Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study.

BACKGROUND: Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up. PATIENTS AND METHODS: ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib. CONCLUSIONS: These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

Diagnostic accuracy of the jetting sign and a dilatation ratio of left renal vein in CT urography for detecting anterior nutcracker syndrome.

AIM: To investigate the diagnostic value of computed tomography (CT) urography findings of anterior nutcracker syndrome (NCS). MATERIALS AND METHODS: The study included patients with left renal vein (LRV) compression at the aortomesenteric portion at CT urography who underwent renal venography or cystoscopy. Patients with a renocaval pressure gradient of ≥3 mmHg on renal venography or bloody urine jetting from the left ureteral orifice on cystoscopy were defined as the NCS group; the remaining patients comprised the non-NCS group. CT findings were analysed using the jetting of contrast medium flow from the LRV to the inferior vena cava (jetting sign), aortomesenteric distance, presence of collateral veins, and a dilatation ratio of LRV diameter at the aortomesenteric portion (arterial phase/delayed phases). Clinical findings, including age, gender, and body-mass-index, were also analysed. CT features and clinical findings were compared between the NCS and non-NCS groups. Diagnostic performance of CT parameters was assessed using receiver operating characteristic curve analysis. RESULTS: A total of 70 patients (21 men, mean age 44.4 ± 17.2 years) with NCS (n=13) and non-NCS (n=57) were included. Younger age (<40 years), presence of the jetting sign, and a lower dilatation ratio of LRV diameter between the arterial and delayed phases (<1.7) were found to be significant independent factors for predicting the NCS group (OR 24.5, 18.9, 19.4, respectively, p<0.05 for all). The combination of the presence of the jetting sign and a dilatation ratio of LRV diameter of <1.7 obtained the highest AUC of 0.88. CONCLUSION: The jetting sign and the dilatation ratio of LRV diameter between the arterial and delayed phases can both be very useful in the diagnosis of anterior nutcracker syndrome during CT urography.

Globular adiponectin acts as a melanogenic signal in human epidermal melanocytes.

BACKGROUND: Adiponectin is an adipocyte-derived cytokine that circulates as a full-length protein and a fragment containing the globular domain of adiponectin (gAd). A recent study has reported the antimelanogenic effects of full-length adiponectin. OBJECTIVES: To examine the involvement of gAd in melanogenesis and its mechanisms of action. METHODS: The effects of gAd on melanogenesis and its mechanisms of action were investigated in human epidermal melanocytes and reconstructed epidermis, including melanin content, cellular tyrosinase activity, cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activity, expression and phosphorylation of signalling molecules. RESULTS: Exogenous gAd increased melanin content, and the mRNA levels of microphthalmia-associated transcription factor (MITF) and its downstream genes TRP1, but not TRP2, were increased by gAd. However, cAMP production and PKA activity were not affected by gAd. Moreover, attempts to elucidate the underlying mechanism behind the gAd-mediated effect revealed that gAd could regulate melanogenesis by upregulating MITF through phosphorylation of the cAMP response element-binding protein (CREB). In addition, upregulation of MITF was mediated by activation of adenosine monophosphate-activated protein kinase (AMPK)-p38 mitogen-activated protein kinase (MAPK) signalling. Taken together, these findings indicate that promotion of melanogenesis by gAd occurs through increased expression of MITF, which is mediated by activation of the AMPK-p38 MAPK-CREB pathway. CONCLUSIONS: These findings suggest that gAd contributes to epidermal homeostasis via its effect on melanocyte biology, and products of adipose tissue could affect epidermal biology.

Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy.

Background: Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure. Methods and materials: Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25. Results: Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%). Conclusions: DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. ClinicalTrials.gov: NCT01839773.

Performance of the Minto model for the target-controlled infusion of remifentanil during cardiopulmonary bypass.

We studied the predictive performance of the Minto pharmacokinetic model during cardiopulmonary bypass in patients undergoing cardiac surgery. Patients received remifentanil target-controlled infusion using the Minto model during total intravenous anaesthesia with propofol. From 56 patients, 275 arterial blood samples were drawn before, during and after bypass to determine the plasma concentration of remifentanil, and the predicted concentrations were recorded at each time. For pooled data, the median prediction error and median absolute prediction error were 21.3% and 21.8%, respectively, and 22.1% and 22.3% during bypass. Both were 148.4% during hypothermic circulatory arrest and measured concentrations were more than three times greater than predicted (26.9 (17.0) vs. 7.1 (1.6) ng.ml-1 ). The Minto model showed considerable bias but overall acceptable precision during bypass. The target concentration of remifentanil should be reduced when using the Minto model during hypothermic circulatory arrest.

