Pharmaceutical Industry Payments to Medical Oncologists in the Netherlands: Trends and Patterns Provided by an Open-Access Transparency Data Set.

PURPOSE: Health care expenditure related to oncologic treatments is skyrocketing although many treatments offer marginal, if any, clinical benefit. Financial conflicts of interest (fCOI) resulting from pharmaceutical industry (pharma) payments to physicians is increasingly recognized as a predictive factor for regulatory board approval and guideline incorporation of low-value treatments. We sought to study the extent to which pharma payments to medical oncologists occur in the Netherlands, the amount of money involved, and whether these occur more frequently and are higher for key opinion leaders (KOLs). METHODS: In our cross-sectional retrospective database study, we used several Dutch open-access databases and extracted data registered between 2019 and 2021. RESULTS: A cumulative amount of €899,863 was paid to 48.8% of the 408 registered medical oncologists. Over time, there was a marked decline in both the proportion of medical oncologists receiving payments (from 40.4% in 2019 to 19.1% in 2021) and the mean annual value of payments (from €2,962 in 2019 to €2,188 in 2021) with the latter mainly resulting from a decline in hospitality-related transactions. KOLs were more likely to receive industry payments and received a higher median payment value. DISCUSSION: Our findings should contribute to the increasing awareness in the Netherlands of the potential effects of fCOI.

Plasma asymmetric dimethylarginine concentrations in sickle cell disease are related to the hemolytic phenotype.

Asymmetric dimethylarginine (ADMA) is associated with pulmonary hypertension (PHT) in sickle cell disease (SCD). We studied the relationship of ADMA to other SCD-related complications. Plasma ADMA and associated parameters were determined in 52 HbSS/HbSbeta(0)-thalassemia and 24 HbSC/HbSbeta(+)-thalassemia patients. As expected ADMA levels were higher in HbSS/HbSbeta(0)-thalassemia patients with PHT (p=0.018), but also in those with other hemolysis-associated complications such as leg ulcers (p=0.012), cholelithiasis (p=0.008) and priapism (p=0.02) compared with counterparts without these complications. ADMA levels did not differ between patients with and without other disease related complications such as retinopathy and avascular osteonecrosis. Higher ADMA concentrations therefore seem to be associated to the hemolytic phenotype of SCD.

Elevated circulating stromal-derived factor-1 levels in sickle cell disease.

Inflammation and angiogenesis are of importance in the pathophysiology of sickle cell disease (SCD). Recently, the chemokine stromal-derived factor-1 (SDF-1) has been shown to be a key mediator of angiogenesis and inflammation. In this study we determined serum SDF-1 levels in consecutive adult sickle cell patients during the clinically asymptomatic state as well as during painful crisis. Serum SDF-1 levels were significantly elevated in HbSS/HbSbeta(0)-thalassaemia patients [n = 42; 5,177 pg/ml (2,438-7,246)] compared to HbSC/HbSbeta(+)-thalassaemia patients [n = 16; 2,405 pg/ml (1,365-3,047)] and healthy HbAA controls [n = 45; 2,894 pg/ml (2,577-3,334)] (p = 0.001). No significant increments were observed during painful crisis (n = 40). SDF-1 levels were significantly higher in SCD patients with pulmonary hypertension (PHT) compared to patients without PHT. Elevated circulating SDF-1 levels occur in patients with SCD and may play a role in the pathophysiology of SCD-related PHT.

Plasma annexin A5 and microparticle phosphatidylserine levels are elevated in sickle cell disease and increase further during painful crisis.

