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1.
ESMO Open ; 9(2): 102226, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38458658

ABSTRACT

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer (GC), published in late 2022 and the updated ESMO Gastric Cancer Living Guideline published in July 2023, were adapted in August 2023, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with GC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with GC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), coordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with GC across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.


Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/diagnosis , Stomach Neoplasms/therapy , Follow-Up Studies , Asia , Medical Oncology , Societies, Medical
2.
Commun Biol ; 7(1): 316, 2024 Mar 13.
Article in English | MEDLINE | ID: mdl-38480906

ABSTRACT

Warming can have profound impacts on ecological communities. However, explorations of how differences in biogeography and productivity might reshape the effect of warming have been limited to theoretical or proxy-based approaches: for instance, studies of latitudinal temperature gradients are often conflated with other drivers (e.g., species richness). Here, we overcome these limitations by using local geothermal temperature gradients across multiple high-latitude stream ecosystems. Each suite of streams (6-11 warmed by 1-15°C above ambient) is set within one of five regions (37 streams total); because the heating comes from the bedrock and is not confounded by changes in chemistry, we can isolate the effect of temperature. We found a negative overall relationship between diatom and invertebrate species richness and temperature, but the strength of the relationship varied regionally, declining more strongly in regions with low terrestrial productivity. Total invertebrate biomass increased with temperature in all regions. The latter pattern combined with the former suggests that the increased biomass of tolerant species might compensate for the loss of sensitive species. Our results show that the impact of warming can be dependent on regional conditions, demonstrating that local variation should be included in future climate projections rather than simply assuming universal relationships.


Subject(s)
Ecosystem , Rivers , Animals , Biomass , Biodiversity , Invertebrates
3.
Struct Dyn ; 10(3): 034103, 2023 May.
Article in English | MEDLINE | ID: mdl-37388296

ABSTRACT

Time-resolved x-ray liquidography (TRXL) is a potent method for investigating the structural dynamics of chemical and biological reactions in the liquid phase. It has enabled the extraction of detailed structural aspects of various dynamic processes, the molecular structures of intermediates, and kinetics of reactions across a wide range of systems, from small molecules to proteins and nanoparticles. Proper data analysis is key to extracting the information of the kinetics and structural dynamics of the studied system encrypted in the TRXL data. In typical TRXL data, the signals from solute scattering, solvent scattering, and solute-solvent cross scattering are mixed in the q-space, and the solute kinetics and solvent hydrodynamics are mixed in the time domain, thus complicating the data analysis. Various methods developed so far generally require prior knowledge of the molecular structures of candidate species involved in the reaction. Because such information is often unavailable, a typical data analysis often involves tedious trial and error. To remedy this situation, we have developed a method named projection to extract the perpendicular component (PEPC), capable of removing the contribution of solvent kinetics from TRXL data. The resulting data then contain only the solute kinetics, and, thus, the solute kinetics can be easily determined. Once the solute kinetics is determined, the subsequent data analysis to extract the structural information can be performed with drastically improved convenience. The application of the PEPC method is demonstrated with TRXL data from the photochemistry of two molecular systems: [Au(CN)2-]3 in water and CHI3 in cyclohexane.

5.
Science ; 378(6621): 785-790, 2022 11 18.
Article in English | MEDLINE | ID: mdl-36395220

ABSTRACT

Inherent symmetry of a quantum system may protect its otherwise fragile states. Leveraging such protection requires testing its robustness against uncontrolled environmental interactions. Using 47 superconducting qubits, we implement the one-dimensional kicked Ising model, which exhibits nonlocal Majorana edge modes (MEMs) with [Formula: see text] parity symmetry. We find that any multiqubit Pauli operator overlapping with the MEMs exhibits a uniform late-time decay rate comparable to single-qubit relaxation rates, irrespective of its size or composition. This characteristic allows us to accurately reconstruct the exponentially localized spatial profiles of the MEMs. Furthermore, the MEMs are found to be resilient against certain symmetry-breaking noise owing to a prethermalization mechanism. Our work elucidates the complex interplay between noise and symmetry-protected edge modes in a solid-state environment.

