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Digging Deep in the Microbiome to Diagnose Clostridioides difficile Infection

Clostridioides difficileDiagnosticsMetabolomicsMicrobiome




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Limitations of Animal Studies for Predicting Toxicity in Clinical Trials: Part 2: Potential Alternatives to the Use of Animals in Preclinical Trials

Dramatically rising costs in drug development are in large part because of the high failure rates in clinical phase trials. The poor correlation of animal studies to human toxicity and efficacy have led many developers to question the value of requiring animal studies in determining which drugs should enter in-human trials. Part 1 of this 2-part series examined some of the data regarding the lack of concordance between animal toxicity studies and human trials, as well as some of the potential reasons behind it. This second part of the series focuses on some alternatives to animal trials (hereafter referred to as animal research) as well as current regulatory discussions and developments regarding such alternatives.




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Design of the {beta}3-Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure Trial

Combined pre-and post-capillary hypertension (CpcPH) is a relatively common complication of heart failure (HF) associated with a poor prognosis. Currently, there is no specific therapy approved for this entity. Recently, treatment with beta-3 adrenergic receptor (β3AR) agonists was able to improve pulmonary hemodynamics and right ventricular (RV) performance in a translational, large animal model of chronic PH. The authors present the design of a phase II randomized clinical trial that tests the benefits of mirabegron (a clinically available β3AR agonist) in patients with CpcPH due to HF. The effect of β3AR treatment will be evaluated on pulmonary hemodynamics, as well as clinical, biochemical, and advanced cardiac imaging parameters. (Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure [SPHERE-HF]; NCT02775539)




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Overdiagnosis of lung cancer with low-dose computed tomography screening: meta-analysis of the randomised clinical trials

In low-dose computed tomography (LDCT) screening for lung cancer, all three main conditions for overdiagnosis in cancer screening are present: 1) a reservoir of slowly or nongrowing lung cancer exists; 2) LDCT is a high-resolution imaging technology with the potential to identify this reservoir; and 3) eligible screening participants have a high risk of dying from causes other than lung cancer. The degree of overdiagnosis in cancer screening is most validly estimated in high-quality randomised controlled trials (RCTs), with enough follow-up time after the end of screening to avoid lead-time bias and without contamination of the control group.

Nine RCTs investigating LDCT screening were identified. Two RCTs were excluded because lung cancer incidence after the end of screening was not published. Two other RCTs using active comparators were also excluded. Therefore, five RCTs were included: two trials were at low risk of bias, two of some concern and one at high risk of bias. In a meta-analysis of the two low risk of bias RCTs including 8156 healthy current or former smokers, 49% of the screen-detected cancers were overdiagnosed. There is uncertainty about this substantial degree of overdiagnosis due to unexplained heterogeneity and low precision of the summed estimate across the two trials.

Key points

  • Nine randomised controlled trials (RCTs) on low-dose computed tomography screening were identified; five were included for meta-analysis but only two of those were at low risk of bias.

  • In a meta-analysis of recent low risk of bias RCTs including 8156 healthy current or former smokers from developed countries, we found that 49% of the screen-detected cancers may be overdiagnosed.

  • There is uncertainty about the degree of overdiagnosis in lung cancer screening due to unexplained heterogeneity and low precision of the point estimate.

  • If only high-quality RCTs are included in the meta-analysis, the degree of overdiagnosis is substantial.

  • Educational aims

  • To appreciate that low-dose computed tomography screening for lung cancer meets all three main conditions for overdiagnosis in cancer screening: a reservoir of indolent cancers exists in the population; the screening test is able to "tap" this reservoir by detecting biologically indolent cancers as well as biologically important cancers; and the population being screened is characterised by a relatively high competing risk of death from other causes

  • To learn about biases that might affect the estimates of overdiagnosis in randomised controlled trials in cancer screening




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    The STELVIO trial, a game changer for bronchoscopic lung volume reduction in patients with severe emphysema

    Chronic obstructive pulmonary disease (COPD) is characterised by persistent respiratory symptoms and airflow limitation, which is caused by small airway disease (bronchiolitis) and alveolar destruction (emphysema) [1]. Patients primarily suffering from severe emphysema are often limited in exercise capacity due to the consequences of hyperinflation [2].




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    Lung cancer incidence and mortality with extended follow-up in the National Lung Screening Trial

    Since lung cancer (LC) is still the leading cause of cancer deaths worldwide [1], early detection through screening represents an important opportunity to improve LC survival and is a priority area for cancer care. The National Lung Screening Trial (NLST) aimed to compare low-dose helical computed tomography (LDCT) with chest radiography in LC screening of current or former heavy smokers. The trial found a relative reduction in mortality from LC of 20% in those who had undergone LDCT screening. LC screening has regained prominence in the thoracic oncology literature with the completion of NELSON and other European trials, which support the role of LC screening in achieving early diagnosis and reducing mortality. A growing number of implementation pilots are providing an impetus towards organised, national programmes for LC screening, which are in need of long-term follow-up data such as those presented in this study.




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    Lung cancer incidence and mortality with extended follow-up in the National LungScreening Trial

    A 78-year-old male presented at the emergency room complaining of dry cough, fever up to 38.5 °C and malaise for 1 month. He had visited a general practitioner and received amoxicillin 500 mg three times a day for 7 days for a presumed chest infection, without improvement. He had a history of diabetes and arterial blood hypertension, for which he was receiving metformin 1000 mg twice a day and amlodipine 10 mg a day for 7 years. He reported no alcohol abuse and was an ex-smoker of 20 pack-years (quit 30 years ago). He had no recent hospitalisations or any medical interventions.




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    Sleep Restriction and Memory and Learning in Adolescents




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    Plasma Thymidine Kinase Activity as a Biomarker in Patients with Luminal Metastatic Breast Cancer Treated with Palbociclib within the TREnd Trial

    Purpose:

    Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC.

