Eltrombopag or Intravenous Immunoglobulin as a Bridge to Splenectomy in Adults With Chronic Idiopathic Thrombocytopenic Purpura: A Canadian Economic Analysis

BackgroundChronic idiopathic thrombocytopenia purpura (ITP) in adults is a potentially serious disorder affecting 6000 to 7000 Canadians. Initial treatment consisting of corticosteroids usually begins when the platelet count is persistently below 20 × 10⁹/L or if the patient has bleeding complications. In cases in which corticosteroid resistance develops or in which they are contraindicated, splenectomy is the recommended second-line therapy. In many of these patients, intravenous immunoglobulin (IVIG; 1 g/kg/day for 2 days then 1 g/kg/day monthly) is often used as a bridge to surgery. Eltrombopag is a new orally administered agent that activates the thrombopoietic receptor and stimulates human megakaryocytes. Clinical trials have demonstrated that eltrombopag is safe and effective in the treatment of adults with chronic ITP. Therefore, it represents an attractive option to IVIG for use as a bridge to splenectomy. In this study, a cost-minimization analysis was conducted to test the hypothesis that eltrombopag is a cost-effective alternative to IVIG for this indication.Patients and MethodsThe economic analysis was conducted from the Canadian societal perspective using a 4-month time horizon. Estimates for direct medical costs in these patients were obtained from 6 hematologists from across Canada. The base case analysis considered direct costs for drug therapy, outpatient pharmacy fees, medical consultations and visits, laboratory and diagnostic procedures, as well as costs for secondary pharmacotherapy in cases in which the primary agent had to be discontinued because of side effects. For IVIG, the analysis also included visits to the infusion clinic, chair time to receive the infusion, nursing time, pharmacy preparation, as well as indirect costs (eg, time off work, patient travel). A 1-way sensitivity analysis was then undertaken on the key cost drivers to test the stability of the primary findings.ResultsTotal direct and indirect costs for IVIG were $24,134 for 4 months of therapy with drug cost contributing to 84% of the total. In contrast, total costs for eltrombopag were approximately $14,651 for an overall savings of $9,543 per patient. The sensitivity analysis suggested that the base case findings were stable and were only modestly affected by variations in drug cost and duration of therapy.ConclusionGiven its oral route of administration and cost-saving potential, eltrombopag would be an economically attractive alternative to IVIG when the intent of therapy is to create a bridge to surgery.     

Olaparib Use in Patients With Metastatic Breast Cancer Harboring Somatic BRCA1/2 Mutations or Mutations in Non-BRCA1/2, DNA Damage Repair Genes

BackgroundPoly-ADP ribose polymerase (PARP) inhibitors (PARPi) are active in patients with germline BRCA1/2 (gBRCA1/2)-mutated breast cancer, accounting for 5% to 10% of all breast cancers. Another 5% to 10% harbor somatic BRCA1/2 (sBRCA1/2) mutations or mutations in non-BRCA1/2, homologous recombination repair (HRR) genes but until recently, there were no data for the use of PARPi in these patients. This study examines the use of olaparib in patients with metastatic breast cancer harboring sBRCA1/2 or germline or somatic non-BRCA1/2, HRR mutations and demonstrates potential activity of PARPi in this setting.MethodsIn this retrospective, single institution study, patients who were treated with off-label, off-protocol olaparib for metastatic breast cancer harboring sBRCA1/2 or germline or somatic non-BRCA1/2, HRR mutations were identified. The primary aim was to describe these patients’ demographics, tumor characteristics, mutations, safety and tolerability, response rates, progression free survival, PARPi-associated survival and subsequent treatment.ResultsSeven patients were treated off-label, off-trial with olaparib for sBRCA1/2-mutated cancers (n = 4) or non-BRCA1/2, HRR-mutated cancers (n = 3). All patients with sBRCA1/2-mutated cancers responded to PARP inhibition; patients with non-BRCA1/2, HRR-mutated cancers did not respond. The median progression free survival in patients with a sBRCA1/2 mutation was 6.5 months (range 5-9 months) vs. 3 months (range 2-4 months) in patients with non-BRCA1/2, HRR mutations.ConclusionThis single institution experience adds to recent larger reports confirming evidence for PARPi therapy in patients with metastatic breast cancer harboring sBRCA1/2 mutations. No activity was observed in patients with either germline or somatic non-BRCA1/2, HRR-mutated cancers.     

