Micro-morphological feature visualization, auto-classification, and evolution quantitative analysis of tumors by using SR-PCT.

Tissue micro-morphological abnormalities and interrelated quantitative data can provide immediate evidences for tumorigenesis and metastasis in microenvironment. However, the multiscale three-dimensional nondestructive pathological visualization, measurement, and quantitative analysis are still a challenging for the medical imaging and diagnosis. In this work, we employed the synchrotron-based X-ray phase-contrast tomography (SR-PCT) combined with phase-and-attenuation duality phase retrieval to reconstruct and extract the volumetric inner-structural characteristics of tumors in digesting system, helpful for tumor typing and statistic calculation of different tumor specimens. On the basis of the feature set including eight types of tumor micro-lesions presented by our SR-PCT reconstruction with high density resolution, the AlexNet-based deep convolutional neural network model was trained and obtained the 94.21% of average accuracy of auto-classification for the eight types of tumors in digesting system. The micro-pathomophological relationship of liver tumor angiogenesis and progression were revealed by quantitatively analyzing the microscopic changes of texture and grayscale features screened by a machine learning method of area under curve and principal component analysis. The results showed the specific path and clinical manifestations of tumor evolution and indicated that these progressions of tumor lesions rely on its inflammation microenvironment. Hence, this high phase-contrast 3D pathological characteristics and automatic analysis methods exhibited excellent recognizable and classifiable for micro tumor lesions.

Diagnosis and prognostic significance of extramural venous invasion in neuroendocrine tumors of the small intestine.

Extramural venous invasion (EMVI) is an established independent prognostic factor in colorectal carcinoma where it is linked to hematogenous spread (i.e., liver metastases), influencing the decision for adjuvant chemotherapy. However, its prognostic significance in small intestinal neuroendocrine tumors (NETs) has not been studied, nor is it routinely assessed or reported. We reviewed primary small bowel NETs (14 jejunum, 82 ileum, 8 not specified) from 104 patients (52 women; median age 60.5, range: 24-84). EMVI was identified in 58 cases (55.8%), including in 13 of 21 equivocal cases using an elastin stain. In univariate analysis, EMVI was associated with lymphovascular and perineural invasion, tumor stage, and lymph node and distant metastases, whereas in multivariate analysis, only distant metastases remained significant (p < 0.001). Liver metastases were present in 55 cases (52.9%) and were significantly associated in univariate analysis with lymphovascular and perineural invasion, tumor stage, lymph node metastases, and EMVI, whereas in multivariate analysis, only EMVI remained significant (p < 0.001; odds ratio (OR) = 59.42). Eight patients developed metachronous liver metastases during follow-up (mean 22.9 ± 22.0 months, range: 4.7-73.2) and all (100%) were positive for EMVI. In contrast, of 49 patients who never developed liver metastases over significantly longer follow-up (mean 71.0 ± 32.4 months, range: 6.6-150.4; p < 0.001), only 7 (14.3%) had EMVI (p < 0.001). In Kaplan-Meier analysis, 8 of 15 patients with EMVI (53.3%) developed metachronous liver metastases, compared with 0 of 42 patients without EMVI (p < 0.001). In contrast, nonhepatic distant metastases, seen in 26 (25.0%) patients, were not associated with EMVI in multivariate or Kaplan-Meier analyses. Our data demonstrate that EMVI is common in small bowel NETs and strongly correlates with development of liver metastases. Therefore, its evaluation is critical and should be assessed in combination with adjuvant techniques such as elastin staining, if necessary. Moreover, inclusion of EMVI in pathology reporting guidelines should be considered.

Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling.

Therapeutic targeting of tumor angiogenesis with VEGF inhibitors results in demonstrable, but transitory efficacy in certain human tumors and mouse models of cancer, limited by unconventional forms of adaptive/evasive resistance. In one such mouse model, potent angiogenesis inhibitors elicit compartmental reorganization of cancer cells around remaining blood vessels. The glucose and lactate transporters GLUT1 and MCT4 are induced in distal hypoxic cells in a HIF1α-dependent fashion, indicative of glycolysis. Tumor cells proximal to blood vessels instead express the lactate transporter MCT1, and p-S6, the latter reflecting mTOR signaling. Normoxic cancer cells import and metabolize lactate, resulting in upregulation of mTOR signaling via glutamine metabolism enhanced by lactate catabolism. Thus, metabolic symbiosis is established in the face of angiogenesis inhibition, whereby hypoxic cancer cells import glucose and export lactate, while normoxic cells import and catabolize lactate. mTOR signaling inhibition disrupts this metabolic symbiosis, associated with upregulation of the glucose transporter GLUT2.

