Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): A randomised, double-blind, placebo-controlled, phase 3 trial
Li J.,Fudan University |
Qin S.,Chinese People's Liberation Army |
Xu R.,Sun Yat Sen University |
Yau T.C.C.,University of Hong Kong |
And 16 more authors.
The Lancet Oncology | Year: 2015
Background: In the international randomised phase 3 CORRECT trial (. NCT01103323), regorafenib significantly improved overall survival versus placebo in patients with treatment-refractory metastatic colorectal cancer. Of the 760 patients in CORRECT, 111 were Asian (mostly Japanese). This phase 3 trial was done to assess regorafenib in a broader population of Asian patients with refractory metastatic colorectal cancer than was studied in CORRECT. Methods: In this randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam, we recruited Asian patients aged 18 years or older with progressive metastatic colorectal cancer who had received at least two previous treatment lines or were unable to tolerate standard treatments. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function, without other uncontrolled medical disorders. We randomly allocated patients (2:1; with a computer-generated unicentric randomisation list [prepared by the study funder] and interactive voice response system; block size of six; stratified by metastatic site [single vs multiple organs] and time from diagnosis of metastatic disease [<18 months vs ≥18 months]) to receive oral regorafenib 160 mg once daily or placebo on days 1-21 of each 28 day cycle; patients in both groups were also to receive best supportive care. Participants, investigators, and the study funder were masked to treatment assignment. The primary endpoint was overall survival, and we analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01584830. Findings: Between April 29, 2012, and Feb 6, 2013, we screened 243 patients and randomly assigned 204 patients to receive either regorafenib (136 [67%]) or placebo (68 [33%]). After a median follow-up of 7·4 months (IQR 4·3-12·2), overall survival was significantly better with regorafenib than it was with placebo (hazard ratio 0·55, 95% CI 0·40-0·77, one-sided p=0·00016; median overall survival 8·8 months [95% CI 7·3-9·8] in the regorafenib group vs 6·3 months [4·8-7·6] in the placebo group). Drug-related adverse events occurred in 132 (97%) of 136 regorafenib recipients and 31 (46%) of 68 placebo recipients. The most frequent grade 3 or higher regorafenib-related adverse events were hand-foot skin reaction (22 [16%] of 136 patients in the regorafenib group vs none in the placebo group), hypertension (15 [11%] vs two [3%] of 68 patients in the placebo group), hyperbilirubinaemia (nine [7%] vs one [1%]), hypophosphataemia (nine [7%] vs none), alanine aminotransferase concentration increases (nine [7%] vs none), aspartate aminotransferase concentration increases (eight [6%] vs none), lipase concentration increases (six [4%] vs one [1%]), and maculopapular rash (six [4%] vs none). Drug-related serious adverse events occurred in 12 (9%) patients in the regorafenib group and three (4%) in the placebo group. Interpretation: This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting. Funding: Bayer HealthCare Pharmaceuticals. © 2015 Elsevier Ltd.
Thai K.T.D.,University of Amsterdam |
Nishiura H.,University Utrecht |
Nishiura H.,Japan Science and Technology Agency |
Hoang P.L.,Cho Ray Hospital |
And 6 more authors.
PLoS Neglected Tropical Diseases | Year: 2011
Background: This study aims to estimate the age-specific risks of clinical dengue attack (i.e., the risk of symptomatic dengue among the total number of dengue virus (DENV) infections) during primary and secondary infections. Methods: We analyzed two pieces of epidemiological information in Binh Thuan province, southern Vietnam, i.e., age-specific seroprevalence and a community-wide longitudinal study of clinical dengue attack. The latter data set stratified febrile patients with DENV infection by age as well as infection parity. A simple modeling approach was employed to estimate the age-specific risks of clinical dengue attack during primary and secondary infections. Results: Using the seroprevalence data, the force of infection was estimated to be 11.7% (95% confidence intervals (CI): 10.8-12.7) per year. Median age (and the 25-75 percentiles) of dengue fever patients during primary and secondary infections were 12 (9-20) and 20 (14-31) years, respectively. The estimated age-specific risk of clinical dengue increases as a function of age for both primary and secondary infections; the estimated proportion of symptomatic patients among the total number of infected individuals was estimated to be <7% for those aged <10 years for both primary and secondary infections, but increased as patients become older, reaching to 8-11% by the age of 20 years. Conclusions/Significance: For both primary and secondary infections, higher age at DENV infection was shown to result in higher risk of clinical attack. Age as an important modulator of clinical dengue explains recent increase in dengue notifications in ageing countries in Southeast Asia, and moreover, poses a paradoxical problem of an increase in adult patients resulting from a decline in the force of infection, which may be caused by various factors including time-dependent variations in epidemiological, ecological and demographic dynamics. © 2011 Thai et al.
