The potential of individualized dosing of ravulizumab to improve patient-friendliness of paroxysmal nocturnal haemoglobinuria treatment at reduced costs

Contains fulltext : 237767.pdf (Publisher’s version ) (Open Access)Ravulizumab is a very expensive complement C5-inhibitor for the treatment of paroxysmal nocturnal haemoglobinuria, with a fixed-dosing interval of 8 weeks. For lifelong treatment, a cost-effective and patient-friendly dosing strategy is preferred. We therefore explored alternative ravulizumab dosing regimens in silico based on the thorough dose-finding studies of the manufacturer. Extending the interval to 10 weeks or individually extending the interval to a mean of 12.8 weeks based on pharmacokinetic monitoring resulted in noninferior efficacy in terms of lactate dehydrogenase normalization, with drug cost savings up to 37%. We here show the potential of individualized ravulizumab dosing to improve patient-friendliness at reduced costs

Impact of mucositis on oral bioavailability and systemic exposure of ciprofloxacin Gram-negative infection prophylaxis in patients with haematological malignancies

Background Patients with haematological malignancies frequently endure neutropenia and gastrointestinal (GI)-mucositis after high-dose chemotherapy. In these patients, ciprofloxacin is used for Gram-negative infection prophylaxis. Objectives We investigate ciprofloxacin pharmacokinetics after oral administration in patients with haematological malignancies and explore the impact of GI-mucositis on oral bioavailability and clearance in order to assure adequate systemic exposure. Methods Adult haematological patients from two Dutch University Medical Centres received 500 mg twice daily oral ciprofloxacin for Gram-negative prophylaxis. The ciprofloxacin plasma concentrations were collected at various timepoints after oral ciprofloxacin administration and at various days after completion of chemotherapy. Data obtained after oral and intravenous ciprofloxacin administration in 28 healthy volunteers without mucositis served as a control group (391 samples). For haematological patients the degree of GI-mucositis was assessed using the Daily Gut Score (DGS), plasma citrulline and albumin. Data were analysed by non-linear mixed-effects modelling. Results In total, 250 blood samples were collected in 47 patients with a wide variety of haematological malignancies between 0-30 days after start of chemotherapy. Mucositis was generally mild [DGS median (IQR) 1 (1-1) and citrulline 16 mu mol/L (12-23)]. The time to C-max was slower in haematological patients compared with healthy volunteers although no association with the degree of mucositis (defined as DGS or citrulline) could be identified. Ciprofloxacin bioavailability and clearance were 60% and 33.2 L/h, respectively. Conclusions This study supports oral dosing of ciprofloxacin as Gram-negative infection prophylaxis in haematological patients with mild-to-moderate mucositis capable of oral intake.Pharmacolog

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy

Background Mucositis is a significant toxicity of cancer therapy with numerous systemic sequelae. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for the management of mucositis. Methods The literature was reviewed systematically to identify interventions for mucositis. Studies were rated according to the presence of major and minor flaws according to previously published criteria. The body of evidence for each intervention and in each treatment setting was assigned a level of evidence based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible. Results The guideline covers evidence from 1197 publications related to oral or gastrointestinal mucositis. Thirteen new guidelines were developed for or against the use of various interventions in specific treatment settings, and 11 previous guidelines were confirmed after aa review of new evidence. Thirteen previously established guidelines were carried over because there was no new evidence for these interventions. Conclusions The updated MASCC/ISOO Clinical Practice Guidelines for mucositis provide professional health caregivers with a clinical setting-specific, evidence-based tool to help with the management of mucositis in patients who have cancer

High prevalence of postpartum hemorrhage in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study

BackgroundWomen with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, may have a higher risk of postpartum hemorrhage (PPH). Information on this patient category is lacking in the existing PPH guidelines because data on PPH in patients with RBDs are scarce.ObjectiveTo describe the prevalence of PPH in women with an RBD and evaluate the use of peripartum hemostatic prophylaxis.MethodsIn the Rare Bleeding Disorders in the Netherlands (RBiN) study, patients with RBDs (n = 263) were included from all 6 Dutch hemophilia treatment centers. Patient–reported information on delivery, peripartum hemostatic prophylaxis, and occurrence of PPH was collected retrospectively. If available, information about the precise volume of postpartum blood loss was extracted from electronic patient files. PPH was defined as blood loss ≥500 mL (World Health Organization guideline).ResultsA total of 244 pregnancies, including 193 livebirths, were reported by 85 women. A considerable proportion of these women experienced PPH, ranging from 30% in factor V deficiency to 100% in hyperfibrinolysis. Overall, PPH was reported in 44% of deliveries performed with and 53% of deliveries performed without administration of peripartum hemostatic prophylaxis. Blood loss was significantly higher in deliveries without administration of hemostatic prophylaxis (median 1000 mL) compared to deliveries with administration of prophylaxis (median 400 mL) (p = 0.011). Patients with relatively mild deficiencies also frequently experienced PPH when peripartum hemostatic prophylaxis was omitted.ConclusionPPH is common in rare coagulation factor deficiencies, both severe and mild, and fibrinolytic disorders, especially when peripartum prophylactic hemostatic treatment was not administered. The use of prophylactic hemostatic treatment was associated with less postpartum blood loss.Thrombosis and Hemostasi

Long-Term Outcome of Patients With a Hematologic Malignancy and Multiple Organ Failure Admitted at the Intensive Care

