Rivaroxaban versus Low-Molecular-Weight Heparin for Venous Thromboembolism in Gastrointestinal and Pancreatobiliary Cancer.

BACKGROUND: Low-molecular-weight heparin (LMWH) is the standard treatment for venous thromboembolism (VTE) in patients with active cancer. However, use of factor Xa inhibitors, such as rivaroxaban, is increasing on the basis of limited clinical evidence. The present single-center study compared the incidence of bleeding and other treatment outcomes in gastrointestinal and pancreatobiliary cancer (GI tract cancer) patients administered rivaroxaban or LMWH for the treatment of VTE. METHODS: Retrospective data from 281 GI tract cancer patients who were treated for VTE with rivaroxaban (n = 78) or LMWH (n = 203) between 1 January 2012 and 31 December 2016, were analyzed. Primary end-point was the incidence of major and clinically relevant bleeding. Secondary outcomes included the incidence of recurrent VTE and mortality. RESULTS: Clinically relevant bleeding occurred in 19 patients (24.4%) in the rivaroxaban group and 31 (15.3%) in the LMWH group (P = 0.074). No inter-group difference was observed for rate of VTE recurrence (3.8% with rivaroxaban vs. 3.9% with LMWH; P > 0.999) or incidence of major bleeding (5.1% with rivaroxaban vs. 8.9% with LMWH; P = 0.296). Multivariate Cox proportional hazards analysis for age, cancer type, metastasis, history of chemotherapy or recent surgery, and Eastern Cooperative Oncology Group performance status revealed a 1.904-fold higher risk of bleeding with rivaroxaban than LMWH (1.031-3.516; P = 0.040). No significant inter-group difference was found in terms of hazard ratio for all-cause mortality. CONCLUSION: Compared to LMWH, rivaroxaban was associated with a higher incidence of clinically relevant bleeding in GI tract cancer patients presenting with VTE.

A Retrospective Study on Efficacy and Safety of Rivaroxaban and Dalteparin for Long-Term Treatment of Venous Thromboembolism in Patients with Lung Cancer.

BACKGROUND: Standard therapy for cancer-associated venous thromboembolism (VTE) is low-molecular-weight heparin. The use of direct oral anticoagulants for cancer-associated VTE has increased; however, their efficacy and safety in lung cancer patients remain unclear. OBJECTIVES: We examined the efficacy and safety of rivaroxaban compared with dalteparin for cancer-associated VTE in patients with primary lung cancer. METHODS: A single-center retrospective study of 204 patients with primary lung cancer who were prescribed rivaroxaban (n = 131) or dalteparin (n = 73) for VTE was performed. The primary endpoint was a composite event including recurrence and major or clinically relevant nonmajor bleeding. Secondary endpoints included the incidence of recurrence, major and clinically relevant nonmajor bleeding, all-cause mortality, and bleeding or pulmonary embolism-related mortality. RESULTS: The composite event occurred in 38 (29.0) and 12 (16.4%) patients in the rivaroxaban and dalteparin (p = 0.045) groups, respectively. The multivariate Cox proportional hazards model for age, Eastern Cooperative Oncology Group performance score, and bleeding risk factors revealed the rivaroxaban group showed a 1.176-fold composite event risk without statistical significance (0.595-2.324, p = 0.641). There was no statistically significant intergroup difference for the incidence of VTE recurrence (5.3% in the rivaroxaban group versus 2.7% in the dalteparin group, p = 0.495) and major or clinically relevant nonmajor bleeding (23.7% in the rivaroxaban group versus 13.7% in the dalteparin group, p = 0.089). There was no significant difference in the all-cause mortality rate (hazard ratio 0.864, 95% CI 0.624-1.196, p = 0.337). CONCLUSIONS: There was no difference in the safety and efficacy profile of rivaroxaban compared with dalteparin. Therefore, rivaroxaban may be a valuable treatment option for lung cancer-associated VTE.

