CXCL12 in Malignant Glial Tumors: A Possible Role in Angiogenesis and Cross-Talk between Endothelial and Tumoral Cells

CXCL12 (stromal cell-derived factor-1/CXCL12) regulates leukocyte, endothelial and hematopoietic precursor migration, bone-marrow myelopoiesis and angiogenesis. CXCL12 and its receptor CXCR4 are over-expressed in malignant gliomas, which are highly vascularized tumors with a poor prognosis. We studied the expression of CXCL12 and CXCR4 in glioma cell lines, endothelial cells, tissue sections and endocavitary fluids from patients with gliomas. We then analyzed the proliferative and the apoptotic effect of CXCL12 in endothelial cells and glioma primary cultures. We observed the release of CXCL12 in supernatants of human brain microvascular endothelial cells and at variable levels, in post-surgical endocavitary fluids. CXCL12 was expressed in both glioma and endothelial cells as assessed by immunostaining of surgical brain sections. CXCR4 was found in cells lines and primary cultures from malignant gliomas as well as in endothelial cells and was increased by vascular endothelial growth factor and basic fibroblast growth factor (bFGF). CXCL12 inhibited bFGF-induced proliferation of endothelial cells and increased the survival of endothelial cells. The survival of primary cells obtained from glioma specimens was also enhanced in the presence of CXCL12. We point out the presence and the release of CXCL12 in tumor microenvironment and we observed a modulating effect of CXCL12 on proliferation and survival of both endothelial and tumoral cells. Our data support in vivo studies suggesting a role in angiogenesis played by CXCL12, which could represent a possible prognostic factor.     

Dexamethasone Mediated Inhibition of Local IL-2 Immunotherapy is Dose Dependent in Experimental Brain Tumors

Local delivery of cytokines has been shown to have a potent anti-tumor activity against a wide range of malignant brain tumors. In this study, we examined the role of systemic immunosuppression using dexamethasone on the efficacy of local IL-2 immunotherapy in treating experimental murine CNS tumors.An endothelial cell line secreting hIL-2 (NTC-121) was injected intracranially in C57BL/6 mice (n= 10/group) along with B16/F10 (wild type) melanoma cells. A separate set of animals also received daily injections of either 1 mg/k or 10 mg/kg of dexamethasone. Sixty percent of mice treated with IL-2 (P < 0.001 vs. control) vs. 55%(P < 0.005) of mice treated with IL-2 and 1 mg/kg of dexamethasone were long-term survivors (LTS) of >120 days. There was no difference in survival between control animals that received only wild type cells or animals that were treated with IL-2 and 10 mg/kg of dexamethasone. Histopathological examination of brains from animals sacrificed at different times showed an accumulation of CD8 + T-cells around the site of the injected tumor only in the IL-2 group and the group that received 1 mg/kg of dexamethasone.These results suggest that while high doses of dexamethasone can completely inhibit the immune response observed with IL-2, lower and more likely therapeutic doses of dexamethasone do not inhibit local IL-2 immunotherapy.     

Flor-Essence<Superscript>®</Superscript> herbal tonic does not inhibit mammary tumor development

Background: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence^® tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. Methods: Female Sprague-Dawley rats were given water or exposed to 3 or 6% Flor-Essence^® beginning at 1 day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethyl-benz[a]anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. Results: Control rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0 and 59.4% for the 3 and 6% Flor-Essence^® groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0 and 97.3% for rats consuming 3 and 6% Flor-Essence^®, respectively. Mean mammary tumor multiplicity (±SES) for the controls was 2.8 (±0.5) and statistically different from the 3 or 6% Flor-Essence^® groups with 5.2 (±0.7), and 4.8 (±0.6), respectively (p £ 0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. Conclusions: Flor-Essence^® can promote mammary tumor development in the Sprague-Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth     

Modulation of DNA hypomethylation as a surrogate endpoint biomarker for chemoprevention of colon cancer

