Anemia in rheumatoid arthritis : the role of iron, erythropoietin and cytokines

The various causes of anemia in RA as well as the factors associated with ACD were discussed. It is clear that many causes must be excluded before the diagnosis ACD in RA can be made.In the discussion of factors like iron absorption, the role of the MPS, ineffective erythropoiesis and Epo it became clear that many of these studies lack proper description of the patients iron status. Factors like ineffective erythropoiesis and the iron retention by the MPS were first associated with ACD but later also with iron deficiency. In a number of studies on the role of EpO iron deficient patients were not sufficiently separated from ACD making interpretation of the results difficult. A number of mediators of erythropoiesis were discussed. Their effects on erythropoiesis are not consistent while only a few of them were specifically studied in ACD in RA. This thesis was performed to assess reliable methods to classify anemic RA patients which is inevitable for studies concerning pathogenesis of ACD. The other objective was to study the specific role in ACD of iron availability to erythroblasts and the effects of Epo, TNFa and IL-6 on (in vitro) erythropoiesis

Waterloopkunde: een eeuw wiskunde en werkelijkheid

Onderzoekers van het Waterloopkundig Lab, de Deltadienst van Rijkswaterstaat, TNO en het Mathematisch Centrum bestudeerden in vredige competitie het dynamisch gedrag van de Haringvlietsluizen. De uiteenlopende tradities om dewiskunde in dienst te stellen van de waterbouwkunde, schaalmodellen, analogons, wiskundige modellen en rekenwerk, kwamen in een zogenaamde klapclub samen. De beslissing bleef uit. Korte tijd later raakten al deze inspanningen op de achtergrond door de revolutie in de richting van een heel nieuw type rekenmodellen

Anaemia of chronic disease in rheumatoid arthritis - Raised serum interleukin-6 (IL-6) levels and effects of IL-6 and anti-IL-6 on in vitro erythropoiesis

Serum and bone marrow from 21 patients with rheumatoid arthritis (RA) were studied in order to establish the pathogenetic role of interleukin-6 (IL-6) in anemia of chronic disease (ACD). Erythroid colony growth, using burst forming units of erythroblasts (BFUe) as a parameter, was impaired in ACD and not in nonanemic RA controls. Serum IL-6 was elevated in ACD and it correlated well with parameters of disease activity such as erythrocyte sedimentation rate and C-reactive protein. IL-6 addition to bone marrow cultures had inconsistent effects while anti-IL-6 addition resulted in impaired erythroid colony growth, suggesting stimulatory effects of IL-6 produced in the medium, which may be masked by simultaneous production of cytokines with suppressive effects. It was concluded that elevated serum IL-6 in ACD reflects disease activity. It probably plays no pathogenetic role in ACD. Its stimulatory effects on erythroid growth might counteract suppressive effects of other interleukins

Bevacizumab for metachronous metastatic colorectal cancer: A reflection of community based practice

Background: Although the efficacy of bevacizumab has been established in patients with metastatic colorectal cancer (mCRC), population-based studies are needed to gain insight into the actual implementation of bevacizumab in daily practice. Since these studies are lacking for patients with metachronous metastases, the aim of this study is to evaluate the current role of bevacizumab in the treatment of metachronous metastases of CRC. Methods: Data on the use of bevacizumab as palliative treatment of metachronous metastases were collected for patients diagnosed with M0 CRC between 2003 and 2008 in the Eindhoven Cancer Registry (n = 361). Median follow up was 5.3years. Results: One hundred eighty-five patients received bevacizumab in addition to first-line palliative chemotherapy (51%), ranging from 36% to 80% between hospitals of diagnosis (p < 0.0001). Combined cytostatic regimens (CAPOX/FOLFOX in 97%) were prescribed in the majority of patients (63%) and were associated with a higher odds for additional treatment with bevacizumab than single-agent cytostatic regimens (OR 9.9, 95% CI 5.51-18.00). Median overall survival (OS) rates were 21.6 and 13.9months with and without the addition of bevacizumab to palliative systemic treatment respectively (p < 0.0001). The addition of bevacizumab to palliative chemotherapy was associated with a reduced hazard ratio for death (HR 0.6, 95% CI 0.45-0.73) after adjustment for patient- and tumor characteristics and the prescribed chemotherapeutic regimen. Conclusion: Bevacizumab is adopted as a therapeutic option for metachronous metastasized CRC mainly in addition to first-line oxaliplatin-based regimens, and was associated with a reduced risk of death. The presence of inter-hospital differences in the prescription of bevacizumab reflected important differences in attitude and policies in clinical practice. Ongoing efforts should be made to further define the position of targeted agents in the treatment of metastatic colorectal cancer

