Voriconazole in the treatment of aspergillosis,scedosporiosis and other invasive fungal infections in children

OBJECTIVE: To describe the safety and efficacy of voriconazole in children treated within the compassionate release program. METHODS: Children received voriconazole on a compassionate basis for treatment of an invasive fungal infection if they were refractory to or intolerant of conventional antifungal therapy. Voriconazole was administered as a loading dose of 6 mg/kg every 12 h i.v. on Day 1 followed by 4 mg/kg every 12 h i.v. thereafter. When feasible the route of administration of voriconazole was changed from i.v. to oral (100 or 200 mg twice a day for patients weighing < 40 or > or = 40 kg, respectively). Outcome was assessed by investigators at the end of therapy or at the last visit as success (complete or partial response), stable infection, or failure, based on protocol-defined criteria. RESULTS: Sixty-nine children (ages 9 months to 15 years; median, 7 years) received voriconazole; 58 had a proven or probable fungal infection. Among these 58 patients 27 had hematologic malignancies and 13 had chronic granulomatous disease as the most frequent underlying conditions. Forty-two patients had aspergillosis, 8 had scedosporiosis, 4 had invasive candidiasis and 4 had other invasive fungal infections. The median duration of voriconazole therapy was 93 days. At the end of therapy 26 patients (45%) had a complete or partial response. Four patients (7%) had a stable response, 25 (43%) failed therapy and 4 (7%) were discontinued from voriconazole because of intolerance. Success rates were highest in patients with chronic granulomatous disease (62%) and lowest in patients with hematologic malignancies (33%). Two patients experienced treatment-related serious adverse events (ulcerated lips with rash, elevated hepatic transaminases or bilirubin). A total of 23 patients had voriconazole-related adverse events, 3 (13%) of which caused discontinuation of voriconazole therapy. The most commonly reported adverse events included elevation in hepatic transaminases or bilirubin (n = 8), skin rash (n = 8), abnormal vision (n = 3) and a photosensitivity reaction (n = 3). CONCLUSION: These data support the use of voriconazole for treatment of invasive fungal infections in pediatric patients who are intolerant of or refractory to conventional antifungal therapy.     

Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma.

Although point mutations of the 5' noncoding regions of the BCL-6 proto-oncogene are frequently detected in B-diffuse large cell lymphoma (B-DLCL), a thorough analysis of the clinical correlation of these mutations has not been performed to date. In this study, BCL-6 mutations were examined by DNA direct sequencing in 103 patients with B-DLCL. BCL-6 mutations were found in 53/103 patients, including 38/76 treated with standard chemotherapy and 15/27 treated with autologous stem cell transplantation (ASCT) up front. The presence of BCL-6 mutations was correlated with clinical features at diagnosis and outcome. Mutated patients had a significantly higher LDH level (66% vs 38%, P < 0.05), and bulky disease (51% vs 32%, P = 0.05). In the whole series of patients BCL-6 mutations did not affect CR and OS. Patients with BCL-6 mutations tended to have a prolonged 5-years DFS and FFS compared to those without mutations (DFS 82% vs 63%, FFS 63% vs 49%). Among B-DLCL treated with standard chemotherapy, mutated patients showed a significantly improved 5-year DFS (85% vs 61%, P < 0.05) and, notably, the only four relapses observed among mutated patients occurred in less than 8 months. The multivariate regression analysis (P < 0.01) with DFS as endpoint confirmed the independent prognostic value of BCL-6 mutations. There was a trend for 5-year failure-free survival to be better for patients with BCL-6 mutations (63% vs 43%, P = 0.09). In the 27 patients treated with ASCT, BCL-6 mutations did not correlate with outcome. These results suggest that BCL-6 mutations may predict a higher chance of being free of disease in B-DLCL treated with standard chemotherapy. Larger series of patients need to be analyzed to evaluate the clinical relevance of BCL-6 mutations properly.     

Advances in the management of corticosteroid-induced osteoporosis with bisphosphonates

