Exposure to nonanoic acid alters small intestinal neuroendocrine tumor phenotype.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NET) are highly differentiated and genetically stable malignant tumors, yet they often present with advanced metastatic spread at the time of diagnosis. In contrast to many other types of malignant tumors, primary SI-NET are often asymptomatic and typically smaller in size compared to adjacent lymph node metastases. This study explores the hypothesis that stimulating the chemosensing olfactory receptor 51E1 (OR51E1) decreases SI-NET proliferation suggesting a mechanism that explains a difference in proliferative rate based on tumor location. METHODS: Clinical data was used to address difference in tumor size depending on location. A SI-NET tissue microarray was used to evaluate expression of OR51E1 and olfactory marker protein (OMP). Primary cultured tumor cells from 5 patients were utilized to determine the effect of OR51E1 agonist nonanoic acid on metabolic activity. The SI-NET cell line GOT1 was used to determine effects of nonanoic acid on the transcriptome as well as long-term effects of nonanoic acid exposure with regards to cell proliferation, serotonin secretion, alterations of the cell-cycle and morphology. RESULTS: Tumor size differed significantly based on location. OR51E1 and OMP were generally expressed in SI-NET. Primary SI-NET cells responded to nonanoic acid with a dose dependent altered metabolic activity and this was replicated in the GOT1 cell line but not in the MCF10A control cell line. Nonanoic acid treatment in GOT1 cells upregulated transcripts related to neuroendocrine differentiation and hormone secretion. Long-term nonanoic acid treatment of GOT1 cells decreased proliferation, induced senescence, and altered cell morphology. CONCLUSION: Our results raise the possibility that exposure of intraluminal metabolites could represent a mechanism determining aspects of the SI-NET tumor phenotype. However, we could not causally link the observed effects of nonanoic acid exposure to the OR51E1 receptor.

Validation of an automated measurement method for determination of the ankle-brachial index.

Objective. Lower extremity atherosclerotic disease (LEAD) diagnosis is largely based on ankle-brachial index (ABI) recordings. Equipment that could automatically determine ABI may facilitate LEAD identification within a broad range of health services. We aimed to test the measurement properties of an automated oscillometric ABI measurement device (MESI ABPI MD®) as compared to manual reference ABI measurements in patients with and without LEAD. Design. A total of 153 patients with and without LEAD visiting a vascular surgery clinic underwent manual and automated ABI measurements. In total, 306 limbs were investigated. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the automated ABI device overall validity, with the manual method as reference. Correlation analysis (Spearman) was used to assess patterns of correlation between measurement methods while Bland-Altman plots were used to quantify measurement agreement. Results. Sensitivity and specificity for the automated ABI device were 75 and 67% whereas PPV and NPV were 72 and 71%, respectively. The correlation coefficient (automated versus manual measurements) was r = 0.552, p < .01. Bland-Altman plots revealed proportional bias and a tendency by the automated device to overestimate lower ABI values and underestimate higher ABI values. The best agreement between automated and manual ABI recordings was observed within the normal ABI range. Conclusions. The ABPI MD® device performance was unfavorable. The automated device tended to overestimate lower ABI values while underestimating higher values, which may lead to underdiagnosis of LEAD. Our data do not support the use of this automated ABI measurement device in clinical practice.

The current status of drug-coated devices in lower extremity peripheral artery disease interventions.

Lower limb peripheral artery disease is a leading cause of cardiovascular disease morbidity and mortality. Endovascular revascularization is often indicated to improve walking function and to prevent limb loss but restenosis in the treated vessel segment remains a concern that limits the overall effectiveness of the treatment. The most promising technique to prevent restenosis is the use of drug-coated devices, and the most common drug used to coat lower limb balloon angioplasty balloons and stents is paclitaxel. A systematic review and meta-analysis in 2018 reported a possible increase in late mortality attributable to paclitaxel-coated devices. Since then, their use has been brought into question. Here, we present an update of data focusing on the efficacy and safety of paclitaxel-coated devices in lower limb treatment applications. While paclitaxel-coated devices appear to reduce restenosis rates it is still unclear how these surrogate marker improvements translate to direct patient benefits and uncertainty remains as to whether paclitaxel-coated devices confer an increased risk of long-term mortality. Available randomized clinical data is hampered by trial heterogeneity, insufficient power, potential attrition bias and the lack of a plausible mechanistic explanation. An important step forward is that the ongoing trials that were temporarily halted due to the Katsanos et al. report have now both commenced recruitment and may ultimately resolve this clinical dilemma by virtue of their larger sample sizes. Other possible ways forward are the ongoing investigation of alternative anti-proliferative coating agents and use of new sophisticated vascular imaging techniques to more clearly identify patients at risk of restenosis already in the preoperative setting.