Amgen (Switzerland)

BACKGROUND: This prospective, randomized, controlled trial compared the progression of vascular and cardiac valve calcification in 360 prevalent adult hemodialysis patients with secondary hyperparathyroidism treated with either cinacalcet plus low-dose vitamin D sterols or flexible doses of vitamin D sterols alone. METHODS: Eligible subjects were on hemodialysis for ≥ 3 months with parathyroid hormone (PTH) > 300 pg/mL or PTH 150-300 pg/mL with calcium-phosphorus product > 50 mg(2)/dL(2) while receiving vitamin D. All subjects received calcium-based phosphate binders. Coronary artery calcification (CAC) and aorta and cardiac valve calcium scores were determined both by Agatston and volume scoring using multi-detector computed tomography. Subjects with Agatston CAC scores ≥ 30 were randomized to cinacalcet (30- 180 mg/day) plus low-dose calcitriol or vitamin D analog (≤ 2 μg paricalcitol equivalent/dialysis), or flexible vitamin D therapy. The primary end point was percentage change in Agatston CAC score from baseline to Week 52. RESULTS: Median (P10, P90) Agatston CAC scores increased 24% (-22%, 119%) in the cinacalcet group and 31% (-9%, 179%) in the flexible vitamin D group (P = 0.073). Corresponding changes in volume CAC scores were 22% (-12%, 105%) and 30% (-6%, 133%; P = 0.009). Increases in calcification scores were consistently less in the aorta, aortic valve and mitral valve among subjects treated with cinacalcet plus low-dose vitamin D sterols, and the differences between groups were significant at the aortic valve. CONCLUSIONS: In hemodialysis patients with moderate to severe secondary hyperparathyroidism, cinacalcet plus low-dose vitamin D sterols may attenuate vascular and cardiac valve calcification.

BACKGROUND: A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative. METHODS: The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used. RESULTS: Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62-2.73; <75 pg/mL, HR = 1.46, 95% CI 1.17-1.83]. TD analysis confirmed the results for iPTH. Baseline analysis showed that calcium >2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19-2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04-1.37) and high calcium (HR = 1.74, 95% CI 1.30-2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern (<1.13 mmol/L, HR = 1.18, 95% CI 1.01-1.37; >1.78 mmol/L, HR = 1.32, 95% CI 1.13-1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses. CONCLUSION: Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.

BACKGROUND: Heart failure presents a growing clinical and economic burden in the USA. Robust cost data on the burden of illness are critical to inform economic evaluations of new therapeutic interventions. OBJECTIVES: This systematic literature review of heart failure-related costs in the USA aimed to assess the quality of the published evidence and provide a narrative synthesis of current data. METHODS: Four electronic databases (MEDLINE, EMBASE, EconLit, and the Centre for Reviews and Dissemination York Database, including the NHS Economic Evaluation Database and Health Technology Assessment Database) were searched for journal articles published between January 2014 and March 2020. The review, registered with PROSPERO (CRD42019134201), was restricted to cost-of-illness studies in adults with heart failure events in the USA. RESULTS: Eighty-seven studies were included, 41 of which allowed a comparison of cost estimates across studies. The annual median total medical costs for heart failure care were estimated at $24,383 per patient, with heart failure-specific hospitalizations driving costs (median $15,879 per patient). Analyses of subgroups revealed that heart failure-related costs are highly sensitive to individual patient characteristics (such as the presence of comorbidities and age) with large variations even within a subgroup. Additionally, differences in study design and a lack of standardized reporting limited the ability to compare cost estimates. The finding that costs are higher for patients with heart failure with reduced ejection fraction compared with patients with preserved ejection fraction highlights the need for differentiating among different heart failure types. CONCLUSIONS: The review underpins the conclusion drawn in earlier reviews, namely that hospitalization costs are the key driver of heart failure-related costs. Analyses of subgroups provide a clearer understanding of sources of heterogeneity in cost data. While current cost estimates provide useful indications of economic burden, understanding the nuances of the data is critical to support its application.

