Koung-Shing Chu

Detection of KRAS Oncogene in Peripheral Blood as a Predictor of the Response to Cetuximab Plus Chemotherapy in Patients with Metastatic Colorectal Cancer

Purpose: Previously we developed membrane-arrays as a promising tool to detect circulating tumor cells (CTC) with KRAS oncogene in patients with malignancies. This study was conducted to determinate the predictive values of CTCs with KARS mutation by membrane-arrays for metastatic colorectal cancer patients treated with cetuximab plus chemotherapy. Experimental Design: Seventy-six metastatic colorectal cancer patients receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy were enrolled. KRAS mutation status in the peripheral blood of these patients was analyzed using membrane-arrays, and KRAS mutation status in tumors was analyzed by DNA sequencing. Results: Among 76 metastatic colorectal cancer patients, KRAS mutations in tumors and in peripheral blood were identified in 33 (43.4%) and 30 (39.5%) patients, respectively. The detection sensitivity, specificity, and accuracy of membrane-arrays for CTCs with KRAS oncogene were 84.4%, 95.3%, and 90.8%, respectively, and indeed a highly significant correlation to KRAS mutations in tumors (P < 0.0001) was observed. Forty-five (59.2%) patients responded to cetuximab plus chemotherapy, and 41 and 40 were wild-type KRAS in tumors and peripheral blood, respectively (both P < 0.0001). Patients with tumors that harbor wild-type KRAS are more likely to have a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001). Likewise, patients with CTCs of wild-type KRAS in peripheral blood express a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001). Conclusions: These findings provide evidence that detection of KRAS mutational status in CTCs, by gene expression array, has potential for clinical application in selecting metastatic colorectal cancer patients most likely to benefit from cetuximab therapy.

Preoperative serum carcinoembryonic antigen, albumin and age are supplementary to UICC staging systems in predicting survival for colorectal cancer patients undergoing surgical treatment

BackgroundThe aim of this study was to determine influence of prognostic factors in addition to UICC staging systems, on cancer-specific and overall survival rates for patients with colorectal cancer (CRC) undergoing surgical treatment.MethodsBetween January 1996 and December 2006, a total of 1367 CRC patients who underwent surgical treatment in Kaohsiung Medical University Hospital were analyzed. We retrospectively investigated clinicopathologic features of these patients. All patients were followed up intensively, and their outcomes were investigated completely.ResultsOf 1367 CRC patients, there were seven hundred and fifty-seven males (55.4%) and 610 (44.6%) females. The median follow-up period was 60 months (range, 3–132 months). A multivariate analysis identified that low serum albumin level (P = 0.011), advanced UICC stage (P < 0.001), and high carcinoembryonic antigen (CEA) level (P < 0.001) were independent prognostic factors of cancer-specific survival. Meanwhile, a multivariate analysis showed age over 65 years (P < 0.001), advanced UICC stage (P < 0.001), and high CEA level (P < 0.001) were independent prognostic factors of overall survival. Furthermore, combination of UICC stage, serum CEA and albumin levels as predictors of cancer-specific survival showed that the poorer the prognostic factors involved, the poorer the cancer-specific survival rate. Likewise, combination of UICC stage, age and serum CEA level as predictors of overall survival showed that the poorer the prognostic factors involved, the poorer the overall survival rate. Of these prognostic factors, preoperative serum CEA level was the only significant prognostic factor for patients with stage II and III CRCs in both cancer-specific and overall survival categories.ConclusionPreoperative serum albumin level, CEA level and age could prominently affect postoperative outcome of CRC patients undergoing surgical treatment. In addition to conventional UICC staging system, it might be imperative to take these additional characteristics of factors into account in CRC patients prior to surgical treatment.

Predictive factors of early relapse in UICC stage I–III colorectal cancer patients after curative resection

To predict the clinicopathologic factors for early relapse of UICC stage I–III colorectal cancer (CRC) patients undergoing curative resection and thus to identify a subgroup of patients who are at high risk for postoperative early relapse.

Low-dose dexamethasone effectively prevents postoperative nausea and vomiting after ambulatory laparoscopic surgery.

