The effect of dexamethasone on the uptake of cisplatin in 9L glioma and the area of brain around tumor

The negative influence of dexamethasone (Dex) on the uptake of cisplatin in brain tumors was investigated in rats bearing 9L glioma. Dex or saline was given intraperitoneally prior to intravenous administration of cisplatin 5 mg/kg. Total Platinum (Pt) concentration was quantified with atomic absorption spectroscopy (AAS) in tumor, brain around tumor (BAT), normal brain and plasma. In the second experiment DNA-adducts of cisplatin were determined in tumor and BAT by AAS. In tumor, there was no difference in the Pt concentration and in the DNA-adduct level between the two treatment groups. In BAT, the Pt level in the Dex group was 0.20 µg/g (SD = 0.10 µg/g), which was significantly lower than in the controls (0.53 µg/g (SD=0.21 µg/g); p < 0.001). In addition, the DNA-adduct level in BAT was 23% lower in the Dex treated rats (p=0.05). In normal brain the Pt concentration was 10-fold lower than in tumor tissue. Thus, Dex did not significantly limit the uptake of cisplatin in brain tumor nor did it influence the uptake in normal brain parenchyma. In contrast, in BAT that has a partially disrupted BBB, the concentrations of Pt and DNA-adduct formation were significantly decreased following pretreatment with Dex. The influence of Dex on limiting the effects of chemotherapy for brain tumors needs further study.     

Effect of laparoscopic partial fundoplication on reflux mechanisms

OBJECTIVES: Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism causing gastroesophageal reflux. Since 1994 we have performed laparoscopic partial instead of complete fundoplication as standard surgical treatment for therapy resistant reflux disease to minimize postoperative dysphagia. To better understand the management of gastroesophageal reflux, we conducted a prospective study of the effects of laparoscopic partial fundoplication on TLESRs and other reflux mechanisms. METHODS: From 1994 to 1999, 65 patients underwent laparoscopic partial fundoplication (180-200 degrees) and 28 of these patients (16 female, 12 male, mean age 43 +/- 2 yr [range, 26-66 yr]) agreed to participate in this prospective study on reflux mechanisms. Before and 6 months after surgery, all patients were evaluated by simultaneous recording of pH and lower esophageal sphincter characteristics, using sleeve manometry. RESULTS: After partial fundoplication basal LES pressure increased significantly (p < 0.05), from 14.3 +/- 1.2 mm Hg to 17.8 +/- 1 mm Hg. Partial fundoplication significantly (p < 0.05) decreased the number of TLESRs, from 3.4 +/- 0.8 to 1.6 +/- 0.3 per hour in the fasting period, and from 4.7 +/- 0.5 to 1.9 +/- 0.3 per hour postprandially. The percentage of TLESRs associated with reflux also decreased significantly (p < 0.05), from 45 +/- 7% to 27 +/- 6% after operation. The number of reflux episodes decreased significantly (p < 0.05), from 4.1 +/- 0.7 to 1.3 +/- 0.3 per hour postoperatively. The majority of these episodes were associated with TLESRs: 57% and 46%, pre- and postoperatively, respectively. CONCLUSIONS: Laparoscopic partial fundoplication significantly increased fasting and postprandial LES pressure and significantly decreased TLESR frequency. This resulted in a significant reduction in esophageal acid exposure, with preservation of postprandial LES characteristics.     

Treatment of nasopharyngeal carcinoma with Epstein-Barr virus--specific T lymphocytes

Conventional treatment for nasopharyngeal carcinoma (NPC) frequently fails and is accompanied by severe long-term side effects. Since virtually all undifferentiated NPCs are associated with Epstein-Barr virus (EBV), this tumor is an attractive candidate for cellular immunotherapy targeted against tumor-associated viral antigens. We now demonstrate that EBV-specific cytotoxic T-cell (CTL) lines can readily be generated from individuals with NPC, notwithstanding the patients' prior exposure to chemotherapy/radiation. A total of 10 patients diagnosed with advanced NPC were treated with autologous CTLs. All patients tolerated the CTLs, although one developed increased swelling at the site of pre-existing disease. At 19 to 27 months after infusion, 4 patients treated in remission from locally advanced disease remain disease free. Of 6 patients with refractory disease prior to treatment, 2 had complete responses, and remain in remission over 11 to 23 months after treatment; 1 had a partial remission that persisted for 12 months; 1 has had stable disease for more than 14 months; and 2 had no response. These results demonstrate that administration of EBV-specific CTLs to patients with advanced NPC is feasible, appears to be safe, and can be associated with significant antitumor activity.     