Clinical management of women with metastatic breast cancer: a descriptive study according to age group

BACKGROUND: The primary aim of treatment of a patient who has developed metastatic disease is palliation. The objectives of the current study are to describe and quantify the clinical management of women with metastatic breast cancer from the diagnosis of metastatic disease until death and to analyze differences between age groups. METHODS: Data were collected from the medical files of all patients (n = 116) who had died after December 31, 1999, after a diagnosis of metastatic breast cancer in two teaching hospitals in the south of the Netherlands. RESULTS: Of the 116 patients included in our study, 10 (9%) already had metastatic disease at diagnosis and 106 developed distant disease after the diagnosis of localized breast cancer. Before they died, 70% of the 116 patients developed metastases in one or more bones, 50% in the lung and/or pleura, 50% in the abdominal viscera, 23% in the central nervous system, and 19% in the skin. Patients younger than 50 years were much more likely to develop metastases in the central nervous system than patients 50 years and older. Seventy-seven (66%) of the 116 patients with metastatic breast cancer received chemotherapy. This proportion decreased with age (p = 0.005), as did the number of schemes per patient. Together, they received 132 chemotherapy schemes, of which 35 (27%) resulted in partial remission or stabilization of the disease process. Ninety-eight patients (84%) received hormonal treatment. This proportion did not differ between the three age groups. Together, they received 216 hormonal treatments, 38 (16%) of which resulted in partial remission or stabilization of the disease process. Seventy-nine patients (68%) received palliative radiotherapy. This proportion decreased with age (p = 0.03). Together, they underwent 216 courses, 176 (77%) of which resulted in relief of the complaints. CONCLUSION: Patients aged 70 years and older are less likely to receive chemotherapy or radiotherapy. Part of this difference could be explained by their shorter survival time after the diagnosis of metastatic disease and their lower risk of developing brain and bone metastases. However, more research is needed to understand the age-related differences in the treatment of metastatic breast cancer, and especially how comorbidity and frailty limit therapeutic choices

Real-world Data of Nivolumab for Patients With Advanced Renal Cell Carcinoma in the Netherlands:An Analysis of Toxicity, Efficacy, and Predictive Markers

Background: Nivolumab, a programmed death 1 inhibitor, has been approved as second-line treatment for advanced renal cell carcinoma (RCC) in Europe since 2016. We investigated the toxicity and efficacy of nivolumab as well as potential predictive biomarkers in the Dutch population. Patients and Methods: This was a retrospective, multicenter study of the Dutch national registry of nivolumab for the treatment of advanced RCC. The main outcome parameters included toxicity, objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and time to treatment failure (TTF). In addition, potential predictive and prognostic biomarkers for outcomes were evaluated. Results: Data on 264 patients were available, of whom 42% were International Metastatic RCC Database Consortium (IMDC) poor risk at start of nivolumab, 16% had ≥ 3 lines of previous therapy, 7% had non–clear-cell RCC, 11% had brain metastases, and 20% were previously treated with everolimus. Grade 3/4 immune-related adverse events occurred in 15% of patients. The median OS was 18.7 months (95% confidence interval, 13.7-23.7 months). Progression occurred in 170 (64.4%) of 264 patients, with a 6-and 12-months TTP of 49.8% and 31.1%, respectively. The ORR was 18.6% (49 of 264; 95% confidence interval, 14%-23%). Elevated baseline lymphocytes were associated with improved PFS (P =.038) and elevated baseline lactate dehydrogenase with poor OS, PFS, and TTF (P =.000). On-treatment increase in eosinophils by week 8 predicted improved OS (P =.003), PFS (P =.000), and TTF (P =.014), whereas a decrease of neutrophils was associated with significantly better TTF (P =.023). Conclusions: The toxicity and efficacy of nivolumab for metastatic RCC after previous lines of therapy are comparable with the results in the pivotal phase III trial and other real-world data. On-treatment increase in eosinophil count is a potential biomarker for efficacy and warrants further investigation

Quality of life of patients with chronic lymphocytic leukaemia in the Netherlands: results of a longitudinal multicentre study

