Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance

Novel therapeutic strategies are needed to address the emerging problem of imatinib resistance. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) is being evaluated for imatinib-resistant chronic myelogenous leukemia (CML) and has multiple cellular effects, including the induction of autophagy and apoptosis. Considering that autophagy may promote cancer cell survival, we hypothesized that disrupting autophagy would augment the anticancer activity of SAHA. Here we report that drugs that disrupt the autophagy pathway dramatically augment the antineoplastic effects of SAHA in CML cell lines and primary CML cells expressing wild-type and imatinib-resistant mutant forms of Bcr-Abl, including T315I. This regimen has selectivity for malignant cells and its efficacy was not diminished by impairing p53 function, another contributing factor in imatinib resistance. Disrupting autophagy by chloroquine treatment enhances SAHA-induced superoxide generation, triggers relocalization and marked increases in the lysosomal protease cathepsin D, and reduces the expression of the cathepsin-D substrate thioredoxin. Finally, knockdown of cathepsin D diminishes the potency of this combination, demonstrating its role as a mediator of this therapeutic response. Our data suggest that, when combined with HDAC inhibitors, agents that disrupt autophagy are a promising new strategy to treat imatinib-refractory patients who fail conventional therapy.     

Intravascular ultrasonic study of gender differences in ruptured coronary plaque morphology and its associated clinical presentation

Coronary plaque rupture is a phenomenon underlying most acute coronary events. Although gender is an important determinant of the incidence and clinical course of coronary atherosclerosis, its relation to plaque rupture is unknown. Therefore, we assessed gender differences in native artery plaque rupture characteristics and their related clinical presentations. There were 468 intravascular ultrasound (IVUS) preintervention images of ruptured plaques retrospectively identified. There were 328 men (81.6%) with 387 plaque ruptures and 74 women (18.4%) with 81 plaque ruptures. Patient demographics, angiographic characteristics, and qualitative and quantitative IVUS analyses of ruptured plaques were assessed. On average women were older than men (67.6 +/- 11.8 vs 62.6 +/- 11.4 years, p = 0.001) and more often presented with an acute coronary syndrome (89.2% vs 72.9%, p = 0.003). Older women had smaller vessel areas at the rupture site (p = 0.001), minimum lumen site (p = 0.002), and reference segments (p = 0.002) and smaller lumen areas at the rupture site (p = 0.026) and reference segments (p = 0.03). Ruptured plaques in older women were more often associated with IVUS-evident thrombus (48.1% vs 34.6%, p = 0.022). Independent predictors of acute clinical presentation were female gender (p = 0.006), smoking (p = 0.013), and presence of thrombus (p = 0.049). Independent predictors of the presence of thrombus were female gender (p = 0.025), smaller lumen area (p = 0.023) and larger plaque area (p = 0.008) at the rupture site, longer plaque ruptures (p = 0.016), and smoking (p = 0.045). In conclusion, coronary plaque ruptures are more often associated with thrombus and acute presentations in women than in men.     

Laparoscopic splenectomy in children: experience in a single institution

PURPOSE: To assess the safety and effectiveness of laparoscopic splenectomy in children. MATERIALS AND METHODS: Hospital records of 63 patients who underwent laparoscopic splenectomy between 1998 and 2005 were reviewed retrospectively. In 16 patients concomitant cholecystectomy was performed. All procedures were performed by the same surgeon. The indications for splenectomy were hereditary spherocytosis (n = 35), idiopathic thrombocytopenic purpura (n = 22), autoimmune hemolytic anemia (n = 3), and other diseases (n = 3). Details of operative technique were reviewed and their implications on intraoperative complications are analyzed. The postoperative course and long-term results were assessed. RESULTS: There were 35 girls and 28 boys, whose average age was 11.3 years (range, 3.9-19.5 years). There were 7 conversions, mainly at the beginning of the series. A mild degree of intraoperative bleeding was observed in 23 (36.5%) cases. In two cases (3%) severe bleeding led to conversion. Postoperatively, 1 patient required blood transfusion and 1 patient had signs of mild general infection that was treated conservatively. There was no mortality in this series. The mean operation time was 134 minutes for splenectomy and 174 minutes for splenectomy and cholecystectomy. Operative time did not significantly diminish at the end of the 7-year study period. CONCLUSION: Laparoscopic splenectomy in children performed by an experienced team proved to be safe and effective with minimal side effects and should be recommended as a procedure of choice in children who require splenectomy.     