    Experimental Design:

    Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor–positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the "To Reverse ENDocrine Resistance" (TREnd) trial (n = 46).

    Results:

    Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients (n = 8) showing an increase—correlating with a worse outcome than those with decreased/stable TKa (n = 33; mPFS 3.0 vs 9.0 months; P = 0.002). At T2, mTKa was 251 Du/L; patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months; P = 0.05).

    Conclusions:

    TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib.




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    TBCRC 032 IB/II Multicenter Study: Molecular Insights to AR Antagonist and PI3K Inhibitor Efficacy in Patients with AR+ Metastatic Triple-Negative Breast Cancer

    Purpose:

    Preclinical data demonstrating androgen receptor (AR)–positive (AR+) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR+ (≥10%) breast cancer.

    Patients and Methods:

    Phase Ib patients [estrogen receptor positive (ER+) or TNBC] with AR+ breast cancer received 160 mg enzalutamide in combination with taselisib to determine dose-limiting toxicities and the maximum tolerated dose (MTD). Phase II TNBC patients were randomized to receive either enzalutamide alone or in combination with 4 mg taselisib until disease progression. Primary endpoint was clinical benefit rate (CBR) at 16 weeks.

    Results:

    The combination was tolerated, and the MTD was not reached. The adverse events were hyperglycemia and skin rash. Overall, CBR for evaluable patients receiving the combination was 35.7%, and median progression-free survival (PFS) was 3.4 months. Luminal AR (LAR) TNBC subtype patients trended toward better response compared with non-LAR (75.0% vs. 12.5%, P = 0.06), and increased PFS (4.6 vs. 2.0 months, P = 0.082). Genomic analyses revealed subtype-specific treatment response, and novel FGFR2 fusions and AR splice variants.

    Conclusions:

    The combination of enzalutamide and taselisib increased CBR in TNBC patients with AR+ tumors. Correlative analyses suggest AR protein expression alone is insufficient for identifying patients with AR-dependent tumors and knowledge of tumor LAR subtype and AR splice variants may identify patients more or less likely to benefit from AR antagonists.




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    Tissue Distribution of Doxycycline in Animal Models of Tuberculosis [Pharmacology]

    Doxycycline, an FDA-approved tetracycline, is used in tuberculosis in vivo models for the temporal control of mycobacterial gene expression. In these models, animals are infected with recombinant Mycobacterium tuberculosis carrying genes of interest under transcriptional control of the doxycycline-responsive TetR-tetO unit. To minimize fluctuations of plasma levels, doxycycline is usually administered in the diet. However, tissue penetration studies to identify the minimum doxycycline content in food achieving complete repression of TetR-controlled genes in tuberculosis (TB)-infected organs and lesions have not been conducted. Here, we first determined the tetracycline concentrations required to achieve silencing of M. tuberculosis target genes in vitro. Next, we measured doxycycline concentrations in plasma, major organs, and lung lesions in TB-infected mice and rabbits and compared these values to silencing concentrations measured in vitro. We found that 2,000 ppm doxycycline supplemented in mouse and rabbit feed is sufficient to reach target concentrations in TB lesions. In rabbit chow, the calcium content had to be reduced 5-fold to minimize chelation of doxycycline and deliver adequate oral bioavailability. Clearance kinetics from major organs and lung lesions revealed that doxycycline levels fall below concentrations that repress tet promoters within 7 to 14 days after doxycycline is removed from the diet. In summary, we have shown that 2,000 ppm doxycycline supplemented in standard mouse diet and in low-calcium rabbit diet delivers concentrations adequate to achieve full repression of tet promoters in infected tissues of mice and rabbits.




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    An Individual Participant Data Population Pharmacokinetic Meta-analysis of Drug-Drug Interactions between Lumefantrine and Commonly Used Antiretroviral Treatment [Clinical Therapeutics]

    Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations <200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively.




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    In Vitro Activity of Ceftazidime-Avibactam against Isolates from Respiratory and Blood Specimens from Patients with Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia, in a Phase 3 Clinical Trial [Susceptibility]

    Nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), is increasingly associated with multidrug-resistant Gram-negative pathogens. This study describes the in vitro activity of ceftazidime-avibactam, ceftazidime, and relevant comparator agents against bacterial pathogens isolated from patients with NP, including VAP, enrolled in a ceftazidime-avibactam phase 3 trial. Gram-positive pathogens were included if coisolated with a Gram-negative pathogen. In vitro susceptibility was determined at a central laboratory using Clinical and Laboratory Standards Institute broth microdilution methods. Of 817 randomized patients, 457 (55.9%) had ≥1 Gram-negative bacterial pathogen(s) isolated at baseline, and 149 (18.2%) had ≥1 Gram-positive pathogen(s) coisolated. The most common isolated pathogens were Klebsiella pneumoniae (18.8%), Pseudomonas aeruginosa (15.8%), and Staphylococcus aureus (11.5%). Ceftazidime-avibactam was highly active in vitro against 370 isolates of Enterobacteriaceae, with 98.6% susceptible (MIC90, 0.5 μg/ml) compared with 73.2% susceptible for ceftazidime (MIC90, >64 μg/ml). The percent susceptibility values for ceftazidime-avibactam and ceftazidime against 129 P. aeruginosa isolates were 88.4% and 72.9% (MIC90 values of 16 μg/ml and 64 μg/ml), respectively. Among ceftazidime-nonsusceptible Gram-negative isolates, ceftazidime-avibactam percent susceptibility values were 94.9% for 99 Enterobacteriaceae and 60.0% for 35 P. aeruginosa. MIC90 values for linezolid and vancomycin (permitted per protocol for Gram-positive coverage) were within their respective MIC susceptibility breakpoints against the Gram-positive pathogens isolated. This analysis demonstrates that ceftazidime-avibactam was active in vitro against the majority of Enterobacteriaceae and P. aeruginosa isolates from patients with NP, including VAP, in a phase 3 trial. (This study has been registered at ClinicalTrials.gov under identifier NCT01808092.)




