Primary tumor of pancreatic cancer as a measurable target lesion in chemotherapy trials

BACKGROUND: It is unclear whether primary pancreatic cancer (PC) tumors can be accepted as measurable target lesions in chemotherapy trials. We reviewed recent PC patients to clarify the significance of their computed tomography (CT) responses of the primary tumor after chemotherapy. METHODS: The patient selection criteria were (i) having been admitted between January 2002 and December 2004, (ii) diagnosed as having histologically or cytologically proven adenocarcinoma of the pancreas, (iii) treated with chemotherapy with no previous anticancer treatment and (iv) having been evaluated by follow-up CT to assess the response according to the Response Evaluation Criteria in Solid Tumors criteria. RESULTS: A total of 143 patients met the selection criteria. It was possible to measure the largest diameter of the primary tumor in 119 (83%) of the 143, and primary tumor shrinkage was observed in 10 (8%) of the 119. When regarding the primary as measurable as opposed to non-measurable, the number of patients with measurable disease became 127 from 67, and the frequencies of partial response (PR), stable disease (SD) and progressive disease (PD) became 11, 74 and 15% of the 127 from 18, 52 and 30% of the 67, respectively. In the former situation, large primary tumor sometimes canceled the shrinkage or progression of small metastasis. In each setting, PR or SD represented a favorable prognosis compared with PD, however, there were no statistical differences between the PR and the SD. CONCLUSION: Measuring the primary tumor is acceptable in approximately 80% of PC patients. However, we must be aware that the frequency of SD may increase compared with the PR or PD.     

Phase I study of fixed dose rate infusion of gemcitabine in patients with unresectable pancreatic cancer

OBJECTIVE: The purpose of this study was to determine the feasible dose of gemcitabine when administered as a fixed dose rate infusion (10 mg/m(2)/min) on a weekly schedule to Japanese patients with unresectable advanced pancreatic cancer. METHODS: Patients were required to have histologically or cytologically proven locally advanced or metastatic pancreatic cancer for which they had received no previous chemotherapy. Gemcitabine was administered intravenously weekly for three consecutive weeks every 4 weeks. Patients at three dose levels were scheduled to receive escalating doses of gemcitabine: 1000 mg/m(2) over 100 min (Level 1), 1200 mg/m(2) over 120 min (Level 2) and 1500 mg/m(2) over 150 min (Level 3). RESULTS: A total of 16 patients were enrolled in this study between December 2003 and September 2004. Maximum-tolerated dose was not reached during the first course. Dose-limiting toxicity was Grade 4 neutropenia. Grade 3 or 4 neutropenia was observed at Level 3 in all six patients in the first course, and administration of gemcitabine on Day 8 or 15 was skipped in all six patients. Non-hematologic toxicity was mild and the most common symptoms were anorexia, nausea and vomiting. Partial response was achieved in 1 of the 17 patients (7%). Median overall survival was 7.3 months. CONCLUSIONS: Gemcitabine administered at a rate of 10 mg/m(2)/min was tolerated up to 1500 mg/m(2), but 1200 mg/m(2) represented a more appropriate recommended dose in further studies owing to neutropenia in Japanese patients with advanced pancreatic cancer.     

Production and characterization of a monoclonal antibody specific to Nef-associated factor 1 (Naf1)/A20-binding inhibitor of NF-kappaB activation (ABIN-1)