Effect of somatostatin on lower esophageal sphincter characteristics in man

BACKGROUND: Somatostatin (SST) is known for its inhibitory effect on the gastrointestinal tract. Transient lower esophageal sphincter relaxations (TLESR), low or absent LES pressure (LESP) and swallow-induced LES relaxations are the most important reflux mechanisms. METHODS: We have studied the effect of somatostatin on lower esophageal sphincter (LES) characteristics in man. Nine healthy volunteers participated in four experiments performed in random order and double-blind during continuous infusion of somatostatin (250 microg/h) or saline (control) under fasting and postprandial conditions. Esophageal motility was measured with sleeve manometry combined with pH metry. RESULTS: Under fasting conditions LESP was not influenced by somatostatin. Ingestion of the carbohydrate meal significantly (P < 0.01) decreased LESP. During continuous somatostatin infusion the postprandial decrease in LESP did not occur; LESP was even significantly (P < 0.05) increased over basal levels. Somatostatin did not significantly influence TLESR frequency, neither under basal conditions, nor postprandially. The residual pressure during swallow-induced LES relaxation was significantly (P < 0.05) increased by somatostatin. CONCLUSION: In humans somatostatin prevents postprandial reduction in LESP, does not affect TLESR, but inhibits swallow-induced LES relaxation.     

Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin's disease

Epstein Barr virus (EBV)+ Hodgkin's disease (HD) expresses clearly identified tumor antigens derived from the virus and could, in principle, be a target for adoptive immunotherapy with viral antigen-specific T cells. However, like most tumor-associated antigens in immunocompetent hosts, these potential targets are only weakly immunogenic, consisting primarily of the latent membrane protein (LMP)1 and LMP2 antigens. Moreover, Hodgkin tumors possess a range of tumor evasion strategies. Therefore, the likely value of immunotherapy with EBV-specific cytotoxic effector cells has been questioned. We have now used a combination of gene marking, tetramer, and functional analyses to track the fate and assess the activity of EBV cytotoxic T lymphocyte (CTL) lines administered to 14 patients treated for relapsed EBV+ HD. Gene marking studies showed that infused effector cells could further expand by several logs in vivo, contribute to the memory pool (persisting up to 12 mo), and traffic to tumor sites. Tetramer and functional analyses showed that T cells reactive with the tumor-associated antigen LMP2 were present in the infused lines, expanded in peripheral blood after infusion, and also entered tumor. Viral load decreased, demonstrating the biologic activity of the infused CTLs. Clinically, EBV CTLs were well tolerated, could control type B symptoms (fever, night sweats, and weight loss), and had antitumor activity. After CTL infusion, five patients were in complete remission at up to 40 mo, two of whom had clearly measurable tumor at the time of treatment. One additional patient had a partial response, and five had stable disease. The performance and fate of these human tumor antigen-specific T cells in vivo suggests that they might be of value for the treatment of EBV+ Hodgkin lymphoma.     