6.
SAR QSAR Environ Res ; 33(8): 631-647, 2022 Aug.
Article in English | MEDLINE | ID: mdl-36062308

ABSTRACT

Despite the endeavours and achievements made in treating cancers during the past decades, resistance to available kinase drugs continues to be a major problem in cancer therapies. Thus, it is highly desirable to develop computational models that can predict the bioactivity of a compound against cancer kinases. Here, we present a Long Short-Term Memory (LSTM) framework for predicting the activities of lead molecules against seven different kinases. A total of 14,907 compounds from the ChEMBL database were selected for model building. Two different molecular representations, namely, 2D descriptors and MACCS fingerprints were subjected to the LSTM method for the training process. We also successfully integrated an attention mechanism into our model, which helped us to interpret the contribution of chemical features on kinase activity. The attention mechanism extracted the significant chemical moieties more effectively by taking them into consideration during the activity prediction. The recorded accuracies in the test sets for both 2D descriptors and MACCS fingerprints-based models were 0.81 and 0.78, respectively. The receiver operating characteristic curve (ROC)-area under the curve (AUC) score for both models was in the range of 0.8-0.99. The proposed framework can be a good starting point for the development of new cancer kinase drugs.


Subject(s)
Neoplasms , Quantitative Structure-Activity Relationship , Humans , Neoplasms/drug therapy , ROC Curve
7.
ESMO Open ; 7(5): 100563, 2022 10.
Article in English | MEDLINE | ID: mdl-36029651

ABSTRACT

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA. PATIENTS AND METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR). RESULTS: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA. CONCLUSIONS: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.


Subject(s)
Adenocarcinoma , Stomach Neoplasms , Humans , B7-H1 Antigen/metabolism , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Trastuzumab/pharmacology , Trastuzumab/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Immune Checkpoint Inhibitors
9.
J Appl Microbiol ; 131(4): 2072-2080, 2021 Oct.
Article in English | MEDLINE | ID: mdl-33629458

ABSTRACT

AIMS: To display a short peptide (GSRSHHHHHH) at the C-terminal end of turnip yellow mosaic virus coat protein (TYMVc) and to study its assembly into virus-like particles (TYMVcHis6 VLPs). METHODS AND RESULTS: In this study, recombinant TYMVcHis6 expressed in Escherichia coli self-assembled into VLPs of approximately 30-32 nm. SDS-PAGE and Western blot analysis of protein fractions from the immobilized metal affinity chromatography (IMAC) showed that TYMVcHis6 VLPs interacted strongly with nickel ligands in IMAC column, suggesting that the fusion peptide is protruding out from the surface of VLPs. These VLPs are highly stable over a wide pH range from 3·0 to 11·0 at different temperatures. At pH 11·0, specifically, the VLPs remained intact up to 75°C. Additionally, the disassembly and reassembly of TYMVcHis6 VLPs were studied in vitro. Dynamic light scattering and transmission electron microscopy analysis revealed that TYMVcHis6 VLPs were dissociated by 7 mol l-1 urea and 2 mol l-1 guanidine hydrochloride (GdnHCl) without impairing their reassembly property. CONCLUSIONS: A 10-residue peptide was successfully displayed on the surface of TYMVcHis6 VLPs. This chimera demonstrated high stability under extreme thermal conditions with varying pH and was able to dissociate and reassociate into VLPs by chemical denaturants. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first C-terminally modified TYMVc produced in E. coli. The C-terminal tail which is exposed on the surface can be exploited as a useful site to display multiple copies of functional ligands. The ability of the chimeric VLPs to self-assemble after undergo chemical denaturation indicates its potential role to serve as a nanocarrier for use in targeted drug delivery.


Subject(s)
Tymovirus , Capsid Proteins/genetics , Escherichia coli/genetics , Microscopy, Electron, Transmission , Recombinant Proteins
10.
Clin Oncol (R Coll Radiol) ; 33(7): e305-e314, 2021 07.
Article in English | MEDLINE | ID: mdl-33589348