Expression of phosphatidylserine (PS) on the membrane surface of red blood cells and circulating microparticles (MP) plays an important role in etiology of the hypercoagulable state of sickle cell disease (SCD), as well as in the reduced red cell life span and adhesive interactions between red cells and endothelium. Annexin A5, an intracellular protein abundantly present in endothelial cells and platelets, exhibits high affinity for PS and has been shown to inhibit several of these PS-mediated pathophysiological processes. We determined plasma annexin A5 levels and MP-associated procoagulant activity, a measure of MP-PS exposure, in 17 sickle cell patients (12 HbSS and 5 HbSC) in steady state and at presentation with a painful crisis. Twenty-five HbAA blood donors served as controls. Both annexin A5 and MP-PS were highest in HbSS patients (5.7 ng/mL, IQR 3.7-7.6 and 37.9 nM, IQR 31.9-69.8) as compared to HbSC patients (1.8 ng/mL, IQR 1.7-7.6 and 20.9 nM, IQR 10.9-29.6) and healthy controls (2.5 ng/mL, IQR 1.4-4.4 and 13.1 nM, IQR 9.5-18.5) (p=0.01 and p<0.001, respectively). At presentation with a painful crisis, annexin A5 and MP-PS had increased in 16 of 17 patients (p=0.001 and p<0.001, respectively). Most interestingly, in 7 HbSS patients the proportional increase in MP-PS exposure was higher than the proportional increase in plasma annexin A5 concentration, leading to lower annexin A5/MP-PS ratio of HbSS patients during crisis than HbAA controls (0.0027 (0.0017-0.0049) vs 0.0048 (0.0027-0.0085), p=0.05). In conclusion, patients with SCD have elevated plasma levels of annexin A5- and PS-exposing MP. During crisis both levels increase, but in most HbSS patients MP-PS exposure increases more than annexin A5. Future studies must address a potential role of annexin A5 in modulating PS-related pathophysiological processes in SCD.

Increased serum levels of anti-angiogenic factors soluble fms-like tyrosine kinase and soluble endoglin in sickle cell disease.

The anti-angiogenic factors soluble fms-like tyrosine kinase (sFlt)-1 and soluble endoglin (sEng) have been shown to be of importance in angiogenesis by sequestering and inhibiting vascular endothelial growth factor, placenta-like growth factor and transforming growth factor-beta(1) signaling. Given the potential role of angiogenesis in the pathophysiology of sickle cell disease (SCD)-related complications, serum levels of sFlt-1 and sEng were determined in SCD patients and controls. Both sFlt-1 (p = 0.002) and sEng (p = 0.004) were elevated in patients during clinically asymptomatic SCD with no further increment during painful crisis. These data suggest that sFlt-1 and sEng may be important in the regulation of angiogenesis in SCD.

Plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell disease.

In recent years an important role has been ascribed to a reduced nitric oxide (NO) availability in the pathophysiology of sickle cell disease (SCD). Endogenously produced inhibitors of NO synthase, in particular asymmetric dimethylarginine (ADMA), are currently considered of importance in various vascular disease states characterized by reduced NO availability. We determined ADMA levels in plasma of 12 adult sickle cell patients (eight HbSS and four HbSC), and compared these to plasma levels in race- and age-matched controls. Sickle cell patients were characterized by strongly elevated levels of ADMA [HbSS: median 0.63 micromol/l (interquartile range 0.54-0.85), HbSC: 0.43 micromol/l (0.40-0.46), HbAA: 0.33 micromol/l (0.32-0.35) p<0.001]. ADMA levels were highest in HbSS patients with lowest hemoglobin levels and highest leukocyte counts, and in HbSS patients ADMA levels were positively associated with serum levels of soluble vascular cell adhesion molecule-1. These results suggest an important role of ADMA in limiting NO availability in SCD, and its role in the pathophysiology of SCD should be further investigated.

Protein C and S and inflammation in sickle cell disease.

Reduced activity of naturally occurring anticoagulants (NOAC) protein C and protein S may contribute to vaso-occlusion in sickle cell disease (SCD). We studied whether protein C and S are related to clinical vaso-occlusion, hematological markers of disease severity (hemoglobin levels, leukocyte counts, and percentage of fetal hemoglobin), and inflammation in SCD. Protein C activity, protein S (free and total) antigen, endothelial activation markers (soluble vascular cell adhesion molecule-1 [sVCAM-1], von Willebrand antigen [vWF]), and high sensitive C-reactive protein (hsCRP) levels were measured in 30 HbSS and 20 HbSC patients and in race-matched HbAA controls. NOAC levels were reduced in patients, and endothelial activation markers and hsCRP were elevated (except vWF in HbSC patients). Protein C activity and vWF levels were lower in HbSC patients who experienced painful crises compared to HbSC patients who were clinically asymptomatic. No other differences were observed between patients who did and did not experience vaso-occlusive events (painful crises, stroke, acute chest syndromes) or leg ulcers. A significant positive correlation between total protein S with hemoglobin levels and a significant negative correlation between total and free protein S and sVCAM-1 were detected in HbSS patients. Except perhaps for protein C in relation to painful crises in HbSC patients, these markers were not associated with the occurrence of clinical events. The protein S, hemoglobin, and sVCAM-1 associations may suggest decreased endothelial protein S production due to the more severe endothelial perturbation in HbSS patients with lower hemoglobin levels.

