Isolated cardiac metastasis in a patient with neuroendocrine carcinoma of pancreas discovered on 68Ga-DOTANOC PET/CT

We present an interesting image that demonstrates utility of ⁶⁸Ga-DOTANOC PET/CT for demonstrating rare metastatic sites of neuroendocrime tumor.     

Different administration schedules of darbepoetin alfa affect oxidized and reduced glutathione levels to a similar extent in 5/6 nephrectomized rats

Background

The development of erythropoiesis-stimulating agents (ESAs) with extended serum half-lives has allowed marked prolongation of the administration intervals. The level of oxidative stress is increased in chronic kidney disease, and is reportedly decreased after long-term ESA treatment. However, the effect of different dosing regimens of ESAs on oxidative stress has not been elucidated.

Methods

Five-sixths nephrectomized (NX) rats received either 0.4 μg/kg darbepoetin alfa (DA) weekly or 0.8 μg/kg DA fortnightly between weeks 4 and 10. NX animals receiving saline and a sham-operated (SHAM) group served as controls. The levels of oxidized and reduced glutathione (GSSG, GSH) were followed from blood samples drawn fortnightly.

Results

During the follow-up, the ratios GSSG/GSH showed similar trends in both DA groups, levels being significantly lower than those in the SHAM group at weeks 8 and 10. GSSG levels were lower than the baseline throughout the study in all groups except for NX controls. The GSH levels were increased in all three NX groups (weeks 6–10) compared with both the baseline and the SHAM group

Conclusion

Our results suggest that the extent of oxidative stress is similar in response to different dosing regimens of DA in 5/6 NX rats when comparable hemoglobin levels are maintained. These findings remain to be confirmed in chronic kidney disease patients.     

Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators

Vitamin D receptor (VDR) ligands are therapeutic agents for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. VDR ligands also show immense potential as therapeutic agents for autoimmune diseases and cancers of skin, prostate, colon, and breast as well as leukemia. However, the major side effect of VDR ligands that limits their expanded use and clinical development is hypercalcemia that develops as a result of the action of these compounds mainly on intestine. In order to discover VDR ligands with less hypercalcemia liability, we sought to identify tissue-selective VDR modulators (VDRMs) that act as agonists in some cell types and lack activity in others. Here, we describe LY2108491 and LY2109866 as nonsecosteroidal VDRMs that function as potent agonists in keratinocytes, osteoblasts, and peripheral blood mononuclear cells but show poor activity in intestinal cells. Finally, these nonsecosteroidal VDRMs were less calcemic in vivo, and LY2108491 exhibited more than 270-fold improved therapeutic index over the naturally occurring VDR ligand 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in an in vivo preclinical surrogate model of psoriasis.     

Body Composition Analysis of Patients on Waiting List for Cadaveric Renal Transplantation: A Comparison of Hemodialysis and Peritoneal Dialysis Patients

BackgroundBioelectrical impedance analysis is a simple, noninvasive method of assessing body composition. Dialysis modality and selection of buffer type may have an impact on body composition. The aim of our study was to compare body compositions of patients from the waiting list for cadaveric renal transplantation according to the dialysis modality.MethodsWe examined a total of 152 (110 hemodialysis [HD] and 42 continuous ambulatory peritoneal dialysis [CAPD]) patients. Demographic data were collected from patient charts. The last 6 months routine laboratory evaluations including hemoglobin, serum creatinine, intact parathyroid hormone, albumin, C reactive protein, calcium, phosphorus were collected. Body compositions were measured using the Tanita BC-420MA Body Composition Analyzer (Tanita, Tokyo, Japan). We made a subanalysis of the CAPD group according to buffer choices as follows: lactate-buffered (n = 16) and bicarbonate/lactate–buffered (n = 26) solution users.ResultsThe body weight (P = .022), body mass index (BMI; 25.8 ± 4.7 vs 23.4 ± 4.9 kg/m², P = .009), muscle mass (P = .01), fat-free mass (P = .013), and visceral fat ratio (9.5 ± 5.4 vs 7.3 ± 4.1 %, P = .022) were significantly higher in the CAPD group. Total body water of CAPD patients were also higher (P = .003), but total body water ratios of HD and CAPD groups were similar. Fat and fat-free mass ratios of patient groups were also similar. Comparing CAPD subgroups we observed that patients using bicarbonate/lactate–buffered solutions had higher body weights (P = .038), BMI (27.1 ± 5 vs 23.7 ± 3.5 kg/m², P = .018) values, and visceral fat ratios (8.0 ± 5.2 vs 4.6 ± 2.5 %, P = .023). These patients also tend to have higher fat mass without statistical significance (P = .074). Fat, muscle, and fat-free mass total body water ratios of peritoneal dialysis subgroups were similar.ConclusionWe believe that body composition analysis should be used as a complementary method for assessing nutritional status of PD and CAPD patients as body weight or BMI measurements do not reflect fat, muscle masses, and visceral fat ratios in these patients. Stable, well nourished CAPD patients should be closely observed and be encouraged to increase daily exercise and/or decrease calorie intake from other sources to decrease risks associated with abdominal obesity.     

