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1.
Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial.
Jiang, YZ, Liu, Y, Xiao, Y, Hu, X, Jiang, L, Zuo, WJ, Ma, D, Ding, J, Zhu, X, Zou, J, et al
Cell research. 2021;(2):178-186
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Abstract
Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: NCT03805399), a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1-8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%-41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%-75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%-48.4% in the ITT population) but with more high grade (≥ 3) adverse events. Somatic mutations of TOP2A and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.
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A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer.
Ott, PA, Hu-Lieskovan, S, Chmielowski, B, Govindan, R, Naing, A, Bhardwaj, N, Margolin, K, Awad, MM, Hellmann, MD, Lin, JJ, et al
Cell. 2020;(2):347-362.e24
Abstract
Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).
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Individualising care in severe bronchopulmonary dysplasia: a series of N-of-1 trials comparing transpyloric and gastric feeding.
Jensen, EA, Zhang, H, Feng, R, Dysart, K, Nilan, K, Munson, DA, Kirpalani, H
Archives of disease in childhood. Fetal and neonatal edition. 2020;(4):399-404
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Abstract
OBJECTIVE Compare rates of hypoxaemia during transpyloric and gastric feedings in very preterm infants with severe bronchopulmonary dysplasia. DESIGN N-of-1 multiple crossover trials with individual patient and pooled data analyses. SETTING Level IV intensive care nursery. PATIENTS Infants receiving positive airway pressure between 36 and 55 weeks postmenstrual age were enrolled between December 2014-July 2016. INTERVENTION N-of-1 trial consisting of two blocks, each with a 4-day gastric and 4-day transpyloric feeding period assigned in random order. MAIN OUTCOME MEASURES The primary outcome was the frequency of daily intermittent hypoxaemic events (SpO2 ≤80% lasting 10-180 s). Secondary outcomes included the daily proportion of time with an SpO2 ≤80% and mean daily fraction of inspired oxygen. RESULTS Of 15 infants, 13 completed the trial and 2 stopped early for transient worsening in respiratory status during gastric feedings. In the intention-to-treat analyses, transpyloric feedings resulted in increased rates of intermittent hypoxaemia in five infants, greater time per day in hypoxaemia in three infants and more supplemental oxygen use in three infants. One infant received more supplemental oxygen during gastric feedings. The remaining study outcomes were similar between the feeding routes in all other infants. Pooling all data, transpyloric feedings resulted in a higher frequency of intermittent hypoxaemic events (median 7.5/day (IQR 1-23.5) vs 3/day (1-11); adjusted incidence rate ratio 1.8, 95% CI 1.3 to 2.5) and a greater proportion of daily hypoxaemia time (median 0.8% (IQR 0.1-2.3) vs 0.4% (0.07-1.8); adjusted mean difference 1.6, 95% CI 1.1 to 2.5). CONCLUSIONS Transpyloric compared with gastric feedings modestly increased rates of hypoxaemia among study participants. TRIAL REGISTRATION NUMBER NCT02142621.
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Improvement of non-invasive markers of NAFLD from an individualised, web-based exercise program.
