The United States Department of Energy and the People's Republic of China (PRC) Chinese Academy of Sciences signed an agreement on 19 August 1987 to carry out a joint research program on the study of ...CO2-induced climate changes. The joint program has four tasks—analysis of general circulation models (GCMs), preparation and analysis of proxy and instrumental data, the study of the relationship between large- and regional-scale climates, and CH4 measurements. The program structure, technical tasks, and the initial research progress are described.
The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are ...standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus-positive patient achieved a durable, complete response to immunotherapy. The level of
amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking
amplification, deletion of
exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance.
Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers.
.
Clinical and molecular heterogeneity are common features of human disease. Understanding the basis for heterogeneity has led to major advances in therapy for many cancers and pulmonary diseases such ...as cystic fibrosis and asthma. Although heterogeneity of risk factors, disease severity, and outcomes in survivors are common features of the acute respiratory distress syndrome (ARDS), many challenges exist in understanding the clinical and molecular basis for disease heterogeneity and using heterogeneity to tailor therapy for individual patients. This report summarizes the proceedings of the 2021 Aspen Lung Conference, which was organized to review key issues related to understanding clinical and molecular heterogeneity in ARDS. The goals were to review new information about ARDS phenotypes, to explore multicellular and multisystem mechanisms responsible for heterogeneity, and to review how best to account for clinical and molecular heterogeneity in clinical trial design and assessment of outcomes. The report concludes with recommendations for future research to understand the clinical and basic mechanisms underlying heterogeneity in ARDS to advance the development of new treatments for this life-threatening critical illness.
Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following ...allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n = 5310); acute lymphoblastic leukemia (ALL, n = 1883); chronic myeloid leukemia (CML, n = 1079); and myelodysplastic syndrome (MDS, n = 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality relative risk RR among disease categories ranged from 1.61 to 1.95 and P values from .0002 to <.0001; 95% confidence interval CI, 1.14-2.61). As a result, CMV reactivation was associated with lower overall survival for AML (RR = 1.27; 95% CI, 1.17-1.38; P <.0001), ALL (RR = 1.46; 95% CI, 1.25-1.71; P <.0001), CML (RR = 1.49; 95% CI, 1.19-1.88; P = .0005), and MDS (RR = 1.31; 95% CI, 1.09-1.57; P = .003). In conclusion, CMV reactivation continues to remain a risk factor for poor posttransplant outcomes and does not seem to confer protection against hematologic disease relapse.
•Cytomegalovirus after bone marrow transplantation remains associated with lower survival but not prevention of leukemia relapse.
We evaluated 917 adult lymphoma patients who received haploidentical (n = 185) or HLA-matched unrelated donor (URD) transplantation either with (n = 241) or without antithymocyte globulin (ATG; n = ...491) following reduced-intensity conditioning regimens. Haploidentical recipients received posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, whereas URD recipients received calcineurin inhibitor-based prophylaxis. Median follow-up of survivors was 3 years. The 100-day cumulative incidence of grade III-IV acute GVHD on univariate analysis was 8%, 12%, and 17% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .44). Corresponding 1-year rates of chronic GVHD on univariate analysis were 13%, 51%, and 33%, respectively (P < .001). On multivariate analysis, grade III-IV acute GVHD was higher in URD without ATG (P = .001), as well as URD with ATG (P = .01), relative to haploidentical transplants. Similarly, relative to haploidentical transplants, risk of chronic GVHD was higher in URD without ATG and URD with ATG (P < .0001). Cumulative incidence of relapse/progression at 3 years was 36%, 28%, and 36% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .07). Corresponding 3-year overall survival (OS) was 60%, 62%, and 50% in the 3 groups, respectively, with multivariate analysis showing no survival difference between URD without ATG (P = .21) or URD with ATG (P = .16), relative to haploidentical transplants. Multivariate analysis showed no difference between the 3 groups in terms of nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). These data suggest that reduced-intensity conditioning haploidentical transplantation with posttransplant cyclophosphamide does not compromise early survival outcomes compared with matched URD transplantation, and is associated with significantly reduced risk of chronic GVHD.