[FIRST EXPERIENCE OF APPLICATION OF TECHNOLOGY OF A TWO-STREAM LOW-FREQUENCY ULTRASOUND TECHNOLOGY IN ABDOMINAL SURGERY].

Biophysical peculiarities of action on tissues of a two-strem low-frequency ultrasound (TSLFU) technology, elaborated by "Arobella Medical LLC" (USA) firm, were studied. Capacity of ultrasound to separate a pathologically-changed and healthy tissues, to divide the structures in accordance to their bioacoustical parameters constitutes the technology peculiarities. The presence of such a biophysical effect permits to achieve high resectability (R0) in patients with oncological diseases. Antibacterial effect and stimulation of intraorgan microcirculation with ultrasound irradiation were noted. Biophysical peculiarities of TSLFU were successfully applied in surgical treatment of 48 patients, suffering inflammatory and oncological diseases of the abdominal cavity organs.

Inhibition of intestinal adenoma formation in APC(Min/+) mice by Riccardin D, a natural product derived from liverwort plant Dumortiera hirsuta.

BACKGROUND: Mutation of tumor suppressor gene, adenomatous polyposis coli (APC), is the primary molecular event in the development of most intestinal carcinomas. Animal model with APC gene mutation is an effective tool for study of preventive approaches against intestinal carcinomas. We aimed to evaluate the effect of Riccardin D, a macrocyclic bisbibenzyl compound, as a chemopreventive agent against intestinal adenoma formation in APC(Min/+) mice. METHODS: APC(Min/+) mice were given Riccardin D by p.o. gavage for 7 weeks. Mice were sacrificed, and the number, size and histopathology of intestinal polyps were examined under a microscope. We performed immunohistochemical staining, western blotting, reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) in intestinal polyps to investigate the mechanism of chemopreventive effect of Riccardin D. RESULTS: Riccardin D treatment resulted in a significant inhibition of intestinal adenoma formation, showing a reduction of polyp number by 41.7%, 31.1% and 44.4%, respectively, in proximal, middle and distal portions of small intestine. The activity of Riccardin D against polyp formation was more profound in colon, wherein Riccardin D decreased polyp number by 79.3%. Size distribution analysis revealed a significant reduction in large-size polyps (2-3 mm) by 40.0%, 42.5% and 33.3%, respectively, in proximal, middle and distal portions of small intestine, and 77.8% in colon. Histopathological analysis of the intestinal polyps revealed mostly hyperplastic morphology without obvious dysplasia in Riccardin D-treated mice. Molecular analyses of the polyps suggested that the inhibitory effect of Riccardin D on intestinal adenoma formation was associated with its abilities of reduction in cell proliferation, induction of apoptosis, antiangiogenesis, inhibition of the Wnt signaling pathway and suppression of inflammatory mediators in polyps. CONCLUSIONS: Our results suggested that Riccardin D exerts its chemopreventive effect against intestinal adenoma formation through multiple mechanisms including anti-proliferative, apoptotic, anti-angiogenic and anti-inflammatory activity.

The role of color histograms in predicting the prognosis of patients with digestive tract adenocarcinoma.

OBJECTIVES: To establish the correlation between the degree of vascularisation detected using power Doppler ultrasonography in digestive tract adenocarcinoma and the prognosis of these patients. MATERIAL AND METHOD: Ultrasonography was performed in 45 patients diagnosed with digestive tract adenocarcinoma (16 stomach-35.6%, 6 cecum and ascending colon-13.3%, 2 transverse colon-4.4%, 5 descending colon 11.1%, 13 sigmoid colon-28.9%, and 3 rectum-6.7%). The degree of maximum tumor vascularization was determined using the highest percentage of colored pixels obtained in the histogram- maximum color pixels density (MCPD). The hepatic Doppler perfusion index (HDPI) was also calculated. The presence and development of liver metastases was evaluated by ultrasonography and computed tomography. The patients were monitored for a period of 18 months. The results of each method in detecting and predicting the development of liver metastases were compared. RESULTS: MCPD and HDPI had fairly similar results (p>0.05) in establishing the positive and negative predicting values for the entire group of patients with liver metastasis (55.9% compared to 66.7%, p>0.05, and 53.3%, compared to 54.6%, p>0.05) and the group that developed liver metastases during follow-up (80.0% compared to 90.0%, p>0.05, and 61.5%, compared to 75.0%, p>0.05). When comparing MCPD and HDPI for the group of patients who had or developed metastases, MCPD had an equal sensitivity (86.4%, compared to 90.9%, p >0.05), a higher specificity (65.0% compared to 46.5%, p<0.05), but a lower accuracy (60.0% compared to 73.3%, p<0.05). In detecting patients who developed metastases during the 18 months follow-up, MCPD had a superior sensitivity (85.7% compared to 64.3%, p<0.05), a lower specificity (66.7% compared to 88.9%, p<0.05) and an equal accuracy (78.3% vs. 73.9%, p >0.05.). CONCLUSIONS: The calculation of MCPD using color histograms can be a simple and quick method in the evaluation and prognosis of patients with digestive tract adenocarcinoma.