ABSTRACT

AIMS: Multiple studies have shown conflicting results on the correlation between the EGFR T790M quantitative level and survival outcomes in osimertinib-treated patients. We sought to validate such correlations using data from an osimertinib early access programme (EAP) providing access for metastatic non-small cell lung cancer patients with limited treatment options. PATIENTS AND METHODS: This observational, multicentre, retrospective analysis included EAP participants who received osimertinib until disease progression, intolerable toxicities or death. Digital droplet polymerase chain reaction-based quantitative plasma genotyping was carried out upon disease progression and data were analysed to explore the relationships between T790M mutant allele fraction (MAF), T790M copy number, MAF ratio and post-osimertinib overall survival. Real-world treatment outcomes and safety were also evaluated. RESULTS: Data from 156 EAP participants were analysed (median follow-up 37.7 months). The median age was 62 years, 62.2% were women, 79.5% were never-smokers, 60.9% had Eastern Cooperative Oncology Group performance status 0/1. In patients with available plasma data (n = 114), T790M MAF (%) showed no significant relationships with overall survival (hazard ratio 1.02; 95% confidence interval 0.99-1.04) or time to treatment discontinuation (TTD) (hazard ratio 1.01; 95% confidence interval 0.98-1.04). Absolute T790M copy number and T790M to activating EGFR mutation MAF ratio also showed no prognostic value. The investigator-assessed response rate was 42.3% and the disease control rate was 85.5%. The median TTD was 15.8 (95% confidence interval 12.5-18.5) months and the median overall survival was 22.3 (95% confidence interval 18.6-26.1) months. CONCLUSION: T790M MAF did not correlate with TTD or overall survival in this EAP cohort but limitations should not be overlooked. Observed survival outcomes and the toxicity profile were consistent with data from other real-world series.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Protein Kinase Inhibitors , Acrylamides , Alleles , Aniline Compounds , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Middle Aged , Mutation , Retrospective Studies
11.
Med J Malaysia ; 75(5): 561-567, 2020 09.
Article in English | MEDLINE | ID: mdl-32918427

ABSTRACT

INTRODUCTION: This study aimed to validate the Malay version of the short form Smartphone Addiction Scale (SAS-M-SF) and to examine its psychometric properties in a cohort of pre-university adolescents. METHODS: We obtained the validity and reliability evidence for the SAS-M-SF using a group of 307 pre-university students in Universiti Putra Malaysia (UPM), Serdang, Selangor, Malaysia with a mean age of 18.4±0.2 years (70.4% female and 29.6% male). A questionnaire containing the Malay version of Smartphone Addiction Scale (SAS-M), the Malay version of the short form Smartphone Addiction Scale (SAS-M-SF), and the Malay version of the Internet Addiction Test (IAT-M) was administered on the adolescents. RESULTS: The SAS-M-SF displayed good internal consistency (Cronbach's α=0.80). Using principle component analysis, we identified a 4-factor SAS-M-SF model. A significant correlation between the SAS-M-SF and the IAT-M was found, lending support for concurrent validity. The prevalence of smartphone addiction was 54.5% based on cut-off score of ≥36 with a sensitivity of 70.2% and a specificity of 72.5%. CONCLUSIONS: The 10-item SAS-M-SF is a valid and reliable screening tool for smartphone addiction among adolescents. The scale can help clinicians or educators design appropriate intervention and prevention programs targeting smartphone addiction in adolescents at clinical or school settings.


Subject(s)
Internet Addiction Disorder , Smartphone , Surveys and Questionnaires/standards , Adolescent , Cross-Sectional Studies , Female , Humans , Internet Addiction Disorder/epidemiology , Malaysia/epidemiology , Male , Psychometrics
13.
Transplant Proc ; 51(3): 749-760, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30979460