With increasing number of therapies available for the treatment of multiple myeloma, it is timely to examine the course of patients' journeys. We investigated patient characteristics, treatment durations and outcomes, and symptom burden across the treatment pathway in Belgium, France, Germany, Italy, Spain, Switzerland and the UK. In total, 435 physicians retrospectively reviewed 4997 patient charts. Profiles of patients diagnosed with multiple myeloma during the last 12 months were similar across countries; bone pain was the most common presentation. Median duration of first-line therapy was 6 months, followed by a median treatment-free interval of 10 months; both these decreased with increasing lines of therapy, as did time to progression. Depth of response, as assessed by the treating physician, also decreased with each additional line of therapy: 74% of patients achieved at least a very good partial response at first line, compared with only 11% at fifth line. Deeper responses were associated with longer time to progression, although these were physician-judged. Toxicities and co-morbidities increased with later treatment lines, and were more likely to have led to discontinuation of treatment. These real-world data provide an insight into patient outcomes and treatment decisions being made in clinical practice.

PURPOSE: The use of electronic patient-reported outcomes (PRO) systems is increasing in cancer clinical care settings. This review comprehensively identifies existing PRO systems and explores how systems differ in the administration of PRO assessments, the integration of information into the clinic workflow and electronic health record (EHR) systems, and the reporting of PRO information. METHODS: Electronic PRO (e-PRO) systems were identified through a semistructured review of published studies, gray literature, and expert identification. System developers were contacted to provide detailed e-PRO system characteristics and clinical implementation information using a structured review form. RESULTS: A total of 33 unique systems implemented in cancer clinical practice were identified. Of these, 81% provided detailed information about system characteristics. Two system classifications were established: treatment-centered systems designed for patient monitoring during active cancer treatment (n = 8) and patient-centered systems following patients across treatment and survivorship periods (n = 19). There was little consensus on administration, integration, or result reporting between these system types. Patient-centered systems were more likely to provide user-friendly features such as at-home assessments, integration into larger electronic system networks (eg, EHRs), and more robust score reporting options. Well-established systems were more likely to have features that increased assessment flexibility (eg, location, automated reminders) and better clinical integration. CONCLUSION: The number of e-PRO systems has increased. Systems can be programmed to have numerous features that facilitate integration of PRO assessment and routine monitoring into clinical care. Important barriers to system usability and widespread adoption include assessment flexibility, clinical integration, and high-quality data collection and reporting.

Medication-related osteonecrosis of the jaw (MRONJ) is primarily an adverse side effect of denosumab or bisphosphonates (particularly when used at high doses to prevent skeletal-related events [SREs] in patients with cancer and bone metastases) or possibly anti-angiogenic cancer treatment. While the implementation of preventive measures over recent years has reduced the risk of MRONJ in patients with bone metastases due to cancer, it is imperative to balance the risk of MRONJ against the beneficial effects of treatment with denosumab or bisphosphonates on the skeletal health of patients. Despite growing awareness of MRONJ within the medical community, there is a lack of large-scale, prospective clinical studies in this rapidly evolving field. Discussing preventive measures with patients and implementing them, both before and during treatment with bisphosphonates or denosumab, is the best option to reduce the risk of MRONJ. In particular, avoiding bone trauma and preventing and treating dental infections before and during denosumab or bisphosphonate therapy is crucial to minimize the risk of MRONJ. If MRONJ develops, conservative (non-surgical) treatment can provide symptom relief, but achieving mucosal closure remains challenging. When management of symptoms and mucosal healing are the ultimate goals of therapy, or after failure of conservative treatment, a surgical approach may be beneficial. This critical review, based on a best-evidence review of currently available literature, provides clear practical guidelines to help to prevent, manage and treat MRONJ. Overall, a multidisciplinary, pragmatic approach to MRONJ should be adopted, prioritizing patient's quality of life and management of their skeletal malignant disease.

