Clinical practice guidelines for patients with gastrointestinal stromal tumor in Taiwan.

For many years, the understanding of gastrointestinal stromal tumors (GISTs), which are the most common mesenchymal tumors of the gastrointestinal tract, has been very limited. However, it is now possible to provide a more precise definition through the use of pathology classification and molecular techniques. Coupled with the advancement of clinical practice, especially the development of targeted therapy, there is now a much better insight into its treatment. At present, organizations such as the National Comprehensive Cancer Network in the USA and the European Society for Medical Oncology in Europe have established a consensus and drawn up guidelines for the diagnosis, treatment, and follow-up of GISTs.With experts coming from various districts in Taiwan and combining the most recent clinical data and experiences, the Taiwan Surgical Society of Gastroenterology drafted the first national GIST treatment guidelines after a consensus meeting in 2007. Following subsequent advances in GIST diagnosis and treatment, further revisions and modifications have been made to the original guidelines. We present here the updated consensus and recommendations of the Taiwan Surgical Society of Gastroenterology for the diagnosis and treatment of GIST. We hope these guidelines can help enhance the quality of diagnosis, treatment, and care of patients with GIST in Taiwan.

Effects of S/B remedy containing Scutellaria baicalensis and Bupleurum scorzonerifolfium on hepatic interleukin-6 related signal transducer and activator of transcription 3 activation in mice through cell-cell interaction.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in regulating interleukin 6 (IL-6) related growth control of the liver. Our previous study demonstrated that a mixture containing Scutellaria baicalensis and Bupleurum scorzonerifolfium (S/B remedy) modulated the growth of hepatocytes during liver regeneration after 2/3 partial hepatectomy. The aim of this study was to investigate whether S/B remedy induced mouse hepatic STAT3 activation directly in hepatocytes or indirectly via non-parenchymal cell-hepatocyte interaction. Direct S/B remedy effects were studied using primarily isolated hepatocytes; while C57BL/6J mice were used to study indirect effects of S/B remedy using gadolinium chloride to deplete Kupffer cells' function. The results showed that S/B remedy and its active constituents did not directly activate growth-related signaling in primarily isolated hepatocytes. However, S/B remedy induced STAT3 and subsequently suppressor of cytokine signaling (SOCS3) activation in mouse liver and increased serum IL-6 level in a dose-dependent manner, which could be partially blocked by pretreatment with gadolinium chloride. Oligonucloetide microarray analysis from S/B remedy-treated peripheral blood leukocytes demonstrated an up-regulation of IL-6 gene expression. We conclude that S/B remedy did not directly induce STAT3 activation in vitro, but induced hepatic IL-6 related STAT3 activation through non-parenchymal cell-hepatocyte interaction in vivo. The results provide important information on the molecular mechanisms of S/B remedy for treatment of human liver diseases.

Herb-related aneuploidy in breast fibroadenoma.

There is consensus that attitudes toward seeking complementary and alternative medicine (CAM) are different between oriental and western patients. A 16-year-old girl who presented with enlarged breast tumours also had a 3-year history of "Si-Wu-Tang" (SWT) intake. Pathology of the resected breast tumour disclosed a giant fibroadenoma with aneuploid status. A cohort study was conducted between two groups of patients with fibroadenomas: SWT intake (+) group and SWT intake (-) group. Patients were told to discontinue SWT intake for 3 months, and this was followed by breast ultrasonographic examination in both groups. The tumour sizes before and after discontinued SWT intake were 2.3±0.11 cm and 1.5±0.12 cm in the SWT (+) group, and 1.7±0.15 cm and 1.6±0.14 cm in SWT (-) group, respectively (p<0.05). It is concluded that this report provides important information for patients with breast tissue diseases and that continuous intake of medicinal herbs is recommended only under the guidance of trained CAM providers.

The management of high-risk patients with primary hyperparathyroidism - minimally invasive parathyroidectomy vs. medical treatment.