Purpose“To evaluate the prophylactic effect of low-dose dexamethasone (5 mg) on postoperative nausea and vomiting (PONV) in women undergoing ambulatory laparoscopic surgery. Metoclopramide and saline served as controls.MethodsOne hundred twenty women (n=40 in each of the three groups) undergoing ambulatory laparoscopic tubal ligation under general anesthesia were enrolled in this randomized, double-blinded, placebo-controlled study. After tracheal intubation, group I receivediv dexamethasone 5 mg, whereas groups II and III receivediv metoclopramide 10 mg and saline, respectively.ResultsPatients in group I reported a lower incidence of PONV and requested less rescue antiemetics than those in group III during the first four postoperative hours (P < 0.0l). Patients in group I reported a lower incidence of PONV than those in groups II (P < 0.05) and III (P < 0.0l) during the 24-hr postoperative period. Groups II and III did not differ from each other in the incidence of PONV and the proportion of patients who requested rescue antiemetics.ConclusionProphylacticiv dexamethasone 5 mg significantly reduces the incidence of PONV in women undergoing ambulatory laparoscopic tubal ligation. At this dose, dexamethasone is more effective than metoclopramide 10 mg or placebo.RésuméObjectifÉvaluer l’effet prophylactique d’une faible dose de dexaméthasone (5 mg) sur les nausées et vomissements postopératoires (NVPO) chez des patientes de chirurgie laparoscopique ambulatoire. Le métoclopramide et une solution salée ont servi de témoins.MéthodeCent vingt femmes (n = 40 dans chacun des trois groupes formés de façon aléatoire), devant subir une ligature des trompes sous anesthésle générale en chirurgie laparoscopique ambulatoire, ont participé à l’étude randomisée, en double Insu et contrôlée contre placebo. Après l’intubation endotrachéale, les patientes du groupe I ont reçu 5 mg de dexaméthasone iv tandis que celles des groupes II et III ont reçu 10 mg de métoclopramide ou de solution salée iv, respectivement.RésultatsLes patientes du groupe I ont signalé une plus faible Incidence de NVPO et ont demandé moins d’antiémétiques de secours que les patientes du groupe III pendant les quatre premières heures postopératoires (P < 0,01). Les patients du groupe I ont eu moins de NVPO que celles des groupes II (P < 0,05) et III (P < 0,01) pendant une période de 24 h après l’intervention. Aucune différence intergroupe quant à l’incidence de NVPO et au nombre de patientes qui ont eu recours aux antiémétiques n’a été notée entre les patientes des groupes II et III.ConclusionL’administration iv de 5 mg de dexaméthasone réduit significativement l’incidence de NVPO chez des patientes qui subissent une ligature des trompes en chirurgie laparoscopique ambulatoire. Cést plus efficace que 10 mg de métoclopramide ou de placebo.

Intrathecal tri-cyclic antidepressants produce spinal anesthesia.

Abstract Tri‐cyclic antidepressants (TCAs) have been widely used in treating major depressive disorders. Recent studies further demonstrated that TCAs have potent sodium channel blocking effect, and amitriptyline, one of the TCAs, has a potent spinal anesthetic effect. The aim of the study was to evaluate the spinal anesthetic effect of various TCAs and to see whether these TCAs could likewise act as local anesthetics after a single intrathecal injection. Bupivacaine, a potent and long‐acting traditional local anesthetic, acted as control. The spinal anesthetic effect of nine TCAs (amitriptyline, doxepin, imipramine, trimipramine, clomipramine, protriptyline, desipramine, nortriptyline, and amoxapine) and three traditional local anesthetics (bupivacaine, lidocaine, and mepivacaine) was evaluated in rats and so were dose–response studies of amitriptyline, bupivacaine, and lidocaine. Under a given concentration of 5 mM, bupivacaine had the most potent spinal blockade of motor, propioception, and nociception (P<0.001) and the longest duration of action of nociception (P<0.01) among the three traditional local anesthetics. Under this concentration, amitriptyline had a similar potency but longer duration of spinal blockade of motor, propioception, and nociception (P<0.001) than did bupivacaine, whereas several other TCAs had similar or less potencies of spinal blockade than did bupivacaine. In dose–response studies, amitriptyline had a more potent (P<0.005) and longer duration (P<0.001) of spinal blockade than did bupivacaine. We concluded that intrathecal amitriptyline had a more potent and longer duration of spinal anesthetic effect than did bupivacaine, whereas several other TCAs had similar or less potencies than did bupivacaine.