Abstract Background: CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) therapy is standard treatment for aggressive Non-Hodgkin’s Lymphoma (NHL), and frequently results in myelosuppression. The resulting febrile neutropenia (FN) and chemotherapy-induced anaemia (CIA) may be treated with Granulocyte Colony Stimulating Factor (G-CSF) and Erythropoiesis-Stimulating Agents (ESAs), respectively. IMPACT is an observational study, ongoing since February 2007, to examine supportive care management practices in NHL patients undergoing CHOP chemotherapy. Since the beginning of this study, European treatment guidelines for use of ESAs in CIA changed: from initiation at 11 g/dL with the goal to achieve hemoglobin (Hb) within 11–13 g/dL, to, as of February 2008, initiation at 10 g/dL and target range of 10–12 g/dL. This planned interim analysis describes anaemia and transfusion outcomes from this ongoing study as of April 2008. Methods: European patients with diffuse large-B-cell lymphoma (DLBCL), planning at least 3 cycles of CHOP-14 or -21 +/− rituximab were included in the study. This subset analysis evaluated only those patients not participating in a clinical trial. Patients were retrospectively or prospectively followed up to the end of chemotherapy treatment to a maximum of 8 chemotherapy cycles. CIA treatment was according to local standard of care, either with or without ESAs. Data were collected on Hb at ESA initiation, reasons for ESA treatment, Hb achieved during the ESA treatment phase, Hb level at first transfusion, and transfusion incidence. Results: For this interim analysis, data were available for 454 patients (mean age 60.5 [SD 14.8] years and 54% male), of whom 64% received CHOP-21; 35% of patients received treatment for CIA comprising ESA and/or transfusion. Among patients who received ESAs (N=112), the most frequent reasons for initiating treatment included Hb level (79%) or perceived risk of CIA (24%). Forty-one percent of ESA-treated patients had Hb levels &amp;lt;10 g/dL at ESA initiation; overall, the mean (SD) Hb at initiation was 10.16 (1.22) g/dL. The median (Q1, Q3) chemotherapy cycle at which patients received their initial dose of ESA was 3 (1, 4). Among patients treated with ESAs, 61% achieved a Hb level between 10–12 g/dL during the ESA treatment phase; and 27% experienced a Hb rate of rise 31g/dL in 14 days. Twenty percent (n=22) of ESA-treated patients received transfusions. Among these, the mean (SD) Hb level at first transfusion was 9.15 (0.94) g/dL; 36% (n=8) of ESA-treated patients received their first transfusion in cycle 1. Conclusions: While the number of the patients available for this interim analysis is small, the results do provide some perspective on anaemia treatment in this population. European patients with DLBCL receiving CHOP-14 or -21 may experience treatment-related anaemia that can be managed with ESAs. Any ESA1 (N=112) Darbepoetin alfa (N=59) Epoetin alfa (N=21) Epoetin beta (N=30) 1Two additional patients labeled as receiving ‘Other’ ESA treatment included. 2Assessment of Achieved Hb excludes Hb values within 28 days after a transfusion. Note: week 1 indicates first week of ESA initiation. Age, mean (SD), years 64.3 (12.8) 63.5 (13.8) 65.3 (10.1) 65.7 (12.4) Men, n (%) 56 (50) 31 (53) 11 (52) 13 (43) ECOG 0–1, n (%) 88 (79) 46 (78) 13 (62) 27 (90) CHOP-21, n (%) 81 (72) 43 (73) 13 (62) 23 (77) Hb (g/dL) at initiation of ESA treatment, n (%) Achieved Hb (g/dL) week 1 to end of ESA treatment, n (%)2 Hb at initiation &amp;lt;10 46 (41) 22 (37) 11 (52) 13 (43) Achieved Hb ≥10 g/dL 32 (70) 15 (68) 8 (73) 9 (69) Achieved Hb 10–12 g/dL 28 (61) 14 (64) 6 (55) 8 (62) Hb at initiation &amp;lt;11 87 (78) 47 (79) 17 (81) 21 (70) Achieved Hb ≥11 g/dL 44 (51) 27 (57) 7 (41) 10 (48) Hb at initiation &amp;lt;12 100 (89) 54 (92) 18 (86) 26 (87) Achieved Hb ≥12 g/dL 35 (35) 19 (35) 5 (28) 11 (42)

