Pharmacokinetic drug interactions of the non-vitamin K antagonist oral anticoagulants (NOACs)

The use of warfarin, the most commonly prescribed oral anticoagulant, is being questioned by clinicians worldwide due to warfarin several limitations (a limited therapeutic window and significant variability in dose-response among individuals, in addition to a potential for drug-drug interactions). Therefore, the need for non-vitamin K antagonist oral anticoagulants (NOACs) with a rapid onset of antithrombotic effects and a predictable pharmacokinetic (PK) and pharmacodynamic (PD) profile led to the approval of five new drugs: the direct factor Xa (F-Xa) inhibitors rivaroxaban, apixaban, edoxaban and betrixaban (newly approved by FDA) and the direct thrombin (factor-IIa) inhibitor dabigatran etexilate. The advantages of NOACs over warfarin are a fixed-dosage, the absence of the need for drug monitoring for changes in anti-coagulation and fewer clinically significant PK and PD drug\u2013drug interactions. NOACs exposure will likely be increased by the administration of strong P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4-inhibitors and may increase the risk of bleeds. On the contrary, P-gp inducers could significantly decrease the NOACs plasma concentration with an associated reduction in their anticoagulant effects. This manuscript gives an overview of NOACs PK profiles and their drug-drug interactions potential. This is meant to be of help to physicians in choosing the best therapeutic approach for their patients

PCNA-Li, Ki 67 immunostaining, p53 activity and histopathological variables in predicting the clinical outcome in patients with parathyroid carcinoma

Parathyroid carcinoma is uncommon and no reliable histological markers are available for predicting the clinical outcome of patients. The aim of this study was to assess the correlation between survival, histopatological markers, proliferating cell nuclear antigen (PCNA), Ki-67 antigen and the expression of the p53 nuclear protein in patients with confirmed parathyroid carcinoma (PC). The routine histological specimens from 15 patients (11 men, 4-women, median age 65 years) with confirmed PC who had died of the disease were reviewed. New specimens were also stained with the streptavidin-biotin-peroxidase complex standard technique. The labelling index (LI) of PCNA was quantified by counting 1000 cells from multiple areas in a random fashion, while immunostaining of both Ki-67 and p53 was evaluated as the percentage of positive cells. The PCNA-LI, Ki-67 (%) and p53 (%) values were 14.9 +/- 4.1 (median 13, range 2-70), 13.9 +/- 3.9 (median 11%, range 3-65%) and 38.5 +/- 4.6 (median 29%, range 19-65%), respectively. There was an inverse correlation between age of the patients and p53 (R = -0.73, p = 0.002), but no correlation with both PCNA-LI (R = 0.07, p = 0.72) and Ki-67 (R = -0.07, p = 0.79). A significant relationship (R = 0.93, p < 0.01) between PCNA-LI and Ki-67 was found, while p53 did not correlate with either PCNA-LI (R = -0.11, p = 0.71) or Ki-67 (R = -0.05, p = 0.86). An inverse correlation (R = -0.63, p = 0.01) between survival and the presence of spindle cells and coagulation necrosis together in the standard slides was observed, but there was no correlation (p = NS) between survival and PCNA-LI (R = 0.05), Ki -67 (R = 0.05) or p53 (R = 0.25). In conclusion, none of the tested immunohistochemical markers were useful in predicting the clinical outcome of patients with PC. However, the presence of spindle cells and coagulation necrosis together in the standard specimens should be considered as a negative prognostic factor

Liver transplantation for the management of hepatoblastoma

Abstract INTRODUCTION: Hepatoblastoma (HEP) is the most frequent liver malignancy occurring in childhood. Surgical resection currently represents the gold standard for treatment. In patients with initially unresectable tumors, chemotherapy may induce remarkable reductions in size. In nonresponder patients, liver transplantation (OLTx) may offer a chance of cure. MATERIALS AND METHODS: From 1990 to 2003, a total of 400 OLTx (31 pediatric transplants) have been performed at Padua University. Seven patients (4 males and 3 females) underwent OLTx for hepatoblastoma. All patients presented with bilobar liver involvement and had received chemotherapy according to the SIOPEL-1. In all patients preoperative staging was negative for extrahepatic involvement. RESULTS: The mean age of the pts was 8.2 years (range 6.4 months to 34 years). Mean follow-up after OLTx was 41.4 months (median 36, range 3 to 108 months). Actuarial patient survival rates after OLTx for hepatoblastoma are 83.3%, 83.3%, and 56% at 1, 3, and 5 years, respectively. Five of seven subjects with HEP are alive after transplant at 3, 12, 36, 65, and 108 months. Two patients died owing to recurrent disease after 6 and 60 months, respectively, from transplantation. Another subject, primarily treated with surgical resection, shows HEP recurrence at 40 months after OLTx. The remaining 4 patients are alive and well at a mean follow-up of 28 months (median 24, range 3 to 65 months). CONCLUSIONS: Liver transplantation may represent a valid therapeutic option for patients with unresectable HEP, but it is contraindicated in cases of recurrence following previous resection surgery. Neo-adjuvant chemotherapy is of paramount importance to obtain good long-term results

Liver transplantation for the management of hepatoblastoma

Hepatoblastoma (HEP) is the most frequent liver malignancy occurring in childhood. Surgical resection currently represents the gold standard for treatment. In patients with initially unresectable tumors, chemotherapy may induce remarkable reductions in size. In nonresponder patients, liver transplantation (OLTx) may offer a chance of cure