Metronomic dosing enhances the anti-angiogenic effect of epothilone B.

BACKGROUND: High doses (10 nM) of epothilone B, a microtubule stabilizer, will inhibit the development of human tumor-derived angiogenesis following short (14 d) drug exposure times. Metronomic dosing regimes use lower drug doses and prolonged drug exposure times in an attempt to decrease toxicity compared with standard dosing schedules. We hypothesized that epothilone B would be an effective anti-angiogenic agent when administered at very low doses over an extended period of time. METHODS: Fragments of four fresh human tumors were cultured in a fibrin-thrombin matrix and maintained in nutrient media plus 20% fetal bovine serum (FBS) for 56 d. Tumor fragments (n=40-60 per group) were exposed to weekly doses of epothilone B at concentrations of 10, 5, 1, 0.5, or 0.1 nM. All of these concentrations are clinically achievable. Tumor angiogenesis was assessed weekly on d 14-56 using a validated visual grading system. This system rates neovessel growth, density, and length on a 0-16 scale [angiogenic index, (AI)]. The average change in AI between d 14 and 56 was calculated for all samples and used to evaluate the metronomic response. RESULTS: Epothilone B produced a dose-dependent anti-angiogenic response in all tumors. Two of the four tumors demonstrated a clear and significant metronomic anti-angiogenic effect over time. CONCLUSIONS: Epothilone B, when dosed by a metronomic schedule may have a significant anti-angiogenic effect on human solid tumors. This study provides evidence for the potential use of epothilone B on a metronomic dosing schedule.

Infiltration of thymidine phosphorylase-positive macrophages is closely associated with tumor angiogenesis and survival in intestinal type gastric cancer.

Thymidine phosphorylase (TP), an enzyme catalyzing the reversible phospholysis of thymidine, deoxyuridine and their analogs at their respective bases and 2-deoxyribose-1-phosphate, thus promoting angiogenesis, is often expressed in macrophages present in tumor stroma. In this study, we investigated whether infiltration of TP-positive macrophages as well as tumor-associated macrophages affected tumor angiogenesis. TP was expressed in human macrophage-like cells, but not in gastric cancer cells in culture. The expression level of TP, the number of infiltrating CD68+ and CD163+ macrophages, and microvessel density (MVD) in the tumor were further analyzed by immunohistochemistry in 111 patients with gastric cancer. Biostatistical analysis of digitized data obtained by image analysis showed that TP expression was significantly correlated with the number of infiltrating macrophages and MVD in intestinal type gastric cancer (p<0.05). The number of infiltrating macrophages was also correlated with MVD in both the intestinal and diffuse types (p<0.05). An increased number of CD68+ macrophages was significantly associated with poor outcome in patients with intestinal type (p<0.001), but not diffuse type cancer. TP could be a specific marker enzyme that is expressed in tumor-infiltrating macrophages, being associated with tumor angiogenesis and poor prognosis in patients with intestinal-type gastric cancer.

Increased angiogenesis in Cdk4(R24C/R24C):Apc(+/Min) intestinal tumors.