Prophylacticiv ondansetron reduces nausea, vomiting and pruritus following epidural morphine for postoperative pain control

PurposeTo evaluate the prophylactic effect of ondansetron on nausea and vomiting following epidural morphine for postoperative pain control.MethodsSeventy women (n = 35 in each group) undergoing abdominal total hysterectomy under epidural anesthesia were enrolled in this randomized, double-blinded, and placebo-controlled study. At the end of surgery, all patients received epidural morphine 3 mg for postoperative pain relief. Before morphine injection, the ondansetron group receivediv ondansetron 4 mg, whereas the placebo group received iv saline.ResultsPatients in the ondansetron group reported a lower frequency of total postoperative nausea and vomiting (22%) and lower frequency of rescue antiemetic request (12%) than those in the placebo group (52% and 39%, respectively;P < 0.05). In addition, ondansetron was associated with a reduced incidence of pruritus following epidural morphine (28% vs 58%;P < 0.05).ConclusionWe conclude that iv ondansetron 4 mg is effective in the prevention of nausea, vomiting, and pruritus following epidural morphine for postoperative pain control.RésuméObjectifÉvaluer l’effet prophylactique de l’ondansétron sur les nausées et les vomissements qui suivent l’administration péridurale de morphine analgésique postopératoire.MéthodeSoixante-dix femmes (n = 35 dans chaque groupe) devant subir une hystérectomie abdominale totale sous anesthésie péridurale ont participé à l’étude randomisée, en double aveugle et contrôlée contre placebo. À la fin de l’opération, toutes les patientes ont reçu une analgésie péridurale avec 3 mg de morphine. Avant l’injection de la morphine, 4 mg d’ondansétron iv ont été administrés dans le groupe ondansétron et une solution saline dans le groupe placebo.RésultatsLes patientes ayant reçu l’ondansétron ont présenté une plus faible fréquence de nausées et de vomissements postopératoires totaux (22 %) et ont demandé moins d’antiémétique de secours (12 %), comparées aux femmes du groupe placebo (52 % et 39 %, respectivement; P < 0,05). Aussi, l’ondansétron a été associé à une incidence réduite de prurit après l’administration péridurale de morphine (28 % vs 58%; P < 0,05).ConclusionL’administration iv de 4 mg d’ondansétron est efficace pour prévenir les nausées, les vomissements et le prurit qui suivent l’administration péridurale de morphine analgésique postopératoire.

The xanthine derivative KMUP-1 inhibits models of pulmonary artery hypertension via increased NO and cGMP-dependent inhibition of RhoA/Rho kinase

Background and purpose:  KMUP‐1 is known to increase cGMP, enhance endothelial nitric oxide synthase (eNOS) and suppress Rho kinase (ROCK) expression in smooth muscle. Here, we investigated the mechanism of action of KMUP‐1 on acute and chronic pulmonary artery hypertension (PAH) in rats.

Baicalin, a flavonoid from Scutellaria baicalensis Georgi, activates large-conductance Ca2+-activated K+ channels via cyclic nucleotide-dependent protein kinases in mesenteric artery.

Baicalin isolated from Scutellaria baicalensis is a traditional Chinese herbal medicine used for cardiovascular dysfunction. The ionic mechanism of the vasorelaxant effects of baicalin remains unclear. We investigated whether baicalin relaxes mesenteric arteries (MAs) via large-conductance Ca2+-activated K+ (BK(Ca)) channel activation and voltage-dependent Ca2+ channel (VDCC) inhibition. The contractility of MA was determined by dual wire myograph. BK(Ca) channels and VDCCs were measured using whole-cell recordings in single myocytes, enzymatically dispersed from rat MAs. Baicalin (10-100 microM) attenuated 80 mM KCl-contracted MA in a concentration-related manner. L-NAME (30 microM) and indomethacin (10 microM) little affected baicalin (100 microM)-induced vasorelaxations. Contractions induced by iberiotoxin (IbTX, 0.1 microM), Bay K8644 (0.1 microM) or PMA (10 microM) were abolished by baicalin 100 microM. In MA myocytes, baicalin (0.3-30 microM) enhanced BK(Ca) channel activity in a concentration-dependent manner. Increased BK(Ca) currents were abolished by IbTX (0.1 microM). Baicalin-mediated (30 microM) BK(Ca) current activation was significantly attenuated by an adenylate cyclase inhibitor (SQ 22536, 10 microM), a soluble guanylate cyclase inhibitor (ODQ, 10 microM), competitive antagonists of cAMP and cGMP (Rp-cAMP, 100 microM and Rp-cGMP, 100 microM), and cAMP- and cGMP-dependent protein kinase inhibitors (KT5720, 0.3 microM and KT5823, 0.3 microM). Perfusate with PMA (0.1 microM) abolished baicalin-enhanced BK(Ca) currents. Additionally, baicalin (0.3-30 microM) reduced the amplitude of VDCC currents in a concentration-dependent manner and abolished VDCC activator Bay K8644-enhanced (0.1 microM) currents. Baicalin produced MA relaxation by activating BK(Ca) and inhibiting VDCC channels by endothelium-independent mechanisms and by stimulating the cGMP/PKG and cAMP/PKA pathways.