BACKGROUND: Chronic kidney disease (CKD) is a powerful risk factor for all-cause mortality and its most common aetiology, cardiovascular (CV) mortality. Mineral metabolism disturbances occur very early during the course of CKD but their control has been poor. A number of studies have assessed the relationship between all-cause mortality, CV mortality and events with mineral disturbances in CKD patients, but with considerable discrepancy and heterogeneity in results. Thus, a systematic review was conducted to assess methodological and clinical heterogeneity by comparing designs, analytical approaches and results of studies. METHODS: Medline, EMBASE and Cochrane databases were systematically searched for articles published between January 1980 and December 2007. RESULTS: Thirty-five studies were included in the review. All-cause mortality was the most commonly assessed outcome (n = 29). Data on CV mortality risk (n = 11) and CV events (congestive heart failure, stroke, myocardial infarction) (n = 4) are limited. The studies varied in populations scrutinized, exposure assessments, covariates adjusted and reference mineral levels used in risk estimation. A significant risk of mortality (all-cause, CV) and of CV events was observed with mineral disturbances. The data supported a greater mortality risk with phosphorus, followed by calcium and parathyroid hormone (PTH). The threshold associated with a significant all-cause mortality risk varied from 3.5-3.9 mg/dL (reference: 2.5-2.9) to 6.6-7.8 mg/dL (reference: 4.4-5.5) for high phosphorus, <3 mg/dL (reference: 5-7) to <5 mg/dL (reference: 5-6) for low phosphorus, 9.7-10.2 mg/dL (reference: < or =8.7) to >10.5 mg/dL (reference: 9-9.5) for high calcium, < or =8.8 mg/dL (reference: >8.8) to <9 mg/dL (reference: 9-9.5) for low calcium and >300 pg/mL (reference: 200-300) to >480 pg/mL (reference: < or =37) for PTH. Thresholds at which the CV mortality risk significantly increased were >5.5 (reference: 3.5-5.5) and >6.5 mg/dL (reference: <6.5) for phosphorus and >476.1 pg/mL (reference: <476.1) for PTH. CONCLUSIONS: Serious limitations were observed in the quality and methodology across studies. In spite of enormous heterogeneity across studies, a significant mortality risk was observed with mineral disturbances in dialysis patients. Data on risk in pre-dialysis patients were less conclusive due to even more limited (numerically) evidence.

The fully human monoclonal antibody denosumab was approved for treatment of osteoporosis in 2010 on the basis of its potent antiresorptive activity, which produces clinically meaningful increases in bone mineral density (BMD) and reduces fracture risk at key skeletal sites. At that time, questions remained regarding the long-term safety and efficacy of this receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor; and with clinical experience, new questions have arisen regarding its optimal use. Here, we examine these questions through the lens of data from the FREEDOM trial program and other studies to determine where denosumab fits in the osteoporosis treatment landscape. Clinical consensus and evidentiary support have grown for denosumab as a highly effective anti-osteoporosis therapy for patients at high risk of fracture. In the 10-year FREEDOM Extension study, denosumab treatment produced progressive incremental increases in BMD, sustained low rates of vertebral fracture, and further reduction in nonvertebral fracture risk without increased risk of infection, cancer, or immunogenicity. There was no evidence that suppression of bone turnover or mineralization was excessive, and rates of osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) were very low. It is now recognized, however, that transitioning to another anti-osteoporosis therapy after denosumab discontinuation is essential to mitigate a transient rebound of bone turnover causing rapid BMD loss and increased risk of multiple vertebral fractures (MVFs). Taken together, the available data show that denosumab has a favorable benefit/risk profile and is a versatile agent for preventing osteoporotic fractures in the short and long term. Video abstract: Denosumab in the Treatment of Osteoporosis-10 Years Later (MP4 62727 KB).