Natural T-helper immunity against human papillomavirus type 16 (HPV16) E7-derived peptide epitopes in patients with HPV16-positive cervical lesions: identification of 3 human leukocyte antigen class II-restricted epitopes

Tumor-specific T-helper (Th) immunity was found to play a pivotal role in the natural and vaccine-induced immune defense against tumors. Since the majority of cervical cancers express human papillomavirus type 16 (HPV16) E7 oncoprotein, it is important to investigate the Th response against this target antigen in detail. By means of PBMC cultures from HLA-typed healthy donors, we identified the central part of HPV16 E7 (E7(41-72)) as the major immunogenic region within this antigen. Furthermore, we mapped 3 distinct Th epitopes within this region (DR15/E7(50-62), DR3/E7(43-77), DQ2/E7(35-50)). In a parallel approach, employing IFN-gamma ELISPOT analysis, we detected Th immunity against HPV16 E7 in subjects with HPV16+ lesions. Several of these responses matched with the 3 Th epitopes defined in our study. A number of other HPV16+ subjects did not display any E7-specific type 1 cytokine-producing T-cell immunity, indicating failure of the immune response. Our combined data argue for more extensive as well as longitudinal analysis of HPV16-specific T-cell immunity using the ELISPOT assay described, as well as for HPV-specific vaccination of individuals with HPV+ lesions.     

A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells.

The transduction of primary T cells to express chimeric T cell receptors (cTCR) for redirected targeting of tumor cells is an attractive strategy for generating tumor-specific T cells for adoptive therapy. However, tumor cells rarely provide costimulatory signals and hence cTCRs that transmit just a CD3zeta signal can only initiate target cell killing and interferon-gamma release and fail to induce full activation. Although incorporation of a CD28 component results in IL-2 release and limited proliferation, T cell activation remains incomplete. OX40 transmits a potent and prolonged T cell activation signal and is crucial for maintaining an immunological response. We hypothesize that the CD28-OX40-CD3zeta tripartite cytoplasmic domain will provide a full complement of activation, proliferation, and survival signals for enhanced anti-tumor activity.     

Effect of Somatostatin on Lower Esophageal Sphincter Characteristics in Man

Background: Data from previous studies on intestinal metaplasia at the gastroesophageal junction have been conflicting, which makes the diagnosis of Barrett's esophagus less obvious. This may partly be due to the lack of a reliable classification of the Z-line appearance. We previously proposed such a classification (the ZAP classification) that was shown to correlate with the prevalence of intestinal metaplasia. The use of different immunohistochemical techniques has increased in the study of intestinal metaplasia. In the present study our aim was to 1) evaluate the impact of different antibodies, namely cytokeratin (CK) 7, 13, and 20, CaCO3/73, and FBB2/29, in order to differentiate between Barrett's esophagus and cardia intestinal metaplasia, and 2) explore the staining patterns in different ZAP grades. Methods: Thirty-nine specimens with intestinal metaplasia were compared - 9 from Barrett's esophagus, 6 from cardia, and 24 from the Z-line. The Z-line specimens were evaluated with respect to ZAP grade. Results: No differences were encountered regarding staining patterns for CK13 and CaCO3/73 in Barrett's esophagus and cardia. The staining pattern of CK7/20 was significantly different between Barrett's esophagus and cardia. CK7/20 showed a rising frequency of Barrett's esophagus staining pattern with rising ZAP grade. Conclusion: CK7/20 is a feasible marker for Barrett's esophagus. Intestinal metaplasia in different ZAP grades differs regarding expression of immunohistochemical markers.     

Paramagnetic self‐assembled nanoparticles as supramolecular MRI contrast agents

Nanometer‐sized materials offer a wide range of applications in biomedical technologies, particularly imaging and diagnostics. Current scaffolds in the nanometer range predominantly make use of inorganic particles, organic polymers or natural peptide‐based macromolecules. In contrast we hereby report a supramolecular approach for the preparation of self‐assembled dendritic‐like nanoparticles for applications as MRI contrast agents. This strategy combines the benefits from low molecular weight imaging agents with the ones of high molecular weight. Their in vitro properties are confirmed by in vivo measurements: post injection of well‐defined and meta‐stable nanoparticles allows for high‐resolution blood‐pool imaging, even at very low Gd(III) doses. These dynamic and modular imaging agents are an important addition to the young field of supramolecular medicine using well‐defined nanometer‐sized assemblies. Copyright © 2012 John Wiley & Sons, Ltd.