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1.
J Cancer Policy ; 41: 100493, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38876202

ABSTRACT

BACKGROUND: Financial conflicts of interest (FCOI) of medical professionals and associated organizations with pharmaceutical companies (pharma) might contribute to the use of low value oncological treatments. Value criteria for oncological drug approvals in the Netherlands have recently become more stringent leading to objections by cancer patient advocacy organizations (cPAOs). Considering the importance of cPAOs input in cancer patient care we analyzed whether pharma funding of cPAOs occurs in the Netherlands. METHODS: The cPAO websites and available annual reports were evaluated for disclosure of pharma funding for the years 2021 and 2022. Also, data from the Dutch Healthcare Transparency Registry (DHTR) were extracted. RESULTS: Twenty-one of 34 (61.8 %) cPAOs received pharma funding (with 20 registered in the DHTR), and for 13 (29.4 %) cPAOs no reporting of pharma funding could be found. Three of the cPAOs disclosed pharma funding directly on their main website. Online educational material was available from 22 cPAOs on their websites with pharma funding disclosed on the educational material in 5. The total registered amount of pharmaceutical funding was €667,232.00 in 2021 and €536,098.00 in 2022. The median (and interquartile ranges) DHTR registered amount of support per cPAO that received funding in the studied period was €23,799.50 (14,823.75-84,663.30). The most common funding category as defined in the DHTR was project sponsorship. CONCLUSIONS: Financial support by the pharmaceutical industry is common for Dutch cPAOs. Given the importance of cPAOs and their objective input in the societal debate on the availability of cancer drugs, the potential influence of pharma sponsoring should be critically evaluated.

2.
Lancet Reg Health Am ; 25: 100584, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37681018

ABSTRACT

The quality of evidence leading to new oncological treatments suffers shortcomings, as has recently been addressed for drug approvals. In this 'Personal view', we evaluate the unintended effects of adopting stereotactic radiosurgery as the standard of care for patients with limited number of symptomatic brain metastases and favourable prognostic factors in international guidelines in view of the limitations in the evidence of efficacy and effectiveness, with special focus on countries with relatively limited resources.

4.
Ned Tijdschr Geneeskd ; 1662022 07 28.
Article in Dutch | MEDLINE | ID: mdl-36300482

ABSTRACT

The number of new oncological treatments is increasing rapidly, even though many offer limited benefit to patients. In these cases, the scientific research leading to approvals is marred by shortcomings. Nonetheless, many drugs of limited value are approved by regulatory agencies. One of the factors contributing thereto is financial conflict of interest (FCI) with the pharmaceutical industry (Pharma). This occurs at different levels, including researchers, opinion leaders and editors of medical journals. FCI contributes to patient exposure to treatments that offer limited or no benefit and to unjust spending of valuable resources while providing large revenues for Pharma. The important step of the 'NederlandsTijdschriftvoorGeneeskunde' (NTVG) to omit all pharmaceutical advertisement as well as advertisement for pharmaceutical industry sponsored medical education sends an important signal and is a first step to revalue the important relationship with the pharmaceutical industry.


Subject(s)
Antineoplastic Agents , Conflict of Interest , Humans , Advertising , Drug Industry , Antineoplastic Agents/therapeutic use , Pharmaceutical Preparations
7.
Br J Cancer ; 125(11): 1477-1485, 2021 11.
Article in English | MEDLINE | ID: mdl-34400802

ABSTRACT

Important breakthroughs in medical treatments have improved outcomes for patients suffering from several types of cancer. However, many oncological treatments approved by regulatory agencies are of low value and do not contribute significantly to cancer mortality reduction, but lead to unrealistic patient expectations and push even affluent societies to unsustainable health care costs. Several factors that contribute to approvals of low-value oncology treatments are addressed, including issues with clinical trials, bias in reporting, regulatory agency shortcomings and drug pricing. With the COVID-19 pandemic enforcing the elimination of low-value interventions in all fields of medicine, efforts should urgently be made by all involved in cancer care to select only high-value and sustainable interventions. Transformation of medical education, improvement in clinical trial design, quality, conduct and reporting, strict adherence to scientific norms by regulatory agencies and use of value-based scales can all contribute to raising the bar for oncology drug approvals and influence drug pricing and availability.


