Leiomyosarcoma of sacrum: imaging and histopathologic findings

European Radiology - A rare case of low-grade primary leiomyosarcoma of the sacrum is described in a young woman who suffered from pain in the right sacroiliac region. A lytic sacral mass was...     

FAS/FAS ligand ratio: a marker of oxaliplatin-based intrinsic and acquired resistance in advanced colorectal cancer.

PURPOSE: Oxaliplatin-5-fluorouracil combinations have increased responses in first-line therapy up to 40% in advanced colorectal cancer. Unfortunately, those patients who will respond are unknown and initially sensitive patients become rapidly resistant to current therapies. FAS (CD95) and FAS ligand (FASL; CD95L) have been implicated in chemosensitivity through leading to apoptosis in response to DNA-damaging drugs. Whereas the proapoptotic role of FAS and FASL is well characterized, the function of their soluble forms as predictors of chemosensitivity remains unknown. PATIENTS AND METHODS: Blood samples were obtained from 68 patients with advanced colorectal cancer who received oxaliplatin-5-fluorouracil combinations in first-line therapy. Computed tomographic scans were done every 3 months and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. ELISA soluble FAS and soluble FASL analysis were done before treatment and every 3 months until disease progression. Ratios between soluble FAS and soluble FASL were established and its values and variations through time were related to treatment responses. RESULTS: We found a significant increase in soluble FAS levels and a significant decrease in FASL at 3 months compared with baseline (13.2 versus 10.02 ng/mL; P=0.0001; 0.07 versus 0.14 ng/mL; P=0.007, respectively). A significant increase in the soluble FASL levels up to 9 months (fourth to fifth extractions; 0.26 ng/mL) of therapy compared with first to third extractions (0.11 ng/mL; P=0.003) was also found. A random effect regression statistical model determined that >1.2-fold increase in soluble FAS/soluble FASL ratio was a marker of chemosensitivity (P = 0.001). CONCLUSIONS: These data strongly indicate that an increment of soluble FAS/soluble FASL ratio after treatment could be an excellent marker of chemosensitivity in colorectal cancer. On the other hand, a decreased ratio after treatment can be a predictor of chemoresistance despite an initial response.     

Value of Doppler sonography for predicting clinical outcome after renal artery revascularization in atherosclerotic renal artery stenosis.

OBJECTIVE: The purpose of this study was to prospectively evaluate the usefulness of Doppler sonography for predicting blood pressure and renal function improvement after percutaneous renal angioplasty in patients with unilateral atherosclerotic renal artery stenosis. METHODS: Thirty-six patients with successfully revascularized unilateral atherosclerotic renal artery stenosis were included. Patients were evaluated by Doppler sonography before treatment, with the resistive index (RI) and acceleration being measured in both kidneys. Blood pressure, number of antihypertensive drugs, and serum creatinine concentration were assessed before treatment and thereafter during a 23 +/- 15-month (mean +/- SD) period. RESULTS: In 20 of the 36 patients (55%), the RI was less than 0.80 before revascularization. After treatment, blood pressure improved in 17 (85%) of those 20 patients and improved in 8 (50%) of 16 patients with an RI of greater than 0.80 (P < .05). Twenty-five patients had renal insufficiency pretreatment, and 11 (44%) had a baseline RI of less than 0.80. Improvement in renal function after angioplasty was shown in 5 (45%) of these 11 patients and in 4 (28.5%) of 14 in the group with high RI (P > .05, not significant). On analysis of acceleration, blood pressure improved in 9 (69%) of 13 patients with acceleration of greater than 3 m/s(2) and in 16 (69.5%) of 23 with acceleration of less than 3 m/s(2) (P > .05). In patients with renal insufficiency, 5 (50%) of 10 cases with normal baseline acceleration and 4 (27%) of 15 with low acceleration showed improvement in renal function (P > .05). CONCLUSIONS: An elevated RI should not exclude patients from a revascularization procedure because, although renal RI does correlate with blood pressure response to revascularization, it is not a useful parameter in predicting renal function outcome. Acceleration has no prognostic value.     