Sickle cell disease; a general overview.

Sickle cell disease (SCD) is a heterogeneous disorder, with clinical manifestations including chronic haemolysis, an increased susceptibility to infections and vaso-occlusive complications often requiring medical care. Patients with SCD can develop specific and sometimes life-threatening complications, as well as extensive organ damage reducing both their quality of life and their life expectancy. Proven effective treatment options for sickle cell patients are limited to hydroxyurea, blood transfusions and bone marrow transplantation. With the increasing prevalence of SCD in the Netherlands, a fundamental understanding of its pathophysiology and clinical syndromes is of importance for local medical practitioners.

Erythropoiesis and serum sVCAM-1 levels in adults with sickle cell disease.

Sickle cell patients are characterized by stress erythropoiesis involving cytokines, growth factors, and adhesion molecules. We set out to determine whether serum soluble vascular cell adhesion molecule-1 (sVCAM-1) levels, which are inversely related to red blood cell counts in sickle cell disease (SCD), reflect erythropoietic activity in adult HbSS patients. Serum levels of sVCAM-1 were compared to erythropoietin (EPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and soluble transferrin receptor (sTfR) levels in 29 adults with HbSS, and their respective levels were also compared to 29 race- and age-matched HbAA controls. EPO and sTfR levels were increased as compared to healthy controls, whereas IL-3 and GM-CSF were not. No significant correlation of sVCAM-1 levels could be detected with any of the measured erythropoietic markers. Patients, but not controls, with detectable IL-3 levels had lower sTfR and GM-CSF levels as compared to patients with undetectable IL-3 levels. Even though a link of sVCAM-1 to erythropoiesis could not be established, it cannot be ruled out that sVCAM-1 levels reflect the release of young red blood cells into the circulation. IL-3 and GM-CSF levels suggest that different rates of erythropoiesis may be characterized by specific cytokine profiles in SCD. Further research should focus on the potential cytokines and adhesion molecules involved in sickle cell erythropoiesis, as this may increase our understanding of sickle cell complications and may provide us with potential markers for risk assessment in sickle cell disease as well.

Steady-state sVCAM-1 serum levels in adults with sickle cell disease.

Cytokines and adhesion molecules play an important role in the pathophysiology of vaso-occlusion in sickle cell disease (SCD), and their in vivo profiles are potential tools for assessing SCD severity. We compared steady-state soluble vascular cell adhesion molecule-1 (sVCAM-1) serum levels to clinical (painful crisis frequency, occurrence of acute chest syndrome, leg ulcers, and cerebrovascular disease) and related hematological parameters of SCD severity (such as HbF%, hemoglobin levels, and leukocyte counts) in 29 HbSS adults. Serum sVCAM-1 levels were not related to clinical severity, but an inverse correlation was demonstrated between sVCAM-1 and hemoglobin levels (r=-0.71, p<0.001) with a positive correlation to serum lactate dehydrogenase levels (r=0.59, p=0.008). Based upon these results, steady-state serum sVCAM-1 levels do not seem to reflect clinical disease severity. However, as VCAM-1 is involved in hematopoiesis, sVCAM-1 levels might reflect bone marrow activity in SCD. This underlies the pleiotropic nature of adhesion molecules in vivo and the need for further research in this area, especially since therapies targeting (cellular) adhesive interactions involving the endothelium are emerging for SCD.

No effect of acenocoumarol therapy on levels of endothelial activation markers in sickle cell disease.