The discovery of oncogenic driver mutations rendering non-small cell lung cancer (NSCLC) targetable by small-molecule inhibitors, and the development of immunotherapies, have revolutionised NSCLC treatment. Today, instead of non-selective chemotherapies, all patients with advanced NSCLC eligible for treatment (and increasing numbers with earlier, less extensive disease) require fast and comprehensive screening of biomarkers for first-line patient selection for targeted therapy, chemotherapy, or immunotherapy (with or without chemotherapy). To avoid unnecessary re-biopsies, biomarker screening before first-line treatment should also include markers that are actionable from second-line onwards; PD-L1 expression testing is also mandatory before initiating treatment. Population differences exist in the frequency of oncogenic driver mutations: EGFR mutations are more frequent in Asia than Europe, whereas the converse is true for KRAS mutations. In addition to approved first-line therapies, a number of emerging therapies are being investigated in clinical trials. Guidelines for biomarker testing vary by country, with the number of actionable targets and the requirement for extensive molecular screening strategies expected to increase. To meet diagnostic demands, rapid screening technologies for single-driver mutations have been implemented. Improvements in DNA- and RNA-based next-generation sequencing technologies enable analysis of a group of genes in one assay; however, turnaround times remain relatively long. Consequently, rapid screening technologies are being implemented alongside next-generation sequencing. Further challenges in the evolving landscape of biomarker testing in NSCLC are actionable primary and secondary resistance mechanisms to targeted therapies. Therefore, comprehensive testing on re-biopsies, collected at the time of disease progression, in combination with testing of circulating tumour DNA may provide important information to guide second- or third-line therapies. Furthermore, longitudinal biomarker testing can provide insights into tumour evolution and heterogeneity during the course of the disease. We summarise best practice strategies for Europe in the changing landscape of biomarker testing at diagnosis and during treatment.

PURPOSE: The concomitant use of intravenous (IV) iron as a supplement to erythropoiesis-stimulating agents in patients with chemotherapy-induced anemia is controversial. This study was designed to evaluate the efficacy and safety of darbepoetin alpha given with IV iron versus with local standard practice (oral iron or no iron). PATIENTS AND METHODS: In this multicenter, randomized, open-label, phase III study, 396 patients with nonmyeloid malignancies and hemoglobin (Hb) less than 11 g/dL received darbepoetin alpha 500 microg with (n = 200) or without (n = 196) IV iron once every 3 weeks (Q3W) for 16 weeks. RESULTS: The hematopoietic response rate (proportion of patients achieving Hb >or= 12 g/dL or Hb increase of >or= 2 g/dL from baseline) was significantly higher in the IV iron group: 86% versus 73% in the standard practice group (difference of 13% [95% CI, 3% to 23%]; P = .011). Fewer RBC transfusions (week 5 to the end of the treatment period) occurred in the IV iron group: 9% versus 20% in the standard practice group (difference of -11% [95% CI, -18% to -3%]; P = .005). Both treatments were well tolerated with no notable differences in adverse events. Serious adverse events related to iron occurred in 3% of patients in the IV iron group and were mostly gastrointestinal in nature. CONCLUSION: Addition of IV iron to darbepoetin alpha Q3W in patients with chemotherapy-induced anemia was well tolerated, resulting in an improved hematopoietic response rate and lower incidence of transfusions compared with darbepoetin alpha alone.

PURPOSE: We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective-retrospective analysis of a randomized, multicenter phase III study of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183). EXPERIMENTAL DESIGN: Outcomes were from the study's primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints. RESULTS: The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR, 0.70 (95% confidence interval [CI], 0.54-0.91); P = 0.007 vs. 0.73 (95% CI, 0.59-0.90); P = 0.004; OS HR, 0.81 (95% CI, 0.63-1.03); P = 0.08 vs. 0.85 (95% CI, 0.70-1.04); P = 0.12]. Patients with RAS mutations were unlikely to benefit from panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the panitumumab-FOLFIRI group versus 10% in the FOLFIRI group. CONCLUSIONS: Patients with RAS mutations were unlikely to benefit from panitumumab-FOLFIRI and the benefit-risk of panitumumab-FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC. Clin Cancer Res; 21(24); 5469-79. ©2015 AACR.See related commentary by Salazar and Ciardiello, p. 5415.