Risk factors for suboptimal drug concentration of posaconazole oral suspension in patients with hematologic malignancy.

Absorption of posaconazole oral suspension is influenced by several factors including diet, medications, and mucosal integrity. However, there are few prospective data about which is the most important modifiable factor in routine clinical practice. We prospectively analyzed clinical risk factors associated with low posaconazole trough concentrations in 114 patients receiving anticancer chemotherapy due to acute myeloid leukemia or myelodysplastic syndrome who received posaconazole oral suspension. In multivariate analyses, risk factors for drug level<500ng/mL included low calorie intake, mucositis≥grade 2, H2 blocker famotidine and proton-pump inhibitor. The only significant risk factor for drug level<700ng/mL was famotidine use (adjusted relative risk, 3.18; 95% confidence interval, 1.07-9.11; P=0.038). In conclusion, medication of H2 blocker famotidine should be cautious in patients with hematologic malignancy receiving posaconazole suspension.

An Accelerator Mass Spectrometry-Enabled Microtracer Study to Evaluate the First-Pass Effect on the Absorption of YH4808.

14 C-labeled YH4808, a novel potassium-competitive acid blocker, was intravenously administered as a microtracer at 80 µg (11.8 kBq or 320 nCi) concomitantly with the nonradiolabeled oral drug at 200 mg to determine the absolute bioavailability and to assess the effect of pharmacogenomics on the oral absorption of YH4808. The absolute bioavailability was low and highly variable (mean, 10.1%; range, 2.3-19.3%), and M3 and M8, active metabolites of YH4808, were formed 22.6- and 38.5-fold higher after oral administration than intravenous administration, respectively. The product of the fraction of an oral YH4808 dose entering the gut wall and the fraction of YH4808 passing on to the portal circulation was larger in subjects carrying the variants of the CHST3, SLC15A1, and SULT1B1 genes. A combined LC+AMS is a useful tool to construct a rich and highly informative pharmacokinetic knowledge core in early clinical drug development at a reasonable cost.

PPARγ neddylation essential for adipogenesis is a potential target for treating obesity.

The preadipocyte-to-adipocyte differentiation (adipogenesis) is a key process in fat mass increase and thus it is regarded as a compelling target for preventing or treating obesity. Of adipogenic hormone receptors, peroxisome proliferator-activated receptor gamma (PPARγ) has crucial roles in adipogenesis and lipid accumulation within adipocytes. Here we demonstrate that the NEDD8 (neuronal precursor cell expressed, developmentally downregulated 8)-based post-translation modification (neddylation) of PPARγ is essential for adipogenesis. During adipogenesis, NEDD8 is robustly induced in preadipocytes and conjugates with PPARγ, leading to PPARγ stabilization. When the neddylation process was blocked by NEDD8-targeting siRNAs (or viral vectors) or an inhibitor MLN4924, adipocyte differentiation and fat tissue development were substantially impaired. We also demonstrate that MLN4924 effectively prevents the high-fat diet-induced obesity and glucose intolerance in mice. This study provides a better understanding of how the PPARγ signaling pathway starts and lasts during adipogenesis and a potential anti-obesity strategy that targets the neddylation of PPARγ.

Neuroprotective Effects of Endurance Exercise Against High-Fat Diet-Induced Hippocampal Neuroinflammation.