OBJECTIVE: Parathyroidectomy (PTx) for high-risk primary hyperparathyroidism (PHPT) patients poses a surgical challenge. We hypothesize that a minimally invasive parathyroidectomy (MIP) under local anaesthesia may minimize the perioperative risks and facilitate easier clinical care than medical treatment for these patients. DESIGN AND PATIENTS: We performed a prospective, nonrandomized, controlled study of 33 PHPT patients evaluated as poor general anaesthesia risks. The outline of the diseased parathyroids and the thyroid were mapped by Tc(99m) sestamibi scan and focused sonogram. MIPs were performed under local anaesthesia (group 1, 19 patients). Medical treatment with bisphosphonates was continued for patients refusing operation (group 2, 14 patients). MEASUREMENTS: Serum Ca, PO(4), and i-PTH were measured the following morning, every 6 months in the first postoperative year and then yearly for group 1 patients, or every 3 months for group 2 patients. American Society of Anaesthesiologists (ASA) and New York Heart Association (NYHA) class designations were re-evaluated every 3 months. RESULTS: In group 1, there were no operative complications, mortality or recurrent hypercalcaemia during a mean follow-up of 35.5 months. Group 2 patients had a significantly higher incidence of episodes of hypercalcaemic crisis, deteriorating renal function and weight-bearing bone fractures, while group 1 patients had a higher incidence of improved ASA and NYHA class, better 3-year overall survival rate (83.1%vs. 60.8%, P = 0.032), and less medical costs. CONCLUSION: MIP can be safely performed under local anaesthesia and it facilitates clinical care in high-risk PHPT patients. It is recommended for those selected by image localization.

Si-Wu-Tang and its constituents promote mammary duct cell proliferation by up-regulation of HER-2 signaling.

OBJECTIVE: The consumption of over-the-counter natural products by perimenopausal women remains a challenging problem. It is our aim to investigate the proliferative effect of Si-Wu-Tang (SWT) and its constituents on MCF7 breast cancer cells as well as the SWT-modulated cell signaling and HER-2 gene expression. DESIGN: By using the MCF7 (ER+, HER-2 low), BT474 (ER+, HER-2 high), MDAMB231 (ER-, HER-2 low), and SKBR3 (ER-, HER-2 high) mammary duct cell lines as our in vitro model, the mitogenic effects of SWT and its constituents were assessed by trypan blue dye exclusion assay and DNA flow cytometry. SWT-modulated cell signaling and HER-2 gene expression were evaluated in the MCF7 line by Western blot and reverse transcriptase-polymerase chain reaction analyses. RESULTS: The results showed that SWT and some of its constituents dose-dependently stimulated cell proliferation of MCF7 cells. The activation of HER-2, its downstream signaling molecules AKT and ERK1/2, as well as HER-2 gene up-regulation were involved in SWT-stimulated cell proliferation. The addition of neutralizing antibody against HER-2 abrogated the SWT-up-regulated HER-2 expression, indicating a positive feedback control for the action of HER-2 in this setting. Ferulic acid, one of the major compounds in SWT, not only promoted cell proliferation of MCF7, BT474, MDAMB231, and SKBR3 cells, but also increased the phosphorylation of HER-2, AKT, and ERK1/2, as well as overexpression of HER-2, on MCF7 cells. CONCLUSIONS: We conclude that SWT and its active constituents stimulate mammary duct cell proliferation by modulating HER-2, PI3K/AKT, and MAPK signaling and the positive feedback of HER-2 gene expression. This provides important information for perimenopausal women who are at risk of or have breast cancer or other growths in breast tissue.

Postresectional adjuvant intraportal chemotherapy in patients with hepatocellular carcinoma: a case-control study.