Cyclin dependent kinase 4 (Cdk4) is a cell cycle regulator involved in early G1 cell cycle progression and has been indirectly implicated in angiogenesis in the Min mouse system, a mouse that harbors a mutation in the Apc gene. Apc(+/Min) mice when crossed with Ink4a/arf-/- mice, exhibited increased angiogenesis of colorectal tumors suggesting that dysregulation of Cdk4 (due to loss of Ink4a-mediated suppression) may contribute to enhanced angiogenesis. To demonstrate a direct role for Cdk4 in angiogenesis, we crossed mice that have an activated Cdk4, Cdk4(R24C/R24C) mice, with Apc(+/Min) mice and examined levels of angiogenesis in intestinal tumors formed. Our results show an increase in the percentage of highly vascularized tumors in Cdk4(R24C/R24C):Apc(Min/+) and Cdk4(+/R24C):Apc(Min/+) mice compared to Cdk4(+/+):Apc(Min/+) mice. In addition immunohistochemical analysis showed an increase in CD-31 staining localized to endothelial cells of Cdk4(R24C/R24C):Apc(Min/+) mouse tumors, supporting the hypothesis of increased vasculature in these tumors. Further analysis showed an increase in the expression of the E2F1 target proteins Vegf-b and Cyclin A in Cdk4(R24C/R24C):Apc(+/Min) intestinal tumors. Together these data suggest that the dysregulated Cdk4 gene plays an important role in angiogenesis during intestinal tumor formation and may in part act via increasing E2F1 target proteins. This is the first report to show that Cdk4 has a direct role in angiogenesis in vivo and may be an important drug target to reduce or prevent angiogenesis during intestinal tumor formation.

[Tumors of the lower gastrointestinal tract : Indication and extent of lymph node dissection]. / Tumoren des unteren Gastrointestinaltrakts : Indikation und Ausmass der Lymphknotendissektion.

Lymph node dissection is almost always indicated in the treatment of advanced colorectal carcinoma with curative intent. Investigation of at least 12 regional lymph nodes is required for adequate staging. The extent and quality of lymph node dissection influence the long-term prognosis, especially locoregional recurrences and long-term survival. The extent of lymphadenectomy depends on the tumour site and the pattern of potential lymphatic spread following the course of the blood vessels supplying the tumour. Important principles are central ligation of the supplying arteries and draining veins right at their roots, preservation of autonomous nerves at the trunk of the superior mesenteric artery and the aorta and preservation of the integrity of the mesocolon or mesorectum. The number of regional lymph nodes examined as well as the number of lymph nodes with metastases influence the prognosis. Systematic lymph node dissection is also recommended for carcinomas of the small bowel and in most neuroendocrine tumours or carcinomas but is not required for gastro-intestinal stromal tumours.

Phospholipase Cepsilon promotes intestinal tumorigenesis of Apc(Min/+) mice through augmentation of inflammation and angiogenesis.

Apc(Min/+) mice, carrying an inactivated allele of the adenomatous polyposis coli gene, are widely used as an animal model for human colorectal tumorigenesis, where tumor environment, such as inflammation, is known to play a critical role in tumor progression. We previously demonstrated that phospholipase C (PLC)epsilon, an effector of Ras and Rap small GTPases, plays a crucial role in two-stage skin chemical carcinogenesis using 12-O-tetradecanoyl-phorbor-13-acetate (TPA) as a promoter through augmentation of TPA-induced inflammation. Here, we show that Apc(Min/+) mice lacking PLCepsilon (PLCepsilon(-/-)) exhibit marked resistance to spontaneous intestinal tumorigenesis compared with those with the PLCepsilon(+/+) background. Time course of the development of tumors, which are histopathologically classified into low- and high-grade adenomas with increasing dysplasia and size, and adenocarcinomas indicates that not only the low-grade adenoma formation but also the progression to high-grade adenoma are suppressed in PLCepsilon(-/-);Apc(Min/+) mice. Low-grade adenomas of PLCepsilon(-/-);Apc(Min/+) mice exhibit accelerated apoptosis and reduced cellular proliferation. They also show marked attenuation of tumor angiogenesis and reduction in expression of vascular endothelial growth factor. In contrast, high-grade adenomas of PLCepsilon(-/-);Apc(Min/+) mice exhibit marked attenuation of tumor-associated inflammation without significant differences in apoptosis and proliferation. These results suggest that PLCepsilon plays crucial roles in intestinal tumorigenesis through two distinct mechanisms, augmentation of angiogenesis and inflammation, depending on the tumor stage.

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.

Genetic deletion of mPGES-1 suppresses intestinal tumorigenesis.