Characterization of the SPECT 5-HT2A receptor ligand 123I-R91150 in healthy volunteers: part 2--ketanserin displacement.

As part of the radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) characterization study, ketanserin challenges were performed on healthy volunteers with the aim of assessing the specificity of (123)I-R91150 binding to subtype 2A of the 5-hydroxytryptamine receptor (5-HT(2A)), the sensitivity of (123)I-R91150 SPECT in measuring ligand displacement, the relationship between ketanserin plasma concentrations and (123)I-R91150 displacement, and the suitability of the cerebellum as a reference region for quantification. METHODS: Dynamic SPECT was performed on 6 healthy men (mean age +/- SD, 21 +/- 0.89 y) from the time of (123)I-R91150 injection until 470 min afterward. Ketanserin was administered intravenously at 210 min after injection at 3 doses: 0.1 mg/kg (n = 2), 0.05 mg/kg (n = 2), and 0.015 mg/kg (n = 2). Blood samples for measurement of ketanserin plasma concentrations were drawn. MRI was performed on all subjects and coregistered to the SPECT data for region-of-interest drawing on cortical regions and cerebellum. The simplified reference tissue model (SRTM) was considered the gold standard for quantification, and results were compared with those obtained with the tissue ratio method (TR). The percentage (123)I-R91150 displacement was calculated with both methods as the percentage difference between baseline and postketanserin scans. RESULTS: Depending on the cerebral regions with the maximum ketanserin dose studied, SRTM and TR mean displacements were 57.1%-95.4% and 71.9%-101.2%, respectively, for the 0.1 mg/kg dose; 51.7%-91.4% and 56.7%-102.8%, respectively, for the 0.05 mg/kg dose; and 7.7%-54.5% and 13.8%-47.0%, respectively, for the lowest dose, 0.015 mg/kg. A good correlation was found between the 2 methods. No ketanserin-induced displacement was observed in the cerebellum time-activity curves, supporting the use of the cerebellum as a reference region. The relationship between displacement and ketanserin plasma concentration fit with a rectangular hyperbola, with a 5.6 ng/mL concentration associated with 50% of the maximum displacement (EC(50)). EC(50) values calculated using occupancies derived both with SRTM and with TR were in good agreement. CONCLUSION: (123)I-R91150 SPECT is sensitive enough to measure ketanserin dose-dependent displacement in cerebral regions rich in 5-HT(2A) receptors. These results support the selectivity of (123)I-R91150 for 5-HT(2A) receptors and its use as a SPECT ligand for measurements of drug-induced 5-HT(2A) receptor occupancy in humans.     

Reevaluation of ambiguous genetic variants in sudden unexplained deaths of a young cohort

Sudden death cases in the young population remain without a conclusive cause of decease in almost 40% of cases. In these situations, cardiac arrhythmia of genetic origin is suspected as the most plausible cause of death. Molecular autopsy may reveal a genetic defect in up to 20% of families. Most than 80% of rare variants remain classified with an ambiguous role, impeding a useful clinical translation. Our aim was to update rare variants originally classified as of unknown significance to clarify their role. Our cohort included fifty-one post-mortem samples of young cases who died suddenly and without a definite cause of death. Five years ago, molecular autopsy identified at least one rare genetic alteration classified then as ambiguous following the American College of Medical Genetics and Genomics’ recommendations. We have reclassified the same rare variants including novel data. About 10% of ambiguous variants change to benign/likely benign mainly because of improved population frequencies. Excluding cases who died before one year of age, almost 21% of rare ambiguous variants change to benign/likely benign. This fact makes it important to discard these rare variants as a cause of sudden unexplained death, avoiding anxiety in relatives’ carriers. Twenty-five percent of the remaining variants show a tendency to suspicious deleterious role, highlighting clinical follow-up of carriers. Periodical reclassification of rare variants originally classified as ambiguous is crucial, at least updating frequencies every 5 years. This action aids to increase accuracy to enable and conclude a cause of death as well as translation into the clinic. 