Corticosteroids are widely used as anti-inflammatory and immunosuppressive agents to treat a variety of chronic conditions. Long-term (>1 year) corticosteroid use can lead to bone loss, and therefore, osteopenia or osteoporosis. Corticosteroid-induced osteoporosis (CIO) leads to increased bone fragility and subsequently fractures, which, in turn, lead to a loss of physical, emotional and social health for the patient and increased costs for healthcare providers. A wealth of data exists demonstrating the efficacy of the oral bisphosphonates, etidronate, alendronate and risedronate in increasing bone mineral density in patients with CIO or preventing bone loss in patients commencing corticosteroid therapy. Data regarding fracture prevention are less clear, as statistically significant reductions in the incidence of fractures have only been reported for patient subgroups or meta-analyses. However, many treatment guidelines recommend the use of oral bisphosphonates for the prevention and treatment of CIO. These guidelines are, however, not reflected in prescribing practice, and the majority of patients do not receive adequate concomitant therapy. This review summarizes the available data for bisphosphonates in CIO. Therapeutic adherence with oral bisphosphonates is an issue, with approximately 50% of patients discontinuing therapy within the first year. The primary reasons for this are poor gastrointestinal tolerability and the frequency with which complex dosing requirements must be followed. The inconvenience of taking daily or weekly bisphosphonate therapy is of particular importance in patients with CIO who may be regularly taking several other medications. Data obtained in studies with ibandronate indicate that bisphosphonate administration by rapid intravenous injection provides an effective, well-tolerated and practical alternative to current oral regimens in the management of patients with CIO.     

The retinoid induced pancreatic cancer redifferentiation-apoptosis sequence and the mitochondria: a suggested obligatory sequence of events

Retinoic acid induces redifferentiation and apoptosis in pancreatic adenocarcinoma cell lines. Redifferentiation includes early reversion into aerobic metabolism as reflected by an increase of mitochondrial activity and mass with normal membrane potential and terminal ductal cell differentiation. Cells in such a state either attempt to correct their DNA abnormalities or commit suicide by apoptosis. In some cell systems, such as pancreatic ductal cells, the stem cells show potential to transdifferentiate into functional normal endocrine cell type. However, since it is impossible to correct a highly corrupted genome, cells eventually succumb to apoptosis. Mitochondrial changes appear to be the enforcing factor for this process. The Transformation--Normalizing-redifferentiation--Apoptosis sequence has been shown by several studies, utilizing various cell types, apoptotic inducers, biomarkers and time frames. Although some studies have shown concomitant apoptosis and redifferentiation, others have reported apoptosis without prior redifferentiation. However, utilizing the appropriate time frame and the markers of earlier mitochondrial changes, one would detect a scenario similar to the retinoid model. This situation can be achieved by delaying apoptosis or reducing the inducer concentration in such systems. The final physiological fate of a normal terminally differentiated cells is apoptosis. Similarly, it is suggested that a degree of normalizing redifferentiation of transformed cells might be expected prior to apoptosis. The former seemed obligatory at least in the retinoid-pancreatic model.     

Low-dose radiotherapy for extranodal marginal zone B lymphoma of the lip: Case report and literature review

Non-Hodgkin lymphoma (NHL) of the lip is extremely rare. It is usually indolent and in early stages a local approach is often indicated. We present a case report of a patient with extranodal NHL of the lip treated with chemotherapy and low-dose radiation treatment (RT). The patient was affected by B-cell NHL of the marginal zone, Stage IAE. After a few months of observation with progressive disease, the patient was submitted to two cycles of chemotherapy with no response. Therefore, he was treated with very low-dose RT consisting of two fractions of 2 Gy. Complete response was observed and after 1-year follow-up, persistent complete response was recorded. In cases of localized disease, especially in patients with comorbidities of poor performance status (PS), low-dose RT can be an appropriate approach with excellent outcomes in terms of effectiveness and low risk of toxicity.     

Variations of energy biochemical metabolites in periparturient dairy Saanen goats

The Saanen goat is one of the highest milk-producing goat breeds and has a high reproductive yield. Twelve pregnant dairy Saanen does were selected to study the variations in energy-related blood metabolites during periparturition and to highlight the negative energy balance (NEB) rate during this critical period. Blood from the jugular vein was collected from each doe on days 29, 14 and 6 before the expected kidding time and also 12 h and on days 7, 13, 19, 21, 28, 35 and 42 postpartum. The concentrations of β-hydroxybutyrate (BHBA), non-esterified fatty acid (NEFA), cholesterol, triglyceride, glucose, total protein, albumin, blood urea nitrogen and aspartate aminotransferase (AST) activity were determined. Since serum metabolites were measured over time, a repeated measures approach using ANOVA with mixed linear models was used. The results of our study indicated that the changes in BHBA concentrations were between 134 and 375 μmol/l. There was a low number of does with BHBA concentrations above 1,000 μmol/l. However, the number of does with abnormal NEFA concentrations (≥0.6 mmol/l) was high. The NEFA results were in agreement with the increased proportion of does with AST concentrations greater than the cutoff level (≥100 U/l). We conclude that similar to dairy cows, NEB occurs in dairy Saanen goats during the periparturition period. NEFA concentration reflected a NEB better than BHBA in dairy Saanen goats.