpoints included catheter accessibility, preservation of the feeding arteries, local tumor response based on the Response Evaluation Criteria in Cancer of the Liver (RECICL) and adverse events related to TAE based on the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Twenty-three patients with liver tumors (n = 9), uterine fibroids (n = 3) and other tumors (n = 11) were enrolled. The technical success rate was 95.7 % (22 of 23 patients). Catheter accessibility and preservation of the feeding arteries were obtained in all 55 target vessels (100 %). Local tumor response rates were 46.7 and 55.8 % at 4 and 12 weeks, respectively. Eighteen (78.3 %) patients developed 53 symptomatic events including grade ≧3 events: hypertension 21.7 %, pain 8.7 %, vomiting 4.3 % and anorexia 4.3 %, all related to postembolization syndromes. CONCLUSION: TAE using TGMs was technically feasible and safe for devascularization of hypervascular tumors.

The role of hypoxia-inducible factor-2 in digestive system cancers.

Hypoxia is an all but ubiquitous phenomenon in cancers. Two known hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α, primarily mediate the transcriptional response to hypoxia. Despite the high homology between HIF-1α and HIF-2α, emerging evidence suggests differences between both molecules in terms of transcriptional targets as well as impact on multiple physiological pathways and tumorigenesis. To date, much progress has been made toward understanding the roles of HIF-2α in digestive system cancers. Indeed, HIF-2α has been shown to regulate multiple aspects of digestive system cancers, including cell proliferation, angiogenesis and apoptosis, metabolism, metastasis and resistance to chemotherapy. These findings make HIF-2α a critical regulator of this malignant phenotype. Here we summarize the function of HIF-2 during cancer development as well as its contribution to tumorigenesis in digestive system malignancies.

Mystery Story about Erythropoietin (Epo) and Erythropoietin Receptor (EpoR) are Disguised?

In this review we would like to focus our attention upon very controversial reports on Erythropoietin (Epo) and Erythropoietin Receptor (EpoR) expression in cancer patients. The effects of Epo on cancerous tissues are poorly understood. Hypoxia results in an increase in the level of the production of both Epo and EpoR via activation of the hypoxia-inducible factor 1 (HIF-1) pathway. HIF-1α, promotes the expression of vascular endothelial growth factor (VEGF). The signaling through VEGF in both a paracrine and an autocrine manner is required for the homeostasis of adult vessels. Macrophages stimulate vessel sprouting via a soluble factor other than VEGF, rather than through direct contact with endothelial cells. The intriguing questions are set about many researches to link Epo/EpoR expression and function in order to establish one of the mechanisms of tumor growth, disease progression of cancer patient. However, it is uncertain role in tumour angiogenesis as promoter and stimulator of tumour growth which should need to be furtherly validated.

Targeting the vasculature of visceral tumors: novel insights and treatment perspectives.

BACKGROUND: Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, describes a crucial process in tumor growth, disease progression, and metastasis. Therefore, the upcoming strategy of inhibiting tumor angiogenesis has generated different treatment modalities, which have been transferred into clinical practice in recent years. Currently, this concept is applied to target the vasculature of different visceral tumors and intensive clinical research has just started. MATERIALS AND METHODS: This review summarizes the modifications of systemic treatment of visceral tumors by targeting the vasculature in the past years. Moreover, novel targets and treatment strategies will be discussed to evaluate future directions. RESULTS: Leading antiangiogenic drugs combined with systemic chemotherapy have been applied with increasing success during the last years. Therefore, the concept of combining vascular targeting agents with established chemotherapeutic regimens has been increasingly adopted into the therapies of different visceral tumors. CONCLUSION: Targeting the vasculature of visceral tumors in combination with established standard tumor therapies includes major clinical potential for future therapy concepts.

Development of new drug strategies in infrequent digestive tumors: esophageal, biliary tract, and anal cancers.