Elevated levels of prostaglandin E(2) (PGE(2)) are often found in colorectal cancers. Thus, nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors, are among the most promising chemopreventive agents for colorectal cancer. However, their long-term use is restricted by the occurrence of adverse events believed to be associated with a global reduction in prostaglandin production. In the present study, we evaluated the chemopreventive efficacy of targeting the terminal synthase microsomal PGE(2) synthase 1 (mPGES-1), which is responsible for generating PGE(2), in two murine models of intestinal cancer. We report for the first time that genetic deletion of mPGES-1 in Apc-mutant mice results in marked and persistent suppression of intestinal cancer growth by 66%, whereas suppression of large adenomas (>3 mm) was almost 95%. This effect occurred despite loss of Apc heterozygosity and beta-catenin activation. However, we found that mPGES-1 deficiency was associated with a disorganized vascular pattern within primary adenomas as determined by CD31 immunostaining. We also examined the effect of mPGES-1 deletion on carcinogen-induced colon cancer. The absence of mPGES-1 reduced the size and number of preneoplastic aberrant crypt foci (ACF). Importantly, mPGES-1 deletion also blocked the nuclear accumulation of beta-catenin in ACF, confirming that beta-catenin is a critical target of PGE(2) procarcinogenic signaling in the colon. Our data show the feasibility of targeting mPGES-1 for cancer chemoprevention with the potential for improved tolerability over traditional nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors.

Blue rubber bleb nevus syndrome: manifestations at computed tomography.

Blue rubber bleb nevus syndrome (BRBNS) is a rare condition that consists of multiple venous malformations involving several organ systems, particularly the skin and the gastrointestinal tract, but any part of the body may be affected. Less than 250 cases have been reported in the literature. The authors describe the thoracic, abdominal, and pelvic imaging characteristics at computed tomography (CT) in a 50-year-old man with BRBNS.

Inhibition of VEGF-A prevents the angiogenic switch and results in increased survival of Apc+/min mice.

Anti-VEGF-A monoclonal antibodies, in combination with chemotherapy, result in a survival benefit in patients with metastatic colorectal and non-small cell lung cancer, but little is known regarding the impact of anti-VEGF-A therapy on benign or premalignant tumors. The Apc+/min mice have been widely used as a model recapitulating early intestinal adenoma formation. To investigate whether tumor growth in Apc+/min mice is mediated by VEGF-A-dependent angiogenesis, we used two independent approaches to inhibit VEGF-A: monotherapy with a monoclonal antibody (Mab) targeting VEGF-A and genetic deletion of VEGF-A selectively in intestinal epithelial cells. Short-term (3 or 6 weeks) treatment with anti-VEGF-A Mab G6-31 resulted in a nearly complete suppression of adenoma growth throughout the small intestine. Growth inhibition by Mab G6-31 was associated with a decrease in vascular density. Long-term (up to 52 weeks) treatment with Mab G6-31 led to a substantial increase in median survival. Deletion of VEGF-A in intestinal epithelial cells of Apc+/min mice yielded a significant inhibition of tumor growth, albeit of lesser magnitude than that resulting from Mab G6-31 administration. These results establish that inhibition of VEGF-A signaling is sufficient for tumor growth cessation and confers a long-term survival benefit in an intestinal adenoma model. Therefore, VEGF-A inhibition may be a previously uncharacterized strategy for the prevention of the angiogenic switch and growth in intestinal adenomas.

Genetic and pathologic characteristics of gastrointestinal stromal tumors in extragastric lesions.

The goal of this study was to investigate differences in the clinicopathologic and genetic characteristics of gastric and extragastric gastrointestinal stromal tumors (GISTs). We evaluated 13 extragastric GISTs and compared them with 56 gastric GISTs, which were described previously. DNA was extracted from paraffin-embedded tumor specimens, and exons 9, 11, 13, and 17 of the KIT gene and exons 12 and 18 of the platelet-derived growth factor receptor alpha (PDGFRA) gene were amplified by polymerase chain reaction and sequenced. Immunohistochemistry was performed for KIT, CD34, Ki-67 (as a marker of cell proliferation), and CD31 (as a marker of microvessel density), and apoptosis was assessed by in situ DNA nick end-labeling. Of the 13 extragastric GISTs 7 (54%) had a mutation in exon 11 of KIT, and 2 (15%) had a mutation in exon 13 of KIT. Deletions in exon 11 of KIT were the most common mutation encountered in the extragastric GISTs. The extragastric GISTs, especially small intestinal GISTs, showed larger deletions, leading to deletions of amino acid residues in the KIT protein, and higher vascularity than did the gastric GISTs. These data suggest that extragastric GISTs differ from gastric GISTs with respect to associated mutations and angiogenic activity.

Hypoxia-inducible factor-1alpha is associated with risk of aggressive behavior and tumor angiogenesis in gastrointestinal stromal tumor.