•Risk of grade III-IV acute and chronic GVHD is significantly lower with haploidentical compared with URD transplantation.•Relapse risk, NRM, PFS, and OS was similar in haploidentical transplants compared with unrelated donor transplants.
Abstract Background In active surveillance (AS) for prostate cancer there are few data on long-term outcomes associated with novel imaging markers. Objective To determine long-term outcomes with ...respect to the apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (DW-MRI) in a prospective AS cohort. Early results have already been published; we now present findings with long-term follow-up. Design, setting, and participants A subset of patients ( n = 86) underwent pre-enrolment DW-MRI in a prospective AS study between 2002 and 2006. Inclusion criteria were untreated prostate cancer, clinical T1/T2a/N0M0, Gleason ≤ 3 + 4, and prostate-specific antigen (PSA) <15 ng/ml. Protocol follow-up was by biopsy at 18–24 mo and then every 24 mo, with regular PSA measurement. Intervention Men underwent baseline DW-MRI in addition to standard sequences. ADC was measured from the index lesion on T2-weighted images. To avoid influencing treatment decisions, DW-MRI sequence results were not available to the AS study investigators. Outcome measurements and statistical analysis Baseline ADC was analysed with respect to time to radical treatment (TRT) and time to adverse histology (TAH). Kaplan-Meier analysis and univariate and multivariate regression analyses were performed. Results and limitations The median follow-up was 9.5 yr (interquartile range 7.9–10.0 yr). On univariate analysis, ADC below the median was associated with shorter TAH (hazard ratio HR 2.13, 95% confidence interval CI 1.17–3.89; p < 0.014) and TRT (HR 2.54, 95% CI 1.49–4.32; p < 0.001). Median TRT was 9.3 yr (95% CI 7.0–11.6 yr) for patients with ADC above the median and only 2.4 yr (95% CI 1.5–6.0 yr) for ADC below the median. For TRT, addition of ADC to a multivariate model of baseline variables resulted in a significant improvement in model fit (HR 1.33, 95% CI 1.14–1.54; p < 0.001). Receiver operating characteristic analysis for TRT revealed an area under the curve of 0.80 (95% CI 0.70–0.88). The number of variables included in the multivariate model was limited by sample size. Conclusions Long-term follow-up for this study provides strong evidence that ADC is a useful marker when selecting patients for AS. Routine DW-MRI is now being evaluated in our ongoing AS study for initial assessment and as an alternative to repeat biopsy. Patient summary Before entering a study of close monitoring for the initial management of prostate cancer, patients had a type of magnetic resonance imaging scan that looks at the movement of water within cancers. These scans may help in predicting whether patients should receive close monitoring or whether immediate treatment should be given.
Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome ...P450 isoforms 4 and 5 genes (
) and the ATP-binding cassette B1 gene (
) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in
and
and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between
or
germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and
genotype were independently associated with subtherapeutic tacrolimus trough concentrations while
or
genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.
Up-titration of allopurinol in patients with gout Jennings, Claudine G., MBChB; Mackenzie, Isla S., PhD; Flynn, Rob, PhD ...