Recurrent gliomas: Comparison of computed tomography (CT)-guided ( 125) I seed implantation therapy and traditional radiochemotherapy

Background: Primary brain tumors have always been associated with high morbidity and mortality. Glioma is the most common type of malignant brain tumors,with a high probability of recurrence after surgical excision and with poor prognosis.The purpose of this study was to compare the therapeutic efficacy of computed tomography (CT)-guided interstitial ( 125) I seed implantation with traditional radiochemotherapy for treatment of recurrent gliomas. Results: The response rate at 1, 3, 6 and 12 months after ( 125) I seed implantation was 68.6, 74.3, 77.1 and 62.8% respectively, which was significantly higher than the group treated with the conventional chemoradiation protocol (p < 0.05). Patients exposed to ( 125) I seed implantation had a median survival of 29.0 months, whereas the median survival of those treated with traditional radiochemotherapy was 19.0 months. The difference observed between the two groups was significant. There were no severe complications or mortality associated with either treatment, except for one case of intracerebral hemorrhage around the tumor area in the ( 125) I seed implants group. Methods: From November 2002 to May 2010, 73 consecutive patients with recurrent gliomas were treated with CT-guided ( 125) I seed implantation (35 cases) or traditional radiochemotherapy (38 cases). Patients were followed up after treatment and the therapeutic effect was evaluated by comparing the response and survival rates of the two groups. In particular, patients treated with ( 125) I seed implantation were monitored for adverse side effects. Conclusions: CT-guided ( 125) I seed implantation is safe and well-tolerated and more importantly, shows superior efficacy compared with conventional radiochemotherapy. This suggests that CT-guided ( 125) I seed implantation could be an alternative approach for recurrent gliomas.     

Accuracy and agreement of a large panel of endosonographers for endomicroscopy-guided virtual biopsy of pancreatic cystic lesions

BackgroundAlthough emerging data evidences that EUS-guided needle-based confocal laser endomicroscopy (nCLE) accurately diagnoses pancreatic cystic lesions (PCLs), there are a lack of interobserver agreement (IOA) studies utilizing reference histopathological diagnosis and for specific PCL subtypes. Hence, we sought to assess the IOA, intra-observer reliability (IOR), and diagnostic performance of EUS-nCLE using a large cohort of patients with histopathological diagnosis amongst a broad panel of international observers.MethodsEUS-nCLE videos (n = 76) of subjects with PCLs [intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystadenoma (SCA), pseudocyst, and cystic-neuroendocrine tumors/solid pseudopapillary neoplasm (cystic-NET/SPN)], simulating clinical prevalence rates were obtained from 3 prospective studies. An international panel of 13 endosonographers with nCLE experience, blinded to all PCL data, evaluated the video library twice with a two-week washout for PCL differentiation (mucinous vs. non-mucinous) and subtype diagnosis.ResultsThe IOA (κ = 0.82, 95% CI 0.77–0.87) and IOR (κ = 0.82, 95% CI 0.78–0.85) were “almost perfect” to differentiate mucinous vs. non-mucinous PCLs. For PCL subtype, IOA was highest for SCA (almost perfect; κ = 0.85), followed by IPMN (substantial, κ = 0.72), and cystic-NET/SPN (substantial, κ = 0.73). The IOA was moderate for MCN (κ = 0.47), and pseudocyst (κ = 0.57). Compared to histopathology, observers differentiated mucinous vs. non-mucinous PCLs with high accuracy (94.8%, 95% CI 93.3–96.1). For detecting specific PCLs subtypes, EUS-nCLE was highly accurate in diagnosing non-mucinous cysts (SCA: 98%; cystic-NET/SPN: 96%; pseudocyst: 96%) and slightly less accurate for mucinous lesions (IPMN: 86%; MCN: 84%).ConclusionDiagnosis of PCLs by EUS-nCLE guided virtual biopsy is very accurate and reliable for the most prevalent pancreatic cysts in clinical practice.     

METTL3 promotes the proliferation and invasion of esophageal cancer cells partly through AKT signaling pathway

Methyltransferase-like 3 (METTL3) is identified as a methyltransferase responsible for N⁶-methyladenosine (m⁶A) modification of mRNA, miRNA and lncRNA. Emerging evidences suggest that METTL3 is involved in tumorigenesis and progression of multiple tumor types. However, the functional role of METTL3 in esophageal cancer (EC) remains unclear. We used specific shRNA to down-regulate the METTL3 expression, and used pcDNA3.1-METTL3 cDNA plasmid to up-regulate the METTL3 expression in Eca-109 and KY-SE150 cells. Biological functions of METTL3 were performed by CCK-8, colony formation, apoptosis analysis, transwell and wound healing assays. Finally, an in-depth mechanism study was performed by an AKT inhibitor. METTL3 knockdown reduced the proliferation, clonality, migration and invasion of Eca-109 and KY-SE150 cells, and induced cell apoptosis, which may be mediated by activation of the mitochondrial apoptotic pathway. Further, METTL3 overexpression promoted the proliferation, clonality, migration and invasion of Eca-109 and KY-SE150 cells, and inhibited cell apoptosis. In addition, METTL3 regulated the expression of Wnt/β-catenin and AKT signaling pathway components. A double-effect inhibitor (BEZ235) inhibited AKT and mTOR phosphorylation and hindered the effect of METTL3 overexpression on the proliferation and migration of Eca-109 and KY-SE150 cells. Our data suggest that METTL3 plays a carcinogenic role in human EC progression partially through AKT signaling pathways, suggesting that METTL3 may serve as a potential therapeutic target for EC therapy.