Huber, Y, Pfirrmann, D, Gebhardt, I, Labenz, C, Gehrke, N, Straub, BK, Ruckes, C, Bantel, H, Belda, E, Clément, K, et al
Alimentary pharmacology & therapeutics. 2019;(8):930-939
Abstract
BACKGROUND Lifestyle modifications remain the cornerstone of treatment in non-alcoholic fatty liver disease (NAFLD). However, they requently fail related to the inability of patients to implement lasting changes. AIMS To evaluate the effects of a short, web-based, individualised exercise program on non-invasive markers of hepatic steatosis, inflammation and fibrosis. METHODS Patients with histologically confirmed NAFLD underwent an 8-week, web-based, individualised exercise program that contained bidirectional feedback. RESULTS Forty-four patients entered the study and 41 completed the assigned training goal (93.2%). In the completer population, 8 weeks of individualised exercise increased the VO2peak by 12.2% compared to baseline (P < .001). ALT and AST decreased by 14.3% (P = .002) and 18.2% (P < .001) and remained at this level until follow-up 12 weeks after the intervention. Markers of inflammation including hsCRP, ferritin, and M30 decreased. In parallel, gut microbiota exhibited increased metagenomic richness (P < .05) and at the taxonomic levels Bacteroidetes and Euryarchaeota increased whereas Actinobacteria phylum decreased. Surrogate scores of steatosis and fibrosis including the fatty liver index (FLI), FiB-4, APRI and transient elastography showed significant reductions. In parallel, a marker of procollagen-3 turnover (PRO-C3) decreased while C4M2, reflecting type IV collagen, degradation increased suggesting beneficial hepatic fibrosis remodelling from exercise. Also, an enhancement in health-related quality of life was reported. CONCLUSION The current study underlines the plausibility and potential of an 8 week individualised web-based exercise program in NAFLD. Clinical trial number: NCT02526732.
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Microfluidic Chip Method for Multi-SNPs Genotyping in Individual Risk Assessment of Micronutrient Deficiency.
Zhang, CH, Huo, JS, Chen, S, Xu, YC, Sun, J, Huang, J
Biomedical and environmental sciences : BES. 2019;(6):471-475
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Actively personalized vaccination trial for newly diagnosed glioblastoma.
Hilf, N, Kuttruff-Coqui, S, Frenzel, K, Bukur, V, Stevanović, S, Gouttefangeas, C, Platten, M, Tabatabai, G, Dutoit, V, van der Burg, SH, et al
Nature. 2019;(7738):240-245
Abstract
Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential3. There is limited intratumoural infiltration of immune cells4 in glioblastoma and these tumours contain only 30-50 non-synonymous mutations5. Exploitation of the full repertoire of tumour antigens-that is, both unmutated antigens and neoepitopes-may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-L-lysine carboxymethylcellulose) and granulocyte-macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8+ T cells. APVAC2 induced predominantly CD4+ T cell responses of T helper 1 type against predicted neoepitopes.
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Phenotyping-based treatment improves obstructive sleep apnea symptoms and severity: a pilot study.
Messineo, L, Magri, R, Corda, L, Pini, L, Taranto-Montemurro, L, Tantucci, C
Sleep & breathing = Schlaf & Atmung. 2017;(4):861-868
Abstract
BACKGROUND Obstructive sleep apnea is a common disorder characterized by multiple pathogenetic roots. Continuous positive airway pressure (CPAP) is almost always prescribed as the first-line treatment to all patients regardless of the heterogeneous pathophysiology, because it mechanically splints the airways open and reduces the collapsibility of the upper airway. Despite its high efficacy, CPAP is burdened by poor adherence and compliance rates. In this pilot study, we treated OSA patients with composite approaches different than CPAP, tailoring the therapeutic choice on OSA phenotypic traits. METHODS We used the CPAP dial down technique to assess phenotypic traits in eight OSA patients with BMI<35. According to these traits, patients received personalized therapies for 2-week period, after which we ran a second polygraphy to compare apnea-hypopnea index (AHI) before and after therapy. RESULTS Two weeks of combined behavioral and pharmacological therapy induced a significant reduction in mean AHI, which dropped from 26 ± 15 at baseline to 9 ± 7 post-treatment (p = 0.01). Furthermore, there was a significant reduction in mean ODI (p = 0.03) and subjective sleepiness (p = 0.01) documented by Epworth Sleepiness Scale (ESS) from baseline to post-treatment recordings. CONCLUSIONS Treating OSA patients with a personalized combination of pharmacological and behavioral therapies according to phenotypic traits leads to a significant improvement in AHI, ODI, and subjective sleepiness.
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An immunogenic personal neoantigen vaccine for patients with melanoma.