Seminars in arthritis and rheumatism,
08/2014, Letnik:
44, Številka:
1
Journal Article
Recenzirano
Abstract Objectives European League against Rheumatism (EULAR) gout management guidelines recommend achieving a target urate level <6.0 mg/dL (<357 µmol/L). Allopurinol is the most widely used ...urate-lowering therapy; however, many gout patients who are prescribed allopurinol do not have urate levels optimally controlled. The objective of this analysis was to review the efficacy and tolerability of allopurinol up-titration in achieving the EULAR target levels. Method The Febuxostat versus Allopurinol Streamlined Trial (FAST) is an ongoing multi-centre study comparing the cardiovascular safety of febuxostat and allopurinol (target recruitment: 5706 patients). Recruited patients were already taking allopurinol and the protocol required up-titration of daily allopurinol dose, in 100 mg increments, to achieve the EULAR urate target level prior to randomisation. We reviewed pre-randomisation data from the first 400 recruited and subsequently randomised FAST patients. Results Of 400 patients, 144 (36%) had urate levels ≥357 µmol/L at screening and required allopurinol up-titration. Higher urate levels were significantly associated with lower allopurinol dose, male sex, increased BMI, increased alcohol intake and diuretic use. Mean fall in urate levels after a single 100-mg dose increase was 71 µmol/L. The number of up-titrations required ranged from one to five (median = 1) with 65% of patients controlled after one 100-mg up-titration. Overall, 97% of up-titrated patients achieved target urate levels with median final allopurinol dose of 300 mg daily. Side effects and complications of up-titration were minimal. Conclusion Overall, 36% of FAST patients were not at target urate levels and required up-titration. Allopurinol up-titration was effective in achieving urate target levels and was generally well tolerated by patients.
The Medical Certificate of Stillbirth (MCS) records data about a baby's death after 24 weeks of gestation but before birth. Major errors that could alter interpretation of the MCS were widespread in ...two UK-based regional studies.
A multicentre evaluation was conducted, examining MCS issued 1 January 2018 to 31 December 2018 in 76 UK obstetric units. A systematic case-note review of stillbirths was conducted by Obstetric and Gynaecology trainees, generating individual 'ideal MCSs' and comparing these to the actual MCS issued. Anonymized central data analysis described rates and types of error, agreement and factors associated with major errors.
There were 1120 MCSs suitable for assessment, with 126 additional submitted data sets unsuitable for accuracy analysis (total 1246 cases). Gestational age demonstrated 'substantial' agreement K = 0.73 (95% CI 0.70-0.76). Primary cause of death (COD) showed 'fair' agreement K = 0.26 (95% CI 0.24-0.29). Major errors 696/1120; 62.1% (95% CI 59.3-64.9%) included certificates issued for fetal demise at <24 weeks' gestation 23/696; 3.3% (95% CI 2.2-4.9%) or neonatal death 2/696; 0.3% (95% CI 0.1-1.1%) or incorrect primary COD 667/696; 95.8% (95% CI 94.1-97.1%). Of 540/1246 43.3% (95% CI 40.6-46.1%) 'unexplained' stillbirths, only 119/540 22.0% (95% CI 18.8-25.7%) remained unexplained; the majority were redesignated as either fetal growth restriction FGR: 195/540; 36.1% (95% CI 32.2-40.3%) or placental insufficiency 184/540; 34.1% (95% CI 30.2-38.2). Overall, FGR 306/1246; 24.6% (95% CI 22.3-27.0%) was the leading primary COD after review, yet only 53/306 17.3% (95% CI 13.5-22.1%) FGR cases were originally attributed correctly.
This study demonstrates widespread major errors in MCS completion across the UK. MCS should only be completed following structured case-note review, with particular attention on the fetal growth trajectory.
•We summarize hematopoietic cell transplantation activity in the United States in 2018.•Key findings include fewer autologous transplantations performed for non-Hodgkin lymphoma and increasing ...numbers of haploidentical transplantations.•There is a continuing increase in transplantation activity in adults age >70 years.
Hematopoietic cell transplantation (HCT) is a well-established treatment to control and/or cure many malignant and nonmalignant diseases involving the hematopoietic system and some solid tumors. We report information about HCT procedures performed in the United States in 2018 and analyze trends and outcomes of HCT as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Overall, compared with 2017, the number of allogeneic HCTs performed in the United States increased by 1%, and the number of autologous HCTs decreased by 5%. Key findings are fewer autologous HCTs performed for non-Hodgkin lymphoma and increasing numbers of haploidentical HCTs, nearly all of which use post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis. There is a continuing increase in HCT in adults age >70 years, particularly for acute myelogenous leukemia and myelodysplastic syndromes. Survival rates by disease, disease stage, donor type, and age are presented. This report, prepared annually by the CIBMTR, provides a snapshot of current transplant activity in the United States.
PDF