Subject(s)
Drug Approval , Drug Costs , Medical Oncology/ethics , Antineoplastic Agents/economics , Antineoplastic Agents/therapeutic use , Bias , COVID-19/epidemiology , Cost Control/ethics , Cost Control/organization & administration , Cost Control/standards , Cultural Evolution , Drug Approval/economics , Drug Approval/legislation & jurisprudence , Drug Approval/organization & administration , Drug Costs/ethics , Drug Costs/legislation & jurisprudence , Humans , Medical Oncology/economics , Medical Oncology/organization & administration , Medical Oncology/standards , Neoplasms/drug therapy , Neoplasms/economics , Neoplasms/mortality , Organizational Innovation , Pandemics
8.
Cancer Chemother Pharmacol ; 88(1): 165-168, 2021 07.
Article in English | MEDLINE | ID: mdl-33817752

ABSTRACT

BACKGROUND: Enzalutamide is an orally administered drug that blocks signaling in the androgen receptor with clinical activity in both chemotherapy-naive and post-chemotherapy patients with castrate-resistant prostate cancer (CRPC). Enzalutamide is generally well-tolerated, but dose reductions are nonetheless needed in case of side effects. CASE: An 82-year-old patient with chemotherapy-naive metastatic castration-resistant prostate cancer was treated with a very low dose of 40 mg enzalutamide once daily. The trough levels of enzalutamide and the active metabolite N-desmethylenzalutamide were 4.5 mg/L and 3.0 mg/L, respectively. This exposure provided a long-term response without any significant side effects. CONCLUSION: Low doses of enzalutamide may be efficacious, while also reducing the risk of side effects. Furthermore, employing a lower dose would reduce healthcare costs and increase access to enzalutamide. Studies exploring the efficacy of lower enzalutamide doses are warranted.


Subject(s)
Benzamides/administration & dosage , Nitriles/administration & dosage , Phenylthiohydantoin/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Aged, 80 and over , Androgen Receptor Antagonists/administration & dosage , Humans , Male , Receptors, Androgen/metabolism
11.
Haematologica ; 98(11): 1797-803, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23911704

ABSTRACT

Activated polymorphonuclear neutrophils play an important role in the pathogenesis of vaso-occlusive painful sickle cell crisis. Upon activation, polymorphonuclear neutrophils can form neutrophil extracellular traps. Neutrophil extracellular traps consist of a meshwork of extracellular DNA, nucleosomes, histones and neutrophil proteases. Neutrophil extracellular traps have been demonstrated to be toxic to endothelial and parenchymal cells. This prospective cohort study was conducted to determine neutrophil extracellular trap formation in sickle cell patients during steady state and painful crisis. As a measure of neutrophil extracellular traps, plasma nucleosomes levels were determined and polymorphonuclear neutrophil activation was assessed measuring plasma levels of elastase-α1-antitrypsin complexes in 74 patients in steady state, 70 patients during painful crisis, and 24 race-matched controls using Enzyme Linked Immunosorbent Assay. Nucleosome levels in steady state sickle cell patients were significantly higher than levels in controls. During painful crisis levels of both nucleosomes and elastase-α1-antitrypsin complexes increased significantly. Levels of nucleosomes correlated significantly to elastase-α1-antitrypsin complex levels during painful crisis, (Sr = 0.654, P<0.001). This was seen in both HbSS/HbSß(0)-thalassemia (Sr=0.55, P<0.001) and HbSC/HbSß(+-)thalassemia patients (Sr=0.90, P<0.001) during painful crisis. Levels of nucleosomes showed a correlation with length of hospital stay and were highest in patients with acute chest syndrome. These data support the concept that neutrophil extracellular trap formation and neutrophil activation may play a role in the pathogenesis of painful sickle cell crisis and acute chest syndrome.