BACKGROUND: The postresectional tumor recurrence rate is high in patients with hepatocellular carcinoma (HCC). Tumor portal venous invasion is the most important factor related to recurrence. Adjuvant intraportal infusion chemotherapy (IPIC) was used in HCC patients to improve the outcomes. METHODS: Between June 1998 and May 1999, 28 HCC patients (IPIC group) underwent postresectional IPIC daily for 2 days with 5-fluorouracil (650 mg/m(2)), leucovorin (45 mg/m(2)), doxorubicin (10 mg/m(2)), and cisplatin (20 mg/m(2)). Treatment was repeated every 3 weeks for six cycles. Patient outcomes were compared with those of 66 matched HCC patients (control group) who underwent hepatectomy without adjuvant therapy. RESULTS: The IPIC group received an average of 5.2 cycles of chemotherapy, starting 5 to 24 days after surgery. The most frequent IPIC-related adverse events were upper abdominal pain, vomiting, and myelosuppression. Five-year disease-free and overall survival rates for the IPIC group were 44.6% and 60.7%, respectively. Subgroup analysis of patients with tumor-node-metastasis stage I and II disease identified significantly lower recurrence rates for the IPIC group (33.3%) than the control group (65.0%; P = .025). For patients with stage I and II disease, 5-year disease-free and overall survival rates for the IPIC group (70.6% and 83.3%, respectively) were significantly higher than those of the control group (33.4% and 46.9%, respectively; P < .05). Patients with stage III disease do not benefit from IPIC. CONCLUSIONS: Postoperative IPIC benefits HCC patients with tumor-node-metastasis stage I and II disease. The survival advantages demonstrated justify a selection of patients for future trials.

Effects of Scutellaria baicalensis Georgi on macrophage-hepatocyte interaction through cytokines related to growth control of murine hepatocytes.

The aim of this study is to elucidate the effects of Scutellaria baicalensis Georgi (SbG) extract and its constituents on macrophage-hepatocyte interaction in primary cultures. By using trans-well primary Kupffer cell culture or conditioned medium (CM) from murine macrophage RAW264.7 cell line (RAW cells), effects of SbG on hepatocyte growth were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and trypan blue exclusion assay. Cytokine production, antibody-neutralization studies, and molecular mechanisms of transforming growth factor (TGF)-beta1 gene expression were elucidated on SbG-treated RAW264.7 cells. In addition, recombinant human TGF-beta1 (r-human TGF-beta1) was added to elucidate the mechanisms of SbG effects on cultured hepatocytes. Immunohistochemistry using anti-NF-kappaB antibody was used to determine the possible signal transduction pathways in primary hepatocyte culture. The results showed that SbG stimulated the proliferation of cultured hepatocytes, possibly through NF-kappaB, but not of Toll-like receptor 4 activation; whereas SbG-RAW-CM and SbG in trans-well significantly suppressed the proliferation of hepatocytes. Antibody-neutralization studies revealed that TGF-beta1 was the main antimitotic cytokine in SbG-treated RAW cells CM. The growth stimulation effect of SbG on cultured hepatocytes was inhibited by exogenous administration of r-human TGF-beta1. Furthermore, SbG induced NF-kB translocation into the nuclei of cultured cells. In the RAW264.7 line, SbG and baicalin stimulated TGF-beta1 gene expression via NF-kappaB and protein kinase C activation. We conclude that SbG stimulates hepatocyte growth via activation of the NF-kappaB pathway and induces TGF-beta1 gene expression through the Kupffer cell-hepatocyte interaction, which subsequently results in the inhibition of SbG-stimulated hepatocyte growth.

Interval appendectomy after conservative treatment of an appendiceal mass.

INTRODUCTION: The purpose of this study was to clarify the role of interval appendectomy after conservative treatment of an appendiceal mass. METHODS: From January 1998 to December 2003, patients with an appendiceal mass who received conservative treatment at the Taipei Veterans General Hospital were studied retrospectively. Data on demographics, rate of appendicitis recurrence, duration of hospital stay, and complication rate were collected and analyzed. RESULTS: A total of 165 patients were included (89 males, 76 females). The mean age was 53.6 years (range 7-89 years). The rate of appendicitis recurrence after conservative treatment was 25.5%; most recurred within 6 months after discharge (83.3%). The benefit of preventing recurrence is less than 16% if interval appendectomy is performed 6 weeks after discharge and less than 10% if it is done 12 weeks later. The complication rate of appendectomy performed before or after recurrence was 10% in both groups. The duration of the second hospital stay for patients who underwent interval appendectomy before or after recurrence was 4.43 +/- 3.32 vs. 6.75 +/- 5.73 days (P = 0.023). Of the 165 patients, 17 (10.3%) had their diagnosis changed after survey or surgery, and 5 (3.03%) were found to have colon cancer upon follow-up. CONCLUSIONS: Patients who recovered from conservative treatment of an appendiceal mass should undergo colonoscopy or barium enema to detect any underlying diseases and to rule out coexistent colorectal cancer. Routine interval appendectomy benefits less than 20% of patients.

