Abstract We performed a comprehensive cost calculation identifying the main cost drivers of treatment of chronic lymphocytic leukaemia in daily practice. In our observational study 160 patient charts ...were reviewed repeatedly to assess the treatment strategies from diagnosis till the study end. Ninety-seven patients (61%) received ≥1 treatment lines during an average follow-up time of 6.4 years. The average total costs per patient were €41,417 (€539 per month). The costs varied considerably between treatment groups and between treatment lines. Although patients were treated with expensive chemo(immuno-)therapy, the main cost driver was inpatient days for other reasons than administration of chemo(immuno-)therapy.
Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated thrombocytopenia. The diagnosis is made after exclusion of other secondary causes of thrombocytopenic disorders. The primary treatment ...goal is to prevent severe bleeding rather than achieve normal platelet counts. In adults ITP usually has an insidious onset and chronic course. Although ITP is a relatively common haematological disorder, there are important unresolved issues in its management, especially for chronic refractory ITP patients. New therapeutic agents have changed strategies for ITP treatment. This article reviews the treatment indications and options of chronic ITP in adults in the literature and compares them with the treatment indications and treatment options used by the Dutch internist.
In the human pancreas, a close topographic relationship exists between duct cells and beta cells. This explains the high proportion of duct cells in isolated human islet preparations. We investigated ...whether human duct cells are a source of TNFalpha-mediated interactions with beta cells and immune cells. This cytokine has been implicated in the development of autoimmune diabetes in mice.
Human duct cells were isolated from donor pancreases and examined for their ability to produce TNFalpha following a stress-signalling pathway. Duct-cell-released TNFalpha was tested for its in vitro effects on survival of human beta cells and on activation of human dendritic cells.
Exposure of human pancreatic duct cells to interleukin-1beta (IL-1beta) induces TNFalpha gene expression, synthesis of the 26,000 M(r) TNFalpha precursor and conversion to the 17,000 M(r) mature form, which is rapidly released. This effect is NO-independent and involves p38 MAPK and NF-kappaB signalling. Duct-cell-released TNFalpha contributed to cytokine-induced apoptosis of isolated human beta cells. It also induced activation of human dendritic cells.
Human pancreatic duct cells are a potential source of TNFalpha that can cause apoptosis of neighbouring beta cells and initiate an immune response through activation of dendritic cells. They may thus actively participate in inflammatory and immune processes that threaten beta cells during development of diabetes or after human islet cell grafts have been implanted.
The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision‐making. Analysis were performed on advanced ...melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune‐ or targeted therapy, who met ≥1 trial exclusion criteria. These criteria were derived from the KEYNOTE‐006 and CHECKMATE‐067/‐066 phase III trials. Prognostic importance of factors associated with overall survival (OS) was assessed with the Kaplan‐Meier method, Cox models, predicted OS probabilities of prognostic subgroups and a conditional inference survival tree (CIST). A nationwide population‐based registry was used as data source. Of 2536 systemically treated patients with advanced melanoma, 1004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria strongly associated with OS in systemically treated ineligible patients were Eastern Cooperative Oncology Group Performance Score (ECOG PS) ≥2, brain metastases (BM) and lactate dehydrogenase (LDH) of >500 U/L. Patients with ECOG PS of ≥2 with or without symptomatic BM had a predicted mOS of 6.5 and 11.3 months and a 3‐year survival probability of 9.3% and 23.6%, respectively. The CIST showed the strongest prognostic covariate for survival was LDH, followed by ECOG PS. The prognosis of patients with LDH of >500 U/L is poor, but long‐term survival is possible. The prognosis of ineligible patients with advanced melanoma in real‐world was very heterogeneous and highly dependent on LDH value, ECOG PS and symptomatic BM.
What's new?
By necessity, randomized controlled trials (RCTs) exclude many patients. However, these ineligible patients are often still treated with new systemic therapies on an individual basis. In this study, the authors examined how various subgroups of ineligible patients fared following treatment for advanced melanoma. They found that several criteria were strongly associated with prognosis in these patients, including lactate dehydrogenase (LDH) levels. These results should provide clinicians with a decision tree of prognostic factors to help guide treatment decisions.