Obesity contributes to systemic inflammation, which is associated with the varied pathogenesis of neurodegenerative diseases. Growing evidence has demonstrated that endurance exercise (EE) mitigates obesity-induced brain inflammation. However, exercise-mediated anti-inflammatory mechanisms remain largely unknown. We investigated how treadmill exercise (TE) reverses obesity-induced brain inflammation, mainly focusing on toll-like receptor-4 (TLR-4)-dependent neuroinflammation in the obese rat brain after 20 weeks of a high-fat diet (HFD). TE in HFD-fed rats resulted in a significant lowering in the homeostasis model assessment of insulin resistance index, the area under the curve for glucose and abdominal visceral fat, and also improved working memory ability in a passive avoidance task relative to sedentary behaviour in HFD-fed rats, with the exception of body weight. More importantly, TE revoked the increase in HFD-induced proinflammatory cytokines (tumour necrosis factor α and interleukin-1ß) and cyclooxygenase-2, which is in parallel with a reduction in TLR-4 and its downstream proteins, myeloid differentiation 88 and tumour necrosis factor receptor associated factor 6, and phosphorylation of transforming growth factor ß-activated kinase 1, IkBα and nuclear factor-κB. Moreover, TE reduced an indicator of microglia activation, ionised calcium-binding adapter molecule-1, and also decreased glial fibrillary acidic protein, an indicator of gliosis formed by activated astrocytes in the cerebral cortex and the hippocampal dentate gyrus, compared to HFD-fed sedentary rats. Finally, EE up-regulated the expression of anti-apoptotic protein, Bcl-2, and suppressed the expression of pro-apoptotic protein, Bax, in the hippocampus compared to HFD-fed sedentary rats. Taken together, these data suggest that TE may exert neuroprotective effects as a result of mitigating the production of proinflammatory cytokines by inhibiting the TLR4 signalling pathways. The results of the present study suggest that the unique combination of the beneficial effects of TE on the restoration of the blood profile and the anti-inflammatory and anti-apoptotic effects on cognitive function should inspire further investigations into its therapeutic potential for metabolic disorders and neurodegenerative diseases.

Role of proton pump inhibitors in preventing hypergastrinemia-associated carcinogenesis and in antagonizing the trophic effect of gastrin.

Gastrin is the main hormone stimulating gastric acid secretion, but it exerts proliferative and anti-apoptotic actions on various cancer cell types, in addition to its well-known trophic effect on enterochromaffin-like cells. As treatment with proton pump inhibitors (PPIs) increases the biosynthesis and secretion of gastrin, it has been postulated that treatment with PPIs could increase the risk of cancer, especially in Barrett's esophagus, gastric carcinoids, and colorectal cancer (CRC). Some tumors produce gastrin of their own, which can act in an autocrine manner to promote tumor growth. In addition, gastrin is known to foster the tumor microenvironment. However, in spite of these potentially increased cancer risks due to PPI-induced hypergastrinemia, prospective, large-scale cohort studies did not show an increase in CRC prevalence. The question as to why the long-term use of PPIs was not associated with an increased cancer risk of CRC might be answered by the fact that the PPIs antagonized the trophic effects of hypergastrinemia. Furthermore, the blockade of proton pumps or potassium channels in cancer cells could limit the abnormal glycolytic energy metabolism of cancer cells. Apart from their suppressive effect on gastric acids, PPIs exert an anti-tumor effect through the selective induction of apoptosis as well as an anti-inflammatory effect, and they protect cells from developing chemo- or radiotherapeutic resistance. Moreover, the anti-carcinogenic actions of PPIs were augmented with PPI-induced hypergastrinemia. Together with their potential targeted killing of cancer stem cells, these effects demonstrate their potential anti-cancer actions.

Staging accuracy of endoscopic ultrasound performed by nonexpert endosonographers in patients with resectable esophageal squamous cell carcinoma: is it possible?

The accuracy of endoscopic ultrasound (EUS) is operator-dependent. According to learning curve study, the accuracy of EUS T-staging for esophageal cancer has been reported to be greater in an investigator who had performed at least 100 EUS examinations. We determined comparative study regarding T-staging accuracy of EUS for esophageal squamous cell carcinoma between expert and nonexpert endoscopic ultrasonographers. We retrospectively identified 73 consecutive patients with esophageal squamous cell carcinoma who underwent EUS and endoscopic mucosal resection, endoscopic submucosal dissection, or surgery. EUS was performed by expert (Group 1) and nonexpert (Group 2) endoscopic ultrasonographers in multitertiary hospitals. Groups 1 and 2 were 37 and 36 patients during 2005-2011, respectively. Forty-two patients (57.5%) of the overall patients underwent surgical exploration. Correct endoscopic ultrasonographic T-staging of Group 1 was observed in 34 (91.9%) patients, while that of Group 2 was observed in 26 (72.2%) patients. And there was significant difference in correct endoscopic ultrasonographic T-staging between Group 1 and Group 2 (P = 0.035). The incorrect endoscopic ultrasonographic T-staging of Group 1 were three cases that were overstaging (8.1%), but in Group 2 there were seven overstaging (19.4%) and three understaging (8.3%). There was no significant difference in overstaging or understaging of incorrect endoscopic ultrasonographic T-staging between Group 1 and Group 2 (P = 0.528). This study first provides evidence that endoscopic ultrasonographic T-staging of nonexpert endoscopic ultrasonographers was inferior to be correct, compared with that of expert endoscopic ultrasonographers. EUS staging for esophageal cancer should be performed by expert endoscopic ultrasonographers to provide appropriate management strategy.

