The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis

To determine whether MDR1 reversal by the addition of the P-glycoprotein (P-gp) inhibitor PSC-833 to standard induction chemotherapy would improve event-free survival (EFS), 419 untreated patients with acute myeloid leukemia (AML) aged 60 years and older were randomized to receive 2 induction cycles of daunorubicin and cytarabine with or without PSC-833. Patients in complete remission were then given 1 consolidation cycle without PSC-833. Neither complete response (CR) rate (54% versus 48%; P = .22), 5-year EFS (7% versus 8%; P = .53), disease-free survival (DFS; 13% versus 17%; P = .06) nor overall survival (OS; 10% in both arms; P = .52) were significantly improved in the PSC-833 arm. An integrated P-gp score (IPS) was determined based on P-gp function and P-gp expression in AML cells obtained prior to treatment. A higher IPS was associated with a significantly lower CR rate and worse EFS and OS. There was no significant interaction between IPS and treatment arm with respect to CR rate and survival, indicating also a lack of benefit of PSC-833 in P-gp-positive patients. The role of strategies aimed at inhibitory P-gp and other drug-resistance mechanisms continues to be defined in the treatment of patients with AML

An observational efficacy and safety analysis of the treatment of acute invasive aspergillosis using voriconazole

The purpose of this study was to evaluate efficacy and safety of voriconazole in patients with acute invasive aspergillosis (IA) in a real-life, clinical setting. This was a multicenter observational study in adult patients treated with voriconazole for invasive mycosis. The study evaluated clinical response, mortality, use of other licensed antifungal therapy (OLAT), and treatment duration. This sub-analysis evaluated treatment and outcome data specifically from adult patients with proven/probable IA, while safety data were assessed in patients with proven/probable/possible IA. Of the 141 patients enrolled, 113 were adults with proven/probable IA and six had possible IA. Voriconazole treatment duration ranged from 1 to 183 days (median, 49.5 days). Voriconazole was used exclusively in 64% (72/113) of patients and in combination/sequentially with OLAT in 36%. Overall successful treatment response was 50% (57/113 patients). Twelve percent (14/113) of patients were switched to OLAT, either because of insufficient response (four patients) or for safety reasons (10 patients). Overall and attributable (entirely or partially due to fungal infection) mortality rates were 52% (59/113) and 17%, respectively. Treatment-related adverse events were reported for 18% (22/119) of patients. This observational study confirms the results of previous clinical trials demonstrating voriconazole as an effective and safe agent for treatment of confirmed acute IA

A dominant gain-of-function mutation in universal tyrosine kinase <i>SRC </i>causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies

The Src family kinase (SFK)member SRC is amajor target in drug development because it is activated in many human cancers, yet deleterious SRC germline mutations have not been reported. We used genome sequencing and Human Phenotype Ontology patient coding to identify a gain-of-function mutation in SRC causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in nine cases. Modeling of the E527K substitution predicts loss of SRC's self-inhibitory capacity, whichwe confirmedwith in vitro studies showing increased SRC kinase activity and enhanced Tyr419 phosphorylation in COS-7 cells overexpressing E527K SRC. The active form of SRC predominates in patients' platelets, resulting in enhanced overall tyrosine phosphorylation. Patientswith myelofibrosis have hypercellular bone marrow with trilineage dysplasia, and their stem cells grown in vitro form more myeloid and megakaryocyte (MK) colonies than control cells. These MKs generate platelets that are dysmorphic, low in number, highly variable in size, and have a paucity of a-granules. Overactive SRC in patient-derived MKs causes a reduction in proplatelet formation, which can be rescued by SRC kinase inhibition. Stem cells transduced with lentiviral E527K SRC formMKs with a similar defect and enhanced tyrosine phosphorylation levels. Patient-derived and E527K-transduced MKs show Y419 SRC- positive stained podosomes that induce altered actin organization. Expression of mutated src in zebrafish recapitulates patients' blood and bone phenotypes. Similar studies of platelets andMKs may reveal the mechanism underlying the severe bleeding frequently observed in cancer patients treated with next-generation SFK inhibitors. © 2016 by the American Association for the Advancement of Science; all rights reserved

Malignant mesothelioma

Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10–20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis

ECONOMIC EVALUATION OF VORICONAZOLE VERSUS CASPOFUNGIN FOR THE TREATMENT OF INVASIVE ASPERGILLOSIS IN BELGIUM

OBJECTIVE:To perform an economic evaluation of voriconazole versus caspofungin in first line treatment of invasive aspergillosis (IA). These 2 antifungal drugs have a more favorable toxicity profile than the conventional amphotericin B and have a lower cost than the expensive liposomal/lipid formulation of amphotericin B. No head-to-head comparative study was conducted with voriconazole and caspofungin in IA. Based on the clinical trials of both antifungals, a conservative approach of similar efficacy has been considered. METHODS: The analysis is based on a simplified cost-minimization model with results from the National Health system RIZIV/INAMI perspective (year 2008). Only limited direct costs were considered, namely the drug cost over the episode of treatment. Treatment duration and patients' weight were key parameters. Their values were obtained from the Belgian observational VORIBEL study (Pfizer data on file) for voriconazole treatment. Treatment duration for caspofungin was derived from the EORTC study where almost 50% of the patients were recruited in Belgian centres. Mean cost and incremental cost were calculated. Univariate sensitivity analyses were carried out on weight, treatment duration as well as on route of administration. RESULTS: In invasive aspergillosis, the weighted cost per episode of fungal infection was 11.996 (sic) with voriconazole treatment (voriconazole IV followed by oral voriconazole) and 13.657 (sic) with caspofungin treatment (intravenous caspofungin only). The incremental saving with voriconazole treatment was 1.661 (sic) per patient. The cost-saving results of voriconazole were confirmed with varying treatment duration within realistic range. 41% of the patients in the VORIBEL study were fully treated with oral formulation. For these patients a saving of 6.375 (sic) was achieved with the use of oral voriconazole. CONCLUSION: Voriconazole is a cost-saving option compared with caspofungin in the treatment of invasive aspergillosis

Primary immune thrombocytopenia in adults

The Belgian Hematological Society (BHS) guideline panel on adult primary immune thrombocytopenia (ITP) reviewed the recent literature on diagnosis and treatment to make recommendations on the best strategies for frontline and subsequent-line treatment. No treatment is necessary for patients with platelet counts higher than 30000/ l in the absence of bleeding symptoms. Patients newly diagnosed or relapsing after a long-term treatment-free period can be managed with corticosteroids with or without intravenous immunoglobulins. A second line therapy is indicated for those patients who are intolerant or unresponsive to or relapse after initial corticosteroid treatment and have a risk of bleeding. The guideline panel recommends splenectomy as it is the treatment with the highest curative potential and an acceptable safety pro le. If possible, splenectomy should be delayed to at least twelve months after diagnosis as spontaneous remission can occur in this time period. Thrombopoietin receptor (TPO-R) agonists are recommended for patients who are refractory to or relapse after splenectomy or who have a contra-indication to splenectomy irrespective of the duration of ITP. The guideline panel agrees that rituximab, azathioprine, cyclophosphamide, cyclosporine A, danazol, dapsone, mycophenolate mofetil and vincristine/vinblastine are potential treatment options, especially for patients refractory to TPO-R agonists