Background: Results on overall survival in randomised studies of mono- versus combination chemotherapy in advanced colorectal cancer patients may have been biased by an imbalance in salvage ...treatments. This is the first randomised study that evaluates sequential versus combination chemotherapy with a fluoropyrimidine, irinotecan and oxaliplatin. Patients and methods: A total of 820 patients were randomised between first-line capecitabine, second-line irinotecan and third-line capecitabine + oxaliplatin (arm A) versus first-line capecitabine + irinotecan, and second-line capecitabine + oxaliplatin (arm B). The primary end point was overall survival. We present the results of an interim analysis on the safety data in the first 400 patients. Results: In first-line the incidence of grade 3–4 diarrhoea, nausea, vomiting and febrile neutropenia was significantly higher in arm B. However, when toxicity over all lines was considered only grade 3 hand–foot syndrome occurred more frequently in arm A (12% versus 6%, respectively, P = 0.041). The incidence of cardiovascular toxicity was low. In two out of five patients with sudden death (one in arm A, four in arm B) cardiovascular risk factors were present. Conclusions: Both treatment arms had an acceptable safety profile. These data imply that the results on survival will be the major determinant for the selection of either strategy. Capecitabine plus irinotecan appears to be a feasible first-line treatment for patients with advanced colorectal carcinoma.
Background
The acute‐phase response and anaemia of chronic disease are characterized by hypoferraemia associated with an increased ferritin synthesis, which might be mediated by the activated ...cytokine cascade.
Methods
We examined the prolonged effects of isolated limb perfusion (ILP) with recombinant human tumour necrosis factor α (rTNF), recombinant human interferon γ (rIFN‐γ) and melphalan on interleukin (IL) 6 and acute‐phase protein levels, iron status and serum transferrin receptor (sTfR) levels in 12 patients with melanoma or sarcoma. Patients were treated with ILP during 90 min after pretreatment with rIFN‐γ during 2 days.
Results
After ILP, leakage of TNF resulted in systemic peak levels at 3 min followed by an increase in IL‐6 with maximum levels at 4 h. C‐reactive protein (CRP) rose at 4 h to peak levels at day 2, whereas α1‐antitrypsin and α1‐acid glycoprotein increased to maximum levels at day 3. Albumin and transferrin levels decreased after ILP and recovered after day 2. Serum iron and sTfR levels decreased during pretreatment and after ILP to minimum levels at 8 h and day 1 respectively. This was associated with an increase in serum ferritin levels, which paralleled CRP values.
Conclusions
Our data point to a central role for the cytokine network in the modulation of iron metabolism in the acute‐phase response and anaemia of chronic disease. TNF, possibly via induction of IL‐6, and IFN‐γ induce hypoferraemia, which may in part result from a decrease in tissue iron release based on a primary stimulation of ferritin synthesis. The fall in sTfR levels may reflect an impaired erythroid growth and/or TfR expression mediated by TNF and IFN‐γ.
Enterovirus infections have been implicated in the development of type I diabetes mellitus. They may cause β cell destruction either by cytolytic infection in the pancreas or indirectly by ...contributing to autoimmune reactivity. We sought evidence for these 2 mechanisms in a case of acute-onset diabetes mellitus that occurred during severe echovirus 9 infection. The virus was isolated and administered to cultured human β cells. No viral proliferation was observed, and no β cell death was induced, while parallel exposure to Coxsackie B virus serotype 3 resulted in viral proliferation and massive β cell death. Although the viral protein 2C exhibited a sequence similar to that of the β cell autoantigen glutamic acid decarboxylase (GAD65), no cross-reactive T cell responses were detected. The patient did not develop antibodies to GAD65 either. Absence of evidence for direct cytolytic action or an indirect effect through molecular mimicry with GAD65 in the present case raises the possibility of another indirect pathway through which enteroviruses can cause diabetes mellitus.
PDF