Subject(s)
Anemia, Sickle Cell/blood , Anemia, Sickle Cell/epidemiology , Neutrophil Activation/physiology , Nucleosomes/metabolism , Pain/blood , Pain/epidemiology , Adult , Anemia, Sickle Cell/diagnosis , Female , Humans , Male , Middle Aged , Pain/diagnosis , Prospective Studies , Young Adult
12.
Ann Hematol ; 91(7): 1097-105, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22318468

ABSTRACT

Oxidative stress is of importance in the pathophysiology of sickle cell disease (SCD). In this open label randomized pilot study the effects of oral N-acetylcysteine (NAC) on phosphatidylserine (PS) expression as marker of cellular oxidative damage (primary end point), and markers of hemolysis, coagulation and endothelial activation and NAC tolerability (secondary end points) were studied. Eleven consecutive patients (ten homozygous [HbSS] sickle cell patients, one HbSß(0)-thalassemia patient) were randomly assigned to treatment with either 1,200 or 2,400 mg NAC daily during 6 weeks. The data indicate an increment in whole blood glutathione levels and a decrease in erythrocyte outer membrane phosphatidylserine exposure, plasma levels of advanced glycation end-products (AGEs) and cell-free hemoglobin after 6 weeks of NAC treatment in both dose groups. One patient did not tolerate the 2,400 mg dose and continued with the 1,200 mg dose. During the study period, none of the patients experienced painful crises or other significant SCD or NAC related complications. These data indicate that N-acetylcysteine treatment of sickle cell patients may reduce SCD related oxidative stress.


Subject(s)
Acetylcysteine/pharmacology , Anemia, Sickle Cell/metabolism , Oxidative Stress/drug effects , Acetylcysteine/administration & dosage , Administration, Oral , Adult , Anemia, Sickle Cell/blood , Anemia, Sickle Cell/drug therapy , Biomarkers/blood , Biomarkers/metabolism , Down-Regulation/drug effects , Female , Free Radical Scavengers/administration & dosage , Free Radical Scavengers/pharmacology , Glutathione/analysis , Glutathione/blood , Hemolysis/drug effects , Humans , Male , Middle Aged , Oxidative Stress/physiology , Phosphatidylserines/blood , Phosphatidylserines/metabolism , Pilot Projects , Young Adult
13.
Biochim Biophys Acta ; 1812(11): 1412-7, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21558001

ABSTRACT

Erythrocytes are both an important source and target of reactive oxygen species in sickle cell disease. Levels of glutathione, a major antioxidant, have been shown to be decreased in sickle erythrocytes and the mechanism leading to this deficiency is not known yet. Detoxification of reactive oxygen species involves the oxidation of reduced glutathione (GSH) into glutathione-disulfide (GSSG) which is actively transported out of erythrocyte. We questioned whether under oxidative conditions, GSSG efflux is increased in sickle erythrocytes. Erythrocytes of 18 homozygous sickle cell patients and 9 race-matched healthy controls were treated with 2,3-dimethoxy-l,4-naphthoquinone, which induces intracellular reactive oxygen species generation, to stimulate GSSG production. Intra- and extracellular concentrations of GSH and GSSG were measured at baseline and during 210-minute 2,3-dimethoxy-l,4-naphthoquinone stimulation. While comparable at baseline, intracellular and extracellular GSSG concentrations were significantly higher in sickle erythrocytes than in healthy erythrocyte after 210-minute 2,3-dimethoxy-l,4-naphthoquinone stimulation (69.9 ± 3.7 µmol/l vs. 40.6 ± 6.9 µmol/l and 25.8 ± 2.7 µmol/l vs. 13.6 ± 1.7 µmol/l respectively, P<0.002). In contrast to control erythrocytes, where GSH concentrations remained unchanged (176 ± 8.4 µmol/l vs. 163 ± 13.6 µmol/l, NS), GSH in sickle erythrocytes decreased significantly (from 167 ± 8.8 µmol/l to 111 ± 11.8 µmol/l, P<0.01) after 210-minute 2,3-dimethoxy-l,4-naphthoquinone stimulation. Adding multidrug resistance-associated protein-1 inhibitor (MK571) to erythrocytes blocked GSSG efflux in both sickle and normal erythrocytes. GSSG efflux, mediated by multidrug resistance-associated protein-1, is increased in sickle erythrocytes, resulting in net loss of intracellular glutathione and possibly higher susceptibility to oxidative stress.