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    Comparison of Treatment Outcomes between Analysis Populations in the RESTORE-IMI 1 Phase 3 Trial of Imipenem-Cilastatin-Relebactam versus Colistin plus Imipenem-Cilastatin in Patients with Imipenem-Nonsusceptible Bacterial Infections [Clinical Therapeutic

    The RESTORE-IMI 1 phase 3 trial demonstrated the efficacy and safety of imipenem-cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare the outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility. Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem-REL-susceptible pathogens were randomized 2:1 to IMI-REL plus placebo or colistin plus IMI for 5 to 21 days. The primary endpoint was a favorable overall response. Key endpoints included the clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat (mMITT) population, where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT (SmMITT) population, where eligibility was based on local, site-level testing. The SmMITT (n = 41) and MITT (n = 31) populations had similar baseline characteristics, including sex, age, illness severity, and renal function. In both analysis populations, favorable overall response rates in the IMI-REL treatment group were >70%. Favorable clinical response rates at day 28 were 71.4% for IMI-REL and 40.0% for colistin plus IMI in the mMITT population, whereas they were 75.0% for IMI-REL and 53.8% for colistin plus IMI in the SmMITT population. Day 28 all-cause mortality rates were 9.5% for IMI-REL and 30.0% for colistin plus IMI in the mMITT population, whereas they were 10.7% for IMI-REL and 23.1% for colistin plus IMI in the SmMITT population. The outcomes in the SmMITT population were generally consistent with those in the mMITT population, suggesting that outcomes may be applicable to the real-world use of IMI-REL for treating infections caused by imipenem-nonsusceptible Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02452047.)




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    Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis [Clinical Therapeutics]

    This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (P = 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (P < 0.0001). The mean NTZ MIC for Mycobacterium tuberculosis isolates was 12.3 μg/ml; the mean NTZ maximum concentration (Cmax) in plasma was 10.2 μg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against M. tuberculosis. Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.)




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    Predominant Distribution of OXA-48-Like Carbapenemase in Fecal Colonization [Letters]




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    Pemigatinib Is Active in Some FGFR2-Altered Cholangiocarcinomas [Clinical Trials]

    Pemigatinib was effective in patients with cholangiocarcinomas with FGFR2 fusions or rearrangements.




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    Somatic Copy-Number Alterations Contribute to Brain Metastasis [Metastasis]

    In lung cancer, brain metastasis was associated with somatic amplification of MYC, YAP1, or MMP13.




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    Bemarituzumab Is Active in FGFR2b-High Gastroesophageal Adenocarcinoma [Clinical Trials]

    The FGFR2b inhibitor bemarituzumab was effective in high-FGFR2b gastroesophageal adenocarcinoma.




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    Strong HPV Vaccine Response Predicts Better Survival with Chemotherapy [Clinical Trials]

    Patients with HPV16+ cervical cancer and high T-cell responses to an HPV16 vaccine survived longer.




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    Gastrin Blocks Symmetric Stem-Cell Division and Gastric Tumorigenesis [Gastric Cancer]

    Symmetric division of stem cells positive for gastrin receptor CCK2R is linked to gastric cancer.




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    FDA Pushes Enrollment of Older Adults in Trials [News in Brief]

    In a draft guidance, the FDA urges researchers to take steps to increase enrollment of adults age 65 and older in clinical trials of investigational of cancer drugs. Noting that a drug's risk–benefit profile can vary significantly across age groups, the FDA recommends including older adults in early-phase studies and modifying trial designs and recruitment strategies to make it easier for them to participate.




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    RNA sequencing profiles and diagnostic signatures linked with response to ramucirumab in gastric cancer [RESEARCH REPORT]

    Gastric cancer (GC) is the fifth-ranked cancer type by associated mortality. The proportion of early diagnosis is low, and most patients are diagnosed at the advanced stages. First-line therapy standardly includes fluoropyrimidines and platinum compounds with trastuzumab for HER2-positive cases. For recurrent disease, there are several alternative options including ramucirumab, a monoclonal therapeutic antibody that inhibits VEGF-mediated tumor angiogenesis by binding with VEGFR2, alone or in combination with other cancer drugs. However, overall response rate following ramucirumab or its combinations is 30%–80% of the patients, suggesting that personalization of drug prescription is needed to increase efficacy of treatment. We report here original tumor RNA sequencing profiles for 15 advanced GC patients linked with data on clinical response to ramucirumab or its combinations. Three genes showed differential expression in the tumors for responders versus nonresponders: CHRM3, LRFN1, and TEX15. Of them, CHRM3 was up-regulated in the responders. Using the bioinformatic platform Oncobox we simulated ramucirumab efficiency and compared output model results with actual tumor response data. An agreement was observed between predicted and real clinical outcomes (AUC ≥ 0.7). These results suggest that RNA sequencing may be used to personalize the prescription of ramucirumab for GC and indicate potential molecular mechanisms underlying ramucirumab resistance. The RNA sequencing profiles obtained here are fully compatible with the previously published Oncobox Atlas of Normal Tissue Expression (ANTE) data.