Purpose Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics. Patients and Methods We used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups. Results MRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different ( P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype-specific MRD values allowed more refined risk group stratification. Conclusion A single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse.

CD31(+)CD45RA(+)RO(-) lymphocytes contain high numbers of T cell receptor circle (TREC)-bearing T cells; however, the correlation between CD31(+)CD4(+) lymphocytes and TREC during aging and under lymphopenic conditions has not yet been sufficiently investigated. We analyzed TREC, telomere length and telomerase activity within sorted CD31(+) and CD31(-) CD4(+) lymphocytes in healthy individuals from birth to old age. Sorted CD31(+)CD45RA(+)RO(-) naive CD4(+) lymphocytes contained high TREC numbers, whereas CD31(+)CD45RA(-)RO(+) cells (comprising < or =5% of CD4(+) cells during aging) did not contain TREC. CD31(+) overall CD4(+) cells remained TREC rich despite an age-related tenfold reduction from neonatal (100 : 1000) to old age (10 : 1000). Besides a high TREC content, CD31(+)CD45RA(+)RO(-)CD4(+) cells exhibited significantly longer telomeres and higher telomerase activity than CD31(-)CD45RA(+)RO(-)CD4(+) cells, suggesting that CD31(+)CD45RA(+)RO(-)CD4(+) cells represent a distinct population of naive T cells with particularly low replicative history. To analyze the value of CD31 in lymphopenic conditions, we investigated six children after allogeneic hematopoietic stem cell transplantation (HSCT). Reemerging overall CD4(+) as well as naive CD45RA(+)RO(-)CD4(+) cells predominantly expressed CD31 and correlated well with the recurrence of TREC 5-12 months after HSCT. Irrespective of limitations in the elderly, CD31 is an appropriate marker to monitor TREC-rich lymphocytes essentially in lymphopenic children after HSCT.

Genomic selection involves breeding value estimation of selection candidates based on high-density SNP genotypes. To quantify the potential benefit of genomic selection, accuracies of estimated breeding values (EBV) obtained with different methods using pedigree or high-density SNP genotypes were evaluated and compared in a commercial layer chicken breeding line. The following traits were analyzed: egg production, egg weight, egg color, shell strength, age at sexual maturity, body weight, albumen height, and yolk weight. Predictions appropriate for early or late selection were compared. A total of 2,708 birds were genotyped for 23,356 segregating SNP, including 1,563 females with records. Phenotypes on relatives without genotypes were incorporated in the analysis (in total 13,049 production records). The data were analyzed with a Reduced Animal Model using a relationship matrix based on pedigree data or on marker genotypes and with a Bayesian method using model averaging. Using a validation set that consisted of individuals from the generation following training, these methods were compared by correlating EBV with phenotypes corrected for fixed effects, selecting the top 30 individuals based on EBV and evaluating their mean phenotype, and by regressing phenotypes on EBV. Using high-density SNP genotypes increased accuracies of EBV up to two-fold for selection at an early age and by up to 88% for selection at a later age. Accuracy increases at an early age can be mostly attributed to improved estimates of parental EBV for shell quality and egg production, while for other egg quality traits it is mostly due to improved estimates of Mendelian sampling effects. A relatively small number of markers was sufficient to explain most of the genetic variation for egg weight and body weight.