ABSTRACT

BACKGROUND: This 24-week, multicenter, randomized, exploratory, comparative, open-label, phase-IV study assessed the safety and efficacy of prolonged-release tacrolimus (PR-T) with reduced-dose versus standard-dose corticosteroids in stable kidney transplant recipients in Korea after converting from cyclosporine-based therapy. METHODS: At baseline, patients were converted from cyclosporine-based to PR-T-based immunosuppression and randomized (1:1) to receive either corticosteroids maintained at prestudy dose (standard-dose group) or tapered from week 4 to 50% of the prestudy dose by week 12 (reduced-dose group). Patients were seen at baseline and weeks 1, 4, 12, and 24. The primary endpoint was change in estimated glomerular filtration rate (Modification-of-Diet-in-Renal-Disease-4) between baseline and week 24. Secondary endpoints included either acute rejection or patient-reported satisfaction with PR-T. Adverse events (AEs) were recorded. RESULTS: Overall, 150 patients were randomized into a reduced-dose group (n = 73) and a standard-dose group (n = 77). At week 24, mean ± standard deviation for corticosteroid dose was 2.5 ± 0.9 mg and 5.0 ± 1.3 mg, respectively. Mean change in estimated glomerular filtration rate from baseline to week 24 was +1.5 ± 9.1 mL/min/1.73 m2 (P = .1567) and +3.4 ± 10.6 mL/min/1.73 m2 (P = .0065), respectively, and not significantly different between groups. There were no acute rejection episodes. Most respondents (>70%) considered PR-T more convenient than cyclosporine. AE incidence was similar between groups. The most common AEs experienced by ≥3% of patients in either treatment group were gastrointestinal events (20.8% and 28.6% of patients receiving reduced- and standard-dose corticosteroids, respectively). Most AEs in both treatment groups were mild or moderate in severity. CONCLUSION: Renal function was maintained following conversion from cyclosporine to PR-T, irrespective of corticosteroid regimen; PR-T enables reduced corticosteroid dosage.


Subject(s)
Adrenal Cortex Hormones/administration & dosage , Graft Rejection/prevention & control , Immunosuppressive Agents/administration & dosage , Kidney Transplantation , Tacrolimus/administration & dosage , Adult , Cyclosporine/therapeutic use , Delayed-Action Preparations/therapeutic use , Female , Glomerular Filtration Rate , Humans , Immunosuppression Therapy/methods , Immunosuppressive Agents/adverse effects , Male , Middle Aged , Patient Satisfaction , Republic of Korea , Research Design , Tacrolimus/adverse effects , Transplant Recipients
14.
Transplant Proc ; 51(3): 842-844, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30979473

ABSTRACT

BACKGROUND: Hepatitis B core antibody-positive (HBcAb+) graft is known as a risk for de novo hepatitis B virus (HBV) infection in recipients after liver transplantation (LT). However, little is known about the possibility or incidence of de novo HBV infections after LT in hepatitis B surface antigen-negative (HBsAg-)/HBcAb+ recipients using HBsAg-/HBcAb- grafts. The study aimed to evaluate the prevalence of de novo HBV infection in HBsAg-/HBcAb+ recipients using HBsAg-/HBcAb- grafts. A retrospective review was performed with the records of 1129 adult patients who underwent primary LT at a single institution in an HBV endemic area between January 2000 and December 2013. A total of 78 patients (6.9%) were reviewed for de novo HBV infection after LT. De novo HBV infection was developed in 1 patient (1.28%). The patient was a 65-year-old woman who underwent LT due to alcoholic liver cirrhosis. De novo HBV was not related to graft loss or death and well treated with tenofovir. In conclusion, de novo HBV infections may occur in HBsAg-/HBcAb+ recipients using HBsAg-/HBcAb- grafts, and caution is needed in these patients.


Subject(s)
Hepatitis B/epidemiology , Liver Transplantation , Adult , Aged , Female , Hepatitis B Core Antigens , Hepatitis B virus/immunology , Humans , Male , Middle Aged , Prevalence , Retrospective Studies
15.
Hong Kong Med J ; 25(1): 21-9, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30670673

ABSTRACT

OBJECTIVE: Sudden arrhythmia death syndrome (SADS) accounts for about 30% of causes of sudden cardiac death (SCD) in young people. In Hong Kong, there are scarce data on SADS and a lack of experience in molecular autopsy. We aimed to investigate the value of molecular autopsy techniques for detecting SADS in an East Asian population. METHODS: This was a two-part study. First, we conducted a retrospective 5-year review of autopsies performed in public mortuaries on young SCD victims. Second, we conducted a prospective 2-year study combining conventional autopsy investigations, molecular autopsy, and cardiac evaluation of the first-degree relatives of SCD victims. A panel of 35 genes implicated in SADS was analysed by next-generation sequencing. RESULTS: There were 289 SCD victims included in the 5-year review. Coronary artery disease was the major cause of death (35%); 40% were structural heart diseases and 25% were unexplained. These unexplained cases could include SADS-related conditions. In the 2-year prospective study, 21 SCD victims were examined: 10% had arrhythmogenic right ventricular cardiomyopathy, 5% had hypertrophic cardiomyopathy, and 85% had negative autopsy. Genetic analysis showed 29% with positive heterozygous genetic variants; six variants were novel. One third of victims had history of syncope, and 14% had family history of SCD. More than half of the 11 first-degree relatives who underwent genetic testing carried related genetic variants, and 10% had SADS-related clinical features. CONCLUSION: This pilot feasibility study shows the value of incorporating cardiac evaluation of surviving relatives and next-generation sequencing molecular autopsy into conventional forensic investigations in diagnosing young SCD victims in East Asian populations. The interpretation of genetic variants in the context of SCD is complicated and we recommend its analysis and reporting by qualified pathologists.