Surrogate end-point biomarkers are being developed as indicators of the efficacy of chemopreventive agents. These biomarkers are molecular and biological end-points that can be modulated by chemopreventive agents in accordance with their efficacy to prevent cancer. DNA hypomethylation is a common alteration found in colon tumors that has the potential of being modulated by chemopreventive agents and thus being useful as a surrogate end-point biomarker. Agents that were either effective or ineffective in preventing colon cancer were evaluated for the ability to modulate DNA hypomethylation in azoxymethane-induced colon tumors in male F344 rats. DNA methylation was determined by Dot Blot Analysis using a mouse monoclonal anti-5-methylcytosine antibody. Colon tumors had a 70% reduction in DNA methylation relative to normal colonic mucosa. DNA methylation in the tumors was increased by 7 days of treatment with agents that have been shown to prevent colon cancer (calcium chloride, alpha-diflouromethylornithine [DFMO], piroxicam, and sulindac), whereas agents shown not to prevent colon cancer in rats (low dose aspirin, 2-carboxyphenyl retinamide [2-CPR], quercetin, 9-cis retinoic acid, and rutin) did not increase DNA methylation. The results suggest that the ability to reverse the DNA hypomethylation in colon tumors could be useful as a surrogate end-point biomarker for chemoprevention of colon cancer.     

Desmoplastic infantile ganglioglioma: MRI and histological findings case report

Desmoplastic infantile gangliogliomas (DIG) are rare intracranial tumors occurring during the 1st year of life. They arise invariably in the supratentorial region and have a great size at presentation, commonly involving more than one lobe. They are composed of a solid peripheral component of variable size, which involves the superficial cerebral cortex and the leptomeninges, and a large cystic part. Despite the great size at presentation and occasional mitotic activity in the variable undifferentiated component, this entity constitutes a distinct clinicopathological entity with benign prognosis. We hereby present the MRI and histological findings of two cases of DIG in infants aged 9 and 10 months, respectively.     

Phase II study on 9-nitrocamptothecin (RFS 2000) in patients with advanced or metastatic urothelial tract tumors

OBJECTIVE: To investigate the antitumor activity and the safety of RFS2000, an oral topoisomerase I inhibitor, in patients with advanced or metastatic urothelial tract tumors refractory to one prior chemotherapy regimen. PATIENTS AND METHODS: Eligible patients were to have failed first line treatment for advanced or metastatic disease. Patients received RFS2000 as one daily oral intake at the dose of 1.5 mg/m(2)/day according to a "5 days on/2 days" off schedule continuously. One cycle was arbitrarily defined as a 3 week period. Sufficient oral fluid intake to prevent cystitis previously described in phase I trials with RFS2000 was recommended. Gehan design was used for sample size determination. Anti-tumor activity was evaluated according to the RECIST criteria and toxicity according to CTC version 2. RESULTS: Twenty patients received a total of 57 cycles (range 1-8). Grade 3-4 toxicity was observed in 10 patients requiring dose or schedule modifications. Hematological grade 3-4 toxicity was observed in 16% of the cycles. Only one patient experienced a partial response. CONCLUSIONS: RFS2000 could be administered orally as a "5 days on/2 days off" schedule continuously with a median dose intensity of 90.6% with an acceptable toxicity profile. However, RFS2000 did not exert significant activity in patients with advanced/metastatic urothelial tract tumors failing prior chemotherapy. The results of this study do not suggest further investigation of RFS2000 at the present dose and schedule for the treatment of urothelial tract tumors in this refractory population.     

Neuroendocrine differentiation in gastric adenocarcinomas; correlation with tumor stage and expression of VEGF and p53

Studies on neuroendocrine differentiation (NED) in conventional gastric adenocarcinomas and its significance on tumor behavior are limited. Our aim was to search for the expression of neuroendocrine differentiation in conventional gastric adenocarcinomas and correlate it with tumor type, stage and expression of VEGF and p53. Forty-two gastrectomy specimens with gastric adenocarcinoma were stained with chromogranin A to detect neuroendocrine differentiation and 45% of the cases were found to be NED (+). No significant correlation was found between NED and tumor type. However, NED was more frequent in advanced stage cases independently of tumor type. VEGF expression was also considerably more frequent in NED (+) tumors compared to NED (−) ones (84% vs. 56%). Moreover, we found a significant correlation between NED and the presence of lymph node metastases. P53 expression in NED (+) tumors was 68%. There was no significant correlation between VEGF and p53 in NED (+) cases. In conclusion, neuroendocrine differentiation is a frequent finding in conventional gastric adenocarcinomas, and although it does not seem to play a specific role in tumor progression, it seems that neuroendocrine cells are one of the factors contributing to angiogenesis by expressing VEGF, especially in advanced stage cases, affecting the incidence of lymph node metastases. Further studies with larger series should be performed to confirm this observation.     