Purpose: To describe the health-related quality of life (HRQoL) of an unselected population of patients with chronic lymphocytic leukaemia (CLL) including untreated patients. Methods: HRQoL was measured by the EORTC QLQ-C30 including the CLL16 module, EQ-5D, and VAS in an observational study over multiple years. All HRQoL measurements per patient were connected and analysed using area under the curve analysis over the entire study duration. The total patient group was compared with the general population, and three groups of CLL patients were described separately, i.e. patients without any active treatment (“watch and wait”), chlorambucil treatment only, and patients with other treatment(s). Results: HRQoL in the total group of CLL patients was compromised when compared with age- and gender-matched norm scores of the general population. CLL patients scored statistically worse on the VAS and utility score of the EQ-5D, all functioning scales of the EORTC QLQ-C30, and the symptoms of fatigue, dyspnoea, sleeping disturbance, appetite loss, and financial difficulties. In untreated patients, the HRQoL was slightly reduced. In all treatment stages, HRQoL was compromised considerably. Patients treated with chlorambucil only scored worse on the EORTC QLQ-C30 than patients who were treated with other treatments with regard to emotional functioning, cognitive functioning, bruises, uncomfortable stomach, and apathy. Conclusions: CLL patients differ most from the general population on role functioning, fatigue, concerns about future health, and having not enough energy. Once treatment is indicated, HRQoL becomes considerably compromised. This applies to all treatments, including chlorambucil, which is considered to be a mild treatment

Clinical outcome of patients with metastatic melanoma of unknown primary in the era of novel therapy

Melanoma of unknown primary (MUP) is considered different from melanoma of known primary (MKP), and it is unclear whether these patients benefit equally from novel therapies. In the current study, characteristics and overall survival (OS) of patients with advanced and metastatic MUP and MKP were compared in the era of novel therapy. Patients were selected from the prospective nation-wide Dutch Melanoma Treatment Registry (DMTR). The following criteria were applied: diagnosis of stage IIIc unresectable or IV cutaneous MKP (cMKP) or MUP between July 2012 and July 2017 and treatment with immune checkpoint inhibition and/or targeted therapy. OS was estimated using the Kaplan-Meier method. The stratified multivariable Cox regression model was used for adjusted analysis. A total of 2706 patients were eligible including 2321 (85.8%) patients with cMKP and 385 (14.2%) with MUP. In comparative analysis, MUP patients more often presented with advanced and metastatic disease at primary diagnosis with poorer performance status, higher LDH, and central nervous system metastases. In crude analysis, median OS of cMKP or MUP patients was 12 months (interquartile range [IQR] 5 - 44) and 14 months (IQR 5 - not reached), respectively (P = 0.278). In adjusted analysis, OS in MUP patients was superior (hazard rate 0.70, 95% confidence interval 0.58-0.85; P < 0.001). As compared to patients with advanced and metastatic cMKP, MUP patients have superior survival in adjusted analysis, but usually present with poorer prognostic characteristics. In crude analysis, OS was comparable indicating that patients with MUP benefit at least equally from treatment with novel therapies

Discontinuation of anti-PD-1 monotherapy in advanced melanoma:Outcomes of daily clinical practice

There is no consensus on the optimal treatment duration of anti-PD-1 for advanced melanoma. The aim of our study was to gain insight into the outcomes of anti-PD-1 discontinuation, the association of treatment duration with progression and anti-PD-1 re-treatment in relapsing patients. Analyses were performed on advanced melanoma patients in the Netherlands who discontinued first-line anti-PD-1 monotherapy in the absence of progressive disease (n = 324). Survival was estimated after anti-PD-1 discontinuation and with a Cox model the association of treatment duration with progression was assessed. At the time of anti-PD-1 discontinuation, 90 (28%) patients had a complete response (CR), 190 (59%) a partial response (PR) and 44 (14%) stable disease (SD). Median treatment duration for patients with CR, PR and SD was 11.2, 11.5 and 7.2 months, respectively. The 24-month progression-free survival and overall survival probabilities for patients with a CR, PR and SD were, respectively, 64% and 88%, 53% and 82%, 31% and 64%. Survival outcomes of patients with a PR and CR were similar when anti-PD-1 discontinuation was not due to adverse events. Having a PR at anti-PD-1 discontinuation and longer time to first response were associated with progression [hazard ratio (HR) = 1.81 (95% confidence interval, CI = 1.11-2.97) and HR = 1.10 (95% CI = 1.02-1.19; per month increase)]. In 17 of the 27 anti-PD-1 re-treated patients (63%), a response was observed. Advanced melanoma patients can have durable remissions after (elective) anti-PD-1 discontinuation