Jitendra Patel

Percutaneous transthoracic needle biopsy of the lung: review of 612 lesions.

PURPOSE The results and complications of 651 pulmonary fine-needle aspiration biopsies (FNABs) were reviewed. The number of needle passes and needle size were correlated to pneumothorax and chest tube placement rates. MATERIALS AND METHODS FNAB of the lung was performed on 651 occasions in 612 patients with 18- to 22-gauge Franseen needles. Diagnostic rates were calculated. The number of needle passes performed and needle size used were evaluated for their association with pneumothorax and subsequent chest tube placement. RESULTS Diagnostic accuracy was 94% with sensitivity for malignancy of 95%. Positive and negative predictive values were 99.5% and 90%, respectively. Pneumothorax occurred in 26.9% of patients with 9.2% requiring chest tube placement. Increasing numbers of needle passes and larger needle sizes did not increase the rates of pneumothorax or chest tube placement. CONCLUSIONS FNAB of the lung has excellent diagnostic rates and remains the procedure of choice for diagnosing pulmonary lesions. This large study contradicts perceptions that pneumothorax and chest tube placement rates decrease with thinner needles and fewer passes.

Epigenetic Inactivation of the Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) Gene in Human Prostate Tumors

Gene silencing via CpG island methylation in the promoter region is one of the mechanisms by which tumor suppressor genes are inactivated in human cancers. Previous studies have shown that the tissue inhibitors of metalloproteinases (TIMP)-2 gene, which is an endogenous inhibitor of matrix metalloproteinases involved in cell invasion and tumorigenesis, is downregulated or silenced in a variety of human cancer cell lines. Here, we investigated the mechanism underlying TIMP-2 expression in prostate cancer cell lines and primary prostate tumor samples. We observed a strong correlation between promoter hypermethylation and lost expression of TIMP-2 gene, which was supported by other results demonstrating that promoter demethylation by 5-aza-2′-deoxycytidine and trichostatin A reactivated TIMP-2 and restored its expression in TIMP-2-silenced metastatic prostate cell lines. These results were further substantiated by a chromatin immunoprecipitation assay, showing the preferential binding of MeCP2 to methylated CpG island in TIMP-2-silenced metastatic prostate cell lines. In vitro Matrigel invasion assays showed that re-expression of TIMP-2 after a combined treatment with 5-aza and trichostatin-A in metastatic prostate cells resulted in a significant reduction of tumor cell invasion. Furthermore, CpG methylation of TIMP-2 promoter was also shown in primary prostate tumors that expressed decreased TIMP-2 protein levels. These results suggest that the downregulation of the TIMP-2 gene is associated with promoter methylation and that this may play an important role in prostate cancer progression during the invasive and metastatic stages of the disease.

Demethylation-Linked Activation of Urokinase Plasminogen Activator Is Involved in Progression of Prostate Cancer

Increased expression of urokinase plasminogen activator (uPA) has been reported in various malignancies including prostate cancer. However, the mechanism by which uPA is abnormally expressed in prostate cancer remains elusive. Here, we show that uPA is aberrantly expressed in a high percentage of human prostate cancer tissues but rarely expressed either in tumor-matched nonneoplastic adjacent tissues or benign prostatic hyperplasia samples. This aberrant expression is associated with cancer-linked demethylation of the uPA promoter. Furthermore, treatment with demethylation inhibitor S-adenosylmethionine or stable expression of uPA short hairpin RNA significantly inhibits uPA expression and tumor cell invasion in vitro and tumor growth and incidence of lung metastasis in vivo. Collectively, these findings strongly suggest that DNA demethylation is a common mechanism underlying the abnormal expression of uPA and is a critical contributing factor to the malignant progression of human prostate tumors.

Suppression of the uPAR–uPA System Retards Angiogenesis, Invasion, and In Vivo Tumor Development in Pancreatic Cancer Cells