Partial elimination of lymphocytes in mice with Ehrlich carcinoma

Elimination of about 30% lymphocyte population was observed in female Balb/c mice on day 11 after transplantation of Ehrlich carcinoma in comparison with animals without tumor. It was hypothesized that the eliminated population can block the tumor growth. Studies of the temporal and quantitative parameters of lymphocyte elimination with consideration for tumor size are considered to be perspective. The described model can be used for studies of immunodeficiency in animals with tumors.     

Cyclin D1 amplification and p16(MTS1/CDK4I) deletion correlate with poor prognosis in head and neck tumors

OBJECTIVES/HYPOTHESIS: Cyclin D1, a cell cycle regulator localized to chromosome 11q13, is amplified in several human tumors including head and neck squamous cell carcinoma (HNSCC). Amplification and/or overexpression of cyclin D1 have been correlated to a poor prognosis. Deletion of the p16 gene, localized to 9p21, has also been observed in a significant proportion of HNSCC. The p16 gene regulates cyclin D1-CDK4 activity and prevents retinoblastoma tumor suppressor gene phosphorylation, thereby downregulating cellular proliferation. Detection of cyclin D1 amplification and p16 deletion using a simple and sensitive method will be valuable for the development of effective treatment modalities for head and neck cancer. STUDY DESIGN: We have used fluorescence in situ hybridization (FISH) to study cyclin D1 amplification and p16 gene deletion in head and neck tumors. Both single- and dual-color FISH were performed. METHODS: Paraffin-embedded tissues from 103 patients with HNSCC were analyzed using genomic DNA probes for cyclin D1 and p16. Dual-color FISH was performed with chromosome 11 or 9 centromeric probes as a control. Twenty-eight of these samples were analyzed for p16 expression by immunohistochemistry. RESULTS: Cyclin D1 amplification was observed in 30% (31/103) of patients, and p16 deletion in 52% (54/103). Lack of p16 expression was observed in 64% (18/28) of patients. There was a good correlation between the deletion of p16 sequences and the loss of p16 expression (P = .008). Amplification of cyclin D1 had a statistically significant association with recurrence, distant metastasis, and survival at 36 months. There was a significant association between p16 deletion and the development of distant metastases. Cyclin D1 amplification and p16 deletion together correlated with recurrence, distant metastasis, and survival. CONCLUSIONS: We demonstrate that FISH is a simple and sensitive method for detecting cyclin D1 amplification and p16 deletion in head and neck cancer. Our results suggest that these two genetic aberrations together portend a poorer outcome than either of the abnormalities alone in head and neck cancer.     

颌骨牙源性钙化囊肿病变性质的探讨

目的：明确所谓牙源性钙化囊肿（calcifying odontogenic cyst,COC)各临床病理亚型的特点及其病变性能。方法：回顾分析21例被笼统诊断为COC病例资料,通过对临床、X线、病理、治疗及预后特点的综合分析,将本组病例分为囊肿、良性肿瘤和恶性肿瘤3类病损进行观察。结果：囊肿组16例（男性9例、女性7例）,10－19岁为高发年龄,前磨牙区好发,随访13例患者无复发。良性肿瘤组4例,临床病理表现各异,其中2例表现为所谓实性型COC,1例为COC伴发成釉细胞瘤,1例为COC伴发牙源性纤维黏液瘤;这组病例均发生于下颌,其中2例有多次复发史。恶性肿瘤组1例,肿瘤呈实性,除表现某些COC特点外,具有显著的组织学恶性特点。结论：以往被笼统归类为COC的病变可表现囊肿,良性肿瘤或恶性肿瘤等多种病理和行为特点,因此其命名和分类应作相应修改,临床治疗也应区别对待。