Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors

Southern Brazil has one of the highest incidences of childhood adrenocortical tumors (ACTs), occurring 10-15 times more frequently than worldwide estimates. The reasons for this increase remain elusive. In an attempt to further characterize the genetic changes in childhood ACTs, we recently detected a consistent gain of 9q (or a portion of it) in eight of nine cases of pediatric ACTs and amplification of 9q34 in the majority of these cases using comparative genomic hybridization. Other studies involving both childhood and adult ACTs have corroborated these findings. To follow up on these results, we examined whether the steroidogenic factor 1 (SF-1) gene, which is located in this chromosomal region and plays an important role in the development and function of the adrenal cortex is amplified in these ACT cases. We detected increased copy number of the SF-1 gene in all eight cases with 9q gain, suggesting an association between an increased copy number of the SF-1 gene and adrenocortical tumorigenesis.     

Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lymphoblastic leukemia

There is conflicting information about the influence of body mass index (BMI) on the pharmacokinetics, toxicity, and outcome of chemotherapy. We compared pharmacokinetics, outcome, and toxicity data across 4 BMI groups (underweight, BMI < or = 10th percentile; normal; at risk of overweight, BMI > or = 85th and < 95th percentile; overweight, BMI > or = 95th percentile) in 621 children with acute lymphoblastic leukemia (ALL) treated on 4 consecutive St Jude Total Therapy studies. Chemotherapy doses were not adjusted to ideal BMI. Estimates of overall survival (86.1% +/- 3.4%, 86.0% +/- 1.7%, 85.9% +/- 4.3%, and 78.2% +/- 5.5%, respectively; P = .533), event-free survival (76.2% +/- 4.2%, 78.7% +/- 2.1%, 73.4% +/- 5.5%, and 72.7% +/- 5.9%, respectively; P = .722), and cumulative incidence of relapse (16.0% +/- 3.7%, 14.4% +/- 1.8%, 20.6% +/- 5.1%, and 16.7% +/- 5.1%, respectively; P = .862) did not differ across the 4 groups. In addition, the intracellular levels of thioguanine nucleotides and methotrexate polyglutamates did not differ between the 4 BMI groups (P = .73 and P = .74, respectively). The 4 groups also did not differ in the overall incidence of grade 3 or 4 toxicity during the induction or postinduction periods. Further, the systemic clearance of methotrexate, teniposide, etoposide, and cytarabine did not differ with BMI (P > .3). We conclude that BMI does not affect the outcome or toxicity of chemotherapy in this patient population with ALL.     

Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital

St Jude Total Therapy Study XIIIB for childhood acute lymphoblastic leukemia (ALL) incorporated more stringent risk classification, early intensification of intrathecal chemotherapy, reinduction treatment, and the addition of dexamethasone to postremission therapy to increase the proportion of event-free survivors without jeopardizing their quality of life. Cranial irradiation was reserved for the 12% of patients who had T-cell ALL and a presenting leukocyte count of 100 x 10(9)/L or more, or CNS-3 (5 or more leukocytes/microL with identifiable blast cells in an atraumatic sample or the presence of cranial nerve palsy) status. Among the 247 consecutive patients enrolled in the study, 117 were classified as having lower-risk leukemia and received mainly antimetabolite-based continuation therapy; the 130 cases with higher-risk leukemia received more intensive continuation chemotherapy with multiple drug pairs administered in weekly rotation. The 5-year event-free survival estimate was 80.8% +/- 2.6% (SE); the 8-year rate was 78.6% +/- 5.8%. The 5-year cumulative risk of an isolated central nervous system (CNS) relapse was 1.7% +/- 0.8%, and that of isolated plus combined CNS relapse was 3.0% +/- 1.1%. The 5-year cumulative risks of etoposide-related myeloid malignancies were 1.8% +/- 1.3% in the lower-risk patients who received a cumulative dose of 1.2 g/m(2) and 5.0% +/- 2.0% in the higher-risk patients who received a cumulative dose of up to 14.4 g/m(2) (P = .18). Independent adverse prognostic features included the presence of MLL-AF4 or BCR-ABL fusion gene and minimal residual leukemia of 0.01% or more at the end of the 6-week remission induction phase. Our results suggest the efficacy of early intensification of intrathecal chemotherapy and provide the basis for studies omitting cranial irradiation altogether.     

The prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: results of the international study Relapsed AML 2001/01

The prognostic significance of early response to treatment has not been reported in relapsed pediatric acute myeloid leukemia. In order to identify an early and easily applicable prognostic factor allowing subsequent treatment modifications, we assessed leukemic blast counts in the bone marrow by morphology on days 15 and 28 after first reinduction in 338 patients of the international Relapsed-AML2001/01 trial. Both day 15 and day 28 status was classified as good (≤20% leukemic blasts) in 77% of patients. The correlation between day 15 and 28 blast percentages was significant, but not strong (Spearman correlation coefficient = 0.49, P<0.001). Survival probability decreased in a stepwise fashion along with rising blast counts at day 28. Patients with bone marrow blast counts at this time-point of ≤5%, 6–10%, 11–20% and >20% had 4-year probabilities of survival of 52%±3% versus 36%±10% versus 21%±9% versus 14%±4%, respectively, P<0.0001; this trend was not seen for day 15 results. Multivariate analysis showed that early treatment response at day 28 had the strongest prognostic significance, superseding even time to relapse (< or ≥12 months). In conclusion, an early response to treatment, measured on day 28, is a strong and independent prognostic factor potentially useful for treatment stratification in pediatric relapsed acute myeloid leukemia. This study was registered with ISRCTN code: 94206677.     

Hyperuricemia,Hypertension, and Chronic Kidney Disease: an Emerging Association

Uric acid is a product of purine metabolism and has been linked to gout and kidney calculi. Chronic kidney disease (CKD) and hypertension (HTN) are two major public health problems, and both are associated with increased risk of cardiovascular events. Emerging evidence suggests a pathogenic role of hyperuricemia in the development of HTN and CKD, in addition to progression of CKD, by inducing renal inflammation, endothelial dysfunction, and activation of the renin-angiotensin system. In addition, several epidemiological studies have linked hyperuricemia with an increased risk of HTN and CKD. A few clinical trials have assessed the use of uric acid-lowering therapies such as allopurinol and febuxostat in the management of HTN and delaying progression of CKD. To date, most of these trials are short-term with a small sample size; however, their results are encouraging and provide a rationale for larger randomized controlled trials to establish the role of uric acid-lowering therapies in the management of HTN, in addition to prevention of CKD progression and cardiovascular events.     

The impact of metabolic syndrome and prevalent liver disease on living donor liver transplantation: a pressing need to expand the pool

Background and aims

Organ shortage has been the ongoing obstacle to expanding liver transplantation worldwide. Living donor liver transplantation (LDLT) is hoped to improve this shortage. The aim of the present study is to analyze the impact of metabolic syndrome and prevalent liver disease on living donations.

Methods

From July 2007 to May 2012, 1065 potential living donors were evaluated according to a stepwise evaluation protocol. The age of the worked-up donors ranged from 18 to 45 years.

Results

Only 190 (18 %) were accepted for donation, and 875 (82 %) were rejected. In total, 265 (24.9 %) potential donors were excluded because of either diabetes or a body mass index >28. Some potential donors were excluded at initial screening because of incompatible blood groups (115; 10.8 %), social reasons (40; 3.8 %), or elevated liver enzymes (9; 1 %). Eighty-five (8 %) donors were excluded because of positive hepatitis serology. Steatosis resulted in the exclusion of 84 (8 %) donors. In addition, 80 (7.5 %) potential donors were rejected because of variations in biliary anatomy, and 20 (2 %) were rejected because of aberrant vascular anatomy. Rejection due to biliary-related aberrancy decreased significantly in the second half of our program (11 vs. 4 %, p = 0.001). In total, 110 (10.3 %) potential donors were rejected because of insufficient remnant volume (<30 %) as determined by CT volumetry, whereas 24 (2.2 %) were rejected because of a graft-to-recipient body weight ratio less than 0.8 %.