In Vitro MIC Values of Rifampin and Ethambutol and Treatment Outcome in Mycobacterium avium Complex Lung Disease.

Although it is known that the in vitro MICs of rifampin and ethambutol are poorly correlated with the clinical response in Mycobacterium avium complex (MAC) lung disease (MAC-LD), evidence for this is limited. This study investigated the association between treatment outcome and the in vitro MICs of rifampin and ethambutol in patients with MAC-LD. Among patients diagnosed with macrolide-susceptible MAC-LD between January 2008 and December 2013, 274 patients who were treated with a standard regimen for ≥12 months until August 2017 and whose in vitro MIC results were available were enrolled at a tertiary referral center in South Korea. The MICs of antimicrobial agents were determined using the broth microdilution method. The mean age of the included patients was 60.4 years. The overall treatment success rate was 79.6% (218/274 patients) and tended to decrease with increasing MICs of rifampin and ethambutol, particularly at MICs of ≥8 µg/ml. Treatment success rate was significantly different between MAC isolates with MICs of ≥8 µg/ml for rifampin and ethambutol and those with MICs of <8 µg/ml for rifampin and/or ethambutol (64.9% versus 85.3%, P < 0.001). Multivariate analysis showed that an MIC of ≥8 µg/ml for both drugs and initial sputum acid-fast bacillus (AFB) smear positivity were independent risk factors for an unfavorable response (adjusted odds ratio [OR] = 3.154, 95% confidence interval [CI] = 1.641 to 6.063, and P = 0.001 for an MIC of ≥8 µg/ml; adjusted OR = 2.769, 95% CI = 1.420 to 5.399, and P = 0.003 for initial sputum AFB smear positivity). These findings suggest that the in vitro MICs of rifampin and ethambutol may be related to treatment outcome in MAC-LD.

Improvement in Ventilation-Perfusion Mismatch after Bronchoscopic Lung Volume Reduction: Quantitative Image Analysis.

Purpose To evaluate whether bronchoscopic lung volume reduction (BLVR) increases ventilation and therefore improves ventilation-perfusion (V/Q) mismatch. Materials and Methods All patients provided written informed consent to be included in this study, which was approved by the Institutional Review Board (2013-0368) of Asan Medical Center. The physiologic changes that occurred after BLVR were measured by using xenon-enhanced ventilation and iodine-enhanced perfusion dual-energy computed tomography (CT). Patients with severe emphysema plus hyperinflation who did not respond to usual treatments were eligible. Pulmonary function tests, the 6-minute walking distance (6MWD) test, quality of life assessment, and dual-energy CT were performed at baseline and 3 months after BLVR. The effect of BLVR was assessed with repeated-measures analysis of variance. Results Twenty-one patients were enrolled in this study (median age, 68 years; mean forced expiratory volume in 1 second [FEV1], 0.75 L ± 0.29). After BLVR, FEV1 (P < .001) and 6MWD (P = .002) improved significantly. Despite the reduction in lung volume (-0.39 L ± 0.44), both ventilation per voxel (P < .001) and total ventilation (P = .01) improved after BLVR. However, neither perfusion per voxel (P = .16) nor total perfusion changed significantly (P = .49). Patients with lung volume reduction of 50% or greater had significantly better improvement in FEV1 (P = .02) and ventilation per voxel (P = .03) than patients with lung volume reduction of less than 50%. V/Q mismatch also improved after BLVR (P = .005), mainly owing to the improvement in ventilation. Conclusion The dual-energy CT analyses showed that BLVR improved ventilation and V/Q mismatch. This increased lung efficiency may be the primary mechanism of improvement after BLVR, despite the reduction in lung volume. © RSNA, 2017 Online supplemental material is available for this article.

Analgesic effect of electroacupuncture on paclitaxel-induced neuropathic pain via spinal opioidergic and adrenergic mechanisms in mice.