PURPOSE OF REVIEW: In the last years, interesting advances have been reported in the treatment of infrequent digestive tumors. The increasing development of new targeted therapies in human cancer has also impacted in these rare gastrointestinal malignancies providing a wide range of possibilities in the design of future clinical trials. RECENT FINDINGS: The inhibition of angiogenesis and the blockage of the epidermal growth factor receptor pathway have provided the most interesting activity in recently reported studies for esophageal and biliary tract carcinomas. Additionally, several targeted therapies have been developed to target the main kinase proteins of the most important pathways of these malignancies. The results of the biggest phase III trial in locally advanced anal carcinoma have been recently published. Finally, the inhibition of epidermal growth factor receptor has also showed promising activity in anal carcinomas. SUMMARY: Recent advances in the knowledge of molecular mechanism of carcinogenesis have led to meaningful changes in the management of gastrointestinal cancers. Although the major advances in targeted therapy have been introduced in the treatment of colorectal cancer, new interesting approaches have been reported in less frequent gastrointestinal tumors such as esophageal, biliary tract, and anal canal carcinoma opening a new hope in the treatment of these rare tumors in the molecular targeted therapy era.

[Contrast medium sonography of neuroendocrine tumors of the gastroenteropancreatic system]. / Kontrastmittelsonographie neuroendokriner Tumoren des gastroenteropankreatischen Systems.

Ultrasonography is at present the primary diagnostic imaging method in patients with abdominal complaints. The innovations in echo enhancers in the last decade in connection with improved software and hardware have substantially extended the diagnostic spectrum of ultrasonography. Thus contrast-enhanced sonography with pulse inversion technology at low mechanical index allows a continuous evaluation of the perfusion of organs and tumors. Neuroendocrine tumors represent a heterogeneous group of endodermal/epithelial tumors, which are often hypervascularized. The morphology and the perfusion behavior of neuroendocrine tumors should be known because the therapeutic options differ substantially from those of other tumors. Contrast-enhanced sonography has already proven to be a valuable alternative in the diagnosis of neuroendocrine neoplasms and their metastases in relation to the established radiological procedures.

[Arterial embolization of hepatic metastases from neuroendocrine tumors]. / Arterielle Embolisation von Lebermetastasen neuroendokriner Tumoren.

Neuroendocrine tumors are slowly growing neoplasms and 75% of patients already present with hepatic metastases at the time of diagnosis. Size and growth of liver metastases is of prognostic value. Due to arterial vascularization of metastases, transarterial embolization (TAE) is a suitable procedure, which can also be combined with chemotherapeutic agents. Indications for embolization or chemoembolization (TACE) are growth of liver metastases or inadequate symptom control. The majority of patients show clinical improvement and partial remission can be achieved in 50% of cases with 5-year survival rates of 50-60%. Response rates, survival or complications are not dependent on the embolization technique (TAE or TACE). Embolization is usually performed in several sessions depending on individual tumor stage and disease progression. Embolization is a cost-effective procedure and is included in the treatment algorithm of international guidelines. Therefore, evaluation of new embolization therapies must be evaluated in randomized controlled studies.

Angiogenesis and tumor progression in neuroendocrine digestive tumors.