Phosphatemia is related to chromosomal aberrations of parathyroid glands in patients with hyperparathyroidism

BACKGROUND AND AIMS: It has been well documented that gene and DNA alterations occur frequently in benign primary parathyroid adenomas as well as in parathyroid glands with secondary hyperplasia. However, it has not been shown whether a correlation exists between somatic DNA aberrations and clinical data. METHODS: We analyzed the frequency of chromosomal aberrations in adenomas obtained from 25 patients with primary hyperparathyroidism (pHPT) and 60 parathyroid nodules from 20 uremic patients with secondary hyperparathyroidism (sHPT). The relation of chromosomal aberrations to parathyroid hormone, as well as calcium and phosphate serum concentrations, was assessed. Allelic changes were evaluated by microsatellite allelotyping using 105 polymorphic markers. RESULTS: Somatic chromosomal aberrations were found in 23 out of 25 adenomas, in hyperplastic lesions from 16 out of 20 patients. In pHPT as well as in sHPT a positive correlation was found between the number of chromosomal alterations and serum phosphate concentration (tau=0.270, p=0.05; and tau=0.362, p=0.03, respectively). Only in pHPT was a negative correlation of borderline significance between serum parathormone (PTH) and number of aberrated chromosomes noticed (tau=-0.258, p=0.07). There was no correlation between the number of DNA changes and serum concentration of calcium or tumor volume. CONCLUSION: Hyperphosphatemia may increase the risk of specific and random chromosomal aberrations due to increasing proliferation rate of parathyroid cells in patients with sHPT.     

Short and long-term outcome in diabetic patients with acute myocardial infarction in the invasive era

OBJECTIVES: To investigate the outcome after acute myocardial infarction in diabetic patients compared with non-diabetic patients in a period with invasive treatment as the preferred treatment for acute myocardial infarction (MI). DESIGN: Patient records for all patients admitted with an acute MI in a two-year period from July 1, 2001 to June 30, 2003 were reviewed. RESULTS: A total of 334 patients entered the study: 48 with diabetes mellitus (DM) and 286 without diabetes. ST-elevation infarction occurred in 49% of non-diabetic patients and 36% of diabetic patients. In-hospital mortality was 23% among diabetic patients compared to 5% among non-diabetic patients (p < 0.001). Long-term mortality (median 2 years and 10 months) was 44% in diabetic-patients and 23% in non-diabetic patients (p = 0.001). Diabetic patients were older, more frequently had hypertension and three-vessel disease, but DM was found to be an independent risk factor for death after MI (p = 0.005). CONCLUSIONS: In an era of invasive therapy as the preferred therapy for acute MI, DM is still associated with considerably increased mortality after an acute MI.     

Results of sacral neuromodulation therapy for urinary voiding dysfunction: outcomes of a prospective, worldwide clinical study

PURPOSE: This 5-year, prospective, multicenter trial evaluated the long-term safety and efficacy of sacral neuromodulation in patients with refractory urge incontinence, urgency frequency and retention. MATERIALS AND METHODS: A total of 17 centers worldwide enrolled 163 patients (87% female). Following test stimulation 11 patients declined implantation and 152 underwent implantation using InterStim. Of those treated with implantation 96 (63.2%) had urge incontinence, 25 (16.4%) had urgency frequency and 31 (20.4%) had retention. Voiding diaries were collected annually for 5 years. Clinical success was defined as 50% or greater improvement from baseline in primary voiding diary variable(s). RESULTS: Data for all implanted cases were reported. For patients with urge incontinence mean leaking episodes per day decreased from 9.6 +/- 6.0 to 3.9 +/- 4.0 at 5 years. For patients with urgency frequency mean voids per day decreased from 19.3 +/- 7.0 to 14.8 +/- 7.6, and mean volume voided per void increased from 92.3 +/- 52.8 to 165.2 +/- 147.7 ml. For patients with retention the mean volume per catheterization decreased from 379.9 +/- 183.8 to 109.2 +/- 184.3 ml, and the mean number of catheterizations decreased from 5.3 +/- 2.8 to 1.9 +/- 2.8. All changes were statistically significant (p <0.001). No life threatening or irreversible adverse events occurred. In 102 patients 279 device or therapy related adverse events were observed. At 5 years after implantation 68% of patients with urge incontinence, 56% with urgency frequency and 71% with retention had successful outcomes. CONCLUSIONS: This long-term study demonstrates that InterStim therapy is safe and effective for restoring voiding in appropriately selected cases refractory to other forms of treatment.