Influence of hepatitis B virus reactivation on the recurrence of HBV-related hepatocellular carcinoma after curative resection in patients with low viral load.

It is unclear whether the reactivation of hepatitis B virus (HBV) influences the prognosis of hepatocellular carcinoma (HCC) after resection in patients with chronic hepatitis B. The aim of this study was to identify the influence of HBV reactivation on the recurrence of hepatitis B-related HCC after curative resection in patients with low viral load (HBV DNA <2000 IU/mL). We retrospectively analysed a total of 130 patients who underwent curative resection for HBV-related early stage HCC (single nodule; <5 cm/two or three nodules; <3 cm) with pre-operative HBV DNA levels <2000 IU/mL with serial HBV DNA tests. The predictive factors including HBV reactivation for the recurrence of HBV-related HCC after curative resection were investigated. Fifty-three patients (41%) had HBV reactivation after resection among 130 patients. HBV reactivation was observed in 22 of 53 patients with undetectable baseline HBV DNA and in 31 of 77 patients with detectable baseline HBV DNA. Cumulative recurrence rates after resection at 1, 2 and 3 years were 17.0%, 23.3% and 31.4%, respectively. The multivariable analysis demonstrated that the risk factors for the recurrence were the presence of microvascular invasion (hazard ratio (HR) 2.62, P = 0.003), multinodularity (HR 4.61, P = 0.005), HBV reactivation after resection (HR 2.03, P = 0.032) and HBeAg positivity (HR 2.06, P = 0.044). HBV reactivation after curative resection is associated with the recurrence of HBV-related HCC in patients with low viral load.

Aspirin decreases systemic exposure to clopidogrel through modulation of P-glycoprotein but does not alter its antithrombotic activity.

Decreased oral clopidogrel absorption caused by induction of intestinal permeability glycoprotein (P-gp) expression after aspirin administration was observed in rats. This study evaluated the effect of aspirin coadministration on the pharmacokinetics/pharmacodynamics of clopidogrel in humans. A single 75-mg dose of clopidogrel was orally administered before and after 2 and 4 weeks of once-daily 100-mg aspirin administration in 18 healthy volunteers who were recruited based on CYP2C19 and PON1 genotypes. Plasma concentrations of clopidogrel and its active metabolite, H4, and relative platelet inhibition (RPI) were determined. The P-gp microRNA miR-27a increased by up to 7.67-fold (P = 0.004) and the clopidogrel area under the concentration-time curve (AUC) decreased by 14% (P > 0.05), but the AUC of H4 remained unchanged and RPI increased by up to 15% (P = 0.002) after aspirin administration. These findings indicate low-dose aspirin coadministration may decrease clopidogrel bioavailability but does not decrease its efficacy.

Deubiquitination of Dishevelled by Usp14 is required for Wnt signaling.

Dishevelled (Dvl) is a key regulator of Wnt signaling both in the canonical and non-canonical pathways. Here we report the identification of a regulatory domain of ubiquitination (RDU) in the C-terminus of Dvl. Mutations in the RDU resulted in accumulation of polyubiquitinated forms of Dvl, which were mainly K63 linked. Small interfering RNA-based screening identified Usp14 as a mediator of Dvl deubiquitination. Genetic and chemical suppression of Usp14 activity caused an increase in Dvl polyubiquitination and significantly impaired downstream Wnt signaling. These data suggest that Usp14 functions as a positive regulator of the Wnt signaling pathway. Consistently, tissue microarray analysis of colon cancer revealed a strong correlation between the levels of Usp14 and ß-catenin, which suggests an oncogenic role for Usp14 via enhancement of Wnt/ß-catenin signaling.

Endoscopic submucosal dissection with sentinel node navigation surgery for early gastric cancer.

We combined endoscopic submucosal dissection (ESD) and sentinel node navigation surgery with the purpose of achieving complete resection of early gastric cancer while preserving the organ and assessing pathological nodal status. A total of 13 patients with cT1( ≤ 3 cm)N0 early gastric cancer underwent combined ESD and sentinel node navigation surgery (ESN) at a single tertiary referral center. Sentinel node navigation surgery using indocyanine green was performed during ESD and all suspected sentinel nodes were removed laparoscopically and examined intraoperatively. ESN was converted to gastrectomy with D2 dissection if there was evidence of metastasis on frozen section. ESN was completed in 12 patients and in 1 patient was converted to gastrectomy after sentinel node navigation surgery. En bloc tumor resection was achieved in all cases. Two patients underwent additional gastrectomy because they had tumor-positive vertical margins. In all cases ESN was conducted without intraoperative or postoperative adverse events. ESN is a feasible minimally invasive procedure that allows en bloc tumor resection to be achieved while assessing the pathological status of the lymph nodes.