Cellular protein Naf1 (Nef-associated factor 1) or ABIN-1 (A20-binding inhibitor of NF-kappaB activation) is an important cellular protein, expressed in various human tissues and T-cell lines. Naf1 protein has two isoforms (Naf1alpha and Naf1beta) with different C-termini, produced by alternative splicing. Naf1alpha and Naf1beta have approximately 2800 and 2600 nucleotides, with an open reading frame of 1941 and 1781 nucleotides, encoding the 72-kDa Naf1alpha and 68-kDa Naf1beta proteins, respectively. In the present study, we generated a monoclonal antibody (MAb) against human Naf1, which recognizes full-length, endogenous Naf1 of both isotypes. For this purpose, recombinant 6xHis and myc-tagged N-terminal Naf1(38135), Naf1(N) protein was produced by using the baculovirus expression system. Recombinant Naf1(N) protein was used to immunize Balb/c mice, and a hybridoma cell line producing stable and highly specific MAb with strong affinity to Naf1 was established. We further characterized this antibody by immunofluorescent assay and Western blot analysis to confirm effectiveness in detecting recombinant and endogenous Naf1. By Western blot analysis of recombinant Naf1-N fusion proteins with overlapping N-terminal sequences, the epitope targeted by anti-Naf1 MAb was determined as the 81-88-amino acid region of human Naf1.     

Nafamostat mesilate induces production of interleukin-12 and -18 in human peripheral blood mononuclear cells

Little has been reported on the drugs inducing production of monocyte-derived cytokines like interleukin (IL)-18 and IL-12. We found that nafamostat mesilate elicits IL-12, IL-18, tumor necrosis factor-alpha and interferon-gamma production, and the expression of intercellular adhesion molecules-1, B7.1, B7.2, CD40, and CD40 ligand in human peripheral blood mononuclear cells. The cytokine production and adhesion molecule expression were abolished by anti-IL-12 and IL-18 antibodies. Therefore, IL-18 and IL-12 may play roles in the significant and immediate effects of nafamostat mesilate.     

Regional difference in P-glycoprotein function in rat intestine

It has been reported that inhibition of the P-glycoprotein (P-gp) results in the improved absorption of P-gp substrate in the intestinal tract. In fact, the increased permeability of P-gp substrate across the intestinal epithelium was observed following inhibition of P-gp in in vitro experiments. To develop the formulation containing P-gp inhibitor and P-gp substrate for practical use, it is necessary to know whether the results obtained in the in vitro experiments are reproducible at whole body level. It is also important to find out the regional difference of the P-gp activity in the intestinal tract. In this study, we examined whether verapamil, a specific inhibitor of P-gp, improves the absorption of rhodamine123 (Rho123), a substrate of P-gp, from the jejunum, ileum, and colon of rats using the in situ loop method. The water content in the loop decreased during the experiment, resulting in a significant change of the Rho123 concentration in the loop. Thus, to accurately determine the absorption rate of Rho123, it was necessary to measure the water movement. It was found that there was a regional difference in the water movement, i.e., greatest in colon, followed by ileum. Verapamil did not change the water movement in any intestinal regions. When the concentration of Rho123 in the loop was corrected by water movement, the Rho123 clearance was in the order of ileum (1.15 microL/min/cm), colon (0.83 microL/min/cm) and jejunum (0.47 microL/min/cm). In the presence of verapamil, the Rho123 clearance was significantly increased at jejunum and ileum but not in colon (ileum: 2.08 microL/min/cm, colon: 1.14 microL/min/cm, jejunum: 1.28 microL/min/cm). These results suggest that P-gp inhibits the drug absorption in jejunum and ileum. From these results, it is possible to evaluate the role of P-gp and its regional difference in the in situ experiments. In particular, the inhibition of P-gp results in an increase in absorption of the P-gp substrate limited to jejunum and ileum.     

Supplement of tetrahydrobiopterin by a gene transfer of GTP cyclohydrolase I cDNA improves vascular dysfunction in insulin-resistant rats