Ott, PA, Hu, Z, Keskin, DB, Shukla, SA, Sun, J, Bozym, DJ, Zhang, W, Luoma, A, Giobbie-Hurder, A, Peter, L, et al
Nature. 2017;(7662):217-221
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Abstract
Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.
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Prospective study of individualized or high fixed doses of vitamin D supplementation after bariatric surgery.
Flores, L, Moizé, V, Ortega, E, Rodríguez, L, Andreu, A, Filella, X, Vidal, J
Obesity surgery. 2015;(3):470-6
Abstract
BACKGROUND The degree of bariatric surgery (BS) induced vitamin D (VD) malabsorption is not well established. OBJECTIVE The aim of this study is to evaluate the efficacy and safety of achieving 25-hydroxy VD (25(OH)D) levels ≥75 nmol/L with two regimens of VD supplementation after BS. METHODS We performed two open-label, prospective studies in patients undergoing BS from 2009 to 2011. Postoperatively, all patients received Ca citrate 1,000 mg and 800 IU of VD3/day. In the first study, additional VD3 was prescribed according to preoperative 25(OH)D levels- < 25 nmol/L:2,800 IU/day; 26-50 nmol/L:2,000-1,200 IU/day, 51-62 nmol/L:1,000 IU; >63 nmol/L:0 IU/day-and we evaluated the patients at baseline and at 4 months. In the second study, an additional fixed high dose of 2,000 IU/day of VD3 was administered, and we evaluated patients at baseline and at 4 and 12 months after BS. RESULTS The first study included 176 patients [mean age 44 (11)]; 140 were females. Before BS, 171 subjects (98 %) presented 25(OH)D levels <75 nmol/L. Postoperatively, the mean 25(OH)D levels increased from 40 (17) to 77 nmol/L (29) (p < 0.001) with no differences in parathormone (PTH) or 25(OH)D levels between dose groups. In the second study, we enrolled 52 patients [mean age 45 (10)]; 32 were females. Postoperatively, the mean 25(OH)D levels increased from 32 (12) to 80 (22) and to 75 nmol/L (15) (p < 0.001) at 4 and 12 months, respectively. In both studies, a high percentage of patients achieved 25(OH)D ≥75 nmol/L levels and no subject reported any serious adverse event. CONCLUSIONS Both schedules of daily VD3 supplementation were effective and safe under conditions of clinical practice.
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A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis.
Hayashi, H, Tazoe, Y, Tsuboi, S, Horino, M, Morishita, M, Arai, T, Ohshima, M, Matsuyama, T, Kosuge, K, Yamada, H, et al
Drug metabolism and pharmacokinetics. 2013;(2):164-8
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Abstract
Methotrexate (MTX) exhibits large inter-individual and inter-ethnic differences in the dose required for its anti-rheumatic effect. To maintain low disease activity, patients may require increased MTX doses or co-administration of biologic disease-modifying anti-rheumatic drugs (bDMARDs). The availability of a marker predicting the effect of MTX will make it possible to increase the MTX dose and prescribe bDMARDs to patients at an early stage. To establish individualized medication for rheumatoid arthritis (RA), we investigated genetic polymorphisms of the folate pathway in Japanese RA patients. Eighty-nine patients were treated with MTX alone (MTX group). MTX and bDMARDs were co-administered to 81 patients because of insufficient MTX efficacy (MTX + bDMARDs group); an equally stable therapeutic effect was achieved in both groups. Polymorphism analyses using bDMARD co-treatment as the objective variable revealed a significant association between age and the G80A polymorphism of the reduced folate carrier 1 gene (RFC1) as an explanatory variable. Compared to patients with the A allele, patients with the G allele may have less intracellular MTX uptake and, therefore, poor efficacy; a greater number of them were found to be bDMARD concomitant cases. The results of this study suggest that the RFC1 G80A polymorphism may be a useful marker for predicting MTX efficacy in Japanese patients with RA.