This study was designed to determine the antinociceptive effect and related neuronal mechanism of electroacupuncture (EA) on paclitaxel (PTX)-induced neuropathic pain in mice. PTX (4 mg/kg, i.p.) was administered once a day for 5 consecutive days to induce neuropathic pain. EA stimulation (2 mA, 2 Hz, 30 min) was applied at the ST36 acupoint bilaterally once in every 2 days. Repeated EA stimulation significantly attenuated PTX-induced mechanical allodynia and thermal hyperalgesia. In a separate set of experiment, the antinociceptive effect of a single EA stimulation 8 days after PTX treatment was reduced by intrathecal pretreatment with naloxone (opioid receptor antagonist), idazoxan (alpha2-adrenoceptor antagonist) or propranolol (beta-adrenoceptor antagonist), but not prazosin (alpha1-adrenoceptor antagonist). Moreover, EA remarkably suppressed the PTX-enhanced phosphorylation of the NMDA receptor NR2B subunit in the spinal dorsal horn, and intrathecal pretreatment of naloxone, idazoxan (IDA) or propranolol blocked the effect of EA. In conclusion, EA stimulation at the ST36 acupoint significantly diminished PTX-induced neuropathic pain in mice via the mediation of spinal opioid receptor, alpha2- and beta-adrenoceptors.

A shorter treatment duration may be sufficient for patients with Mycobacterium massiliense lung disease than with Mycobacterium abscessus lung disease.

BACKGROUND: Mycobacterium abscessus complex is the second most common organism isolated from patients with nontuberculous mycobacterial (NTM) lung disease in South Korea. This study aimed to compare clinical features and treatment outcomes of M. abscessus and Mycobacterium massiliense lung disease. METHODS: We retrospectively identified stored clinical isolates of M. abscessus complex as either M. abscessus or M. massiliense and reviewed medical records to compare clinical characteristics and treatment responses. All patients were treated empirically over several months with multidrug regimens, including a macrolide and one or more parenteral agents. RESULTS: Of the 249 patient isolates tested, 128 (59 with M. abscessus and 69 with M. massiliense) met the American Thoracic Society diagnostic criteria for NTM pulmonary disease, and treatment outcomes were analyzed in 48 patients (26 with M. abscessus and 22 with M. massiliense). The clinical and radiologic findings were similar between the two groups. Although the durations of parenteral and total treatment were significantly shorter in patients with M. massiliense than in those with M. abscessus (4.7 months vs 7.4 months, P = .006, and 12.1 months vs 16.3 months, P = .043), the treatment success rate was significantly higher in patients with M. massiliense (95.5%) than in M. abscessus cases (42.3%, P < .001). CONCLUSION: Patients with M. massiliense pulmonary infection responded better to this antibiotic strategy than those with M. abscessus infection. A shortened duration of treatment may be sufficient for M. massiliense pulmonary infection.

Treatment outcomes of refractory MAC pulmonary disease treated with drugs with unclear efficacy.

We aimed to investigate the treatment outcomes of patients with refractory Mycobacterium avium complex (MAC) lung disease treated with regimens containing drugs with unclear efficacy. Of all patients diagnosed with MAC lung disease between April 2004 and September 2012 at a tertiary referral center in South Korea, the outcomes of 51 patients treated with regimens containing drugs with unclear efficacy (clofazimine, moxifloxacin, rifabutin, and linezolid) because of treatment failure after receiving standard treatment were retrospectively analyzed. The mean age (standard deviation) of the 51 patients was 59.0 (10.3) years and 29 (56.9%) were male. The etiologic agent was M. avium in 17 patients (33.3%) and Mycobacterium intracellulare in 34 patients (66.7%); 42 patients (82.4%) had the fibrocavitary form of the disease. Of the 51 patients, 26, 28, 35, and 7 received clofazimine-, moxifloxacin-, rifabutin-, and linezolid-containing regimens (numbers are not mutually exclusive), with median drug administration durations of 147, 128, 209, and 88 days, respectively. Overall, 8 patients (15.7%) had a favorable response. Treatment outcomes did not differ by drug regimen or even by the combination of more than 2 drugs. The treatment outcomes of patients with refractory MAC lung disease were unsatisfactory with regimens containing possibly effective drugs such as clofazimine, moxifloxacin, rifabutin and linezolid.