Subject(s)
Anemia, Sickle Cell/metabolism , Anemia, Sickle Cell/pathology , Antioxidants/metabolism , Erythrocytes/metabolism , Glutathione/metabolism , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Adult , Case-Control Studies , Erythrocytes/cytology , Erythrocytes/drug effects , Female , Glutathione Disulfide/metabolism , Hemoglobins/analysis , Humans , Male , Middle Aged , Multidrug Resistance-Associated Proteins/metabolism , Naphthoquinones/pharmacology , Propionates/pharmacology , Quinolines/pharmacology , Young Adult
14.
Am J Hematol ; 86(6): 484-9, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21544855

ABSTRACT

Sickle cell disease (SCD) is a hemoglobinopathy characterized by hemolytic anemia, increased susceptibility to infections and vaso-occlusion leading to a reduced quality of life and life expectancy. Oxidative stress is an important feature of SCD and plays a significant role in the pathophysiology of hemolysis, vaso-occlusion and ensuing organ damage in sickle cell patients. Reactive oxygen species (ROS) and the (end-)products of their oxidative reactions are potential markers of disease severity and could be targets for antioxidant therapies. This review will summarize the role of ROS in SCD and their potential implication for SCD management.


Subject(s)
Anemia, Sickle Cell/metabolism , Oxidative Stress , Anemia, Sickle Cell/physiopathology , Anemia, Sickle Cell/therapy , Disease Management , Humans , Reactive Oxygen Species
15.
Blood Cells Mol Dis ; 46(3): 189-94, 2011 Mar 15.
Article in English | MEDLINE | ID: mdl-21256776

ABSTRACT

The painful crisis accounts for the majority of sickle cell disease (SCD) related hospital admissions. The prototypic long pentraxin 3 (PTX3), an acute phase protein, is elevated in patients with inflammatory and ischemic states. As the sickle cell painful crisis is associated with both inflammation and tissue ischemia, we questioned whether plasma PTX3 levels are increased during and associated with painful crisis severity. Furthermore, since PTX3 up-regulates endothelial expression of tissue factor we studied PTX levels in relation to markers of endothelial and coagulation activation. Plasma levels of PTX3, ultra-sensitive C-reactive protein (US-CRP), prothrombin fragment 1+2, thrombin-antithrombin (TAT) complexes, von Willebrand Factor antigen and soluble vascular adhesion molecule-1 were determined in 105 asymptomatic sickle cell patients, 33 patients during painful crisis and 30 race matched healthy controls. Plasma PTX3 levels were comparable between patients in asymptomatic state and healthy controls, but significantly higher during painful crisis (P<0.01). US-CRP levels were higher in asymptomatic patients compared to controls (P<0.0001) and increased further during painful crisis (P<0.0001). PTX3 levels at presentation with painful crisis correlated significantly with the duration of subsequent hospital admission (r(s) = 0.43; P = 0.013), whereas US-CRP levels did not. PTX3 levels did not correlate with markers of hypercoagulability. The increase of PTX3 levels during painful crisis and their relation to the duration of subsequent hospital stay suggest that PTX3 might serve both as a diagnostic and severity marker of the painful sickle cell crisis.


Subject(s)
Anemia, Sickle Cell/blood , Anemia, Sickle Cell/complications , C-Reactive Protein/metabolism , Pain/blood , Pain/etiology , Serum Amyloid P-Component/metabolism , Adult , Anemia, Sickle Cell/metabolism , Endothelial Cells/metabolism , Female , Humans , Male , Middle Aged , Thrombophilia/metabolism , Vascular Cell Adhesion Molecule-1/blood , Young Adult
16.
Am J Hematol ; 85(11): 902-4, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20882525

ABSTRACT

The painful crisis is the hallmark of sickle-cell disease (SCD). Bone resorption, as part of physiological bone turnover, results in release into the circulation with subsequent urinary excretion of the collagen cross-links pyridinoline (PYD) and deoxypyridinoline (DPD). Urinary PYD and DPD concentrations could reflect the extent of bone infarction during painful sickle-cell crisis. Urinary concentrations of PYD and DPD, adjusted for urine creatinine, were measured in sickle-cell patients (38 clinically asymptomatics and 27 during painful crisis) and healthy controls (n 5 25) using high-performance liquid chromatography(HPLC). PYD and DPD concentrations were higher in asymptomatic HbSS/HbSb0-thalassemia patients compared to controls (P <0.05) with further increments during painful crisis in both HbSS/HbSb0-thalassemia and HbSC/HbSb1-thalassemia patients (P < 0.05). In the asymptomatic HbSS/HbSb0-thalassemia patients, there was a statistically significant positive correlation between DPD and hemolytic rate.Based on urinary PYD and DPD concentrations, bone degradation is increased in asymptomatic sickle-cell patients, with further increments during painful crisis. Urinary PYD and DPD concentrations are potentially diagnostic and prognostic tools in SCD.