     

Epigenetics of Lipid Phenotypes

Dyslipidemia is a well-established risk factor for cardiovascular disease, the main cause of death worldwide. Blood lipid profiles are patterned by both genetic and environmental factors. In recent years, epigenetics has emerged as a paradigm that unifies these influences. In this review, we have summarized the latest evidence implicating epigenetic mechanisms—DNA methylation, histone modification, and regulation by RNAs—in lipid homeostasis. Key findings have emerged in a number of novel epigenetic loci located in biologically plausible genes (eg, CPT1A, ABCG1, SREBF1, and others), as well as microRNA-33a/b. Evidence from animal and cell culture models suggests a complex interplay between different classes of epigenetic processes in the lipid-related genomic regions. Although epigenetic findings hold the potential to explain the interindividual variability in lipid profiles as well as the underlying mechanisms, they have yet to be translated into effective therapies for dyslipidemia.     

Role of the Egami score to predict immunoglobulin resistance in Kawasaki disease among a Western Mediterranean population

Kawasaki disease is an acute self-limited systemic vasculitis common in childhood. Intravenous immunoglobulin (IVIG) is an effective treatment, and it reduces the incidence of cardiac complications. Egami score has been validated to identify IVIG non-responder patients in Japanese population, and it has shown high sensitivity and specificity to identify these non-responder patients. Although its effectiveness in Japan, Egami score has shown to be ineffective in non-Japanese populations. The aim of this study was to apply the Egami score in a Western Mediterranean population in Catalonia (Spain). Observational population-based study that includes patients from all Pediatric Units in 33 Catalan hospitals, both public and private management, between January 2004 and March 2014. Sensitivity and specificity for the Egami score was calculated, and a logistic regression analysis of predictors of overall response to IVIG was also developed. Predicting IVIG resistance with a cutoff for Egami score ≥3 obtained 26 % sensitivity and 82 % specificity. Negative predictive value was 85 % and positive predictive value 22 %. This low sensitivity implies that three out of four non-responders will not be identified by the Egami score. Besides, logistic regression models did not found significance for the use of the Egami score to predict IVIG resistance in Catalan population although having an area under the ROC curve of 0.618 (IC 95 % 0.538–0.698, p < 0.001). Although regression models found an area under the ROC curve >0.5 to predict IVIG resistance, the low sensitivity excludes the Egami score as a useful tool to predict IVIG resistance in Catalan population.     

Intestinal gas and bloating: effect of prokinetic stimulation

BACKGROUND:  It is unknown if abdominal bloating is attributable to excess abdominal gas or improved by a prokinetic agent.
AIMS:  To assess abdominal gas content in functional abdominal bloating and to ascertain the effect of a prokinetic agent on intestinal gas symptoms in these patients.
METHODS:  In 20 patients, intra-abdominal gas content and symptoms were quantified before and during treatment with pyridostigmine (30 mg/8 hp. o) in this randomized, placebo-controlled, double-blind study. Daily symptoms were quantified for 5 days before and 10 days during treatment, and abdominal gas volume was quantified by CT imaging before and at the fourth day of treatment. A CT scan was also obtained in 10 healthy subjects.
RESULTS:  Before treatment, the total volume of intestinal gas was similar in patients (112 ± 18 mL) and in healthy controls (116 ± 20 mL). The treatment-induced change in total and regional intestinal gas volume was not significantly different between pyridostigmine (−4 ± 18 mL; mean ± SEM) and placebo (0 ± 15 mL). However, pyridostigmine reduced the severity of bloating from 3.3 ± 0.3 to 2.6 ± 0.4 ( P < 0.05), whereas placebo did not (3.2 ± 0.3 vs 3.0 ± 0.4), although the change did not reach statistical difference across groups.
CONCLUSION:  In patients complaining of functional bloating, the volume and distribution of intestinal gas, measured on nonselected days, is comparable to asymptomatic subjects. Prokinetic stimulation improves bloating sensation without detectable changes in gas content.