Objectives: Historically, patients with a hematologic malignancy have one of the highest mortality rates among cancer patients admitted to the ICU. Therefore, physicians are often reluctant to admit these patients to the ICU. The aim of our study was to examine the survival of patients who have a hematologic malignancy and multiple organ failure admitted to the ICU. Design: This retrospective cohort study, part of the HEMA-ICU study group, was designed to study the survival of patients with a hematologic malignancy and organ failure after admission to the ICU. Patients were followed for at least 1 year. Setting: Five university hospitals in the Netherlands. Patients: One-thousand ninety-seven patients with a hematologic malignancy who were admitted at the ICU. Interventions: None. Measurements and Main Results: Primary outcome was 1-year survival. Organ failure was categorized as acute kidney injury, respiratory failure, hepatic failure, and hemodynamic failure; multiple organ failure was defined as failure of two or more organs. The World Health Organization performance score measured 3 months after discharge from the ICU was used as a measure of functional outcome. The 1-year survival rate among these patients was 38%. Multiple organ failure was inversely associated with long-term survival, and an absence of respiratory failure was the strongest predictor of 1-year survival. The survival rate among patients with 2, 3, and 4 failing organs was 27%, 22%, and 8%, respectively. Among all surviving patients for which World Health Organization scores were available, 39% had a World Health Organization performance score of 0–1 3 months after ICU discharge. Functional outcome was not associated with the number of failing organs. Conclusions: Our results suggest that multiple organ failure should not be used as a criterion for excluding a patient with a hematologic malignancy from admission to the ICU

De rode draad

Contains fulltext : 124105.pdf (publisher's version ) (Open Access)Rede uitgesproken bij de aanvaarding van het ambt van hoogleraar Hematologie aan het Radboudumc/de Radboud Universiteit Nijmegen op donderdag 5 september 201321 p

Mucosal Barrier Injury and Stem Cell Transplant Recipients.

Contains fulltext : 26945_mucobaina.pdf (publisher's version ) (Open Access)The intensive chemotherapy with or without radiation therapy used to prepare for a haematopoietic stem cell transplant (HSCT) is unfortunately complicated by damage to the mucosa of the digestive tract. The resultant, mucosal barrier injury (MBI) causes painful ulcerations, which are readily apparent in mouth and are known as mucositis. This makes eating and drinking difficult at a time when patients need optimal nutrition. Moreover until very recently there were no specific remedies of proven value. Patients had to rely on pain relief and other palliative measures to alleviate the symptoms of mucositis. MBI is a dynamic and complex pathobiological process consisting of 4 phases; an inflammatory-, epithelial-, ulcerative/infective- and a healing phase. Initially, small intestinal epithelial cells secrete pro-inflammatory cytokines after exposure to cytotoxic therapy. This phase is mediated by nuclear factor-kappa B activation. Curcumin is able to inhibit this process, resulting in partial amelioration of villous atrophy providing a potentially new approach preventing MBI. MBI was measured among more than 100 HSCT recipients by scoring oral mucositis, determining gut toxicity (nausea, vomiting, diarrhoea and cramps) and by undertaking a permeability test consisting of four sugars (D-xylose, 3-O-methyl-D-glucose, L-rhamnose and lactulose). These features of MBI were significantly correlated with each other but each tool measured a different aspect of MBI. Gut integrity and absorption were still abnormal 3 to 4 weeks after transplant. Novel use was also made of serum citrulline to determine intestinal MBI since the amino acid is a marker of small bowel enterocyte mass. The results showed citrulline to be a more sensitive and specific marker of gut MBI than the other tools. A prospective, randomised, double-blinded, placebo-controlled study with glutamine-dipeptide supplementation failed to ameliorate MBI in HSCT recipients. However it became clear that a significant increase in the levels of inflammatory response markers (IL-8, LBP and CRP) was seen in patients mirroring the pattern of MBI. These markers were already significantly elevated before the onset of fever or bacteraemia during profound neutropenia suggesting that the degree of MBI rather than bacteraemia determines the intensity of this inflammatory response. Hence, aiming either to down-regulate the inflammatory response or at restoring the barrier by stimulating epithelial cell functioning may be more fruitful in protecting HSCT recipients from infectious complications than antimicrobial therapy.RU Radboud Universiteit Nijmegen, 27 juni 2005Promotor : Pauw, B.E. de Co-promotores : Donnelly, J.P., Schattenberg, A.V.M.B.186 p

Implications of treatment-induced mucosal barrier injury.

Contains fulltext : 47635.pdf (publisher's version ) (Closed access)PURPOSE OF REVIEW: This review highlights recent developments in the pathophysiology of treatment-induced mucosal barrier injury, outlines the application of new diagnostic tools, focuses on risk factors and complications, and offers an up-to-date overview on treatment options. RECENT FINDINGS: Treatment-induced mucosal damage is now thought to occur in five phases: initiation, up-regulation and message generation, amplification and signaling, ulceration, and healing. It is now possible to assess gut mucosal damage both by sugar permeability tests and serum citrulline. Amifostine reduces the oral mucositis of stem cell transplantation recipients after radiotherapy and high-dose chemotherapy. Palifermin (recombinant human keratinocyte growth factor 1), a trophic growth factor, has been shown to reduce significantly both the incidence and duration of severe mucositis after myeloablative therapy and may have the potential to reduce gut mucosal damage. SUMMARY: Treatment-induced mucosal barrier injury is a complex, dynamic pathobiological process manifested not only in the oral cavity but throughout the entire digestive tract, diminishing the quality of life and predisposing the patient to serious clinical complications. Therefore, it is important to detect mucosal damage induced by cytotoxic therapy adequately to be able to test the efficacy of new therapeutic options for preventing or ameliorating this complication

Neutropenic enterocolitis: challenges in diagnosis and treatment.

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