Hsueh P.-R.,National Taiwan University Hospital |
Hoban D.J.,University of Manitoba |
Carmeli Y.,Beth Israel Deaconess Medical Center |
Chen S.-Y.,National Taiwan University Hospital |
And 4 more authors.
Journal of Infection | Year: 2011
Urinary tract infections (UTIs) are among the most prevalent infectious diseases in the general population. They cause a substantial financial burden in the community and are associated with significant morbidity and mortality, particularly in hospitals. With increased rates of antimicrobial resistance, especially in the Asia-Pacific region, treatment of complicated UTIs (cUTIs) can be challenging for clinicians. Consideration of an optimal antimicrobial agent should be based on local resistance patterns, patient-specific factors, pharmacokinetic and pharmacodynamic principles, and cost. In the Asia-Pacific region, nearly half of Escherichia coli urinary isolates were resistant (including intermediate and resistant) to levofloxacin or ciprofloxacin and ≥30% were resistant to third-generation cephalosporins (cefotaxime, ceftriaxone, and ceftazidime) and cefepime. Overall, 33% of urinary E. coli isolates exhibited extended-spectrum β-lactamase (ESBL)-producing phenotypes. Prevalence of ESBL-producing urinary E. coli was highest in India (60%), followed by Hong Kong (48%) and Singapore (33%). All urinary isolates of E. coli were susceptible to both ertapenem and imipenem. All urinary isolates of Klebsiella pneumoniae were susceptible to imipenem and 4% of them were resistant to ertapenem. Care should be exercised when using trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones, and cephalosporins for the empirical treatment of UTIs, particularly cUTI among moderately to severely ill patients. Empiric antimicrobial treatment for serious cUTIs in which risk factors for resistant organisms exist should include broad-spectrum antibiotics such as carbapenems (ertapenem, imipenem, meropenem, and doripenem) and piperacillin-tazobactam. Aminoglycosides, tigecycline, and polymyxins (colistin or polymyxin B) can be used for the treatment of multidrug-resistant organisms or serious cUTIs when first-line options are deemed inappropriate or patients fail therapy. Because of considerable variability in different countries, local epidemiological data is critical in the effective management of UTIs in the Asia-Pacific region. © 2011 The British Infection Association.
PubMed | Yamanashi University, Cho Ray Hospital and Kuma Hospital
Type: Journal Article | Journal: Cancer medicine | Year: 2016
BRAF V600E mutation, RET rearrangements, and RAS mutations are the common genetic alterations in differentiated thyroid carcinomas derived from follicular thyroid cells. However, the relationship between these alterations and iodine intake is still controversial. To clarify the influence of iodine intake on the occurrence of differentiated thyroid carcinomas, we performed molecular analyses for two differentiated carcinomas, papillary thyroid carcinomas (PTCs) and follicular thyroid carcinomas (FTCs), from an iodine-rich country (Japan) and an iodine-deficient country (Vietnam). We examined 120 PTCs (67 Japanese and 53 Vietnamese) and 74 FTCs (51 Japanese and 23 Vietnamese). We carried out allele-specific polymerase chain reaction (AS-PCR) for BRAF V600E, PCR and direct sequencing for RAS mutations (codon 12, 13, and 61 in NRAS, HRAS, and KRAS), and RT-PCR for RET/PTC1 and RET/PTC3. BRAF V600E was present in 55/67 (82.1%) Japanese PTCs and 44/53 (83%) Vietnamese PTCs. RET/PTC1 was identified in only one PTC from each country, and no samples had RET/PTC3. NRAS mutation was found in 17/51 (33.3%) Japanese FTCs and 4/23 (17.4%) Vietnamese FTCs. NRAS mutation was cited in codon 61 (20 cases) and codon 12 (one case). None of FTCs had KRAS or HRAS mutations. There were no significant differences in the prevalence of BRAF V600E, RET/PTC, or RAS mutations between the two countries. Our study showed no differences in genetic alterations of thyroid cancers from iodine-rich and iodine-deficient countries, possibly suggesting that iodine intake might not affect the genetic alterations of differentiated thyroid cancer.