Localization of cholecystokinin and vasoactive intestinal peptide in lower biliary tract in cats following electroacupuncture on right Qimen (LR14) and Riyue (GB 24): an immunohistochemistry study.

Accumulating evidence has shown that control of the motility of the sphincter of Oddi (SO) involves a complex interaction between nerves, neurotransmitters and gastrointestinal hormones such as vasoactive intestinal peptide (VIP) and cholecystokinin (CCK). Our previous studies demonstrated that electroacupuncture (EA) modulated the SO motility in cats and rabbits through activation of nonadrenergic non-cholinergic (NANC) pathway. This study was designed to investigate the changes of neurotransmitters such as CCK and VIP in lower biliary tract in cats receiving EA stimulation. After cats were anesthetized with intramuscular injection of ketamine hydrochloride, they were prepared to conduct EA stimulation on right Qimen (LR14) and Riyue (GB 24). The parameters of EA were 6 pulses/ 3 sec and 45 pulses/ 3 sec alternatively in frequency, 1-2 mA in intensity and 20 min in stimulation duration. After the completeness of EA stimulation, visceral organs such as gallbladder, duodenum and the sphincter of Oddi were removed and frozen for immunohistochemistry localization of CCK and VIP. The results showed that the distribution of CCK-labeled cells in duodenum, gallbladder and SO were more and distinct after EA than before EA stimulation. Whereas, the VIP-labeled cells were significantly more and distinct in duodenum and SO, but not in gall bladder. We conclude that EA regulates the biliary motility though increasing the distribution of CCK- and VIP-containing cells in duodenum and the sphincter of Oddi.

Gene expression profiling predicts liver responses to a herbal remedy after partial hepatectomy in mice.

The aim of this study was to demonstrate that regenerating liver responses to a herbal remedy could be presented by gene expression profiling. Compositions of the ingredients in the remedy containing Scutellaria baicalensis Georgi and Bupleurum scorzonerifolfium Wild (S/B remedy) were analyzed and quantified by high performance liquid chromatography. By using a 70% partial hepatectomy in BALB/c mice as an in vivo model, the effects of high dose (50 mg/kg) and low dose (1 mg/kg) S/B remedy were evaluated by cDNA microarray, followed by RT-PCR and real-time PCR confirmation. Factors affecting proliferative activities of mouse hepatocytes were measured by DNA flow cytometry, BrdU incorporation assay and serum interleukin-6 (IL-6) level. Based on global gene expression profiles, the results showed that the low dose S/B remedy down-regulated expression of immediate early genes and cell cycle-related genes, whereas the high dose had opposite effects. The gene expression was further verified by real-time RT-PCR. Proliferative activities, in terms of synthetic phase fractions and G2/M phase fractions, in vehicle, low dose, and high dose groups were 18.45+/-2.56%, 14.65+/-1.06%; 9.27+/-0.85%, 7.80+/-0.11%; and 18.90+/-2.17%, 22.95+/-0.25%, respectively. The serum IL-6 level was also dose-dependent in both low and high dose S/B remedy-treated mice. We conclude that in vivo gene expression profiling correlates with liver responses to a herbal remedy, which provides a new direction for pharmaceutical studies on human diseases.

Preconditioned hyperbaric oxygenation protects the liver against ischemia-reperfusion injury in rats.

Hyperbaric oxygen (HBO) therapy is an effective adjunct in treating ischemia-reperfusion (I/R) injury of brain, small intestine, testis, and crushing extremities. This study was designed to test the hypotheses that preconditioning the rats with HBO could protect the liver against subsequent I/R injury. Daily treatment with one-dose HBO (90 min, 2.5 ATA) was brought about for male Sprague Dawley rats for 1 to 3 days before an I/R injury of liver. Hepatic expression of heat-shock protein 70 (Hsp70), total concentration of glutathione (GSH), activity of catalase, superoxide dismutase (SOD), and serum AST and ALT were estimated before and after HBO, as well as after I/R injury. The results showed that activity of hepatic catalase was decreased by one dose, but not three doses, of HBO as compared with baseline data. However, hepatic Hsp70 expression fluctuated insignificantly. AST and ALT increase less in rats preconditioned with one-dose HBO as compared with those without HBO or with three-dose HBO. Our results showed preconditioning by one-dose HBO protects rat liver against subsequent ischemia-reperfusion injury.