Effects of home-based pulmonary rehabilitation with a metronome-guided walking pace in chronic obstructive pulmonary disease.

Despite documented efficacy and recommendations, pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) has been underutilized. Home-based PR was proposed as an alternative, but there were limited data. The adequate exercise intensity was also a crucial issue. The aim of this study was to investigate the effects of home-based PR with a metronome-guided walking pace on functional exercise capacity and health-related quality of life (HRQOL) in COPD. The subjects participated in a 12-week home-based PR program. Exercise intensity was initially determined by cardiopulmonary exercise test, and was readjusted (the interval of metronome beeps was reset) according to submaximal endurance test. Six-minute walk test, pulmonary function test, cardiopulmonary exercise test, and St. George's Respiratory Questionnaire (SGRQ) were done before and after the 12-week program, and at 6 months after completion of rehabilitation. Thirty-three patients participated in the program. Six-minute walking distance was significantly increased (48.8 m; P = 0.017) and the SGRQ score was also improved (-15; P < 0.001) over the six-month follow-up period after rehabilitation. There were no significant differences in pulmonary function and peak exercise parameters. We developed an effective home-based PR program with a metronome-guided walking pace for COPD patients. This rehabilitation program may improve functional exercise capacity and HRQOL.

The efficacy of rifabutin for rifabutin-susceptible, multidrug-resistant tuberculosis.

OBJECTIVE: We investigated the efficacy of rifabutin (RFB)-containing regimens for the treatment of RFB-susceptible, multidrug-resistant tuberculosis (MDR-TB). METHODS: From 146 patients diagnosed with MDR-TB between January 2006 and December 2009 at Asan Medical Center in South Korea, 31 patients (21.2%) were found to have RFB-susceptible MDR-TB. Of these 31 patients, 14 patients who had been treated with RFB for more than one month were included. Forty-two patients with RFB-resistant MDR-TB were selected as a control group, and the outcomes of both groups were retrospectively compared. RESULTS: Of 14 patients with RFB-susceptible MDR-TB, the mean age was 44.4 years and the proportion of extensively drug-resistant TB (XDR-TB) was 35.7% (5/14). Baseline characteristics and the drug resistance pattern (except RFB) did not differ between the two groups. Treatment success was achieved in 12 (85.7%) patients in the RFB group: cure in 10 (71.4%) and treatment completion in two (14.3%). The treatment success rate was 52.4% (22/42) in the control group (p = 0.032). Treatment failure was more common in patients of the control group (40.5% vs. 14.3%; p = 0.106). CONCLUSIONS: RFB is useful as an additional drug in the treatment of MDR-TB in patients with RFB-susceptible MDR-TB.

Vasorelaxing Activity of Ulmus davidiana Ethanol Extracts in Rats: Activation of Endothelial Nitric Oxide Synthase.

Ulmus davidiana var. japonica Rehder (Urticales: Ulmaceae) (UD) is a tree widespread in northeast Asia. It is traditionally used for anticancer and anti-inflammatory therapy. The present study investigated the effect of an ethanol extract of UD on vascular tension and its underlying mechanism in rats. The dried root bark of UD was ground and extracted with 80% ethanol. The prepared UD extract was used in further analysis. The effect of UD on the cell viability, vasoreactivity and hemodynamics were investigated using propidium iodide staining in cultured cells, isometric tension recording and blood pressure analysis, respectively. Low dose of UD (10~100µg/ml) did not affect endothelial cell viability, but high dose of UD reduced cell viability. UD induced vasorelaxation in the range of 0.1~10µg/ml with an ED(50) value of 2µg/ml. UD-induced vasorelaxation was completely abolished by removal of the endothelium or by pre-treatment with L-NAME, an inhibitor of nitric oxide synthase. UD inhibited calcium influx induced by phenylephrine and high K(+) and also completely abolished the effect of L-NAME. Intravenous injection of UD extracts (10~100 mg/kg) decreased arterial and ventricular pressure in a dose-dependent manner. Moreover, UD extracts reduced the ventricular contractility (+dP/dt) in anesthetized rats. However, UD-induced hypotensive actions were minimized in L-NAME-treated rats. Taken together, out results showed that UD induced vasorelaxation and has antihypertensive properties, which may be due the activation of nitric oxide synthase in endothelium.