This study in 8 countries across Europe found that about 75% of elderly women seen in primary care who were at high risk of osteoporosis-related fractures were not receiving appropriate medication. Lack of osteoporosis diagnosis appeared to be an important contributing factor. INTRODUCTION: Treatment rates in osteoporosis are documented to be low. We wished to assess the osteoporosis treatment gap in women ≥ 70 years in routine primary care across Europe. METHODS: This cross-sectional observational study in 8 European countries collected data from women 70 years or older visiting their general practitioner. The primary outcome was treatment gap: the proportion who were not receiving any osteoporosis medication among those at increased risk of fragility fracture (using history of fracture, 10-year probability of fracture above country-specific Fracture Risk Assessment Tool [FRAX] thresholds, T-score ≤ - 2.5). RESULTS: Median 10-year probability of fracture (without bone mineral density [BMD]) for the 3798 enrolled patients was 7.2% (hip) and 16.6% (major osteoporotic). Overall, 2077 women (55%) met one or more definitions for increased risk of fragility fracture: 1200 had a prior fracture, 1814 exceeded the FRAX threshold, and 318 had a T-score ≤ - 2.5 (only 944 received a dual-energy x-ray absorptiometry [DXA] scan). In those at increased fracture risk, the median 10-year probability of hip and major osteoporotic fracture was 11.2% and 22.8%, vs 4.1% and 11.5% in those deemed not at risk. An osteoporosis diagnosis was recorded in 804 patients (21.2%); most (79.7%) of these were at increased fracture risk. The treatment gap was 74.6%, varying from 53% in Ireland to 91% in Germany. Patients with an osteoporosis diagnosis were found to have a lower treatment gap than those without a diagnosis, with an absolute reduction of 63%. CONCLUSIONS: There is a large treatment gap in women aged ≥ 70 years at increased risk of fragility fracture in routine primary care across Europe. The gap appears to be related to a low rate of osteoporosis diagnosis.

AIM: To provide an overview of thresholds for incremental cost-effectiveness ratios (ICERs) representing willingness-to-pay (WTP) across multiple countries and insights into exemptions pertaining to the ICER (e.g., cancer). To compare ICER thresholds to individual country's estimated ability-to-pay. MATERIALS & METHODS: We included AHRQ/USA, BIQG-GOEG/Austria, CADTH/Canada, DAHTA@DIMDI/Germany, DECIT-CGATS/Brazil, HAS/France, HITAP/Thailand, IQWiG/Germany, LBI-HTA/Austria, MSAC/Australia, NICE/England/Wales and SBU/Sweden. ICER thresholds were derived from systematic literature/website search/expert surveys. WTP was compared with ATP using Spearman's rank correlation. RESULTS: Two general and explicitly acknowledged thresholds (England/Wales, Thailand), implicit thresholds in six countries and different ICER thresholds/decision-making rules in oncology were identified. Correlation between WTP and ability-to-pay was moderate. DISCUSSION: Our overview supports country-specific discussions on WTP and on how to define value(s) within societies.

OBJECTIVES: A systematic literature review was conducted comparing different approaches estimating persistence and adherence in chronic diseases with polypharmacy of oral and subcutaneous treatments. METHODS: This work followed published guidance on performing systematic reviews. Twelve electronic databases and grey literature sources were used to identify studies and guidelines for persistence and adherence of oral and subcutaneous therapies in hypercholesterolemia, type 2 diabetes, hypertension, osteoporosis and rheumatoid arthritis. Outcomes of interest of each persistence and adherence data collection and calculation method included pros: accurate, easy to use, inexpensive; and cons: inaccurate, difficult to use, expensive. RESULTS: A total of 4158 records were retrieved up to March 2017. We included 16 observational studies, 5 systematic reviews and 7 guidelines, in patients with hypercholesterolemia (n = 8), type 2 diabetes (n = 4), hypertension (n = 2), rheumatoid arthritis (n = 1) and mixed patient populations (n = 13). Pharmacy and medical records offer an accurate, easy and inexpensive data collection method. Pill count, medication event monitoring systems (MEMs), self-report questionnaires and observer report are easy to use. MEMS and biochemical monitoring tests can be expensive. Proportion of days covered (PDC) was recommended as a gold standard calculation method for long-term treatments. PDC avoids use of days' supply in calculation, hence is more accurate compared to medication possession ratio (MPR) to assess adherence to treatments in chronic diseases. CONCLUSIONS: Decisions on what method to use should be based on considerations of the route of medication administration, the resources available, setting and aim of the assessment. Combining different methods may provide wider insights into adherence and persistence, including patient behavior.

