Eradication of intractable malignant ascites by abdominocentesis, reinfusion of concentrated ascites, and adoptive immunotherapy with dendritic cells and activated killer cells in a patient with recurrent lung cancer: a case report

<p>Abstract</p> <p>Introduction</p> <p>Malignant ascites is often a sign of a terminal stage in several malignant diseases. To control ascites, drainage and intra-abdominal chemotherapy are often used in those patients but eradication of ascites is difficult and prognosis is poor.</p> <p>Case presentation</p> <p>A 55-year-old woman was admitted to our hospital on 26 January 2007 with dyspnea, abdominal distention and oliguria. Abdominocentesis revealed peritoneal carcinomatosis resulting from abdominal recurrence from lung cancer. To alleviate the dyspnea and abdominal distention, we drained the ascites aseptically and infused them intravenously back into the patient after removal of tumor cells by centrifugation, and then concentration by apheresis. After the drainage of ascites, we intraperitoneally infused activated killer cells and dendritic cells from the patient's tumor-draining lymph nodes, together with 4.5 × 10⁵U interleukin-2 in 50 ml saline by 2.1 ml/hour infuser balloon.</p> <p>Drastic decreases in the tumor cell count and in ascite retention were observed after several courses of ascites drainage, intravenous infusion and intraperitoneal immunotherapy. The plasma protein level was maintained during the treatment notwithstanding the repeated drainage of ascites. Cell surface marker analysis, cytotoxic activities against autologous tumor cells and interferon-gamma examination of ascites suggested the possibility that these effects were mediated by immunological responses of activated killer cells and dendritic cells infused intraperitoneally.</p> <p>Conclusion</p> <p>Combination of local administration of immune cells and infusion of concentrated cell free ascites may be applicable for patients afflicted with refractory ascites.</p

Surgical treatment for pulmonary metastases from esophageal carcinoma after definitive chemoradiotherapy: Experience from a single institution

<p>Abstract</p> <p>Background</p> <p>Surgical treatment for pulmonary metastases is known to be a safe and potentially curative procedure for various primary malignancies. However, there are few reports regarding the prognostic role of surgical treatment for pulmonary metastases from esophageal carcinoma, especially after definitive chemoradiotherapy (CRT).</p> <p>Methods</p> <p>We retrospectively reviewed 5 patients who underwent surgical treatment for pulmonary metastases from esophageal carcinoma at our institution. The primary treatment for esophageal carcinoma was definitive CRT, and a complete response (CR) was achieved in all patients.</p> <p>Results</p> <p>The surgical procedure for pulmonary metastases was wedge resection, and pathological complete resection was achieved in all 5 patients. The disease free interval after definitive CRT varied from 7 to 36 months, with a median of 19 months. There were no perioperative complications, but postoperative respiratory failure occurred in 1 patient. The postoperative hospital stay varied from 4 to 7 days, with a median of 6 days. Three patients are now alive with a good performance status (PS) and are disease free. The other 2 patients died of primary disease. The overall survival after surgical treatment varied from 20 to 90 months, with a median of 29 months.</p> <p>Conclusions</p> <p>Surgical treatment should be considered for patients with pulmonary metastases from esophageal carcinoma who previously received CRT and achieved a CR, because it provides not only a longer survival, but also a good postoperative PS for some patients.</p

Frequency and fate of microRNA editing in human brain

Primary transcripts of certain microRNA (miRNA) genes (pri-miRNAs) are subject to RNA editing that converts adenosine to inosine (A→I RNA editing). However, the frequency of the pri-miRNA editing and the fate of edited pri-miRNAs remain largely to be determined. Examination of already known pri-miRNA editing sites indicated that adenosine residues of the UAG triplet sequence might be edited more frequently. In the present study, therefore, we conducted a large-scale survey of human pri-miRNAs containing the UAG triplet sequence. By direct sequencing of RT–PCR products corresponding to pri-miRNAs, we examined 209 pri-miRNAs and identified 43 UAG and also 43 non-UAG editing sites in 47 pri-miRNAs, which were highly edited in human brain. In vitro miRNA processing assay using recombinant Drosha-DGCR8 and Dicer-TRBP (the human immuno deficiency virus transactivating response RNA-binding protein) complexes revealed that a majority of pri-miRNA editing is likely to interfere with the miRNA processing steps. In addition, four new edited miRNAs with altered seed sequences were identified by targeted cloning and sequencing of the miRNAs that would be processed from edited pri-miRNAs. Our studies predict that ∼16% of human pri-miRNAs are subject to A→I editing and, thus, miRNA editing could have a large impact on the miRNA-mediated gene silencing