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    BRAF V600E-mutated metastatic pediatric Wilms tumor with complete response to targeted RAF/MEK inhibition [RESEARCH REPORT]

    Wilms tumor (WT) is the most common renal malignancy of childhood and accounts for 6% of all childhood malignancies. With current therapies, the 5-yr overall survival (OS) for children with unilateral favorable histology WT is greater than 85%. The prognosis is worse, however, for the roughly 15% of patients who relapse, with only 50%–80% OS reported in those with recurrence. Herein, we describe the extended and detailed clinical course of a rare case of a child with recurrent, pulmonary metastatic, favorable histology WT harboring a BRAF V600E mutation. The BRAF V600E mutation, commonly found in melanoma and other cancers, and previously undescribed in WT, has recently been reported by our group in a subset of epithelial-predominant WT. This patient, who was included in that series, presented with unilateral, stage 1, favorable histology WT and was treated with standard chemotherapy. Following the completion of therapy, the patient relapsed with pulmonary metastatic disease, that then again recurred despite an initial response to salvage chemotherapy and radiation. Next-generation sequencing (NGS) on the metastatic pulmonary nodule revealed a BRAF V600E mutation. After weighing the therapeutic options, a novel approach with dual BRAF/MEK inhibitor combination therapy was initiated. Complete radiographic response was observed following 4 months of therapy with dabrafenib and trametinib. At 12 months following the start of BRAF/MEK combination treatment, the patient continues with a complete response and has experienced minimal treatment-related side effects. This represents the first case, to our knowledge, of effective treatment with BRAF/MEK molecularly targeted therapy in a pediatric Wilms tumor patient.




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    A Case of Euglycemic Diabetic Ketoacidosis Triggered by a Ketogenic Diet in a Patient With Type 2 Diabetes Using a Sodium-Glucose Cotransporter 2 Inhibitor




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    Distribution of Highly Prevalent Musculoskeletal Disorders and Their Association With Diabetes Complications in a Population of 140 Individuals With Type 1 Diabetes: A Retrospective Study in a French Diabetes Center

    Although they are usually not considered to be diabetes complications, musculoskeletal disorders (MSKDs) are common in individuals with type 1 or type 2 diabetes and can strongly interfere with daily diabetes care, especially in people using diabetes technologies. The authors of this retrospective study in a population of 140 patients with type 1 diabetes report the distribution of subtypes of MSKDs and speculate about the mechanisms involved. The authors emphasize the need for multidisciplinary care involving not only the diabetes care team but also orthopedic surgeons. This report should lead to large, prospective studies to increase knowledge about these under-studied complications.




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    Total Antioxidant Capacity and Pancreatic Cancer Incidence and Mortality in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

    Background:

    Total antioxidant capacity (TAC) reflects an individual's overall antioxidant intake. We sought to clarify whether higher TAC is associated with lower risks of pancreatic cancer incidence and mortality in the U.S. general population.

    Methods:

    A total of 96,018 American adults were identified from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. A ferric-reducing ability of plasma score was used to reflect an individual's TAC intake from diet and/or supplements. Cox regression was used to calculate hazard ratios (HR) for pancreatic cancer incidence, and competing risk regression was used to calculate subdistribution HRs for pancreatic cancer mortality. Restricted cubic spline regression was used to test nonlinearity.

    Results:

    A total of 393 pancreatic cancer cases and 353 pancreatic cancer–related deaths were documented. Total (diet + supplements) TAC was found to be inversely associated with pancreatic cancer incidence (HR quartile 4 vs. quartile 1 = 0.53; 95% confidence interval, 0.39–0.72; Ptrend = 0.0002) and mortality (subdistribution HR quartile 4 vs. quartile 1 = 0.52; 95% confidence interval 0.38–0.72; Ptrend = 0.0003) in a nonlinear dose–response manner (all Pnonlinearity < 0.01). Similar results were observed for dietary TAC. No association of supplemental TAC with pancreatic cancer incidence and mortality was found.

    Conclusions:

    In the U.S. general population, dietary but not supplemental TAC level is inversely associated with risks of pancreatic cancer incidence and mortality in a nonlinear dose–response pattern.

    Impact:

    This is the first prospective study indicating that a diet rich in antioxidants may be beneficial in decreasing pancreatic cancer incidence and mortality.




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    Accuracy of Self-reported Colonic Polyps: Results from the Prostate, Lung, Colorectal, and Ovarian Screening Trial Study of Colonoscopy Utilization

    Background:

    Colonoscopy follow-up recommendations depend on the presence or absence of polyps, and if found, their number, size, and histology. Patients may be responsible for conveying results between primary and specialty care or providing medical information to family members; thus, accurate reporting is critical. This analysis assessed the accuracy of self-reported colonoscopy findings.

    Methods:

    3,986 participants from the Study of Colonoscopy Utilization, an ancillary study nested within the Prostate, Lung, Colorectal, and Ovarian Screening Trial, were included. Self-reports of polyp and adenoma were compared to medical records, and measures of sensitivity and specificity were calculated. Correlates of accurate self-report of polyp were assessed using logistic regression and weighted to account for study sampling.

    Results:

    The sensitivity and specificity of self-reported polyp findings were 88% and 85%, respectively, and for adenoma 11% and 99%, respectively. Among participants with a polyp, older age was associated with lower likelihood while polyp severity and non-white race were associated with increased likelihood of accurate recall. Among participants without a polyp, having multiple colonoscopies was associated with lower likelihood while family history of colorectal cancer was associated with increased likelihood of accurate recall. Among both groups, longer time since colonoscopy was associated with lower likelihood of accurate recall.

    Conclusions:

    Participants recalled with reasonable accuracy whether they had a prior polyp; however, recall of histology, specifically adenoma, was much less accurate.

    Impact:

    Identification of strategies to increase accurate self-report of colonic polyps are needed, particularly for patient–provider communications and patient reporting of results to family members.




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    One Size Does Not Fit All: Marked Heterogeneity in Incidence of and Survival from Gastric Cancer among Asian American Subgroups

    Background:

    Asian Americans are at higher risk for noncardia gastric cancers (NCGC) relative to non-Hispanic Whites (NHW). Asian Americans are genetically, linguistically, and culturally heterogeneous, yet have mostly been treated as a single population in prior studies. This aggregation may obscure important subgroup-specific cancer patterns.

