Osteonecrosis is a severe glucocorticoid-induced complication of acute lymphoblastic leukemia treatment. We prospectively screened children (n = 364) with magnetic resonance imaging of hips and ...knees, regardless of symptoms; the cumulative incidence of any (grade 1-4) versus symptomatic (grade 2-4) osteonecrosis was 71.8% versus 17.6%, respectively. We investigated whether age, race, sex, acute lymphoblastic leukemia treatment arm, body mass, serum lipids, albumin and cortisol levels, dexamethasone pharmacokinetics, and genome-wide germline genetic polymorphisms were associated with symptomatic osteonecrosis. Age more than 10 years (odds ratio, = 4.85; 95% confidence interval, 2.5-9.2; P = .00001) and more intensive treatment (odds ratio = 2.5; 95% confidence interval, 1.2-4.9; P = .011) were risk factors and included as covariates in all analyses. Lower albumin (P = .05) and elevated cholesterol (P = .02) associated with symptomatic osteonecrosis, and severe (grade 3 or 4) osteonecrosis was linked to poor dexamethasone clearance (P = .0005). Adjusting for clinical features, polymorphisms of ACP1 (eg, rs12714403, P = 1.9 × 10−6, odds ratio = 5.6; 95% confidence interval, 2.7-11.3), which regulates lipid levels and osteoblast differentiation, were associated with risk of osteonecrosis as well as with lower albumin and higher cholesterol. Overall, older age, lower albumin, higher lipid levels, and dexamethasone exposure were associated with osteonecrosis and may be linked by inherited genomic variation.
Recent clinical trials in children with acute lymphoblastic leukemia (ALL) indicate that severe hypertriglyceridemia (> 1000 mg/dL) during therapy is associated with increased frequency of ...symptomatic osteonecrosis. Interventions to lower triglycerides have been considered, but there have been no pre-clinical studies investigating impact of lowering triglycerides on osteonecrosis risk, nor whether such interventions interfere with the antileukemic efficacy of ALL treatment. We utilized our clinically relevant mouse model of dexamethasone-induced osteonecrosis to determine if fenofibrate decreased osteonecrosis. To test whether fenofibrate affected the antileukemic efficacy of dexamethasone, we utilized a BCR-ABL+ model of ALL. Serum triglycerides were reduced with fenofibrate throughout treatment, with the most pronounced 4.5-fold decrease at week 3 (p<1x10-6). Both frequency (33% versus 74%, p=0.006) and severity (median necrosis score of 0 versus 75; p=6x10-5) of osteonecrosis were reduced with fenofibrate. Fenofibrate had no impact on BCR-ABL+ ALL survival (p=0.65) nor on the antileukemic properties of dexamethasone (p=0.49). These data suggest that lowering triglycerides with fenofibrate reduces dexamethasone-induced osteonecrosis while maintaining antileukemic efficacy, and thus may be considered for clinical trials.
Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we ...utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. Mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone after 6 weeks of treatment (44% vs. 10%, P = 0.006). Similarly, epiphyseal arteriopathy, which we have shown to be an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007). As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001). This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027) and asparaginase (P = 0.036). We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids.
•PSPC ameliorates obesity, glucose intolerance and insulin resistance induced by HFD.•PSPC reduces urine albumin and kidney tissue damage in HFD-treated mice.•PSPC attenuates oxidative stress in the ...kidney of HFD-treated mice.•PSPC inhibits the activation of kidney IKKβ/NF-κB signaling in HFD-treated mice.•PSPC reduces the activation of NLRP3 inflammasome in HFD-treated mice.•PSPC decreases the protein expression of kidney RAGE and TXNIP in HFD-treated mice.
Inflammation plays a crucial role in the pathogenesis of obesity. Purple sweet potato color (PSPC) has potential anti-inflammation efficacy. We evaluated the effect of PSPC on kidney injury induced by high fat diet (HFD) and explored the mechanism underlying these effects. The results showed that PSPC (700mg/kg per day) reduced body weight, ratio of urine albumin to creatinine, inflammatory cell infiltration, and Collagen IV accumulation in mice fed an HFD (60% fat food) for 20weeks. PSPC significantly reduced the expression level of kidney NLRP3 inflammasome including NLRP3 and ASC and Caspase-1, and resulted in decline of IL-1β. Moreover, PSPC inhibited the activation of I kappa B kinase β (IKKβ) and the nuclear translocation of nuclear factor kappa beta (NF-κB). Additionally, PSPC decreased the expression level of oxidative stress-associated AGE receptor (RAGE) and thioredoxin interacting protein (TXNIP) in the upstream of NLRP3 inflammasome. These data imply that the beneficial effects of PSPC on HFD-induced kidney dysfunction and damage are mediated through NLRP3 signaling pathways, suggesting a potential target for the prevention of obesity.
The underlying pathways that lead to relapse in childhood acute lymphoblastic leukemia (ALL) are unknown. To comprehensively characterize the molecular evolution of relapsed childhood B-precursor ...ALL, we used human 500K single-nucleotide polymorphism arrays to identify somatic copy number alterations (CNAs) in 20 diagnosis/relapse pairs relative to germ line. We identified 758 CNAs, 66.4% of which were less than 1 Mb, and deletions outnumbered amplifications by approximately 2.5:1. Although CNAs persisting from diagnosis to relapse were observed in all 20 cases, 17 patients exhibited differential CNA patterns from diagnosis to relapse. Of the 396 CNAs observed in 20 relapse samples, only 69 (17.4%) were novel (absent in the matched diagnosis samples). EBF1 and IKZF1 deletions were particularly frequent in this relapsed ALL cohort (25.0% and 35.0%, respectively), suggesting their role in disease recurrence. In addition, we noted concordance in global gene expression and DNA copy number changes (P = 2.2 × 10−16). Finally, relapse-specific focal deletion of MSH6 and, consequently, reduced gene expression were found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse.