Sickle cell patients are characterized by a chronic inflammatory and hypercoagulable state, depicted by elevated levels of pro-inflammatory cytokines, endothelial adhesion molecules, and elevated markers of thrombin generation. We set out to determine whether anticoagulation with a coumadin derivative reduces inflammation in sickle cell disease. Therefore, serum levels of NFkappaB-regulated endothelial adhesion molecule soluble vascular cell adhesion molecule-1 and serum levels of non-NFkappaB-dependent markers of endothelial activation (soluble cellular fibronectin and von Willebrand factor antigen) were compared during treatment with acenocoumarol (INR 1.6-2.0) and placebo. No effect on circulating levels of the measured parameters was observed during treatment with acenocoumarol as compared to placebo. In the targeted INR range, anticoagulation of sickle cell patients with acenocoumarol does not seem to reduce endothelial activation.

Low adjusted-dose acenocoumarol therapy in sickle cell disease: a pilot study.

Vasoocclusion is a continuous process in sickle cell disease (SCD) and accumulates to significant end organ damage, mostly irrespective of the occurrence of manifest acute vasoocclusive events. As there are indications that reversing the hypercoagulable state may be of clinical benefit in sickle cell patients, we performed a randomized, double blind, placebo-controlled, cross-over pilot study to assess the efficacy and safety of low-adjusted dose acenocoumarol therapy (International Normalized Ratio: 1.6-2.0) in SCD. Treatment consisted of either acenocoumarol or placebo for 14 weeks, after which treatment was discontinued for a period of five weeks. Then, patients initially on acenocoumarol received placebo (and vice versa) for 14 weeks. Therapy efficacy was assessed by comparing the frequency of vasoocclusive complications, the occurrence of bleeding, and clotting activation between acenocoumarol and placebo treatment of each individual patient. Twenty-two patients (14 homozygous [HbSS] and 8 double heterozygous sickle-C [HbSC]; aged 20-59 years) completed the entire study. Acenocoumarol treatment did not result in a significant reduction of acute vasoocclusive events (three painful crises during acenocoumarol, five painful crises during placebo). There was a marked reduction of the hypercoagulable state (depicted by a decrease in plasma levels of prothrombin F1.2 fragments [P = 0.002], thrombin-antithrombin complexes [P = 0.003], and D-dimer fragments [P = 0.001]) without the occurrence of major bleeding. Even though no clinical benefit (pertaining to the frequency of painful crises) was detected in this pilot study, the value of low adjusted-dose acenocoumarol for preventing specific events (such as strokes) and as a long-term treatment of sickle cell patients should be subject of further study.

Duffy phenotype does not influence the clinical severity of sickle cell disease.

The red blood cell Duffy antigen receptor for chemokines serves as a sink for the clearance of chemokines such as interleukin-8 (IL-8) from the circulation. We analyzed the impact of the Duffy phenotype on sickle cell disease (SCD) severity and serum IL-8 levels in 15 Duffy-positive and 36 Duffy-negative sickle cell patients. There was no difference in clinical severity between Duffy-positive and Duffy-negative sickle cell patients. In asymptomatic sickle cell patients the upward deviation of mean serum IL-8 levels was significantly greater in Duffy-negatives (n = 20) than in Duffy-positives (n = 8) (P = 0.011). However, during a vasoocclusive episode, serum IL-8 levels were similar between Duffy-negatives (n = 11) and Duffy-positives (n = 3). Although the Duffy phenotype seems to influence steady-state serum IL-8 levels, it does not seem to have an effect on SCD severity.

Elevated IL-8 levels during sickle cell crisis.

The vaso-occlusive process (VOC) in sickle cell disease is of a complex nature. It involves intricate interactions between sickle red blood cells, endothelium and probably also leukocytes. As these interactions are regulated by cytokines, we analyzed the role of the potent neutrophil chemokine IL-8 by measuring serum levels in sickle cell patients during sickle cell crisis. These results were compared to nonsymptomatics and healthy controls. In patients having a vaso-occlusive crisis both HbSS and HbSC patients showed significantly enhanced serum IL-8 levels compared to healthy controls. Several of these patients showed extremely elevated serum IL-8 levels which were independent of the crisis inducing factor. Furthermore, a sickle cell patient with VOC as a complication of rhGM-CSF treatment similarly showed high IL-8 serum levels at crisis onset. Nonsymptomatic sickle cell patients serum IL-8 levels were comparable to healthy controls. These results implicate a role for IL-8 at or during (the initiation of) sickle cell crisis.