    Methods:

    We utilized data from 13 regional United States cancer registries from 1990 to 2014 to determine secular trends in incidence and survivorship from NCGC. Data were analyzed for NHWs and the six largest Asian American subgroups: Chinese, Japanese, Filipino, Korean, Vietnamese, and South Asian (Indian/Pakistani).

    Results:

    There exists substantial heterogeneity in NCGC incidence between Asian subgroups, with Koreans (48.6 per 100,000 person-years) having seven-fold higher age-adjusted incidence than South Asians (7.4 per 100,000 person-years). Asians had generally earlier stages of diagnosis and higher rates of surgical resection compared with NHWs. All Asian subgroups also demonstrated higher 5-year observed survival compared with NHWs, with Koreans (41.3%) and South Asians (42.8%) having survival double that of NHWs (20.1%, P < 0.001). In multivariable regression, differences in stage of diagnosis and rates of resection partially explained the difference in survivorship between Asian subgroups.

    Conclusions:

    We find substantial differences in incidence, staging, histology, treatment, and survivorship from NCGC between Asian subgroups, data which challenge our traditional perceptions about gastric cancer in Asians. Both biological heterogeneity and cultural/environmental differences may underlie these findings.

    Impact:

    These data are relevant to the national discourse regarding the appropriate role of gastric cancer screening, and identifies high-risk racial/ethnic subgroups who many benefit from customized risk attenuation programs.




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    Maternal Epigenetic Regulation Contributes to Prevention of Estrogen Receptor-negative Mammary Cancer with Broccoli Sprout Consumption

    Cruciferous vegetables have been of special interest due to the rich presence of bioactive compounds such as sulforaphane which show promising potential on cancer prevention and therapy as an epigenetic dietary strategy. Abnormal epigenetic alteration as one of the primary contributors to tumor development is closely related to breast cancer initiation and progression. In the present study, we investigated the effect of dietary broccoli sprouts (BSp), a common cruciferous vegetable, on prevention of estrogen receptor (ER)-negative mammary tumors at three different temporal exposure windows using a spontaneous breast cancer mouse model. Our findings indicate that maternal BSp treatment exhibited profound inhibitory and preventive effects on mammary cancer formation in the nontreated mouse offspring. The BSp diet administered to adult mice also showed suppressive effects on mammary cancer but was not as profound as the maternal BSp preventive effects. Moreover, such protective effects were linked with differentially expressed tumor- and epigenetic-related genes, as well as altered global histone acetylation, DNA methylation, and DNA hydroxymethylation levels. We also found that the expression changes of tumor-related genes were associated with the levels of histone methylation of H3K4 and H3K9 in the gene promoter regions. In addition, BSp-enriched sulforaphane was shown to increase protein expression of tumor suppressor genes such as p16 and p53 and inhibit the protein levels of Bmi1, DNA methyltransferases, and histone deacetylases in ERα-negative breast cancer cell lines. Collectively, these results suggest that maternal exposure to key phytochemicals may contribute to ER-negative mammary tumor prevention in their offspring through epigenetic regulations.




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    Thalamic Massa Intermedia in Children with and without Midline Brain Malformations [PEDIATRICS]

    BACKGROUND AND PURPOSE:

    The massa intermedia is a normal midline transventricular thalamic connection. Massa intermedia aberrations are common in schizophrenia, Chiari II malformation, X-linked hydrocephalus, Cornelia de Lange syndrome, and diencephalic-mesencephalic junction dysplasia, among others. We have noticed that massa intermedia abnormalities often accompany other midline malformations. The massa intermedia has never been formally evaluated in a group of exclusively pediatric patients, to our knowledge. We sought to compare and contrast the prevalence, size, and location of the massa intermedia in pediatric patients with and without congenital midline brain abnormalities.

    MATERIALS AND METHODS:

    Successive 3T brain MR imaging examinations from pediatric patients with and without midline malformations were procured from the imaging data base at a pediatric hospital. Massa intermedia presence, size, morphology, and position were determined using 3D-TIWI with 1-mm isotropic resolution. The brain commissures, septum pellucidum, hypothalamus, hippocampus, vermis, and brain stem were evaluated to determine whether alterations were related to or predictive of massa intermedia abnormalities.

    RESULTS:

    The massa intermedia was more frequently absent, dysmorphic, and/or displaced in patients with additional midline abnormalities than in those without. The massa intermedia was absent in 40% of patients with midline malformations versus 12% of patients with normal findings (P < .001). Massa intermedia absence, surface area, and morphology were predictable by various attributes and alterations of the commissures, hippocampus, hypothalamus, vermis, brain stem, and third ventricle.

    CONCLUSIONS:

    Most pediatric patients have a thalamic massa intermedia centered in the anterior/superior third ventricle. Massa intermedia abnormalities are commonly associated with other midline malformations. Normal-variant massa intermedia absence is a diagnosis of exclusion.




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    Increased Notching of the Corpus Callosum in Fetal Alcohol Spectrum Disorder: A Callosal Misunderstanding? [PEDIATRICS]

    BACKGROUND AND PURPOSE:

    In the medicolegal literature, notching of the corpus callosum has been reported to be associated with fetal alcohol spectrum disorders. Our purpose was to analyze the prevalence of notching of the corpus callosum in a fetal alcohol spectrum disorders group and a healthy population to determine whether notching occurs with increased frequency in the fetal alcohol spectrum disorders population.