The effectiveness of dexmedetomidine infusion for sedating oral cancer patients undergoing awake fibreoptic nasal intubation.

Background and objective Dexmedetomidine is characterized with effects of sedation, analgesia, amnesia and lack of respiratory depression. Hence, it should be suitable for awake fibreoptic intubation (AFOI). Methods We enrolled 30 oral cancer patients with limited mouth openings who were undergoing AFOI for elective surgery. Patients were randomly allocated into two groups; the Dex group (n = 16) that received dexmedetomidine (1.0 μg kg−1) infusion and the Control group (n = 14) that received fentanyl (1.0 μg kg−1) infusion. Main outcomes were evaluated by grading scores presenting conditions for nasal intubation and postintubation. Other analysed parameters included airway obstruction, haemodynamic changes, consumption time for intubation, amnesia level and satisfaction. Results Intubation score (1–5) representing condition for nasal intubation was significantly better in the Dex group [2(1–3)] than in the Control group [3(2–5)] (P = 0.001). Postintubation score (1–3) representing tolerance to intubation also showed more favourable results in the Dex group [1(1–3)] than in the Control group [2(2–3)] (P = 0.002). The Dex group showed significantly reduced haemodynamic response to intubation than the Control group. Incidence requiring temporary haemodynamic support was higher in the Dex group but not of significance. Both levels of amnesia and satisfaction score were significant in the Dex group. Other analysed parameters such as consumption time for intubation, airway obstruction score and postoperative adverse events did not differ significantly. Conclusion Combination of dexmedetomidine loading with topical anaesthesia provides significant benefit for AFOI in intubation condition, patient tolerance, haemodynamic response, amnesia and satisfaction. Dexmedetomidine is effective for AFOI in anticipated difficult airway with only minor and temporary haemodynamic adverse effects.

KMUP-1 inhibits pulmonary artery proliferation by targeting serotonin receptors/transporter and NO synthase, inactivating RhoA and suppressing AKT/ERK phosphorylation.

KMUP-1 inhibits monocrotaline (MCT)-induced pulmonary artery (PA) proliferation by targeting serotonin (5-HT) receptors, inactivating RhoA and reducing phosphorylation of AKT/ERK. In MCT-treated rats, KMUP-1 f (5 mg/kg p.o.; 1mg/kg i.p.x 21 days) decreased proliferation (PCNA-positive) cells and 5-HTT-expression in lung and 5-HT levels in plasma. In isolated PA, KMUP-1 and simvastatin (0.1-100 μM) inhibited 5-HT (10 μM)-induced PA constriction. l-NAME-pretreatment reduced KMUP-1-induced relaxation. In pulmonary arterial smooth muscle cells (PASMCs), KMUP-1 (1-100 μM) and simvastatin (10 μM) inhibited 5-HT-induced cell migration and proliferation and KMUP-1 (1-100 μM) inhibited 5-HT-induced Ca²+ influx. Similar to Y27632, KMUP-1 (1-100 μM) inhibited 5-HT-induced RhoA/ROCK expression, while KMUP-1, Y27632 and simvastatin at 10 μM inhibited 5-HT-induced 5-HTT expression and KMUP-1 inhibited 5-HT-induced phosphorylation of AKT and ERK1/2 in PASMCs. In human pulmonary arterial endothelial cell (HPAEC), KMUP-1 (1-100 μM) increased the expression of eNOS and 5-HT(2B) and also at 10 μM augmented eNOS expression and production of nitric oxide (NO) in 5-HT-treated HPAEC. In radioligand binding, the IC₅₀/K(i) values of KMUP-1 for 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors were 0.34/0.0971, 0.04/0.0254, and 0.408/0.214 μM respectively. In conclusion, KMUP-1 inhibits MCT-induced PA proliferation by binding to 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors, increasing endothelial eNOS/5-HT(2B) receptor expression and NO release and inhibiting 5-HTT/RhoA/ROCK expression and AKT/ERK phosphorylation. KMUP-1 is suggested to be useful in the treatment of 5-HT-induced pulmonary artery proliferation.