Radioimmunotherapy of B-cell lymphoma with radiolabelled anti-CD20 monoclonal antibodies

CD20 has proven to be an excellent target for the treatment of B-cell lymphoma, first for the chimeric monoclonal antibody rituximab (Rituxan™), and more recently for the radiolabelled antibodies Y-90 ibritumomab tiuxetan (Zevalin™) and I-131 tositumomab (Bexxar™). Radiation therapy effects are due to beta emissions with path lengths of 1–5 mm; gamma radiation emitted by I-131 is the only radiation safety issue for either product. Dose-limiting toxicity for both radiolabelled antibodies is reversible bone marrow suppression. They produce response rates of 70%–90% in low-grade and follicular lymphoma and 40%–50% in transformed low-grade or intermediate-grade lymphomas. Both products produce higher response rates than related unlabelled antibodies, and both are highly active in patients who are relatively resistant to rituximab-based therapy. Median duration of response to a single course of treatment is about 1 year with complete remission rates that last 2 years or longer in about 25% of patients. Clinical trials suggest that anti- CD20 radioimmunotherapy is superior to total body irradiation in patients undergoing stem cell supported therapy for B-cell lymphoma, and that it is a safe and efficacious modality when used as consolidation therapy following chemotherapy. Among cytotoxic treatment options, current evidence suggests that one course of anti-CD20 radioimmunotherapy is as efficacious as six to eight cycles of combination chemotherapy. A major question that persists is how effective these agents are in the setting of rituximab- refractory lymphoma. These products have been underutilised because of the complexity of treatment coordination and concerns regarding reimbursement

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk

The effect of pulmonary arterial hypertension specific treatment on the left ventricle in patients with pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by right ventricular (RV) pressure overload, leading to RV dilation, failure and death. In the course of the disease, the left ventricle (LV) is often impaired, due to interventricular interaction. Although the impact of PAH treatment on the RV has been well described, less is known on the LV.To examine effects of advanced PAH treatments on the volumes, function and strain of the left atrium and ventricle.This is a retrospective study. All patients underwent CMR and right heart catheterization, both at diagnosis and at 12-months follow up. Ventricular volumes and LV filling rate were calculated from the stack of short axis cine images using Simpsons method while left atrial (LA) volumes from the 4-chamber cine images using the area-length method. Tissue tracking was used for the evaluation of myocardial deformation. The LV endocardial and epicardial borders were manually delineated in all analysed sections with the initial contour set at end-diastole. All analyses were performed offline using dedicated software.In total, 66 patients (mean age 56.3±17.9 years, 67\ 77\ 23\ and 29 normal controls were included. The improvement in metrics of right and left heart size and function after the initiation of advanced PAH treatment, are presented in panel A. Of note, LV stroke volume was markedly increased (54.6±19.6ml at baseline vs 70.8±21.7ml at follow up, p\lt;0.0001) to reach controls. LV filling was markedly increased in latter two-thirds of the diastolic phase (panel B), especially at atrial kick point (arrow). Change in LA max volume was associated with changes in diastolic filling (r=0.354, p=0.004), LV end-diastolic and end-systolic volumes and stroke volume. These correlations were more robust in patients that increased LV filling compared to those that failed to increase LV filling (panels C-E). No association between changes in LV circumferential strain and LV volume load was observed. A weak correlation of change of LV peak longitudinal strain with stroke volume (r=−0.345, p=0.006), LV end diastolic volume (r=−0.284, p=0.027), LV ejection fraction (r=−0.337, p=0.008) and LA maximum area (r=−0.447, p\lt;0.0001) was observed. The changes of LV strain showed no correlation with the changes in patients' haemodynamics.Improvement in stroke volume after the initiation of advanced PAH treatment is associated with an increase in LA size, LV end diastolic volume and normalisation of strain. This reflects the improved filling state of the left ventricle and the potential of the left atrium to monitor treatment effects.Changes after PAH treatmentType of funding source: Non

Relationship between right ventricular diastolic dysfunction, right atrial phasic function and ventricular filling in pulmonary arterial hypertension

In pulmonary arterial hypertension (PAH) patients, the right ventricle (RV) stiffens due to hypertrophy, fibrosis and intrinsic (sarcomeric) stiffness. In these patients, end-diastolic elastance (stiffness, Eed) is associated with parameters of disease severity and predicts mortality. However, the effect of RV stiffness on RV filling and the effect of increased filling pressures on right atrial (RA) function remain elusive.To examine the relationship between RV diastolic stiffness and RA phasic function and the effect of diastolic dysfunction on ventricular filling in PAH patients.Using single-beat pressure-volume analyses we determined Eed in controls (n=31) and baseline, treatment naive PAH patients (63 idiopathic, 9 hereditary and 25 connective tissue disease associated). We also measured RA reservoir, conduit and active strain by tissue tracking on cardiac magnetic resonance images. Furthermore, interventricular dyssynchrony was defined as a right to left difference in time to peak circumferential strain \gt;52ms (97.5th percentile in controls).End-diastolic pressure was higher in PAH patients (16±7 mmHg) than in controls (8±4 mmHg; p\lt;0.001). Median Eed in patients was 0.635 mmHg/mL (IQR: 0.40–0.99), while in controls it was 0.20 mmHg/mL (IQR: 0.15–0.24). In comparison with controls, patients had reduced RA reservoir (14.3±5.1\9.1±4.3\ p\lt;0.001) and conduit strain (−5.6±3.4\12.4±3.3\ p\lt;0.001), while RA active strain was enhanced (−9.0±4.0\7.5±2.8\ p=0.019). In patients with a stiff RV (Eed above median), RA conduit strain was worse than in patients with a more compliant RV as illustrated in figure A. However, no correlation between RA active strain and Eed was observed (Spearman rho 0.06; p=0.57).Passive filling time of the RV (end-systole until start of atrial contraction) was shorter in patients than in controls (244±136ms vs. 365±103ms; p\lt;0.001). Higher heart rate and ventricular dyssynchrony are causes of a shorter passive filling time in patients as illustrated in figure B. When comparing patients with short vs. long passive filling time (cutoff median of 220ms), the RV passive filling volume was lower (24±15ml vs. 42±19ml; p\lt;0.001). The active filling volume was slightly higher, although not significantly (25±17ml vs. 19±15ml; p=0.12).Stiffening of the RV in PAH patients is accompanied by increased filling pressures and decreased RA conduit strain, while there is no correlation between Eed and RA active strain. Higher heart rate and ventricular dyssynchrony lead to shorter passive filling time of the RV, which in turn leads to lower passive filling volume. In contrast, the active filling volume is preserved in these patients.Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Netherlands Organization for Scientific Researc

A revised age for the Kawakawa/Oruanui tephra, a key marker for the Last Glacial Maximum in New Zealand

The Kawakawa/Oruanui tephra (KOT) is a key chronostratigraphic marker in terrestrial and marine deposits of the New Zealand (NZ) sector of the southwest Pacific. Erupted early during the Last Glacial Maximum (LGM), the wide distribution of the KOT enables inter-regional alignment of proxy records and facilitates comparison between NZ climatic variations and those from well-dated records elsewhere. We present 22 new radiocarbon ages for the KOT from sites and materials considered optimal for dating, and apply Bayesian statistical methods via OxCal4.1.7 that incorporate stratigraphic information to develop a new age probability model for KOT. The revised calibrated age, ±2 standard deviations, for the eruption of the KOT is 25,360 ± 160 cal yr BP. The age revision provides a basis for refining marine reservoir ages for the LGM in the southwest Pacific