    MATERIALS AND METHODS:

    We performed a multicenter search for cases of fetal alcohol spectrum disorders and included all patients who had a sagittal T1-weighted brain MR imaging. Patients with concomitant intracranial pathology were excluded. The corpus callosum was examined for notches using previously published methods. A 2 test was used to compare the fetal alcohol spectrum disorders and healthy groups.

    RESULTS:

    Thirty-three of 59 patients with fetal alcohol spectrum disorders (0–44 years of age) identified across all centers had corpus callosum notching. Of these, 8 had an anterior corpus callosum notch (prevalence, 13.6%), 23 had a posterior corpus callosum notch (prevalence, 39%), and 2 patients demonstrated undulated morphology (prevalence, 3.4%). In the healthy population, the anterior notch prevalence was 139/875 (15.8%), posterior notch prevalence was 378/875 (43.2%), and undulating prevalence was 37/875 (4.2%). There was no significant difference among the anterior (P = .635), posterior (P = .526), and undulating (P = .755) notch prevalence in the fetal alcohol spectrum disorders and healthy groups.

    CONCLUSIONS:

    There was no significant difference in notching of the corpus callosum between patients with fetal alcohol spectrum disorders and the healthy population. Although reported to be a marker of fetal alcohol spectrum disorders, notching of the corpus callosum should not be viewed as a specific finding associated with fetal alcohol spectrum disorders.




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    Advanced ADC Histogram, Perfusion, and Permeability Metrics Show an Association with Survival and Pseudoprogression in Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium [FUNCTIONAL]

    BACKGROUND AND PURPOSE:

    Diffuse intrinsic pontine glioma is a lethal childhood brain cancer with dismal prognosis and MR imaging is the primary methodology used for diagnosis and monitoring. Our aim was to determine whether advanced diffusion, perfusion, and permeability MR imaging metrics predict survival and pseudoprogression in children with newly diagnosed diffuse intrinsic pontine glioma.

    MATERIALS AND METHODS:

    A clinical trial using the poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor veliparib concurrently with radiation therapy, followed by maintenance therapy with veliparib + temozolomide, in children with diffuse intrinsic pontine glioma was conducted by the Pediatric Brain Tumor Consortium. Standard MR imaging, DWI, dynamic contrast-enhanced perfusion, and DSC perfusion were performed at baseline and approximately every 2 months throughout treatment. ADC histogram metrics of T2-weighted FLAIR and enhancing tumor volume, dynamic contrast-enhanced permeability metrics for enhancing tumors, and tumor relative CBV from DSC perfusion MR imaging were calculated. Baseline values, post-radiation therapy changes, and longitudinal trends for all metrics were evaluated for associations with survival and pseudoprogression.

    RESULTS:

    Fifty children were evaluable for survival analyses. Higher baseline relative CBV was associated with shorter progression-free survival (P = .02, Q = 0.089) and overall survival (P = .006, Q = 0.055). Associations of higher baseline mean transfer constant from the blood plasma into the extravascular extracellular space with shorter progression-free survival (P = .03, Q = 0.105) and overall survival (P = .03, Q = 0.102) trended toward significance. An increase in relative CBV with time was associated with shorter progression-free survival (P < .001, Q < 0.001) and overall survival (P = .004, Q = 0.043). Associations of longitudinal mean extravascular extracellular volume fraction with progression-free survival (P = .03, Q = 0.104) and overall survival (P = .03, Q = 0.105) and maximum transfer constant from the blood plasma into the extravascular extracellular space with progression-free survival (P = .03, Q = 0.102) trended toward significance. Greater increases with time were associated with worse outcomes. True radiologic progression showed greater post-radiation therapy decreases in mode_ADC_FLAIR compared with pseudoprogression (means, –268.15 versus –26.11, P = .01.)

    CONCLUSIONS:

    ADC histogram, perfusion, and permeability MR imaging metrics in diffuse intrinsic pontine glioma are useful in predicting survival and pseudoprogression.




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    Treatment Outcomes of Endovascular Embolization Only in Patients with Unruptured Brain Arteriovenous Malformations: A Subgroup Analysis of ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) [INTERVENTIONAL]

    BACKGROUND AND PURPOSE:

    Endovascular embolization only has been advocated for treatment of brain arteriovenous malformations in recent trials. Our aim was to evaluate the results of embolization only in a cohort of patients who were enrolled in the A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) study at 39 clinical sites in 9 countries.

    MATERIALS AND METHODS:

    We analyzed the rates and severity of stroke and death in patients who underwent embolization only. Events were identified through in-person neurologic follow-up visits performed at 6-month intervals during the first 2 years and annually, with telephone contact every 6 months thereafter. All event-related data were reviewed by independent adjudicators.

    RESULTS:

    Among 30 patients who had embolization planned, 26 underwent embolization only. A total of 13 stroke events were reported in the follow-up period among 26 subjects (ischemic, hemorrhagic, or both in 4, 7, and 2 subjects, respectively). The adverse event occurred after the first embolization in 11 of 13 patients. One patient had a major motor deficit, and 2 patients developed major visual field deficits. One event was fatal. The modified Rankin Scale score was 0–2 at last follow-up in 11 of the 12 stroke survivors. Estimated stroke-free survival was 46% at 12 months.

    CONCLUSIONS:

    Although the rates of stroke and/or death were high in patients treated with embolization only in ARUBA, the rates of favorable outcomes following stroke were high during follow-up.




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    Brain Metastases: Insights from Statistical Modeling of Size Distribution [ADULT BRAIN]

    BACKGROUND AND PURPOSE:

    Brain metastases are a common finding on brain MRI. However, the factors that dictate their size and distribution are incompletely understood. Our aim was to discover a statistical model that can account for the size distribution of parenchymal metastases in the brain as measured on contrast-enhanced MR imaging.