BACKGROUND: The objective of this study was to evaluate the relationship of HIF-1alpha expression and tumor angiogenesis, recurrence/distant metastasis, and its value in the prediction of aggressive behavior of gastrointestinal stromal tumor (GIST). METHODS: Paraffin-embedded specimens from 62 patients with GIST were divided into two groups, low risk (n = 31) and high risk (n = 31) according to the tumor size, mitotic count and proliferating cell nuclear antigen (PCNA) index. We investigated the expression of the HIF-1alpha and analyzed correlation with tumor angiogenesis monitored by expression of vascular endothelial growth factor (VEGF) and tumor microvessel density using immunohistochemical staining. The data were analyzed with chi(2) test or Fisher's exact test and multivariate test. RESULTS: There were statistically significant differences between high risk (29/31; 93.5%) and low risk (8/31; 25.8%) of GIST in high expression of HIF-1alpha (P<0.0001). In addition, the incidence of recurrence/distant metastasis was significantly higher in cases of high HIF-1alpha expression (12/35; 34.3%) than in cases of low HIF-1alpha expression (1/24; 4.2%)(P = 0.009). Moreover, high VEGF expression (37/43; 86.0%) and microvessel density (30/32; 93.8%) were significantly higher in high HIF-1alpha expression tumors than in low-expression tumors (P < 0.0001). CONCLUSIONS: Our findings suggest that HIF-1alpha may play an important role in aggressive behavior and tumor angiogenesis in GIST. In addition, high expression of HIF-1alpha was significantly correlated with tumor recurrence/distant metastasis, so it may provide an ancillary prognostic factor for GIST.

Levels of angiogenic peptides in sera from patients with carcinoid tumours during alpha-interferon treatment.

BACKGROUND: Alpha-interferon, a known inhibitor of angiogenesis and cell proliferation, is used in the standard treatment of patients with carcinoid tumors. We studied the levels of two angiogenic peptides (bFGF and VEGF) in sera from patients with carcinoid tumours before and during treatment with alpha-interferon. The aim was to investigate if the antitumoral effect of alpha-interferon in these patients could be at least in part explained by a reduction in the measured angiogenetic peptides. PATIENTS AND METHODS: Sera from 29 patients with carcinoid tumours were collected before and during alpha-interferon treatment and analyzed using commercially available ELISA-kits. RESULTS: Interferon alpha treatment did not cause reduction of bFGF and VEGF levels in serum from patients with carcinoid tumours. In fact there was no correlation between changes in bFGF or VEGF levels and treatment effect. CONCLUSION: The action of alpha-interferon does not seem to be mediated by bFGF or VEGF in patients with carcinoid tumours. If alpha-interferon has an anti-angiogenic effect in this patient group, it is probably mediated by angiogenic peptides other than bFGF and VEGF.

Inhibition by ginsenoside Rg3 of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats.

The effects of concomitant use of bombesin and ginsenoside Rg3 on the incidence of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane were investigated in male inbred Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of azoxymethane (7.4 mg/kg body weight) for 10 weeks and s.c. injection of bombesin (40 microg/kg body weight) every other day, and from week 20, s.c. injections of ginsenoside Rg3 (2.5 or 5.0 mg/kg body weight) every other day until the end of the experiment in week 45. Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal cancers. Although administration of a higher dose of ginsenoside Rg3 with bombesin had little or no effect on the enhancement of intestinal carcinogenesis by bombesin, the location, histologic type, depth of involvement, infiltrating growth pattern, labeling and apoptotic indices and tumor vascularity of intestinal cancers, it significantly decreased the incidence of cancer metastasis. These findings indicate that ginsenoside Rg3 inhibits cancer metastasis through activities that do not affect the growth or vascularity of intestinal cancers.

Long-term survival after embolization of potentially lethal bleeding malignant pelvic tumours.

Transcatheter embolization was performed in 45 patients suffering from potentially lethal bleeding originating from malignant tumours in the pelvic region. In 21 cases, the basic disease was rectosigmoidal and in 20, gynaecological in origin. Uncommon bleeding sites were embolized in four other cases. The median survival time (Kaplan-Meier) was 6 months. Most patients died from tumour cachexia. In 10 cases (22%), recurrent bleeding occurred, in three of these with lethal consequences. Successful reembolization was performed on seven patients. The different embolization materials used showed a minor impact on the therapeutic result. Embolization therapy proved to be an effective measure in potentially lethal malignant pelvic bleeding. Gianturco, Anderson and Wallace (GAW) coils should be given preference where there is urgency, as they are accurate, easily and quickly insertable, and cause few complications.