Enhancing effects of Scutellaria baicalensis and some of its constituents on TGF-beta1 gene expression in RAW 264.7 murine macrophage cell line.

Transforming growth factor beta1 (TGF-beta1) has been implicated as an inhibitor of cell proliferation and a potent inducer of apoptosis. Scutellaria baicalensis Georgi (SbG) has been widely used in Asia and recent investigations have shown that SbG has anticancer, antiviral, and anti-inflammatory effects. The aim of this study is to investigate the modulatory effect of SbG on TGF-beta1 gene expression. By using RAW 264.7 cell line as an in vitro model, the effects of SbG on TGF-beta1 gene expression were evaluated by ELISA, reverse-transcription polymerase chain reaction (RT-PCR) and quantitative PCR. Many inhibitors such as mitogen-activated protein kinase (MAPK) inhibitor (PD98059), p38-MAPK inhibitor (SB203580), NF-kappaB inhibitor (aspirin) and protein kinase C inhibitor (H7) were used to determine the possible signal transduction pathways. The results showed that crude extracts of SbG as well as its pure compounds, baicalin, baicalein and chrysin up-regulated TGF-beta1 gene expression on RAW 264.7 cells in a concentration-dependent manner. However, the flavonoid of SbG, wogonin, did not up-regulate TGF-beta1 expression on gene and protein levels on RAW264.7 cells. The facts that aspirin and H7 but not PD98059 and SB203580 blocked the enhancing effect suggested that NF-kappaB and PKC might be involved in baicalin-enhanced TGF-beta1 gene expression. We conclude that SbG up-regulates TGF-beta1 gene expression on RAW264.7 cells through NF-kappaB and PKC pathways and this might provide evidence to explain the therapeutic effect and potential adverse effects on the clinical use of Scutellaria baicalensis Georgi.

Salvianolic acid B enhances in vitro angiogenesis and improves skin flap survival in Sprague-Dawley rats.

Insufficient angiogenesis and microcirculatory intravascular clotting have been implicated in the pathophysiology of skin flap failure. Salvianolic acid B (Sal B), isolated from Salvia miltiorrhiza, has been reported to enhance angiogenesis in vitro. This study was aimed to determine the efficacy of Sal B on ischemia-reperfusion injury of the skin flap in Sprague-Dawley rats. Sal B was administered intraperitoneally 2 h before operation, and on the 2nd and 4th days after surgical elevation of an extended epigastric adipocutaneous flap (5 x 7 cm) in ketamine-anesthetized rats. Flap ischemia was achieved by ligating the right superficial epigastric artery and vein and clamping the left superficial epigastric artery and vein for 3 h and then released. Percentage of flap necrosis area (FNA) and plasma levels of aspartate aminotransferase, alanine aminotransferase, creatinine, and malondialdehyde were measured at 7 days after the operation. Animals were divided into six groups, including: vehicle, Sal B low dose (5 mg/kg), Sal B high dose (50 mg/kg) and each with [mesh(+)] or without mesh [mesh(-)] placement. In the three groups with mesh(+), FNA in control flaps was 53.7 +/- 6.9%, whereas low-dose and high-dose Sal B significantly improved flap survival with FNA 27.4 +/- 3.8% and 25.3 +/- 4.3%, respectively (P < 0.05, one-way ANOVA). In the three groups with mesh(-), control flaps were 35.9 +/- 4.5%, whereas high-dose Sal B also significantly improved flap survival with FNA 17.9 +/- 4.7% (P < 0.05, one-way ANOVA). There were no differences in aspartate aminotransferase, alanine aminotransferase, creatinine, or malondialdehyde between groups. We conclude that Sal B attenuates ischemia-reperfusion injury of skin flap, and provides therapeutic potential in reconstructive plastic surgery.