Green tea extract inhibits paraquat-induced pulmonary fibrosis by suppression of oxidative stress and endothelin-l expression.

Paraquat-induced pulmonary fibrosis involves two factors, direct injury by oxygen free radicals and indirect injury by inflammatory cells and fibroblasts. Endothelin-1 (ET-1) has been shown to act as a mediator of pulmonary fibrosis, and its formation increases during oxidative stress. We investigated whether green tea extract (GTE), which has antioxidant properties, inhibits paraquat-induced pulmonary fibrosis and whether ET-1 is involved in this process. Paraquat (0.3 mg/kg) was instilled into the right lungs of rats, following which the rats were either not further treated (Group P, n = 7), or they were administered 1% GTE mixed with feed (Group PG; n = 7) or the ET(A) receptor antagonist ZD2574 (10 mg/kg through gavage; Group PZ; n = 7) for two weeks. As control, we used rats instilled with saline (Group N; n = 6). Two weeks after paraquat instillation, we assayed the degree of pulmonary fibrosis by light microscopic morphometry and hydroxyproline content; lipid peroxidation as a marker of oxidative stresses by measurement of malondialdehyde (MDA); ET-1 by immunohistochemistry; and prepro-ET-1 mRNA expression by reverse transcription-polymerase chain reaction. Compared with Group N, significant pulmonary fibrosis was observed in Group P, accompanied by increases in MDA, ET-1, and prepro-ET-1 mRNA expression. Compared with Group P, Group PG showed significant decreases in pulmonary fibrosis, along with decreases in MDA, ET-1, and prepro-ET-1 mRNA expression. We also observed significant decreases in pulmonary fibrosis in Group PZ compared with Group P. These findings suggest that GTE inhibits paraquat-induced pulmonary fibrosis by suppression of oxidative stress and ET-1 expression.

Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs.

RATIONALE: In cigarette smoking-induced chronic obstructive pulmonary disease, structural and functional derangements are characterized by parenchymal destruction and pulmonary hypertension. Statins are 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase inhibitors that have been used as lipid-lowering agents. These drugs also have additional pharmacologic properties, including antiinflammation, scavenging reactive oxygen species, restoring endothelial function, and antithrombogenesis, all of which can counteract the harmful effects of cigarette smoking. OBJECTIVE: We performed assays to determine whether simvastatin could attenuate lung damage induced by chronic cigarette smoking in rats. METHODS: In Sprague-Dawley rats exposed to cigarette smoke for 16 weeks, morphologic changes in the lungs and pulmonary arterial pressure were examined. MAIN RESULTS: Simvastatin inhibited lung parenchymal destruction and development of pulmonary hypertension, and also inhibited peribronchial and perivascular infiltration of inflammatory cells and induction of matrix metalloproteinase-9 activity in lung tissue. Simvastatin additionally prevented pulmonary vascular remodeling and the changes in endothelial nitric oxide synthase expression induced by smoking. In human lung microvascular endothelial cells, simvastatin increased expression of endothelial nitric oxide synthase mRNA. CONCLUSIONS: Simvastatin ameliorated the structural and functional derangements of the lungs caused by cigarette smoking, partly by suppressing inflammation and matrix metalloproteinase-9 induction and preventing pulmonary vascular abnormality. These findings indicate that statins may play a role in the treatment of cigarette smoking-induced chronic obstructive pulmonary disease.