Cost-effectiveness of shifting breast cancer surveillance from a hospital setting to a community-based national screening programme setting

Background: In the Netherlands, breast cancer surveillance after breast conserving surgery (BCS) takes place in a hospital setting for at least five years to detect possible recurrences in early stage. As breast cancer incidence rises and mortality decreases, surveillance expenses increase. This study explores the effectiveness and cost-effectiveness of BCS surveillance as delivered in a hospital setting versus providing BCS surveillance as part of the community-based National Breast Cancer Screening Program (NBCSP). We hypothesise that the NBCSP-based strategy leads to lower costs and a lower proportion of true test results (TTR) compared to the hospital-based strategy and determine to what extent potential lower effectiveness may be balanced with expected cost savings. Materials and Methods: Both strategies are compared on effectiveness and cost-effectiveness in a decision tree from a healthcare perspective over a 5-year time horizon. Women aged 50–75 without distant metastases that underwent BCS in the years 2003–2006 with complete 5 year follow-up were selected from the Netherlands Cancer Registry (n = 14,093). Key input variables were mammography sensitivity and specificity, risk of loco regional recurrence (LRR), and direct healthcare costs. The primary outcome measure was the overall predictive value (measured in true test results). Secondary effectiveness measures were the positive predictive value (PPV) (LRRs detected or true positive test results) and the negative predictive value (NPV) (true negative test results) detected within five years post-treatment. Results are presented for low and high risk patients separately and expressed in incremental cost-effectiveness ratios (ICERs). Results: For low risk patients (with grade 1 tumours, no node involvement, and hormonal treatment), the PPV and NPV for the NBCSP strategy were 3.31% and 99.88%, and 2.74% and 99.95% for the hospital strategy respectively. For high risk patients (grade 3 tumours, over three nodes involved, without hormonal treatment), the PPV and NPV for the NBCSP strategy were 64.1% and 98.9%; and 51.0% and 99.7% for the hospital strategy respectively. For low risk patients the NBCSP saves €202 per patient leading to an ICER of €109/accurate test result. For high risk patients the cost savings are €72 per patient, leading to an ICER of €43/accurate test result. Conclusion: Although the NBCSP-based strategy is cheaper, it cannot replace the hospital-based strategy, since it leads to only half of the accurate test results compared to hospital-based strategy. This contradicts the goal of early detection of LRRs and improving outcomes

Symptom clusters in 1330 survivors of 7 cancer types from the PROFILES registry:A network analysis

BACKGROUND: Research into the clustering of symptoms may improve the understanding of the underlying mechanisms that affect survivors' symptom burden. This study applied network analyses in a balanced sample of cancer survivors to 1) explore the clustering of symptoms and 2) assess differences in symptom clustering between cancer types, treatment regimens, and short‐term and long‐term survivors. METHODS: This study used cross‐sectional survey data, collected between 2008 and 2018, from the population‐based Patient Reported Outcomes Following Initial Treatment and Long Term Evaluation of Survivorship registry, which included survivors of 7 cancer types (colorectal cancer, breast cancer, ovarian cancer, thyroid cancer, chronic lymphocytic leukemia, Hodgkin lymphoma, and non‐Hodgkin lymphoma). Regularized partial correlation network analysis was used to explore and visualize the associations between self‐reported symptoms (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire) and the centrality of these symptoms in the network (ie, how strongly a symptom was connected to other symptoms) for the total sample and for subgroups separately. RESULTS: In the total sample (n = 1330), fatigue was the most central symptom in the network with moderate direct relationships with emotional symptoms, cognitive symptoms, appetite loss, dyspnea, and pain. These relationships persisted after adjustments for sociodemographic and clinical characteristics. Connections between fatigue and emotional symptoms, appetite loss, dyspnea, and pain were consistently found across all cancer types (190 for each), treatment regimens, and short‐term and long‐term survivors. CONCLUSIONS: In a heterogenous sample of cancer survivors, fatigue was consistently the most central symptom in all networks. Although longitudinal data are needed to build a case for the causal nature of these symptoms, cancer survivorship rehabilitation programs could focus on fatigue to reduce the overall symptom burden

The added value of immediate breast reconstruction to health-related quality of life of breast cancer patients