Importance: The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab has been demonstrated to reduce the composite of myocardial infarction, stroke, or cardiovascular death in patients with established atherosclerotic cardiovascular disease. To our knowledge, long-term cost-effectiveness of this therapy has not been evaluated using clinical trial efficacy data. Objective: To evaluate the cost-effectiveness of evolocumab in patients with atherosclerotic cardiovascular disease when added to standard background therapy. Design, Setting, and Participants: A Markov cohort state-transition model was used, integrating US population-specific demographics, risk factors, background therapy, and event rates along with trial-based event risk reduction. Costs, including price of drug, utilities, and transitional probabilities, were included from published sources. Exposures: Addition of evolocumab to standard background therapy including statins. Main Outcomes and Measures: Cardiovascular events including myocardial infarction, ischemic stroke and cardiovascular death, quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER), and net value-based price. Results: In the base case, using US clinical practice patients with atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol levels of at least 70 mg/dL (to convert to millimoles per liter, multiply by 0.0259) and an annual events rate of 6.4 per 100 patient-years, evolocumab was associated with increased cost and improved QALY: incremental cost, $105 398; incremental QALY, 0.39, with an ICER of $268 637 per QALY gained ($165 689 with discounted price of $10 311 based on mean rebate of 29% for branded pharmaceuticals). Sensitivity and scenario analyses demonstrated ICERs ranging from $100 193 to $488 642 per QALY, with ICER of $413 579 per QALY for trial patient characteristics and event rate of 4.2 per 100 patient-years ($270 192 with discounted price of $10 311) and $483 800 if no cardiovascular mortality reduction emerges. Evolocumab treatment exceeded $150 000 per QALY in most scenarios but would meet this threshold at an annual net price of $9669 ($6780 for the trial participants) or with the discounted net price of $10 311 in patients with low-density lipoprotein cholesterol levels of at least 80 mg/dL. Conclusions and Relevance: At its current list price of $14 523, the addition of evolocumab to standard background therapy in patients with atherosclerotic cardiovascular disease exceeds generally accepted cost-effectiveness thresholds. To achieve an ICER of $150 000 per QALY, the annual net price would need to be substantially lower ($9669 for US clinical practice and $6780 for trial participants), or a higher-risk population would need to be treated.

PURPOSE: To report planned final overall (OS) and progression-free survival (PFS) analyses from the phase II PEAK trial (NCT00819780). METHODS: Patients with previously untreated, KRAS exon 2 wild-type (WT) metastatic colorectal cancer (mCRC) were randomised to mFOLFOX6 plus panitumumab or bevacizumab. The primary endpoint was PFS; secondary endpoints included OS, objective response rate, duration of response (DoR), time to response, resection and safety. Treatment effect by tumour RAS status was a prespecified objective. Exploratory analyses included early tumour shrinkage (ETS) and depth of response (DpR). RESULTS: One hundred seventy patients had RAS WT and 156 had RAS WT/BRAF WT mCRC. Median PFS was longer for panitumumab versus bevacizumab in the RAS WT (12.8 vs 10.1 months; hazard ratio (HR) = 0.68 [95% confidence intervals (CI) = 0.48-0.96]; p = 0.029) and RAS WT/BRAF WT (13.1 vs 10.1 months; HR = 0.61 [95% CI = 0.42-0.88]; p = 0.0075) populations. Median OS (68% OS events) for panitumumab versus bevacizumab was 36.9 versus 28.9 months (HR = 0.76 [95% CI = 0.53-1.11]; p = 0.15) and 41.3 versus 28.9 months (HR = 0.70 [95% CI = 0.48-1.04]; p = 0.08), in the RAS WT and RAS WT/BRAF WT populations, respectively. Median DoR (11.4 vs 9.0 months; HR = 0.59 [95% CI = 0.39-0.88]; p = 0.011) and DpR (65.0 vs 46.3%; p = 0.0018) were improved in the panitumumab group. More panitumumab patients experienced ≥30% ETS at week 8 (64 vs 45%; p = 0.052); ETS was associated with improved PFS/OS. No new safety signals occurred. CONCLUSIONS: First-line panitumumab + mFOLFOX6 increases PFS versus bevacizumab + mFOLFOX6 in patients with RAS WT mCRC.