Ho-Pham L.T.,Pham Ngoc Thach University of Medicine |
T Nguyen U.D.,Pham Ngoc Thach University of Medicine |
Pham H.N.,Cho Ray Hospital |
Nguyen N.D.,Garvan Institute of Medical Research |
And 2 more authors.
BMC Musculoskeletal Disorders | Year: 2011
Background: The aim of this study was to examine the effect of different reference ranges in bone mineral density on the diagnosis of osteoporosis. Methods. This cross-sectional study involved 357 men and 870 women aged between 18 and 89 years, who were randomly sampled from various districts within Ho Chi Minh City, Vietnam. BMD at the femoral neck, lumbar spine and whole body was measured by DXA (Hologic QDR4500). Polynomial regression models and bootstraps method were used to determine peak BMD and standard deviation (SD). Based on the two parameters, we computed T-scores (denoted by T VN) for each individual in the study. A similar diagnosis was also done based on T-scores provided by the densitometer (T DXA), which is based on the US White population (NHANES III). We then compared the concordance between T VNand T DXAin the classification of osteoporosis. Osteoporosis was defined according to the World Health Organization criteria. Results: In post-menopausal women, the prevalence of osteoporosis based on femoral neck T VNwas 29%, but when the diagnosis was based on T DXA, the prevalence was 44%. In men aged 50+ years, the T VN-based prevalence of osteoporosis was 10%, which was lower than T DXA-based prevalence (30%). Among 177 women who were diagnosed with osteoporosis by T DXA, 35% were actually osteopenia by T VN. The kappa-statistic was 0.54 for women and 0.41 for men. Conclusion: These data suggest that the T-scores provided by the Hologic QDR4500 over-diagnosed osteoporosis in Vietnamese men and women. This over-diagnosis could lead to over-treatment and influence the decision of recruitment of participants in clinical trials. © 2011 Ho-Pham et al; licensee BioMed Central Ltd.
Tran T.M.,University of Missouri |
Giang N.M.,Cho Ray Hospital
IJC Metabolic and Endocrine | Year: 2014
This article aims to discuss differences in pharmacological treatment through a period of 10. years from 2003 to 2013. Hypertension treatment faces many challenges because of patients' unawareness and adherence, clinical inertia, as well as rapid availability of new medical literature and trials. Since 2003, JNC 7 was published at nearly the same time with ESC/ESH Guidelines and WHO/ISH Statement on management of hypertension [1-3]. However, these guidelines are not homogenous in pharmacological therapy approach. Moreover, during the 10. years since 2003, many new large trials, data, and updated guidelines have resolved some main controversial problems in blood pressure (BP) goals in separate risk-categorized patients, levels of BP for initial antihypertensive therapy, choice of drugs in monotherapy, indication for drug combinations, and preferred combinations for special cases. The latest updated guidelines on hypertension treatment, 2013 ESC/ESH Guidelines for the management of arterial hypertension, not only contain significant changes in the abovementioned problems, but also raise some new questions for the future research . © 2014 The Authors.