Background: Postmastectomy immediate breast reconstruction (IBR) may improve the quality of life (QoL) of breast cancer patients. Guidelines recommend to discuss the option IBR with all patients undergoing mastectomy. However, substantial hospital variation in IBR-rates was previously observed in the Netherlands, influenced by patient, tumour and hospital factors and clinicians’ believes. Information provision about IBR may have a positive effect on receiving IBR and therefore QoL. This study investigated patient-reported QoL of patients treated with mastectomy with and without IBR. Methods: An online survey, encompassing the validated BREAST-Q questionnaire, was distributed to a representative sample of 1218 breast cancer patients treated with mastectomy. BREAST-Q scores were compared between patients who had undergone mastectomy either with or without IBR. Results: A total of 445 patients were included for analyses: 281 patients with and 164 without IBR. Patients who had received IBR showed significantly higher BREAST-Q scores on “psychosocial well-being” (75 versus 67, p < 0.001), “sexual well-being” (62 versus 52, p < 0.001) and “physical well-being” (77 versus 74, p = 0.021) compared to patients without IBR. No statistically significant difference was found for “satisfaction with breasts” (64 versus 62, p = 0.21). Similar results were found after multivariate regression analyses, revealing IBR to be an independent factor for a better patient-reported QoL. Conclusions: Patients diagnosed with breast cancer with IBR following mastectomy report a better QoL on important psychosocial, sexual and physical well-being domains. This further supports the recommendation to discuss the option of IBR with all patients with an indication for mastectomy and to enable shared decision-making

Resveratrol as Add-on Therapy in Subjects With Well-Controlled Type 2 Diabetes: A Randomized Controlled Trial

Item does not contain fulltextOBJECTIVE: To determine whether resveratrol supplementation can improve insulin sensitivity and promote overall metabolic health on top of standard diabetes care. RESEARCH DESIGN AND METHODS: Seventeen subjects with well-controlled type 2 diabetes (T2D) were treated with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. The main outcome measure was insulin sensitivity by the hyperinsulinemic-euglycemic clamp technique. RESULTS: Hepatic and peripheral insulin sensitivity were not affected by resveratrol treatment. Intrahepatic lipid content also remained unaffected by resveratrol; however, the change in intrahepatic lipid content correlated negatively with plasma resveratrol levels (R = -0.68, P = 0.03). Intramyocellular lipid content increased in type 2 muscle fibers (P = 0.03), and systolic blood pressure tended to decrease (P = 0.09) upon resveratrol treatment. In addition, resveratrol significantly improved ex vivo mitochondrial function (state 3 and state U respiration upon malate with octanoyl-carnitine, P < 0.005). Intriguingly, a correlation was found between plasma levels of a metabolite of resveratrol (dihydroresveratrol) and the metformin dose used by the patients (R = 0.66, P = 0.005), suggesting an interaction between metformin and resveratrol. It could be speculated that the lack of a resveratrol-induced insulin-sensitizing effect is caused by this interaction. CONCLUSIONS: Resveratrol supplementation does not improve hepatic or peripheral insulin sensitivity. Our results question the generalized value of resveratrol as an add-on therapy in the treatment of T2D and emphasize the need to perform studies in drug-naive patients with T2D or subjects with prediabetes.1 december 201

International development of a patient-centered core outcome set for assessing health-related quality of life in metastatic breast cancer patients

Purpose For patients living with metastatic breast cancer (MBC), achieving best possible health-related quality of life, along with maximizing survival, is vital. Yet, we have no systemic way to determine if we achieve these goals. A Core Outcome Set (COS) that allows standardized measurement of outcomes important to patients, but also promotes discussing these outcomes during clinical encounters, is long overdue. Methods An international expert group (EG) of patient advocates, researchers, medical specialists, nurse specialists, and pharmaceutical industry representatives (n = 17) reviewed a list of relevant outcomes retrieved from the literature. A broader group (n = 141: patients/patient advocates (n = 45), health care professionals/researchers (n = 64), pharmaceutical industry representatives (n = 28), and health authority representatives (n = 4)) participated in a modified Delphi procedure, scoring the relevance of outcomes in two survey rounds. The EG finalized the COS in a consensus meeting. Results The final MBC COS includes 101 variables about: (1) health-related quality of life (HRQoL, n = 26) and adverse events (n = 24); (2) baseline patient characteristics (n = 9); and (3) clinical variables (n = 42). Many outcome that cover aspects of HRQoL relevant to MBC patients are included, e.g. daily functioning (including ability to work), psychosocial/emotional functioning, sexual functioning, and relationship with the medical team. Conclusion The COS developed in this study contains important administrative data, clinical records, and clinician-reported measures that captures the impact of cancer. The COS is important for standardization of clinical research and implementation in daily practice and has received accreditation by the International Consortium for Health Outcomes Measurement (ICHOM)