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Neovasculature development is a crucial step in the natural history of a cancer. While much emphasis has been placed on proangiogenic growth factors such as VEGF, it is clear that endogenous angiogenesis inhibitors also have critical roles in the regulation of this process. Recent research has identified several cryptic fragments of extracellular matrix/vascular basement membrane proteins that have potent antiangiogenic properties in vivo. It has become apparent that many of these fragments signal via interactions with endothelial integrins, although multiple downstream effector pathways have been implicated and endostatin, the first non-collagenous domain of collagen XVIII, influences an intricate signalling network. The activity of these molecules in animal models suggests that they may have significant clinical activity; however, results of phase I/II trials with endostatin were disappointing. Many possible reasons can be found for the failure of these studies. Weaknesses in trial design, endostatin administration regimen and patient selection are identifiable, and importantly the lack of a clearly defined antiangiogenic mechanism for endostatin hindered assessment of biologically effective dose. Additionally, in vivo immunological and proteolytic function-neutralising mechanisms may have negated endostatin's actions. Lessons learned from these studies will aid the future clinical development of other antiangiogenic extracellular matrix protein fragments

Protein Signature of Lung Cancer Tissues

Lung cancer remains the most common cause of cancer-related mortality. We applied a highly multiplexed proteomic technology (SOMAscan) to compare protein expression signatures of non small-cell lung cancer (NSCLC) tissues with healthy adjacent and distant tissues from surgical resections. In this first report of SOMAscan applied to tissues, we highlight 36 proteins that exhibit the largest expression differences between matched tumor and non-tumor tissues. The concentrations of twenty proteins increased and sixteen decreased in tumor tissue, thirteen of which are novel for NSCLC. NSCLC tissue biomarkers identified here overlap with a core set identified in a large serum-based NSCLC study with SOMAscan. We show that large-scale comparative analysis of protein expression can be used to develop novel histochemical probes. As expected, relative differences in protein expression are greater in tissues than in serum. The combined results from tissue and serum present the most extensive view to date of the complex changes in NSCLC protein expression and provide important implications for diagnosis and treatment

DNA methylation-associated inactivation of TGFβ-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers

The transforming growth factor β (TGFβ)-signalling pathway is deregulated in many cancers. We examined the role of gene silencing via aberrant methylation of DRM/Gremlin and HPP1, which inhibit TGFβ signalling, and RUNX3, which facilitates TGFβ-signalling, of all genes that are thought to be tumour suppressors, are aberrantly expressed, and are thus thought to have important role in human cancers. We examined DRM/Gremlin mRNA expression in 44 cell lines and the promoter methylation status of DRM/Gremlin, HPP1, and RUNX3 in 44 cell lines and 511 primary tumours. The loss of DRM/Gremlin mRNA expression in human cancer cell lines is associated with DNA methylation, and treatment with the methylation inhibitor-reactivated mRNA expression (n=13). Methylation percentages of the three genes ranged from 0–83% in adult tumours and 0–50% in paediatric tumours. Methylation of DRM/Gremlin was more frequent in lung tumours in smokers, and methylation of all three genes was inversely correlated with prognosis in patients with bladder or prostate cancer. Our results provide strong evidence that these TGFβ-related genes are frequently deregulated through aberrant methylation in many human malignancies

The Viral and Cellular MicroRNA Targetome in Lymphoblastoid Cell Lines

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus linked to a number of B cell cancers and lymphoproliferative disorders. During latent infection, EBV expresses 25 viral pre-microRNAs (miRNAs) and induces the expression of specific host miRNAs, such as miR-155 and miR-21, which potentially play a role in viral oncogenesis. To date, only a limited number of EBV miRNA targets have been identified; thus, the role of EBV miRNAs in viral pathogenesis and/or lymphomagenesis is not well defined. Here, we used photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) combined with deep sequencing and computational analysis to comprehensively examine the viral and cellular miRNA targetome in EBV strain B95-8-infected lymphoblastoid cell lines (LCLs). We identified 7,827 miRNA-interaction sites in 3,492 cellular 3′UTRs. 531 of these sites contained seed matches to viral miRNAs. 24 PAR-CLIP-identified miRNA:3′UTR interactions were confirmed by reporter assays. Our results reveal that EBV miRNAs predominantly target cellular transcripts during latent infection, thereby manipulating the host environment. Furthermore, targets of EBV miRNAs are involved in multiple cellular processes that are directly relevant to viral infection, including innate immunity, cell survival, and cell proliferation. Finally, we present evidence that myc-regulated host miRNAs from the miR-17/92 cluster can regulate latent viral gene expression. This comprehensive survey of the miRNA targetome in EBV-infected B cells represents a key step towards defining the functions of EBV-encoded miRNAs, and potentially, identifying novel therapeutic targets for EBV-associated malignancies