Binh T.T.,Oita University |
Binh T.T.,Cho Ray Hospital |
Suzuki R.,Oita University |
Trang T.T.H.,Oita University |
And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015
Metronidazole resistance is a key factor associated with Helicobacter pylori treatment failure. Although this resistance is mainly associated with mutations in the rdxA and frxA genes, the question of whether metronidazole resistance is caused by the inactivation of frxA alone is still debated. Furthermore, it is unclear whether there are other mutations involved in addition to the two genes that are associated with resistance. A metronidazole-resistant strain was cultured from the metronidazole-susceptible H. pylori strain 26695-1 by exposure to low concentrations of metronidazole. The genome sequences of both susceptible and resistant H. pylori strains were determined by Illumina next-generation sequencing, from which putative candidate resistance mutations were identified. Natural transformation was used to introduce PCR products containing candidate mutations into the susceptible parent strain 26695-1, and the metronidazole MIC was determined for each strain. Mutations in frxA (hp0642), rdxA (hp0954), and rpsU (hp0562) were confirmed by the Sanger method. The mutated sequence in rdxA was successfully transformed into strain 26695-1, and the transformants showed resistance to metronidazole. The transformants containing a single mutation in rdxA showed a low MIC (16 mg/liter), while those containing mutations in both rdxA and frxA showed a higher MIC (48 mg/ liter). No transformants containing a single mutation in frxA or rpsU were obtained. Next-generation sequencing was used to identify mutations related to drug resistance. We confirmed that the mutations in rdxA are mainly associated with metronidazole resistance, and mutations in frxA are able to enhance H. pylori resistance only in the presence of rdxA mutations. Moreover, mutations in rpsU may play a role in metronidazole resistance. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
Binh T.T.,Oita University |
Binh T.T.,Cho Ray Hospital |
Shiota S.,Oita University |
Suzuki R.,Oita University |
And 7 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2014
Objectives: Resistance to clarithromycin is the most important factor causing failure of Helicobacter pylori eradication. Although clarithromycin resistance is mainly associated with three point mutations in the 23S rRNA genes, it is unclear whether other mutations are associated with this resistance. Methods: Two types of clarithromycin-resistant strains (low- and high-resistance strains) were obtained from clarithromycin-susceptible H. pylori following exposure to low clarithromycin concentrations. The genome sequences were determined with a next-generation sequencer. Natural transformation was used to introduce the candidate mutations into strain 26695. Etest and an agar dilution method were used to determine the MICs. Results: High-resistance strains contained the mutation A2143G in the 23S rRNA genes, whereas low-resistance strains did not. There were seven candidate mutations in six genes outside of the 23S rRNA genes. The mutated sequences in hp1048 (infB), hp1314 (rpl22) and the 23S rRNA gene were successfully transformed into strain 26695 and the transformants showed an increased MIC of and low resistance to clarithromycin. The transformants containing a single mutation in infB or rpl22 (either a 9 bp insertion or a 3 bp deletion) or the 23S rRNA gene showed low MICs (0.5, 2.0, 4.0 and 32 mg/L, respectively) while the transformants containing double mutations (mutation in the 23S rRNA genes and mutation in infB or rpl22) showed higher MICs (>256 mg/L). Conclusions: Next-generation sequencing can be a useful tool for screening mutations related to drug resistance. We discovered novel mutations related to clarithromycin resistance in H. pylori (infB and rpl22), which have synergic effects with 23S rRNA resulting in higher MICs. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
PubMed | Cho Ray Hospital, International Childrens Heart Fund and Debrecen University
Type: Journal Article | Journal: Asian cardiovascular & thoracic annals | Year: 2016
A 42-year-old man sustained blunt thoracic trauma after a motor vehicle accident. He underwent an urgent operation. Operative findings included a large hematoma, a 4-cm tear in the left atrial appendage, and a long pleuropericardial rupture along the right phrenic nerve. We repaired the left atrial appendage without cardiopulmonary bypass, and closed the pericardial defect primarily. The patient recovered fully and was discharged on the 6th postoperative day.
Xuan B.H.N.,Cho Ray Hospital |
Mai H.L.,Cho Ray Hospital |
Thi T.X.N.,Cho Ray Hospital |
Thi M.T.H.,Cho Ray Hospital |
And 2 more authors.
Nephrology Dialysis Transplantation | Year: 2010
Background. Social hornets attack victims in swarms in Asia, Africa and the Middle East. The venom consists of multiple proteins with myotoxin, haemotoxin, vasodilatory and anticoagulant effects.Methods. We reviewed the records of 65 patients at Cho Ray Hospital (Ho Chi Minh City, Vietnam) attacked by swarms of the lesser banded hornet, Vespa affinis. Patients were divided into four groups. Groups A and B presented within 3days of attack and C and D after 3days with ≤50 or >50 stings, respectively.Results. Varying degrees of acute kidney injury (AKI) were seen in 38 (58.5%) patients in all groups. Twenty nine required renal replacement therapy. AKI was likely to be myoglobin and toxin induced with a clinical course consistent with acute tubular injury. The prognosis for renal recovery is excellent in those who survive. Seven patients (one from Group A and six from Group B) developed non-anaphylactic shock which led to four deaths. The predominant finding in Groups C and D who sought delayed tertiary care is renal failure.Conclusions. This cases which illustrate the varied effects of hornet venom and the need to be vigilant for shock within the first 2days and persistent AKI beyond 3days of attack. © 2009 The Author.