Economic evaluation of posaconazole versus fluconazole prophylaxis in patients with graft-versus-host disease (GVHD) in the Netherlands

The objective of this study was to evaluate the cost-effectiveness of posaconazole versus fluconazole for the prevention of invasive fungal infections (IFI) in graft-versus-host disease (GVHD) patients in the Netherlands. A decision analytic model was developed based on a double-blind randomized trial that compared posaconazole with fluconazole antifungal prophylaxis in recipients of allogeneic HSCT with GVHD who were receiving immunosuppressive therapy (Ullmann et al., N Engl J Med 356:335–347, 2007). Clinical events were modeled with chance nodes reflecting probabilities of IFIs, IFI-related death, and death from other causes. Data on life expectancy, quality-of-life, medical resource consumption, and costs were obtained from the literature. The total cost with posaconazole amounted to €9,428 (95% uncertainty interval €7,743–11,388), which is €4,566 (€2,460–6,854) more than those with fluconazole. Posaconazole prophylaxis resulted in 0.17 (0.02–0.36) quality adjusted life year (QALY) gained compared to fluconazole prophylaxis, corresponding to an incremental cost effectiveness ratio (ICER) of €26,225 per QALY gained. A scenario analysis demonstrated that at an increased background IFI risk (from 9% to 15%) the ICER was €13,462 per QALY. Given the underlying data and assumptions, posaconazole prophylaxis is expected to be cost-effective relative to fluconazole in recipients of allogeneic HSCT developing GVHD in the Netherlands. The cost-effectiveness of posaconazole depends on the IFI risk, which can vary by hospital

Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation

The second extracellular loop (EL2) of rhodopsin forms a cap over the binding site of its photoreactive 11-cis retinylidene chromophore. A crucial question has been whether EL2 forms a reversible gate that opens upon activation or acts as a rigid barrier. Distance measurements using solid-state 13C NMR spectroscopy between the retinal chromophore and the β4 strand of EL2 show that the loop is displaced from the retinal binding site upon activation, and there is a rearrangement in the hydrogen-bonding networks connecting EL2 with the extracellular ends of transmembrane helices H4, H5 and H6. NMR measurements further reveal that structural changes in EL2 are coupled to the motion of helix H5 and breaking of the ionic lock that regulates activation. These results provide a comprehensive view of how retinal isomerization triggers helix motion and activation in this prototypical G protein-coupled receptor. © 2009 Nature America, Inc. All rights reserved

Treatment of aggressive non-Hodgkin's lymphoma in frail patients: cardiac comorbidities and advanced age

The decisive factor in selecting a treatment regimen for a frail patient with aggressive non-Hodgkin's lymphoma is identifying whether a patient is fit enough to tolerate curative-intent anthracycline-containing regimens or too frail and therefore at risk of being undertreated. As cardiac comorbidities are an important contributor to both the health status and the selection of treatment, cardiovascular profiling and baseline risk stratification prior to treatment should be considered. Comprehensive geriatric assessment is an efficient means of identifying elderly patients with non-Hodgkin's lymphoma who may benefit from a curative treatment approach. If anthracycline-based therapy is not suitable, alternative treatment options are available in frail patients with cardiac comorbidities, but these must be adjusted to the patient's health status to achieve a maximal benefit–risk ratio

Relative orientation between the beta-ionone ring and the polyene chain for the chromophore of rhodopsin in native membranes.

Rotational resonance solid state nuclear magnetic resonance has been used to determine the relative orientation of the beta-ionone ring and the polyene chain of the chromophore 11-Z-retinylidene of rhodopsin in rod outer segment membranes from bovine retina. The bleached protein was regenerated with either 11-Z-[8,18-(13)C(2)]retinal or 11-Z-[8,16/17(13)C(2)]retinal, the latter having only one (13)C label at either of the chemically equivalent positions 16 and 17. Observation of (13)C selectively enriched in the ring methyl groups, C16/17, revealed alternative conformational states for the ring. Minor spectral components comprised around 26% of the chromophore. The major conformation (approximately 74%) has the chemical shift resolution required for measuring internuclear distances to (13)C in the retinal chain (C8) separately from each of these methyl groups. The resulting distance constraints, C8 to C16 and C17 (4.05 +/- 0.25 A) and from C8 to C18 (2.95 +/- 0.15 A), show that the major portion of retinylidene in rhodopsin has a twisted 6-s-cis conformation. The more precise distance measurement made here between C8 and C18 (2.95 A) predicts that the chain is twisted out-of-plane with respect to the ring by a modest amount (C5-C6-C7-C8 torsion angle = -28 +/- 7 degrees )

Photoreceptor rhodopsin: structural and conformational study of its chromophore 11-cis retinal in oriented membranes by deuterium solid state NMR.

Rhodopsin is the retinal photoreceptor responsible for visual signal transduction. To determine the orientation and conformation of retinal within the binding pocket of this membrane bound receptor, an ab initio solid state 2H NMR approach was used. Bovine rhodopsin containing 11-cis retinal, specifically deuterated at its methyl groups at the C19 or C20 position, was uniaxially oriented in DMPC bilayers. Integrity of the membranes and quality of alignment were monitored by 31P NMR. Analysis of the obtained 2H NMR spectra provided angles for the individual labelled chemical bond vectors leading to an overall picture for the three dimensional structure of the polyene chain of the chromophore in the protein binding pocket around the Schiff base attachment site

Conformational similarities in the beta-ionone ring region of the rhodopsin chromophore in its ground state and after photoactivation to the metarhodopsin-I intermediate.

