Multicenter investigation of the reliability and validity of the live donor assessment tool as an enhancement to the psychosocial evaluation of living donors

The live donor assessment tool (LDAT) is the first psychosocial assessment tool developed to standardize live donor psychosocial evaluations. A multicenter study was conducted to explore reliability and validity of the LDAT and determine its ability to enhance the psychosocial evaluation beyond its center of origin. Four transplant programs participated, each with their own team of evaluators and unique demographics. Liver and kidney living donors (LDs) undergoing both standard psychosocial evaluation and LDAT from June 2015 to September 2016 were studied. LDAT interrater reliability, associations between LDAT scores and psychosocial evaluation outcome, and psychosocial outcomes postdonation were tested. 386 LD evaluations were compared and had a mean LDAT score of 67.34 ± 7.57. In 140 LDs with two LDATs by different observers, the interrater scores correlated (r = 0.63). LDAT scores at each center and overall stratified to the conventional grouping of psychosocial risk level. LDAT scores of 131 subjects who proceeded with donation were expectedly lower in LDs requiring postdonation counseling (t = ?2.78, P = .01). The LDAT had good reliability between raters and predicted outcome of the psychosocial evaluation across centers. It can be used to standardize language among clinicians to communicate psychosocial risk of LD candidates and assist teams when anticipating postdonation psychosocial needs.     

Gefitinib plus cisplatin and radiotherapy in previously untreated head and neck squamous cell carcinoma: A phase II, randomized, double-blind, placebo-controlled study

Background and purpose

To assess the efficacy and safety of gefitinib given concomitantly and/or as maintenance therapy to standard cisplatin/radiotherapy for previously untreated, unresected, stage III/IV non-metastatic SCCHN.

Materials and methods

In this phase II, double-blind, study, 226 patients were randomized to gefitinib 250 mg/day, 500 mg/day or placebo in two phases: a concomitant phase (gefitinib or placebo with chemoradiotherapy), followed by a maintenance phase (gefitinib or placebo alone). Primary endpoint was local disease control rate (LDCR) at 2 years; secondary endpoints were LDCR at 1 year, objective response rate, progression-free survival, overall survival, and safety and tolerability.

Results

Gefitinib (250 and 500 mg/day) did not improve 2-year LDCR compared with placebo either when given concomitantly with chemoradiotherapy (32.7% vs. 33.6%, respectively; OR 0.921, 95% CI 0.508, 1.670 [1-sided p = 0.607]) or as maintenance therapy (28.8% vs. 37.4%, respectively; OR 0.684, 95% CI 0.377, 1.241 [1-sided p = 0.894]). Secondary efficacy outcomes were broadly consistent with the 2-year LDCR results. In both doses, gefitinib was well-tolerated and did not adversely affect the safety and tolerability of concomitant chemoradiotherapy.

Conclusion

Gefitinib was well-tolerated, but did not improve efficacy compared with placebo when given concomitantly with chemoradiotherapy, or as maintenance therapy alone.     

Preladenant, a selective A2A receptor antagonist, is active in primate models of movement disorders

Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D₂ receptors by antipsychotics, respectively. Adenosine A_2A receptors are selectively localized in the basal ganglia, primarily in the striatopallidal (“indirect”) pathway, where they appear to operate in concert with D₂ receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A_2A receptor activation contributes to the overdrive of the indirect pathway. A_2A receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A_2A receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A_2A receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A_2A receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3–3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders.     

Laser Treatment of Benign Prostatic Hyperplasia in Patients on Oral Anticoagulant Therapy

Because the number of patients requiring oral anticoagulation (OA) is steadily growing, more and more patients requiring surgical treatment of benign prostatic hyperplasia (BPH) are on OA. Laser treatment of BPH was said to offer a higher quality of hemostasis than transurethral resection of the prostate (TURP). Thus, laser was considered an interesting tool for BPH surgery in patients on OA therapy. To date, no randomized studies focusing on laser treatment in patients on OA are available. Compared to TURP, laser seems to decrease the risk of hemorrhage in patients on OA. Therefore, the laser could be considered a useful tool for managing patients on OA, and could be proposed as a first-line therapy for those patients requiring surgery. Continuing platelet aggregation inhibitors during the procedure is feasible. A switch to low molecular weight heparine medication prior to surgery is preferable to the continued use of OA during TURP. No conclusion can be reached regarding the preferred laser technique to treat these patients.     

Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury

Although axonal regeneration after CNS injury is limited, partial injury is frequently accompanied by extensive functional recovery. To investigate mechanisms underlying spontaneous recovery after incomplete spinal cord injury, we administered C7 spinal cord hemisections to adult rhesus monkeys and analyzed behavioral, electrophysiological and anatomical adaptations. We found marked spontaneous plasticity of corticospinal projections, with reconstitution of fully 60% of pre-lesion axon density arising from sprouting of spinal cord midline-crossing axons. This extensive anatomical recovery was associated with improvement in coordinated muscle recruitment, hand function and locomotion. These findings identify what may be the most extensive natural recovery of mammalian axonal projections after nervous system injury observed to date, highlighting an important role for primate models in translational disease research.     

A novel genome-based approach correlates TMPRSS3 overexpression in ovarian cancer with DNA hypomethylation

Objective

In an attempt to analyze more profoundly aberrant DNA hypomethylation in epithelial ovarian cancer (EOC), we applied a novel genome-based approach which includes expression profiling following pharmacologic stimulation of DNA methylation with the methyl donor S-adenosyl-l-methionine (SAM).

Methods

Four different EOC cell lines (OVCAR3, SKOV3, TOV21 and TOV112) were treated with SAM, and gene expression profiling was performed in SAM-treated and control EOC cells. Genes, downregulated upon SAM treatment were considered as potentially hypomethylated in EOC. DNA hypomethylation was independently validated in ovarian tumor and control tissues by bisulfite sequencing PCR (BSP).

Results

Among the genes identified, one of particular interest was the type II serine protease TMPRSS3 gene variants A and D (TMPRSS3-A/D), previously recognized as overexpressed in EOC and representing potential EOC therapeutic targets. Consecutive BSP analysis demonstrated that the common putative promoter region of the TMPRSS3-A/D gene variants was significantly hypomethylated in high-grade serous EOC tumors, compared to low-malignant potential ovarian tumors and normal ovarian tissue.

Conclusions

Our data imply that TMPRSS3-A/D overexpression in EOC is probably due to hypomethylation of their control region thus indicating that TMPRSS3-A/D variants could also represent novel molecular targets for epigenetic therapy of late stages of the disease. Our results also suggest that the frequently observed upregulation of different members of the type II serine proteases gene family in advanced cancer could be due to aberrant DNA hypomethylation. Furthermore, our study introduces a promising discovery approach that could be used for the identification of hypomethylated genes in different experimental cell models.     

Multi-slice computer tomography of left ventricular function with automated analysis software in comparison with conventional ventriculography

PURPOSE: To evaluate the accuracy of left ventricular volumetric and functional parameters from multi-slice computed tomography using automated analysis software, and to correlate results with those of invasive left ventriculography. MATERIALS AND METHODS: In 145 consecutive patients (mean age, 61 years+/-12) known or suspected to have coronary artery disease, a 16-channel multi-slice computed tomography (Philips Mx8000 IDT 16) was performed using a standard technique. Using short-axis secondary multi-slice computed tomography reformations, we determined end-diastolic and end-systolic left ventricular volumes and ejection fraction with a commercially available analysis software capable of automated contour detection. Conventional left ventriculography was performed according to standard techniques within the following 24 h. Bland-Altman analysis was performed to calculate the limits of agreement and systematic errors between multi-slice computed tomography and conventional left ventriculography. RESULTS: As determined by computer tomography, mean end-systolic (53+/-29 mL) left ventricular volumes had an acceptable correlation with conventional ventriculography (67+/-50 mL; r=0.74; p<0.001) and mean end-diastolic (119+/-33 mL) left ventricular volumes a poor correlation with conventional ventriculography measurements (154+/-69 mL; r=0.41). Left ventricular ejection fraction (57%+/-14 versus 55%+/-14 for conventional ventriculography; r=0.79) showed a very good correlation (p<0.001). Bland-Altman analysis showed acceptable limits of agreement (+/-9.2% for ejection fraction) without systematic errors. CONCLUSION: The use of a multi-slice computed tomography with an automatic calculation software has a good correlation with conventional ventriculography findings and could accurately assess left ventricular function, but should not be used for ventricular volumes, because of biased estimations.