Despite existing chemotherapy and surgical resection strategies, pancreatic cancer is one of the major causes of mortality in the United States with a 5-year mean survival rate of less than 5%. The activation of the urokinase-type plasminogen activator receptor–urokinase-type plasminogen activator (uPAR–uPA) system in the development of pancreatic ductal adenocarcinoma has been well established. In the present study, we used 2 pancreatic cancer cell lines, MIA PaCa-2 and PANC-1 to show the effects of uPAR and uPA downregulation. From the results, we observed that RNAi expressing plasmids efficiently downregulated mRNA and protein expression of uPAR and uPA. In vitro and in vivo angiogenic assays revealed a significant decrease in the angiogenic potential of MIA PaCa-2 and PANC-1 cells that were downregulated for both uPAR and uPA. From the angiogenesis antibody array analysis, we observed that the simultaneous downregulation of uPAR and uPA resulted in the downregulation of angiogenin and overexpression of RANTES. Further, FACS analysis showed that the simultaneous downregulation of uPAR and uPA caused the accumulation of cells in the sub-G0/1 phase in both MIA PaCa-2 and PANC-1 cells. In addition, Western blot analysis revealed that downregulation of uPAR and uPA caused the activation of caspase 8 and CAD, which is indicative of apoptosis, and in vivo TUNEL assay confirmed these results. Finally, we observed the nuclear localization of uPA and that uPA interacts with the transcription factor Lhx-2. Taken together, the results of the present study show that the targeting of the uPAR–uPA system has therapeutic potential. Mol Cancer Res; 9(4); 377–89. ©2011 AACR.

N-cadherin mediates angiogenesis by regulating monocyte chemoattractant protein-1 expression via PI3K/Akt signaling in prostate cancer cells.

Over the past decade, evidence continues to mount showing that N-cadherin is a critical protein in cancer progression and metastasis. In the present study, we evaluated the expression of N-cadherin in human prostate cancer tissue specimens and cell lines. Enhanced expression of N-cadherin was observed in both the malignant and bone-metastasized prostate tissue specimens compared to the healthy prostate tissues. Consistent with the tissue array data, N-cadherin was highly expressed in PC3, but not in Du145 and LNCaP human prostate cell lines. Based on cell to cell binding assay, we found that N-cadherin expression facilitates homotypic interaction between human prostate cancer cells and human microvascular endothelial cells (HMEC). Human angiogenesis antibody array and in vitro angiogenesis assay showed that siRNA-mediated knockdown of N-cadherin reduced the secretion of monocyte chemoattractant protein-1 (MCP-1), which played a potential role in stimulating capillary network formation of HMEC. Additionally, culture supernatant of Du145 cells transfected with full-length N-cadherin expressing plasmid showed increased MCP-1 expression and chemoattractant ability compared to normal Du145 cells. Further, we noticed that blocking PI3K activity inhibited N-cadherin mediated MCP-1 expression. Our data demonstrated that N-cadherin in prostate cancer cell mediates cell-cell adhesion and regulates MCP-1 expression via the PI3K/Akt signaling pathway.

New Thrombolytic Brush Catheter in Thrombosed Polytetrafluoroethylene Dialysis Grafts: Preclinical Animal Study

PURPOSE To assess the safety, efficacy, endothelial changes, and risks of pulmonary embolic events after the use of a new thrombolytic brush catheter in mature thrombosed polytetrafluoroethylene (PTFE) dialysis grafts in an animal model. MATERIALS AND METHODS Loop configuration PTFE grafts were implanted in the femoral vessels of 12 canines 4 weeks before mechanical thrombosis was performed. The thrombus was allowed to consolidate for 24 hours in 10 animals, 72 hours in one animal, and 7 days in one animal. Standard percutaneous criss-cross catheter access was performed, and a soft, low-speed, brush (6 mm in diameter), aided by 250,000 U of periprocedural urokinase, was utilized for thrombolysis. The native vessels, just distal to the anastomosis, and lungs were evaluated macro- and microscopically. RESULTS Thrombolysis was complete in all grafts with the exception of a small segment between the crossing of the access vascular sheaths. The total thrombolysis time ranged from 8 to 12 minutes; this included 5 minutes of pulse-spray lacing. No difference in thrombolysis time was found with regard to the age or amount of thrombus. Minimal endothelial changes were noted and no evidence of acute pulmonary embolus was found on necropsy or histologic studies. CONCLUSION This method offers a simple, safe, and efficient means of recanalization of thrombosed PTFE dialysis grafts in this canine model.

Metastatic breast cancer presenting as linitis plastica of the stomach

Early detection and treatment of breast cancer, leading to longer survival, has revealed the natural history of this disease process. Linitis plastica of the stomach is a potential long-term sequela of metastatic breast cancer. Here we present a case of metastatic breast cancer presenting as linitis plastica, as well as the treatment algorithm for this rare clinical entity. The world literature describes a clear pattern of linitis plastica for metastatic infiltrating lobular breast cancer and a discrete nodular pattern for infiltrating ductal cancer, in regard to metastasis to the stomach. To our knowledge, this is the first case of infiltrating ductal cancer presenting as linitis plastica of the stomach.