Chinese medicinal herbs Muh-Shiang Bin-Lang-Wan increases the motility of sphincter of Oddi in anesthetized rabbits through activation of M1 muscarinic receptors.

The sphincter of Oddi (SO) plays an important role in regulating the bile flow into the duodenum. This study was designed to investigate the effect of Chinese Medicinal Herbs Muh-Shiang-Bin-Lang-Wan (MSBLW) and their mechanism of action on regulating the motility of SO in rabbits. The activity of SO in anesthetized rabbits was measured by using a continuously perfused open-tip manometric method. The rabbits were administered with different doses of MSBLW through naso-gastric tubes. The SO motility before and after the administration of MSBLW were recorded, and analyzed with a computer equipped with an off line analysis software. The results showed that the SO activity, in terms of tonic pressure and phasic contraction pressure, were significantly changed. A significant lower tonic pressure and a higher phasic contraction pressure were noticed 40-60 min after administration of MSBLW with a peak response at 0.5-1.0 gm range. The responses were blocked by pretreatment of muscarinic receptors (M1) antagonist, pirenzepine (10 mg/kg, orally). We conclude that MSBLW is effective in increasing the SO motility in rabbits through activation of M1 muscarinic receptors. However, potential application of MSBLW in the treatment of human biliary disorders needs further evaluation.

Preconditioned somatothermal stimulation on median nerve territory increases myocardial heat shock protein 70 and protects rat hearts against ischemia-reperfusion injury.

OBJECTIVE: This study was designed to test the hypotheses that local somatothermal stimulation on the left median nerve territory increases myocardial heat shock protein 70 and that preconditioning of rats with local somatothermal stimulation protects the hearts against subsequent ischemia-reperfusion injury. METHODS: Local somatothermal stimulation was brought about by means of application of a heating rod over and above the left median nerve territory (1.5 cm proximal to the palm crease) in male Sprague-Dawley rats. After rats were treated with local somatothermal stimulation, the gene expression of heat shock protein 70 in regional muscle, heart, and liver was assessed by means of Western blotting and reverse transcription-polymerase chain reaction. In addition, durations of arrhythmia, mortality rates, and mitochondrial functions were compared between groups preconditioned with or without local somatothermal stimulation followed by subsequent myocardial ischemia-reperfusion injury. RESULTS: The results showed that the gene expression of heat shock protein 70 was upregulated in the muscle beneath the area of local somatothermal stimulation, as well as in the heart, although not in the liver. When animals were preconditioned with local somatothermal stimulation on the left median nerve territory followed by subsequent ischemia-reperfusion injury of the heart, there were significant decreases of creatine kinase level from the heart, duration of arrhythmia, mortality rate, and improved mitochondrial respiratory function compared with that seen in those without local somatothermal stimulation preconditioning. CONCLUSION: We conclude that local heat stress preconditioning on the left median nerve territory has a potential cardioprotective effect against subsequent ischemia-reperfusion injury.

Crude extract of Salvia miltiorrhiza and salvianolic acid B enhance in vitro angiogenesis in murine SVR endothelial cell line.

Salvia miltiorrhiza (SM) has been used clinically in Asian countries to improve the microcirculation in the human body. Although a pure compound extracted from SM, salvianolic acid B (Sal B), has been reported to be effective against fibrosis and ischemia-reperfusion injury, possibly through its anti-lipid peroxidation action, the effect of SM on angiogenesis remains unclear. It is our interest to investigate the role of SM on the regulation of the angiogenic process. By using the SVR endothelial cell line as an in vitro system, the effects of Sal B on the gene expression of vascular endothelial growth factor (VEGF) and its receptors VEGF-R1, VEGF-R2 were evaluated by morphology, differentiation assay, reverse-transcribed polymerase chain reaction (RT-PCR) and Western blot analysis. The results showed that both the crude extract of SM and the pure compound Sal B had enhancing effects on cell growth and differentiation. The gene expression of matrix metalloproteinase-2 (MMP-2) was up-regulated after Sal B treatment for 2 h, while VEGF and VEGF-R2 gene expression were up-regulated 40 min after Sal B treatment. We conclude that the crude extract of SM and Sal B enhance angiogenic processes on SVR cells through up-regulation of VEGF and VEGF receptors genes.