Dialysis Patients With the Metabolic Syndrome Need Less Recombinant Human Erythropoietin for Similar Hemoglobin Levels

IntroductionThe metabolic syndrome (MS) components, such as dyslipidemia, prothrombotic status, and increased blood pressure, are risk factors for patients with renal disease. Visceral fat mass is closely related to the MS and atherosclerosis. We investigated the effects of body compositions and MS on anemia parameters and recombinant human erythropoietin (rHuEPO) requirements in maintenance hemodialysis patients.MethodsBody composition (body mass index and bioimpedance analysis) and laboratory data were obtained from 110 dialysis patients. The MS was identified according to ATP-III criteria. Anemia parameters, hemoglobin (Hgb), albumin, C-reactive protein (CRP), calcium, phosphorus, parathormone levels, and rHuEPO requirements over the last 6 months were retrospectively analyzed.ResultsPatients with the MS seem to reach target Hgb levels more frequently (10–12 g/dL; 66.3% vs 84.8%; P = .03) without any difference in total intravenous iron therapy dosage. MS patients also required lower rHuEPO for reaching similar Hgb levels compared with patients without MS (2679.3 ± 1936.1 vs 3702.5 ± 2213.0 U/kg/6 mo; P = .02). There were no differences in serum CRP, albumin, or Hgb levels between the 2 groups (P > .05). We observed that patients with MS had significantly higher fat mass and visceral fat ratio, but similar muscle mass values compared with no-MS counterparts (P = .0001 and .001, respectively). However, when we compared the ratios of these parameters we observed a significant reduction in muscle ratios and a significant increase in fat ratios of MS patients (P = .0001).ConclusionOur results indicate that MS might be an advantage for reaching higher Hgb levels with lower rHuEPO dosages. The possible reason for this might be the good nutritional state and increased fat mass of patients with MS.     

HMR1402, a potassium ATP channel blocker during hyperdynamic porcine endotoxemia: effects on hepato-splanchnic oxygen exchange and metabolism

Objective To assess the effects of the potassium ATP (KATP) channel blocker HMR1402 (HMR) on systemic and hepato-splanchnic hemodynamics, oxygen exchange and metabolism during hyperdynamic porcine endotoxemia.Design Prospective, randomized, controlled study with repeated measures.Setting Animal laboratory.Subjects Eighteen pigs allocated to receive endotoxin alone (control group, CON, n=10) or endotoxin and HMR (6 mg/kg h^–1, n=8).Interventions Anesthetized, mechanically ventilated, and instrumented pigs receiving continuous i.v. endotoxin were resuscitated with hetastarch to maintain mean arterial pressure (MAP) >60 mmHg. Twelve hours after starting the endotoxin infusion, they received HMR or its vehicle for another 12 h.Results HMR transiently increased MAP by about 15 mmHg, but this effect was only present during the first 1 h of infusion. The HMR decreased cardiac output due to a fall in heart rate, and thereby reduced liver blood flow. While liver O₂ delivery and uptake remained unchanged, HMR induced hyperlactatemia [from 1.5 (1.1; 2.0), 1.4 (1.2; 1.8), and 1.2 (0.8; 2.0) to 3.1 (1.4; 3.2), 3.2 (1.6; 6.5), and 3.0 (1.0; 5.5) mmol/l in the arterial, portal and hepatic venous samples, respectively] and further increased arterial [from 8 (3; 13) to 23 (11; 57); p<0.05], portal [from 9 (4; 14) to 23 (14; 39); p<0.05] and hepatic vein [from 7 (0; 15) to 30 (8; 174), p<0.05] lactate/pyruvate ratios indicating impaired cytosolic redox state.Conclusion The short-term beneficial hemodynamic effects of KATP channel blockers have to be weighted with the detrimental effect on mitochondrial respiration.P. Asfar and Z. Iványi equally contributed to this work     

Prognostic significance of thymidylate synthase polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy

Aim There is a lack of prognostic factors of preoperative chemoradiation for locally advanced rectal cancer. Thymidylate synthase (TS) is the most important target of 5‐fluorouracil; three main genetic polymorphisms of TS have been described. We analysed the prognostic value of these in patients with locally advanced rectal cancer treated with fluoropyrimidine‐based chemoradiation. Method Ninety‐nine patients treated between November 2001 and March 2009 were included. All were treated by radiotherapy (5040 cGy) and concomitant fluoropyrimidine‐based chemotherapy. Three polymorphisms were analysed: (i) a double (2R) or triple (3R) repeat of a 28 base pair (bp) tandem sequence upstream of the ATG codon initiation site in the 5′‐terminal regulatory region, (ii) a functional G > C single nucleotide polymorphism present in the second repeat of the 3R alleles and (iii) a 6 bp deletion at nucleotide 1494 in the 3′‐untranslated region. DNA was extracted from paraffin‐embedded core biopsies taken from the tumour and the genotype was analysed using polymerase chain reaction restriction fragment length polymorphism. Results The 6 bp polymorphism was significantly associated with disease‐free survival (+ 6 bp/+ 6 bp vs?6 bp/?6 bp, P = 0.032 logistic regression). No differences were found in disease‐free survival according to the other polymorphisms studied. No relationship was observed between the different TS genotypes and pathological regression. Conclusion The study suggests that the TS 6 bp polymorphism may be a predictor of disease‐free survival in patients with locally advanced rectal cancer treated with fluoropyrimidine‐based chemoradiation.