    MATERIALS AND METHODS:

    Tumor volumes were calculated on the basis of measured tumor diameters from contrast-enhanced T1-weighted spoiled gradient-echo images in 68 patients with untreated parenchymal metastatic disease. Tumor volumes were then placed in rank-order distributions and compared with 11 different statistical curve types. The resultant R2 values to assess goodness of fit were calculated. The top 2 distributions were then compared using the likelihood ratio test, with resultant R values demonstrating the relative likelihood of these distributions accounting for the observed data.

    RESULTS:

    Thirty-nine of 68 cases best fit a power distribution (mean R2 = 0.938 ± 0.050), 20 cases best fit an exponential distribution (mean R2 = 0.957 ± 0.050), and the remaining cases were scattered among the remaining distributions. Likelihood ratio analysis revealed that 66 of 68 cases had a positive mean R value (1.596 ± 1.316), skewing toward a power law distribution.

    CONCLUSIONS:

    The size distributions of untreated brain metastases favor a power law distribution. This finding suggests that metastases do not exist in isolation, but rather as part of a complex system. Furthermore, these results suggest that there may be a relatively small number of underlying variables that substantially influence the behavior of these systems. The identification of these variables could have a profound effect on our understanding of these lesions and our ability to treat them.




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    The Lateral Ventricles: A Detailed Review of Anatomy, Development, and Anatomic Variations [review-article]

    SUMMARY:

    The cerebral ventricles have been studied since the fourth century BC and were originally thought to harbor the soul and higher executive functions. During the infancy of neuroradiology, alterations to the ventricular shape and position on pneumoencephalography and ventriculography were signs of mass effect or volume loss. However, in the current era of high-resolution cross-sectional imaging, variation in ventricular anatomy is more easily detectable and its clinical significance is still being investigated. Interpreting radiologists must be aware of anatomic variations of the ventricular system to prevent mistaking normal variants for pathology. We will review of the anatomy and development of the lateral ventricles and discuss several ventricular variations.




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    Sở hữu ngay Shophouse Metro Star mặt tiền Song Hành Xa Lộ Hà Nội giá chỉ 70 triệu/m2 Lh: 0933836751

    Chỉ cần thanh toán 15% sở hữu ngay Shophouse Metro Star.- Chiết khấu lên đến 10%.- Cam kết cho thuê 111,305 triệu/tháng trong 3 năm.- Cam kết mua lại sau 24 tháng với lợi nhuận 22%.- Shophouse Metro Star vị trí vàng cửa ngõ khu Đông.- Nằm ngay mặt tiền Song Hành, Xa Lộ Hà Nội, li...




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    Chuyên cho thuê căn hộ cao cấp Masteri Millennium 1PN 16tr, 2PN 18tr, 3PN 26 triệu Lh 0901756869

    Chuyên cho thuê căn hộ cao cấp Masteri Millennium giá tốt* Nhận kí gửi căn hộ cho thuê và sang nhượng từ chủ nhà* Cập nhật giá thuê Masteri Millennium hiện tại -1PN diện tích 54m2 giá NTCB 13,5-15 triệu Full nọii thất đẹp giá 16-17 triệu -2PN diện tích 65-77m2 giá NTCB 16 triệ...




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    Công ty CP Chứng khoán Ngân hàng Đầu tư và Phát triển




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    Đất nền sổ riêng rẻ nhất thành phố Bảo Lộc - 399 triệu/ nền - công chứng ngay

    Khu khép kín cao cấp. Đã có sổ riêng từng nền - công chứng ngay trong ngày. Diện tích vàng 5*25= 125m2 full thổ cư. Cơ sở hạ tầng đã làm đầy đủ bao gồm cấp nước, thoát nước, hệ thống điện, cây xanh, công viên, hồ sinh thái, khu vui chơi.Cách chợ 100m. Cách trường học 200 m. Cách hệ thống ngân hàng 200m.Giá chốt 390 triệu/ lô xây tự do. Có trả theo tiến độ chỉ 3% / tháng.Ngân hà...




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    Siêu phẩm Green Valley Bảo Lộc - biệt thự 500m2 - đã có sổ riêng từng nền - giá 550 triệu

    Khu biệt thự Compound Green Valley. Diện tích toàn khu lên đến 100.000m2. Diện tích vàng từng lô 25x20m= 500m2. Giá bán 450 triệu tương đương 900 ngàn/m2. Pháp lý: Đã có sổ riêng từng nền. Quy hoạch nhiều tiện ích cao cấp như:công viên chủ đề hoa ban Sapa. 3000m2 - 200 cây hoa ban Sapa. Khu Compound khép kín bảo vệ 24/24h. Hạ tầng đã hoàn thiện như đường nhựa nội khu, cống thoá...




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    CÔNG TY CỔ PHẦN PHÁT TRIỂN ĐỊA ỐC LUCKY LAND

    Ý nghĩa Lucky Land:

    Lucky: Thể hiện sự may mắn, tin tưởng của quý khách hàng đối với chúng tôi, luôn mang giá trị cao nhất đến cho mọi người.
    Biểu tượng hình cánh diều trong logo: Thể hiện sự thành công, phát triển, không chỉ với công ty chúng tôi, mà đó còn là sự thăng hoa của quý khách hàng khi cộng tác cùng phát triển.

    Mọi hoạt động của chúng tôi luôn được hết lòng phục vụ với sự chuyên nghiệp và chân thành.

    Tầm nhìn:

    Trong tương lai, Lucky Land sẽ phát triển thành tập đoàn đầu tư phát triển bất động sản, chuyên nghiệp, danh tiếng hoạt động mạnh mẽ trên khắp cả nước.