Subject(s)
Arrhythmias, Cardiac/genetics , Death, Sudden, Cardiac/etiology , High-Throughput Nucleotide Sequencing , Medical History Taking/statistics & numerical data , Mutation , Adolescent , Adult , Arrhythmias, Cardiac/complications , Arrhythmias, Cardiac/diagnosis , Autopsy , Cause of Death , Child , Death, Sudden, Cardiac/pathology , Female , Genetic Predisposition to Disease , Genetic Testing , Hong Kong , Humans , Male , Phenotype , Prospective Studies , Retrospective Studies , Young Adult
16.
Colorectal Dis ; 21(1): 38-47, 2019 01.
Article in English | MEDLINE | ID: mdl-30047583

ABSTRACT

AIM: We aimed to isolate and propagate internal and external anal sphincter progenitor cells from the human anal sphincter, with or without radiotherapy, for tailored cell therapy of faecal incontinence. METHODS: Sphincter progenitor cells were isolated from normal internal and external anal sphincters collected from 10 patients with rectal cancer who had undergone abdominoperineal resection with (n = 6) or without (n = 4) preoperative chemoradiotherapy. The isolated cells and differentiated muscle fibres were identified using immunofluorescence assay, western blotting and reverse transcription polymerase chain reaction (RT-PCR). The proliferation of progenitor cells with and without radiotherapy was compared by quantitative 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The immunofluorescence assay before differentiation confirmed that the internal anal sphincter progenitor cells expressed CD34 and neural-glial antigen 2 (NG2), whereas the external anal sphincter progenitor cells expressed CD34 and PAX7. After differentiation, the internal anal sphincter progenitor cells expressed desmin, calponin and α-smooth muscle actin, whereas the external anal sphincter progenitor cells expressed desmin, myogenic factor 4 and myosin heavy chain. The differential expression profiles of both cell types were confirmed by western blotting and RT-PCR. MTT assays showed that the viability of internal and external anal sphincter progenitor cells was significantly lower in the radiotherapy group than that in the nonradiotherapy group. CONCLUSIONS: This study describes the differential harvest internal and external sphincter muscle progenitor cells from human anal sphincters. We confirm that radiotherapy decreases the viability of internal and external anal sphincter progenitor cells.


Subject(s)
Anal Canal/cytology , Cell Proliferation , Cell Survival , Chemoradiotherapy , Muscle Fibers, Skeletal/cytology , Myocytes, Smooth Muscle/cytology , Rectal Neoplasms/therapy , Stem Cells/cytology , Actins/metabolism , Aged , Aged, 80 and over , Anal Canal/metabolism , Antigens/metabolism , Antigens, CD34/metabolism , Calcium-Binding Proteins/metabolism , Case-Control Studies , Cell- and Tissue-Based Therapy , Desmin/metabolism , Fecal Incontinence/therapy , Female , Humans , Male , Microfilament Proteins/metabolism , Middle Aged , Muscle Fibers, Skeletal/metabolism , Myocytes, Smooth Muscle/metabolism , Myogenin/metabolism , Myosin Heavy Chains/metabolism , Neoadjuvant Therapy , PAX7 Transcription Factor/metabolism , Proctectomy , Proteoglycans/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Stem Cells/metabolism , Calponins
18.
Ann Oncol ; 30(2): 250-258, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30566590