Ginsenoside-Rp1 inhibits platelet activation and thrombus formation via impaired glycoprotein VI signalling pathway, tyrosine phosphorylation and MAPK activation.

BACKGROUND AND PURPOSE: Ginsenosides are the main constituents for the pharmacological effects of Panax ginseng. Such effects of ginsenosides including cardioprotective and anti-platelet activities have shown stability and bioavailability limitations. However, information on the anti-platelet activity of ginsenoside-Rp1 (G-Rp1), a stable derivative of ginsenoside-Rg3, is scarce. We examined the ability of G-Rp1 to modulate agonist-induced platelet activation. EXPERIMENTAL APPROACH: G-Rp1 in vitro and ex vivo effects on agonist-induced platelet-aggregation, granule-secretion, [Ca(2+) ](i) mobilization, integrin-α(IIb) ß(3) activation were examined. Vasodilator-stimulated phosphoprotein (VASP) and MAPK expressions and levels of tyrosine phosphorylation of the glycoprotein VI (GPVI) signalling pathway components were also studied. G-Rp1 effects on arteriovenous shunt thrombus formation in rats or tail bleeding time and ex vivo coagulation time in mice were determined. KEY RESULT: G-Rp1 markedly inhibited platelet aggregation induced by collagen, thrombin or ADP. While G-Rp1 elevated cAMP levels, it dose-dependently suppressed collagen-induced ATP-release, thromboxane secretion, p-selectin expression, [Ca(2+) ](i) mobilization and α(IIb) ß(3) activation and attenuated p38(MAPK) and ERK2 activation. Furthermore, G-Rp1 inhibited tyrosine phosphorylation of multiple components (Fyn, Lyn, Syk, LAT, PI3K and PLCγ2) of the GPVI signalling pathway. G-Rp1 inhibited in vivo thrombus formation and ex vivo platelet aggregation and ATP secretion without affecting tail bleeding time and coagulation time, respectively. CONCLUSION AND IMPLICATIONS: G-Rp1 inhibits collagen-induced platelet activation and thrombus formation through modulation of early GPVI signalling events, and this effect involves VASP stimulation, and ERK2 and p38(-MAPK) inhibition. These data suggest that G-Rp1 may have therapeutic potential for the treatment of cardiovascular diseases involving aberrant platelet activation.

Prolonged use of aspirin alters human and rat intestinal cells and thereby limits the absorption of clopidogrel.

Clopidogrel therapy to prevent atherothrombosis faces the challenge of reduced responsiveness. The absorption of clopidogrel is regulated by multidrug-resistance protein 1 (MDR1) in the intestinal epithelium. Given that aspirin induces MDR1 in cancer cells and peripheral blood cells, it may induce MDR1 in intestinal epithelial cells as well, thereby affecting the absorption of clopidogrel. In this study, aspirin treatment induced the expression of MDR1 in human epithelial colorectal (Caco-2) cells in vitro and in rat intestine in vivo, as evidenced by dose-dependent increases in gene, protein, and efflux function. Along with the upregulation of MDR1 proteins by aspirin, clopidogrel absorption was significantly decreased in the aspirin-treated Caco-2 cells and in rat intestine. Our data provide evidence that prolonged use of aspirin may reduce the intestinal absorption of clopidogrel. Further human studies would be necessary to clarify whether these data have any relevance to prevention of stroke or myocardial infarction.

Preoperative inflammation is a prognostic factor for gallbladder carcinoma.

BACKGROUND: Inflammation frequently accompanies gallbladder carcinoma (GBC), but its impact on outcome is unclear. The present study investigated the impact of concomitant inflammation on survival of patients with GBC. METHODS: All patients undergoing surgery for GBC between October 2003 and May 2009 were identified retrospectively from a prospectively collected database. Patients were classified according to whether preoperative inflammation was present (65 patients) or not (23). RESULTS: A total of 88 patients were enrolled. There were no differences in sex, mean age, tumour node metastasis (TNM) stage and radicality of resection between the two groups. The overall 3-year survival rate was lower in patients with preoperative inflammation than in those without (33 versus 73 per cent; P = 0·001). In univariable analysis, preoperative inflammation, T, N and M category, TNM stage, radicality of surgery and tumour differentiation were significant prognostic factors. The presence of preoperative inflammation (hazard ratio (HR) 2·38, 95 per cent confidence interval 1·04 to 5·43), lymph node metastases (HR 5·23, 1·05 to 26·09) and R1 or R2 resection (HR 3·77, 1·47 to 9·72) were independent prognostic factors for poor survival. CONCLUSION: The presence of preoperative inflammation is an independent prognostic factor for poor survival in patients with GBC.