Deficiency of tetrahydrobiopterin (BH4) in the vascular tissue contributes to endothelial dysfunction in the insulin-resistant state. We intended to develop a new gene transfer method by overexpression of its biosynthetic enzyme, GTP cyclohydrolase I (GTP-CH1). The GTP-CH1 cDNA was inserted into a pCAGGS vector, and then plasmid DNA was mixed with atelocollagen, and the aliquot was injected into thigh muscles of insulin-resistant Zucker fatty rats. After 4 weeks, pteridine derivative levels, superoxide anion (O2-), activity of endothelial nitric oxide synthase (eNOS), and endothelium-dependent relaxation were evaluated in the aortas obtained from Zucker lean or fatty rats. The BH4 contents and GTP-CH1 activity in Zucker fatty rats were 50%-55% less than those of Zucker lean rats. However, those impairments were significantly improved by a plasmid DNA injection, and aortic BH4 content reached more than 80% of the level of Zucker lean rats. Increased A23187-stimulated O2- production as well as decreased eNOS activity and endothelial function in insulin-resistant Zucker fatty rats were improved by a plasmid DNA injection to a level similar to that in Zucker lean rats. These findings suggest that intramuscular GTP-CH1 gene transfer using atelocollagen serves as a useful method of long-term systemic delivery of BH4 and the treatment of endothelial dysfunction.     

Anesthetic management of tracheobronchial stent insertion in patients who underwent laser resection, balloon dilatation and tracheostomy in advance

BACKGROUND: We report successful management of tracheobronchial stent insertion under general anesthesia. METHODS: In thirty-two cases, tracheobronchial stent insertion was performed under general anesthesia. The technique for airway management was chosen depending on the type of stent or the constriction level of the airway portion. We employed tracheostomy in order to avoid repeated intubations during the insertion of Dumon or Dynamic stent. In case of severe airway stenosis, laser resection or balloon dilatation was performed before stent insertion. RESULTS: We had 32 successful cases in 36 trials. Four trials failed due to insufficient expansion in one, mismatches of stent angle in one and pneumomediastinum in one. There was no exacerbation of respiratory condition in failed cases. There was no case who needed percutaneous cardiopulmonary support system. CONCLUSIONS: We managed tracheobronchial stent insertion under general anesthesia. Both the airway expansion by laser resection or balloon dilatation before stent insertion and also the insertion of Dumon or Dynamic stent through a tracheostomy were helpful strategies. These techniques facilitated more definitive airway maintenance and stable anesthetic management.     

Comparison of radical retropubic prostatectomy under combined lumbar spinal and epidural anesthesia with that under combined general and epidural anesthesia

PURPOSE: To evaluate the efficacy of combined lumbar spinal and epidural (CLSE) anesthesia in retropubic radical prostatectomy. MATERIALS AND METHODS: Twenty consecutive patients who underwent radical retropubic prostatectomy by a single surgeon (H.K.) under CLSE anesthesia from July of 2003 to February of 2004 were selected as subjects. They were compared with 20 consecutive patients who underwent radical retropubic prostatectomy performed by the same surgeon under combined general and epidural (CGE) anesthesia from April to December of 2002. Both periods were carefully selected to exclude radical prostatectomies with intraoperative complications to evaluate genuine effects of anesthesia. For lumbar spinal anesthesia, 0.5% hyperbaric bupivacaine hydrochloride or 0.5% hyperbaric tetracaine hydrochloride (dissolved in a 10% glucose solution) was used. An epidural tube was inserted for both lumbar spinal anesthesia and general anesthesia mainly for the purpose of controlling a pain after operation. RESULTS: Intraoperative blood loss was significantly less in the CLSE anesthesia group compared with CGE anesthesia group (p = 0.024). Postoperative water drinking was started at 0.4 days (average) for CLSE anesthesia and at 1.1 days (average) for CGE anesthesia (p < 0.0001). Postoperative diet was begun at 0.7 days (average) for CLSE anesthesia and at 1.5 days (average) for CGE anesthesia (p < 0.0001). Compared with the CLSE anesthesia group, the mean of the highest intraoperative mean blood pressure was significantly higher in the CGE anesthesia group (p = 0.002). CONCLUSION: Intraoperative blood loss was less, intraoperative change in blood pressure was less and recovery of postoperative intestinal peristalsis was earlier in patients who underwent prostatectomy under CLSE anesthesia than in patients who underwent prostatectomy under CGE anesthesia. We believe that prostatectomy under CLSE anesthesia is more advantageous than prostatectomy under CGE anesthesia.