Dexamethasone is used widely in oncology, but pharmacokinetic studies are lacking. We evaluated dexamethasone pharmacokinetics in children with acute lymphoblastic leukemia.
We assessed 214 children ...with acute lymphoblastic leukemia who received 418 courses of oral dexamethasone (8 mg/m(2)/d) on days 1 and 8 of reinduction. Extensive asparaginase use preceded reinduction in the 101 children in the standard/high-risk treatment arm but not in the 113 children in the low-risk treatment arm. A one-compartment model with first-order absorption and disposition was fit to dexamethasone plasma concentrations by using maximum a posteriori probability estimation; we evaluated covariates by using linear mixed models.
Interpatient and intrapatient variabilities in apparent clearance were substantial; they were 46% and 53%, respectively. Variability was explained by the serum albumin concentration (P < .0001), concomitant use of fentanyl (P = .008) and ketoconazole (P = .03), and age (P = .006). Apparent clearance was higher in the low-risk arm (P < .001) and was related to a greater serum albumin concentration (P < .001) and to a lower exposure to asparaginase than in the standard/high-risk arm. Hypoalbuminemia, a biomarker of asparaginase activity, was associated with a lower dexamethasone apparent clearance (P = .04) in patients in the standard/high-risk arm that was more pronounced in those not allergic to asparaginase. Ethnicity or gender did not explain apparent clearance variability.
Dexamethasone pharmacokinetics are highly variable and are related to the concurrent use of particular drugs, age, and treatment intensity. Patients allergic to asparaginase may be doubly disadvantaged: they not only suffer from diminished exposure to asparaginase but also, by maintaining high clearance of dexamethasone, may experience fewer antileukemic effects of dexamethasone.
Combination therapy for acute lymphoblastic leukemia (ALL) is highly effective but results in significant toxicity including osteonecrosis. Asparaginase is known to potentiate both the antileukemic ...and osteonecrosis-inducing effects of dexamethasone. The schedule of dexamethasone alters osteonecrosis risk. However, the effects of the interaction with asparaginase are unknown when dexamethasone is given on a discontinuous schedule.
Using the murine model of osteonecrosis, we compared the frequency of osteonecrosis in mice receiving discontinuous dexamethasone (3.5 days/ week) with mice receiving asparaginase and discontinuous dexamethasone. We then tested the effect on antileukemic efficacy using six pediatric ALL xenografts.
The addition of asparaginase to discontinuous dexamethasone did not alter the rate of osteonecrosis compared to dexamethasone alone (7/35 in dexamethasone with asparaginase combination vs. 10/36 in dexamethasone alone, p = 0.62) despite increasing steady-state plasma dexamethasone levels (103.9 nM vs. 33.4 nM, p = 9.2x10-7). Combination therapy with asparaginase and dexamethasone demonstrated synergistic antileukemic effects across all six xenografts studied.
When discontinuous dexamethasone was given, its anti-leukemic activity synergized with asparaginase but the osteonecrosis-worsening effects of asparaginase (above dexamethasone alone) were not observed. Thus, there is a favorable drug interaction (unchanged toxicity, synergistic efficacy) between discontinuous dexamethasone and asparaginase.
Purpose:
Many patients develop a parastomal hernia within the first 2 years of stoma formation, and even surgical repair is associated with high recurrence rates. An intraperitoneal approach is ...typically used for the laparoscopic repair of parastomal hernia; it is unknown whether a totally extraperitoneal technique (TEP) is feasible. Here we describe a laparoscopic TEP approach using a modified Sugarbaker method for the repair of parastomal hernia.
Methods:
Seven patients underwent parastomal hernia repair. The retrograde puncture technique was used to create the extrapneumoperitoneum, and the peritoneum was separated with a laparoscopic TEP approach; the mesh was placed using a modified Sugarbaker technique.
Results:
All patients had an oncologic etiology for stoma creation. The mean (±SD) size of the hernia defect was 3.1 ± 2.7 cm and the mesh size was 303.4 ± 96.8 cm
2
. The mean operative time was 195.5 ± 20.7 min and average length of hospital stay after surgery was 4.8 ± 2.1 days. One patient had intraoperative subcutaneous emphysema. The average follow-up time was 8.5 ± 2.7 months; mild pain occurred in 2 patients, 3 experienced seroma formation (with no special treatment required), and 1 had early intestinal obstruction (which was treated with conservative care). There was no hernia recurrence, wound complications, or infections of the surgical site or mesh during follow-up.
Conclusion:
A laparoscopic TEP technique is technically challenging but feasible. Modified laparoscopic Sugarbaker repair of a parastomal hernia with the TEP technique is safe and effective, although the recurrence rate and late complications require confirmation in more cases with long-term follow-up.
A parastomal hernia is a type of incisional hernia that occurs in abdominal integuments in the proximity of a stoma. It is a frequent late complication following colostomy. Surgical repair is ...currently the only treatment option for parastomal hernia. Here we present the case of a 74-year-old patient with parastomal hernia and a history of open surgery treated with a totally extraperitoneal (TEP) endoscopic approach. There was no recurrence of the hernia at the 3-month follow-up. We discuss the feasibility and possible operative approaches for endoscopic repair of parastomal hernia with the TEP technique.
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