Hybrid natural orifice transluminal endoscopic surgery: endoscopic full-thickness resection of early gastric cancer and laparoscopic regional lymph node dissection--14 human cases.

BACKGROUND AND STUDY AIM: Minimally invasive treatment has become a mainstay management strategy for early gastric cancer (EGC). Full-thickness incision of the gastric wall using natural orifice transluminal endoscopic surgery (NOTES) has been reported but is not easily applicable in clinical settings at present. The aim of the current study was to assess the feasibility of hybrid NOTES, which consists of endoscopic full-thickness gastric resection and a laparoscopic lymphadenectomy. PATIENTS AND METHODS: This was a prospective, pilot study at a single tertiary care referral center. A total of 14 patients with EGC located above the lower third of the stomach underwent hybrid NOTES. Clinically, the patients had contraindications to exclusive treatment using endoscopic submucosal dissection (ESD). The main outcome measure was technical success of hybrid NOTES. RESULTS: All cases were resected en bloc with negative surgical margins. Histologically, four cases were mucosal cancers, and 10 cases were submucosal cancers. The median tumor size was 26 mm (range 12 - 90 mm). Lymphatic vessel invasion was found in four cases without lymph node metastasis (LNM). The median number of obtained lymph nodes was 18 (range 7 - 67). LNM was discovered in one case of undifferentiated submucosal cancer without lymphovascular invasion. Hybrid NOTES was conducted without intraoperative or postoperative adverse events in nine cases. The median operating time and estimated blood loss of successful cases were 143 minutes (range 110 - 253 minutes) and 16 mL (range 5 - 30 mL), respectively. The median hospital stay was 6 days (range 4 - 10 days). Five cases were converted to a subtotal gastrectomy for various reasons. CONCLUSIONS: Hybrid NOTES could be a bridge between endoscopic resection and laparoscopic surgery and may prevent extensive gastrectomy in patients with EGC.

Prevention of development of postoperative dysesthesia in transforaminal percutaneous endoscopic lumbar discectomy for intracanalicular lumbar disc herniation: floating retraction technique.

BACKGROUND: Transforaminal percutaneous endoscopic lumbar discectomy (PELD) has become a routine surgical procedure because it is minimally invasive. Perioperative complications such as dural injury, infection, nerve root irritation and recurrence can occur not only with PELD, but also with conventional open microsurgery. In contrast, post-operative dysesthesia (POD) due to existing dorsal root ganglion (DRG) injury is a unique complication of PELD. When POD occurs, even if the traversing root has been successfully decompressed, it hinders swift recovery and delays the return to daily routines. Thus, prevention of POD is the key to successful and widespread use of PELD. MATERIAL AND METHODS: From January 2006 to December 2008, 154 patients underwent percutaneous endoscopic discectomy by floating retraction technique at 160 disc levels under local anesthesia. This approach towards the superomedial border of the lower pedicle and the cannula can be placed by gentle retraction of the root with perineural fat instead of direct compression of dorsal root ganglion. The clinical outcomes were assessed using the Visual Analogue Scale (VAS, 0-10 point) for radicular pain and low back pain, and using the Oswestry Disability Index (ODI) for functional status. Perioperative complications and recurrence were reviewed. RESULTS: The mean age was 45 years, the mean operative time was 36 min and the mean follow-up period was 3.4 years. The mean hospital stay for endoscopic discectomy was 1.8 days. No patient underwent repeated PELD or convert microsurgery by incomplete removal of the ruptured particle. All patients experienced early relief of symptoms, as determined by VAS and ODI. No patient developed POD. 1 patient experienced dural injury. There was 1 case of discitis. The recurrence rate was 1.95% (3 patients). CONCLUSION: Transforaminal percutaneous endoscopic lumbar discectomy for intracanalicular lumbar disc herniation is a safe and effective procedure. The floating retraction technique is recommended to avoid development of POD.