High-resolution solid-state NMR methods have been used to analyze the conformation of the chromophore in the late photointermediate metarhodopsin-I, from observation of (13)C nuclei introduced into the beta-ionone ring (at the C16, C17, and C18 methyl groups) and into the adjoining segment of the polyene chain (at C8). Bovine rhodopsin in its native membrane was also regenerated with retinal that was (13)C-labeled close to the 11-Z bond (C20 methyl group) to provide a reporter for optimizing and quantifying the photoconversion to metarhodopsin-I. Indirect photoconversion via the primary intermediate, bathorhodopin, was adopted as the preferred method since approximately 44% conversion to the metarhodopsin-I component could be achieved, with only low levels (approximately 18%) of ground-state rhodopsin remaining. The additional photoproduct, isorhodopsin, was resolved in (13)C spectra from C8 in the chain, at levels of approximately 38%, and was shown using rotational resonance NMR to adopt the 6-s-cis conformation between the ring and the polyene chain. The C8 resonance was not shifted in the metarhodopsin-I spectral component but was strongly broadened, revealing that the local conformation had become less well defined in this segment of the chain. This line broadening slowed rotational resonance exchange with the C17 and C18 ring methyl groups but was accounted for to show that, despite the chain being more relaxed in metarhodopsin-I, its average conformation with respect to the ring was similar to that in the ground state protein. Conformational restraints are also retained for the C16 and C17 methyl groups on photoactivation, which, together with the largely preserved conformation in the chain, argues convincingly that the ring remains with strong contacts in its binding pocket prior to activation of the receptor. Previous conclusions based on photocrosslinking studies are considered in view of the current findings

Comparing causes of death of Hodgkin lymphoma and breast cancer patients between medical records and cause-of-death statistics

Simone de Vries,1 Michael Schaapveld,1 Jan WPF Kardaun,2,3 Kim H de Bruin,2 Augustinus DG Krol,4 Pieternella J Lugtenburg,5 Judy N Jacobse,1 Berthe MP Aleman,6 Flora E van Leeuwen1 1Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; 2Department of Health and Care, Statistics Netherlands, The Hague, the Netherlands; 3Department of Public Health, Academic Medical Center, Amsterdam, the Netherlands; 4Department of Radiotherapy, Leiden University Medical Center, Leiden, the Netherlands; 5Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; 6Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands Objective: Obtaining accurate data about causes of death may be difficult in patients with a complicated disease history, including cancer survivors. This study compared causes of death derived from medical records (CODMR) with causes of death derived from death certificates (CODDC) as processed by Statistics Netherlands of patients primarily treated for Hodgkin lymphoma (HL) or breast cancer (BC).Methods: Two hospital-based cohorts comprising 1,215 HL patients who died in the period 1980–2013 and 714 BC patients who died in the period 2000–2013 were linked with cause-of-death statistics files. The level of agreement was assessed for common underlying causes of death using Cohen’s kappa, and original death certificates were reviewed when CODDC and CODMR showed discrepancies. We examined the influence of using CODDC or CODMR on standardized mortality ratio (SMR) estimates.Results: Agreement for the most common causes of death, including selected malignant neoplasms and circulatory and respiratory diseases, was 81% for HL patients and 97% for BC patients. HL was more often reported as CODDC (CODDC=33.1% vs. CODMR=23.2%), whereas circulatory disease (CODDC=15.6% vs. CODMR=20.9%) or other diseases potentially related to HL treatment were more often reported as CODMR. Compared to SMRs based on CODDC, SMRs based on CODMR complemented with CODDC were lower for HL and higher for circulatory disease.Conclusion: Overall, we observed high levels of agreement between CODMR and CODDC for common causes of death in HL and BC patients. Observed discrepancies between CODMR and CODDC frequently occurred in the presence of late effects of treatment for HL. Keywords: cause of death, Hodgkin lymphoma, breast cancer, mortality statistic

Risk of heart failure in survivors of Hodgkin lymphoma: effects of cardiac exposure to radiation and anthracyclines

Hodgkin lymphoma (HL) survivors treated with radiotherapy and/or chemotherapy are known to have increased risks of heart failure (HF), but a radiation dose-response relationship has not previously been derived. A case-control study, nested in a cohort of 2,617 five-year survivors of HL diagnosed before age 51 years during 1965-1995, was conducted. Cases (n=91) had moderate or severe HF as their first cardiovascular diagnosis. Controls (n=278) were matched to cases on age, gender and HL diagnosis date. Treatment and follow-up information were abstracted from medical records. Mean Heart Doses (MHD) and Mean Left Ventricular Doses (MLVD) were estimated by reconstruction of individual treatments on representative computed tomography datasets. Average MLVD was 16.7 Gy for cases and 13.8 Gy for controls (pdifference=0.003). HF rate increased with MLVD: relative to 0 Gy, HF rates following MVLDs of 1-15, 16-20, 21-25 and ≥26 Gy were 1.27, 1.65, 3.84, and 4.39 respectively (ptrend<0.001). Anthracycline-containing chemotherapy increased HF rate by a factor of 2.83 (95%CI: 1.43-5.59), and there was no significant interaction with MLVD (pinteraction=0.09). Twenty-five year cumulative risks of HF following MLVDs of 0-15 Gy, 16-20 Gy, and ≥21 Gy were 4.4%, 6.2% and 13.3%, respectively, in patients treated without anthracycline-containing chemotherapy, and 11.2%, 15.9% and 32.9%, respectively, in patients treated with anthracyclines. We have derived quantitative estimates of HF risk in patients treated for HL following radiotherapy with or without anthracycline-containing chemotherapy. Our results enable estimation of HF risk for patients before treatment, during RT planning and during follow-up