Tumor necrosis factor-producing activity of wogonin in RAW 264.7 murine macrophage cell line.

Wogonin from Scutellaria baicalensis, was demonstrated to increase nitric oxide (NO) in the murine macrophage cell line RAW 264.7. It is our aim to investigate the modulatory effect of wogonin on tumor necrosis factor-alpha (TNF-alpha) gene expression. By using RAW 264.7 as an in vitro model, the effects of wogonin on inducible nitric oxide synthase (NOS2) and TNF-alpha gene expression were evaluated by ELISA and reverse transcribed polymerase chain reaction (RT-PCR). Aspirin and H7 were used to determine the possible signal transduction pathways. The results showed that wogonin at the concentration of 10 (-5) M and 10 (-6) M up-regulated NOS2 gene expression in RAW 264.7 cells. Besides, wogonin up-regulated the gene expression of TNF-alpha, in terms of TNF-alpha secretion and transcription, in a dose dependent manner. The fact that aspirin but not H7 blocks the enhancing effect suggests that NF-kappaB might be involved in wogonin-enhanced TNF-alpha gene expression. We conclude that a low concentration of wogonin up-regulates NOS2 and TNF-alpha gene expression through NF-kappaB pathway.

A phase I study of weekly docetaxel, 24-hour infusion of high-dose fluorouracil/leucovorin and cisplatin in patients with advanced gastric cancer.

OBJECTIVES: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of both docetaxel and 5-fluorouracil (5-FU) when administered weekly in a regimen of docetaxel, 5-FU/leucovorin and cisplatin (DFLP) for 2 consecutive weeks every 3 weeks. PATIENTS AND METHODS: A total of 31 patients with chemo-naive, advanced adenocarcinoma of the stomach were enrolled in the study. Cisplatin and leucovorin dosages were fixed throughout the study at 30 and 300 mg/m2, respectively. 5-FU dosage was fixed at 1,600 mg/m2 while docetaxel was evaluated at weekly 1-hour infusion dosages of 30, 40 and 50 mg/m2 to determine the MTD. Cisplatin, 5-FU and leucovorin were administered together as a 24-hour continuous infusion following docetaxel. Weekly 5-FU dosages of 1,600, 2,000 and 2,400 mg/m2 were then evaluated after setting the docetaxel dosage at the MTD. RESULTS: A total of 95 chemotherapy cycles were administered, with a median of three cycles per patient. The MTD of docetaxel was defined at 40 mg/m2. At a docetaxel dosage of 50 mg/m2 per week, the dose-limiting events of grade 4 febrile neutropenia and grade 3 hypomagnesemia occurred. With fixation of docetaxel to 40 mg/m2, the DLT for 5-FU was found at 2,400 mg/m2 per week. This incurred grade 4 neutropenia such that the MTD of 5-FU was defined at 2,000 mg/m2. Grade 3/4 neutropenia occurred in 14 patients (45%), with 2 patients developing febrile neutropenia. Grade 2 and 3 hypomagnesemia and hypokalemia occurred in 9 (41%) and 4 (18%) patients, respectively, of the first 22 patients treated with a 24-hour infusion of cisplatin and 5-FU/leucovorin immediately following docetaxel. Following a change in the cisplatin administration schedule to a 3-hour infusion after 5-FU/leucovorin infusion, no such complications were observed in 9 subsequently treated patients. Grade 2 diarrhea was recorded in 11 patients (35%). Grade 2/3 asthenia occurred in 9 patients (30%), which resolved after correction of electrolyte disorders. Twenty-six patients were assessable for response analysis. There were 2 (7.8%) complete and 14 (53.8%) partial responses, with the overall response rate being 61.5% (95% confidence interval, 41.5-81.6%). Responses were observed at all dose levels. CONCLUSION: Two consecutive weeks of DFLP infusions every 3 weeks appear to be an active regimen with a tolerable toxicity profile in advanced gastric cancer. For further phase II studies, the recommended dose for this combination is 40 mg/m2 of docetaxel and 2,000 mg/m2 of 5-FU per week.