Subject(s)
Amino Acids/urine , Anemia, Sickle Cell/complications , Bone Resorption/urine , Adolescent , Adult , Aged , Aged, 80 and over , Anemia, Sickle Cell/diagnosis , Anemia, Sickle Cell/urine , Biomarkers/urine , Bone Resorption/etiology , Case-Control Studies , Chromatography, High Pressure Liquid , Hemolysis , Humans , Middle Aged , Pain , Young Adult
17.
Br J Haematol ; 151(1): 62-9, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20678158

ABSTRACT

Oxidative stress plays an important role in the pathophysiology of sickle cell disease (SCD). Plasma levels of advanced glycation end products (AGEs) are increased under oxidative conditions and are associated with disease severity in diabetes and inflammatory diseases. We investigated whether AGEs are increased in sickle cell patients and whether they are associated with SCD-related complications. Plasma levels of the AGEs pentosidine, N(ε) -(carboxymethyl)lysine (CML) and N(ε) -(carboxyethyl)lysine (CEL) were measured using single-column high performance liquid chromatography with fluorescence detection (pentosidine) and ultra performance liquid chromatography-tandem mass spectrometry (CML and CEL). Plasma levels of pentosidine and CML were increased in HbSS/HbSß°-thalassaemia (n=60) and HbSC/HbSß(+) -thalassaemia (n=42) patients during steady state as compared to healthy HbAA controls (n=30) without increments during painful crisis. CEL levels were comparable between all groups. Pentosidine and CML levels correlated significantly to haemolytic rate during the clinically asymptomatic state while pentosidine was significantly related to the number of haemolysis-related organ complications. The increased plasma AGE levels in sickle cell patients and their association with haemolysis and haemolysis-related complications suggest AGEs might be implicated in the pathophysiology of the haemolytic phenotype of SCD. Measurement of AGEs might be useful in predicting organ complications in SCD.


Subject(s)
Anemia, Sickle Cell/blood , Glycation End Products, Advanced/blood , Adolescent , Adult , Anemia, Sickle Cell/complications , Anemia, Sickle Cell/physiopathology , Arginine/analogs & derivatives , Arginine/blood , Biomarkers/blood , Female , Hemolysis/physiology , Humans , Lysine/analogs & derivatives , Lysine/blood , Male , Middle Aged , Oxidative Stress/physiology , Young Adult
20.
Exp Hematol ; 37(9): 1054-9, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19539689

ABSTRACT

OBJECTIVE: Circulating endothelial progenitor cells (EPCs) counts were determined in patients with sickle cell disease (SCD) to elucidate their role in SCD-related ischemia-induced angiogenesis and reendothelialization. MATERIALS AND METHODS: Circulating EPC counts (KDR(+)/CD34(+)/Cd45(dim) cells) and their relation to serum levels of EPC mobilizing growth factors erythropoietin, vascular endothelial growth factor, and interleukin-8 were investigated in SCD patients during asymptomatic state (n=66) and painful crisis (n=36) and compared to healthy controls (n=13). RESULTS: EPC counts were comparable between controls (0; range, 0-1.1 cells/mL) and patients (0; range, 0-0 cells/mL) in asymptomatic state, but were significantly higher during painful crisis (41.7; range, 0-186 cells/mL; p<0.05). Also in a paired analysis of 12 patients who were included both during asymptomatic state and painful crisis, EPC counts increased significantly during painful crisis (from 0 [range, 0-0] to 26 [range, 0-149 cell/mL; p<0.05). EPC counts were not related to any of the measured growth factors. CONCLUSION: The higher EPC counts during painful crisis might indicate a role for EPC mobilization in reendothelialization. As a relationship of EPCs with the established mobilizing growth factors, measured in this study was not observed, the mechanism of EPC mobilization in SCD remains to be elucidated.


Subject(s)
Anemia, Sickle Cell/blood , Endothelial Cells , Erythropoietin/blood , Interleukin-8/blood , Neovascularization, Pathologic/blood , Stem Cells , Vascular Endothelial Growth Factor A/blood , Adult , Female , Humans , Ischemia/blood , Leukocyte Count , Male , Pain
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