ABSTRACT

BACKGROUND: Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated. PATIENTS AND METHODS: Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. RESULTS: Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0-78.2) with nivolumab plus SOX and 76.5% (50.1-93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8-NR) and 10.6 months (5.6-12.5), respectively. CONCLUSION: Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX. CLINICALTRIALS.GOV ID: NCT02746796.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophagogastric Junction/drug effects , Neoplasm Recurrence, Local/drug therapy , Stomach Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Capecitabine/administration & dosage , Drug Combinations , Esophagogastric Junction/pathology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Nivolumab/administration & dosage , Oxaliplatin/administration & dosage , Oxonic Acid/administration & dosage , Prognosis , Stomach Neoplasms/pathology , Survival Rate , Tegafur/administration & dosage
19.
Transplant Proc ; 50(10): 3667-3672, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30577253

ABSTRACT

BACKGROUND: Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is an early biomarker of renal injury. We examined the feasibility of using uNGAL as an early predictor of renal impairment in patients under calcineurin inhibitors in liver transplant recipients. METHODS: From urine samples obtained from liver transplant recipients, the glomerular filtration rate (GFR) at the time of urine sampling was compared with that at 5 to 7 months later. Patients were divided into 3 groups according to initial GFR and then divided into 2 groups according to the uNGAL level of 25 ng/mL. Progression of renal injury (PRI) was defined as a decrease in the GFR of more than 5 mL/min/1.73 m2 in the mild or moderate groups, or if a normal group patient shifted to the mild or moderate group. RESULTS: Fifty-one patients were enrolled. The mean uNGAL level was higher in the moderate group than in the normal and mild groups (18.38 ± 14.31 vs 7.74 ± 8.13; P < .01). A proportion of uNGAL-high was also higher in the moderate group than in the mild group (40% vs 5%; P = .03). uNGAL-high was a risk factor for 6-month PRI (odds ratio, 60.375; 95% confidence interval, 1.283-4088.25; P = .037) and 1-year PRI (odds ratio, 21.311; % confidence interval, 0.947-479.578; P = .054). CONCLUSIONS: A uNGAL of >25 ng/mg can be a marker for moderate renal impairment (GFR of 30-59 mL/min/1.73 m2) and a predictor of PRI at 6 months in patients using calcineurin inhibitors. Renal protection strategies should be considered in liver transplant recipients with a uNGAL of >25 ng/mg in spot urine sampling.


Subject(s)
Acute Kidney Injury/chemically induced , Calcineurin Inhibitors/adverse effects , Immunosuppressive Agents/adverse effects , Lipocalin-2/urine , Liver Transplantation , Acute Kidney Injury/urine , Adult , Biomarkers/urine , Female , Glomerular Filtration Rate , Humans , Liver Transplantation/methods , Male , Middle Aged , Risk Factors
20.
Transplant Proc ; 50(10): 4046-4049, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30577312

ABSTRACT

Alveolar hemorrhage is a life-threatening clinical syndrome often initially thought to be atypical pneumonia. Association with hematopoietic stem cell transplantation is well studied, but not with solid organ transplantation. We report a case of a 54-year-old woman presented with fever and shortness of breath on the third posttransplant day after deceased donor liver transplantation. Imaging studies showed diffuse bilateral pulmonary infiltrates and a positive sequential bronchoalveolar lavage test was revealed during bronchoscopy. Cytomegalovirus antigenemia was present in 8/200,000 white blood cells; Aspergillus galactomannan and Pneumocystis jirovecii were also present. However, only Aspergillus hyphae were found in the sputum culture. Management strategy aimed to treat underlying infections, provide adequate respiratory support, and control inflammation. We proposed that diffuse alveolar hemorrhage should be considered as differential diagnosis in early pulmonary complications after liver transplantation. Early diagnosis and aggressive treatment protocol is the key for a good outcome.


Subject(s)
Hemorrhage/etiology , Liver Transplantation/adverse effects , Pneumonia/complications , Aspergillosis/complications , Aspergillosis/diagnosis , Bronchoscopy , Cytomegalovirus Infections/complications , Cytomegalovirus Infections/diagnosis , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Lung Diseases/etiology , Lung Diseases/microbiology , Middle Aged , Pneumocystis Infections/complications , Pneumocystis Infections/diagnosis , Pneumocystis carinii , Pneumonia/microbiology , Pulmonary Alveoli/pathology
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