Conclusion

Metabolic syndrome and viral hepatitis negatively impacted our living donor pool. Expanding the donor pool requires the implementation of new strategies.

     

Right ventricular function before and after an uncomplicated coronary artery bypass graft as assessed by pulsed wave Doppler tissue imaging of the tricuspid annulus

Background

Right ventricular (RV) function using myocardial velocities before and after a coronary artery bypass graft (CABG) is not known.

Methods

Using pulsed wave Doppler tissue imaging, RV function was studied in 35 patients before and after CABG. Patients were followed-up for 1 year after the CABG. Myocardial velocities at the tricuspid annulus at the RV free wall were recorded from the apical 4-chamber views.

Results

Both the systolic and early diastolic tricuspid annular velocities (TAV) were significantly reduced 1 month after CABG (P < .001 for both). During the follow-up period, there was no improvement in the diastolic TAV. The systolic TAV showed no improvement 3 months after CABG but recovered partially 1 year after the CABG (systolic velocities were 11.8, 8.7, 8.7 and 9.7 cm/s, the early diastolic velocities were 11.0, 8.1, 8.1 and 8.2 cm/s before and 1 month, 3 months and 1 year after the CABG, respectively). The systolic and early diastolic velocities of the interventricular septum were unchanged during the follow-up period. Unlike the right ventricle, the mitral annular systolic velocity was unchanged shortly after CABG and showed signs of improvement after 1 year (6.4, 6.9, 6.8 and 7.3 cm/s respectively before and after CABG). Patients underwent dobutamine stress echocardiography (DSE) before and 3 months after the CABG. The systolic TAV increased significantly during the DSE before CABG (11.8 vs 15.8 cm/s, P < .001). However, the increase in systolic TAV was limited during DSE 3 months after CABG (8.7 vs 9.9 cm/s, P < .05).

Conclusion

RV function, as assessed by TAV, decreased significantly after CABG and the changes were still evident after 1 year. The response of systolic TAV during DSE was more pronounced before CABG than after CABG.     

The effect of bariatric surgery on inflammatory markers in women with polycystic ovarian syndrome

Aim

The aims of this study is to address the improvement in CRP and adiponectin in obese PCOS and non PCOS after bariatric surgery, and to show that obese PCOS women have a slower rate of improvement when compared to obese non PCOS women.

Assessment of the effect of interval from presentation to surgery on outcome in patients with peri-ampullary malignancy

BackgroundDelay between diagnosis of peri-ampullary cancer (PC) and surgery may allow tumour progression and affect outcome. The aim of this study was to explore associations of interval to surgery (IS) with pathological outcomes and survival in patients with PC.MethodA database review of all patients undergoing surgery between 2006 and 2014 was undertaken. IS was measured from diagnosis by imaging. Potential association between IS and survival was measured using Cox regression analysis, and between IS and pathological outcome with multivariate logistic analysis.Results388 patients underwent surgery. The median IS was 49 days (1–551 days), and was not associated with any of the evaluated outcomes in patients with pancreatic (149) or distal bile duct (46) cancer. For patients with ampullary cancer (71) longer IS was associated with improved survival, with median survival of 27.5 months for patients waiting ≤ median IS (35) and 38.3 months for patients waiting > median IS (36) for surgery (p = 0.041). A higher rate of margin positivity (31.4%) was also noted among patients who waited less than the median IS compared to those waiting longer than this interval (11.4%) (p = 0.032).ConclusionFor patients with ampullary cancer there is a paradoxical improvement in outcome among those with a longer IS, which may be explained by progression to inoperability of more aggressive lesions.