BACKGROUND: Clinical observations suggest that in neuroendocrine digestive tumors a high intratumoral microvascular density is associated with good prognosis. We used an experimental orthotopic xenograft model to analyze the relations between angiogenic activity and tumor progression in this tumor subset. MATERIAL AND METHODS: We compared 2 endocrine cell lines: STC-1, a low vascular endothelial growth factor (VEGF)-producing cell line, and INS-r3, a high VEGF-producing cell line. Tumor cells were grafted in the adventitial layer of the caecal wall of nude mice, sacrificed after 8 wk. RESULTS: At 8 wk, "primary" tumors were present in all animals. STC-1 derived tumors were morphologically moderately differentiated, with high proliferative and apoptotic activities; in contrast, INS-r3 derived tumors were well differentiated, with low proliferative and apoptotic activities. VEGF was expressed in <50% grafted STC-1 cells but in >90% of grafted INS-r3 cells. Microvascular density was significantly higher in INS-r3 derived tumors than in STC-1 derived tumors. All STC-1 derived tumors (n = 8) have invaded the mucosa, in contrast to none of the INS-r3 derived tumors (n = 8); liver metastases were detected in 7/8 animals bearing STC-1 derived tumors and in 0/8 animals with INS-r3 derived tumors, despite the presence of lymph node metastases. CONCLUSIONS: Our experimental data concur with clinical findings to suggest that in well differentiated digestive neuroendocrine tumors angiogenesis is disconnected from tumor progression: the development of a highly vascular tumor microenvironment is correlated with VEGF secretion but is not associated with invasive and metastatic properties; it must therefore be regarded as an indirect marker of differentiation.

[Vasculogenic mimicry in the bi-directional differentiation malignant tumors of digestive tract].

OBJECTIVE: To investigate whether vasculogenic mimicry (VM) exists in the bi-directional differentiation malignant tumors of digestive tract. METHODS: 111 specimens of bi-directional differentiation malignant tumors of digestive tract. including malignant gastrointestinal stromal tumors (GIST, n = 80), malignant melanoma (n = 18), and carcinosarcoma (n = 13), underwent periodic acid Schiff (PAS) staining and microscopy. Immunohistochemistry was used to examine the expression of vascular endothelial growth factor (VEGF), and CD31. Microvascular density (MVD) and vasculogenic mimicry density (VMD) were calculated. RESULTS: PAS-positive patterned matrix-associated vascular channels with red blood cells therein were detected in 39.1% (31.5/111) of the tumor samples. (89 +/- 20) and MVD (47 +/- 12) both lower than without VM (76, 126 +/- 18, 78 +/- 13, all P < 0.05) the expression levels of VEGF and MVD in the tumors containing patterned channels were (89 +/- 20) and MVD (47 +/- 12) respectively, both significantly lower than those in the tumors without VM [(126 +/- 18) and (78 +/- 13) respectively, both P < 0. 05]. The higher the malignant degree of tumor, the higher the proportion of the tumor with VM. The levels of MVD and VMD of the GIST, malignant melanoma, and carcinosarcoma with low malignancy were 45 +/- 19, 15 +/- 8, and 38 +/- 25 respectively, all significantly lower than those of the GIST, malignant melanoma, and carcinosarcoma with high malignancy (128 +/- 42, 81 +/- 17, 122 +/- 39, all P < 0.05). CONCLUSION: VM exists in the bi-directional differentiation malignant tumors of digestive tract. The tumor cells obtain blood supply and become metastatic via the mechanism of VM.

Can pretreatment CT perfusion predict response of advanced squamous cell carcinoma of the upper aerodigestive tract treated with induction chemotherapy?

BACKGROUND AND PURPOSE: Treatment of advanced stage squamous cell carcinoma of the upper aerodigestive tract with nonsurgical organ preservation protocols demonstrates improved cure rates with fewer comorbidities compared with surgery and radiation. The purpose of this study was to prospectively assess whether pretreatment evaluation of the primary site with quantitative CT perfusion measurements predicted response to induction chemotherapy and to create a prediction model to predict the response to induction chemotherapy in future patients. METHODS: Seventeen patients who were enrolled in a prospective trial assessing surgical intervention versus a nonsurgical protocol underwent a pretreatment CT perfusion followed by direct laryngoscopy. After induction chemotherapy, tumor response was determined by the surgeon's estimate of tumor volume. The CT perfusion parameters were correlated with the clinical response using a Wilcoxon rank-sum analysis. A logistic regression model was used to create a prediction based on the most significant CT perfusion parameter. RESULTS: Elevated values of blood volume (P = .004) and blood flow (P = .03) were significantly correlated with >50% reduction in tumor volume after chemotherapy. A prediction model based on tumor blood volume demonstrated 91.7% sensitivity and 80.0% specificity, with an area under the receiver operating characteristic curve of 0.95. CONCLUSION: Our preliminary data imply that tumors with elevated blood volume and blood flow were statistically associated with response to induction chemotherapy. These results suggest that pretreatment CT perfusion may be able to identify patients who will successfully respond to induction chemotherapy, which could potentially eliminate this step for subsequent patients when deciding on the appropriate treatment regimen.

Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features.

Angiogenesis, a process related to tumor growth and malignancy, is stimulated by several growth factors. Among these is vascular endothelial growth factor (VEGF), which acts on endothelial cells by binding with 2 specific receptors, VEGFR1 and VEGFR2. Recent studies have demonstrated that VEGF expression is correlated with microvessel density (MVD) and tumor progression. Digestive endocrine tumors are heterogeneous neoplasms exhibiting variable biological aggressiveness and behavior that often are not predictable on morphologic grounds alone. The aims of this study were to evaluate the expression of VEGF, VEGFR1, and VEGFR2 in digestive endocrine tumors and to examine its correlation with MVD and malignancy. A total of 84 specimens from endocrine neoplasms and normal gut and pancreatic tissue were immunohistochemically studied using specific antibodies directed against VEGF, VEGFR1, VEGFR2, endothelial antigens, and gastroenteropancreatic hormones. Ultrastructural immunocytochemistry was performed to identify the cellular localization of VEGF and the VEGFRs. In normal tissues, VEGF immunoreactivity was detected in G cells and PP cells. Ultrastructurally, VEGF was localized within secretory granules. The VEGFRs were not significantly expressed by normal endocrine cells. VEGF-immunoreactive (IR) cells were detected in 40 of 83 tumors, mainly G cell and enterochromaffin cell neoplasms. VEGFR1-IR cells were found in 44 of 82 tumors, and VEGFR2-IR cells were found in 55 of 82 tumors, with no predilection for any specific tumor type. The expression of VEGF and its receptors did not correlate with MVD or malignancy. These results suggest that in normal tissues, endothelial functions may be regulated by VEGF produced by some endocrine cells and that a VEGF/VEGFR binding mechanism may be involved in tumorigenesis, but not in tumor progression and aggressiveness.

Encasement and other deformations of tumor-embedded host arteries due to loss of medial smooth muscles. Morphometric and three-dimensional reconstruction studies on some human carcinomas.

Surgical materials from 20 patients with gastric carcinoma and ten with colonic carcinoma, and autopsy materials from ten patients with pancreatic carcinoma were submitted to the morphometric study of host arteries remaining in and around the tumors, to analyze whether and to what degree the smooth muscles of their media were lost. An explanation would be made of the inertia of tumor-supplying vessels based on their retarded response to vasoactive drugs. It was noted that as arteries advance from a distance toward the inside of a tumor, their media loses smooth muscles gradually, and become amuscular tubes incapable of blood flow regulation. This appears responsible for the abnormal hemodynamics of tumor tissues. Host arteries embedded in cancer were often deformed to aneurysmal or crumpled shapes; this, which also results from relaxation of atonic vessels, was considered to be the pathologic background for the unusual vascular images characteristic of cancer angiograms.

Normal anatomy of the pyloric branch and its diagnostic significance in angiography.

The course of the pyloric branch, usually arising from the distal end of the gastroduodenal artery, was investigated using angiography of 15 specimens and of 200 patients. It was found that the pyloric branch usually supplies the greater curvature of the gastric antrum and of the duodenal bulb, pylorus and the oral portion of the descending duodenum, although there may be some variations. A correct diagnosis of the primary site and extent of a malignant tumor in the gastric antrum, duodenum or pancreatic head, needs a thorough knowledge of the normal anatomy of the pyloric branch.