The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases

Biochemical, structural and cellular studies reveal Jumonji-C (JmjC) domain-containing 7 (JMJD7) to be a 2-oxoglutarate (2OG)-dependent oxygenase that catalyzes (3S)-lysyl hydroxylation. Crystallographic analyses reveal JMJD7 to be more closely related to the JmjC hydroxylases than to the JmjC demethylases. Biophysical and mutation studies show that JMJD7 has a unique dimerization mode, with interactions between monomers involving both N- and C-terminal regions and disulfide bond formation. A proteomic approach identifies two related members of the translation factor (TRAFAC) family of GTPases, developmentally regulated GTP-binding proteins 1 and 2 (DRG1/2), as activity-dependent JMJD7 interactors. Mass spectrometric analyses demonstrate that JMJD7 catalyzes Fe(ii)- and 2OG-dependent hydroxylation of a highly conserved lysine residue in DRG1/2; amino-acid analyses reveal that JMJD7 catalyzes (3S)-lysyl hydroxylation. The functional assignment of JMJD7 will enable future studies to define the role of DRG hydroxylation in cell growth and disease.Fil: Markolovic, Suzana. University of Oxford; Reino UnidoFil: Zhuang, Qinqin. University Of Birmingham; Reino UnidoFil: Wilkins, Sarah E.. University of Oxford; Reino UnidoFil: Eaton, Charlotte D.. University Of Birmingham; Reino UnidoFil: Abboud, Martine I.. University of Oxford; Reino UnidoFil: Katz, Maximiliano Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: McNeil, Helen E.. University Of Birmingham; Reino UnidoFil: Leśniak, Robert K.. University of Oxford; Reino UnidoFil: Hall, Charlotte. University Of Birmingham; Reino UnidoFil: Struwe, Weston B.. University of Oxford; Reino UnidoFil: Konietzny, Rebecca. University of Oxford; Reino UnidoFil: Davis, Simon. University of Oxford; Reino UnidoFil: Yang, Ming. The Francis Crick Institute; Reino Unido. University of Oxford; Reino UnidoFil: Ge, Wei. University of Oxford; Reino UnidoFil: Benesch, Justin L. P.. University of Oxford; Reino UnidoFil: Kessler, Benedikt M.. University of Oxford; Reino UnidoFil: Ratcliffe, Peter J.. University of Oxford; Reino Unido. The Francis Crick Institute; Reino UnidoFil: Cockman, Matthew E.. The Francis Crick Institute; Reino Unido. University of Oxford; Reino UnidoFil: Fischer, Roman. University of Oxford; Reino UnidoFil: Wappner, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Chowdhury, Rasheduzzaman. University of Stanford; Estados Unidos. University of Oxford; Reino UnidoFil: Coleman, Mathew L.. University Of Birmingham; Reino UnidoFil: Schofield, Christopher J.. University of Oxford; Reino Unid

Characterization of human and rodent native and recombinant adenosine A2B receptors by radioligand binding studies

Adenosine A2B receptors of native human and rodent cell lines were investigated using [3H]PSB-298 [(8-{4-[2-(2-hydroxyethylamino)-2-oxoethoxy]phenyl}-1-propylxanthine] in radioligand binding studies. [3H]PSB-298 showed saturable and reversible binding. It exhibited a KD value of 60 ± 1 nM and limited capacity (Bmax = 3.511 fmol per milligram protein) at recombinant human adenosine A2B receptors expressed in human embryonic kidney cells (HEK-293). The addition of sodium chloride (100 mM) led to a threefold increase in the number of binding sites recognized by the radioligand. The curve of the agonist 5′-N-ethylcarboxamidoadenosine (NECA) was shifted to the right in the presence of NaCl, while the curve of the antagonist PSB-298 was shifted to the left, indicating that PSB-298 may be an inverse agonist at A2B receptors. Adenosine A2B receptors were shown to be the major adenosine A2 receptor subtype on the mouse neuroblastoma x rat glioma hybrid cell line NG108-15 cells. Binding studies at rat INS-1 cells (insulin secreting cell line) demonstrated that [3H]PSB-298 is a selective radioligand for adenosine A2B binding sites in this cell line

Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties.

Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg block. In addition, we provide new views on Mg and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological disorders. Of note, the NMDAR channel mutant GluN2B unusually allowed Mg permeation, whereas nearby N615I reduced Ca permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease-causing mutations