    Sứ mệnh:

    • Đối với cộng đồng: Đóng góp, hỗ trợ, chia sẻ tạo ra một hệ sinh thái “Sống xanh" giữa con người và môi trường. Góp phần mang lại cuộc sống hạnh phúc, thịnh vượng, ngày càng phát triển cho cộng đồng.
    • Đối với đối tác, khách hàng: Cam kết tạo ra những kênh đầu tư an toàn, lợi nhuận cao. Kết nối nhanh nhiều sản phẩm phù hợp với những nhóm khách hàng khác nhau
    • Đối với đồng nghiệp: Lucky Land tạo môi trường làm việc chuyên nghiệp, thân thiện và lương thưởng xứng đáng. Luôn khuyến khích chủ động đổi mới và phát huy sáng tạo

    Giá trị cốt lõi:

    1. An toàn: Tài chính, sinh mạng của đối tác, khách hàng, nhân viên là quan trọng nhất
    2. Đoàn kết: Nội bộ gắn kết. Kết nối đối tác, khách hàng nhanh và hiệu quả nhất
    3. Chuyên nghiệp: Tuân thủ kỷ luật, làm đúng quy trình, đơn giản nhưng bài bản
    4. Đam mê: Làm nhiệt tình, chơi hết mình với 100% năng lượng tích cực
    5. Tư duy mở: Luôn học hỏi đổi mới và ngày càng phát triển lớn mạnh

    Lĩnh vực hoạt động:

    •  Đầu tư và phát triển dự án
    •  Môi giới bất động sản: đất nền, đất thổ cư

    Liên hệ Địa ốc Lucky Land:

    Địa chỉ: lô 30, ô 98 KDC Việt – Sing, Tx. Thuận An, P. An Phú, T.Bình Dương
    Website: diaocluckyland.vn
    Hotline: 0986756236

    Trân trọng cảm ơn quý khách và hy vọng sự hợp tác tốt đẹp!




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    CÔNG TY TNHH ĐẦU TƯ VÀ PHÁT TRIỂN KINH DOANH ĐỊA ỐC THIÊN PHÚC

    Lĩnh vực hoạt động: Tư vấn, môi giới, đấu giá bất động sản, đấu giá quyền sử dụng đất

    Khu vực môi giới tốt nhất hiện nay:

    • Bán đất nền khu vực Chơn Thành, Bình Phước
    • Bán đất khu vực Chơn Thành, Bình Phước
    • Bán đất nền khu vực Bình Dương

    Loại bất động sản môi giới chủ yếu: Đất nền dự án

    Công ty TNHH đầu tư và phát triển kinh doanh địa ốc Thiên Phúc chuyên mua bán bất động sản đất nền Chơn Thành. Luôn nỗ lực tận tâm để đem đến cho khách hàng những sản phẩm chất lượng và uy tín với mức giá phù hợp.

    Thiên Phúc nơi bạn có thể đặt niềm tin khi an cư và đầu tư.

    Nhận kí gửi mua bán các loại bất động sản.

    Liên hệ ngay với chúng tôi để được hỗ trợ: 0978.646.343

    Trân trọng cảm ơn quý khách và hy vọng sự hợp tác tốt đẹp!
     




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    CÔNG TY TNHH PHÁT TRIỂN BẤT ĐỘNG SẢN QUANG MINH

    Công ty TNHH Phát triển Bất động sản Quang Minh hoạt động trong lĩnh vực tư vấn bất động sản và đầu tư cho thuê mặt bằng kinh doanh, nhà ở, căn hộ.

    Trải qua quá trình hình thành và phát triển, đến nay công ty đã có chỗ đứng trên thị trường. Với đội ngũ nhân lực trẻ, nhiệt huyết, năng động sẽ đem đến cho Quý khách hàng sự tin cậy, yên tâm.

    Chiến lược trong hai năm tới sẽ mở rộng quy mô nhân sự và phát triển thêm mảng tư vấn và đầu tư mua bán bất động sản thổ cư. Mục tiêu đào tạo khoảng 20 nhân sự có kinh nghiệm, tinh nhuệ trong nghề đầu tư và tư vấn bất động sản cùng đồng hành và phát triển cùng công ty...

    Khu vực môi giới tốt nhất hiện nay: Hoàn Kiếm, Hai Bà Trưng, Đống Đa, Cầu Giấy

    Liên hệ:

    Địa chỉ: 4 Tô Hiến Thành, quận Hai Bà Trưng, Hà Nội
    Văn phòng giao dịch: 4 Thể Giao, quận Hai Bà Trưng, Hà Nội
    Điện thoại: 0988931188 - 0946850055
    Email: Buiquangqmland@gmail.com
     




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    Townhouse for sale on 3/2 Street, District 10, near supermarket & bank, 39,9 billion, 8m x 18,5m

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    Senturia Central Point villa in Hi-Tech-Park District 9 for foreigners Great price great place

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    Townhouse, 126 sqm, Nguyen Huu Canh str, opposite to Sunwah Pearl - 3 mins drive to District 1

    The location is extremely convenient for businessman, travellers, students, employees, who need to work/study/travel in the central districts, just 3 mins drive to district 1.The house has a nice view, located on Nguyen Huu Canh street near the corner of Ngo Tat To and Thu Thiem ...




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    For Sale The Garden Townhouse Lavila Kien A- Nha Be District- 216.11sqm- The Negotiable Price

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    Bên trong biệt thự giá 45 triệu USD của đại gia mê siêu xe

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    Mua đất Triều Khúc (Hà Nội)

    Tôi đang tìm mảnh đất (có nhà kèm theo càng tốt) cho cháu con ông anh. Cháu không có nhu cầu ở ngay, chỉ muốn đất có sổ đỏ và không vướng quy hoạch gì. Tôi biết là HN đắt, nhưng hôm nọ thấy một cụ chia sẻ là mua được căn 3 tầng 35m ở làng Triều Khúc. Liệu mình có tìm được giống thế không các cụ nhỉ? Đa tạ.