Effects of a Ketogenic Diet on [18F]FDG-PET Imaging in a Mouse Model of Lung Cancer

Purpose

Myocardial uptake can hamper visualization of lung tumors, atherosclerotic plaques, and inflammatory diseases in 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) studies because it leads to spillover in adjacent structures. Several preparatory pre-imaging protocols (including dietary restrictions and drugs) have been proposed to decrease physiological [¹⁸F]FDG uptake by the heart, although their effect on tumor glucose metabolism remains largely unknown. The objective of this study was to assess the effects of a ketogenic diet (as an alternative protocol to fasting) on tumor glucose metabolism assessed by [¹⁸F]FDG positron emission tomography (PET) in a mouse model of lung cancer.

Procedures

PET scans were performed 60 min after injection of 18.5 MBq of [¹⁸F]FDG. PET data were collected for 45 min, and an x-ray computed tomograph (CT) image was acquired after the PET scan. A PET/CT study was obtained for each mouse after fasting and after the ketogenic diet. Quantitative data were obtained from regions of interest in the left ventricular myocardium and lung tumor.

Results

Three days on a ketogenic diet decreased mean standard uptake value (SUVmean) in the myocardium (SUVmean 0.95?±?0.36) more than one night of fasting (SUVmean 1.64?±?0.93). Tumor uptake did not change under either dietary condition.

Conclusions

These results show that 3 days on high-fat diets prior to [¹⁸F]FDG-PET imaging does not change tumor glucose metabolism compared with one night of fasting, although high-fat diets suppress myocardial [¹⁸F]FDG uptake better than fasting.

     

Intracellular signaling mechanisms mediating ghrelin-stimulated growth hormone release in somatotropes

Ghrelin is a newly discovered peptide that binds the receptor for GH secretagogues (GHS-R). The presence of both ghrelin and GHS-Rs in the hypothalamic-pituitary system, together with the ability of ghrelin to increase GH release, suggests a hypophysiotropic role for this peptide. To ascertain the intracellular mechanisms mediating the action of ghrelin in somatotropes, we evaluated ghrelin-induced GH release from pig pituitary cells both under basal conditions and after specific blockade of key steps of cAMP-, inositol phosphate-, and Ca2+-dependent signaling routes. Ghrelin stimulated GH release at concentrations ranging from 10-10 to 10-6 m. Its effects were comparable with those exerted by GHRH or the GHS L-163,255. Combined treatment with ghrelin and GHRH or L-163,255 did not cause further increases in GH release, whereas somatostatin abolished the effect of ghrelin. Blockade of phospholipase C or protein kinase C inhibited ghrelin-induced GH secretion, suggesting a requisite role for this route in ghrelin action. Unexpectedly, inhibition of either adenylate cyclase or protein kinase A also suppressed ghrelin-induced GH release. In addition, ghrelin stimulated cAMP production and also had an additive effect with GHRH on cAMP accumulation. Ghrelin also increased free intracellular Ca2+ levels in somatotropes. Moreover, ghrelin-induced GH release was entirely dependent on extracellular Ca2+ influx through L-type voltage-sensitive channels. These results indicate that ghrelin exerts a direct stimulatory action on porcine GH release that is not additive with that of GHRH and requires the contribution of a multiple, complex set of interdependent intracellular signaling pathways.     

Discrepancies in anal manometric pressure measurement—Important or inconsequential?

PURPOSE: Maximum resting and squeeze pressures have been the most widely employed parameters for manometric assessment of the anal sphincters. However, a single maximum value may not always be the best assessment. METHODS: The aim of this study was to compare mean and maximum resting and mean and maximum squeeze pressures in a large sample population. All manometric pressure profiles were reviewed by a single individual blinded to the patient's age and diagnosis. RESULTS: Four hundred sixty-six patients with a measurable high-pressure zone were included in this study. The study population was comprised of 279 females and 186 males. A significant difference was found between mean (56.26 mmHg) and maximum (79.2 mmHg) resting pressures (P<0.01) and also between mean (81.25 mmHg) and maximum (119.50 mmHg) squeeze pressures (P<0.01). A significant difference (P<0.01) was also observed when compared by length of the high-pressure zone. CONCLUSION: The measurement, documentation, and reporting of mean resting and mean squeeze pressures provide a better perspective of anal manometric results, since the two sets of values are significantly different (P<0.01), regardless of the anal canal length. Therefore, these data support the standardized evaluation of both mean and maximum pressures in individual patients and in published series.Read at the meeting of The American Society of Colon and Rectal Surgeons, Orlando, Florida, May 8 to 13, 1994.Dr. Morgado was a visiting surgeon from the Centro Medico, Caracas, Venezuela. He was funded, in part, by a grant from the American Society of Colon and Rectal Surgeons Research Foundation.     

Ablation of pulmonary vein foci for the treatment of atrial fibrillation; percutaneous electroanatomical guided approach.

AIMS: To evaluate the usefulness of three-dimensional (3D) electroanatomical mapping of the pulmonary veins (PV) for guiding radiofrequency (RF) ablation of focal atrial fibrillation (AF) in a single session and to correlate the electrophysiological results with the six month clinical outcome. METHODS AND RESULTS: Sixteen consecutive patients with idiopathic paroxysmal AF (more than 1 episode/month) were studied. A non-fluoroscopic mapping system was used to generate 3D electroanatomic maps of the left atrium and deliver RF energy. In patients with frequent ectopies, mapping was performed using the 'hot-cold' approach (looking for the earliest electrogram in the 3D reconstruction). In patients with infrequent/no ectopies, double/ multiple potentials recorded at the PV were tagged. Pacing at these sites to test for inducibility of ectopy or atrial fibrillation was used to define PV foci. The therapeutic endpoint was defined as suppression of premature beats, dissociation of PV potentials and inability to induce AF. Twenty-five foci were identified (multiple foci in 38%). In the 4 pts with frequent ectopies, Group A, these were suppressed by 4 +/- 4.7 applications. In the 12 pts with infrequent/no ectopies, Group B, an average 4.7 +/- 1.8 applications were delivered per focus; the endpoint was achieved in eight of the patients (13 of 21 foci). By 180 days follow-up, 11 patients were free of symptoms and in sinus rhythm, two had paroxysmal AF episodes and 3 have symptomatic ectopies and are receiving antiarrhythmic drugs. The overall success rate at six months was thus 69%, 100% for group A and 58% for group B. CONCLUSION: Electroanatomic guided RF ablation of paroxysmal AF was highly successful in patients with frequent ectopies. The use of electroanatomical mapping for precise anatomical localization of multiple potentials and for guiding the PV ostia isolation allowed successful RF ablation in 50% of pts with infrequent/no ectopies.     

Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion

Expression of the IL-2 receptor alpha chain (CD25) by peripheral CD4 T cells follows cellular activation. However, CD25 expression by CD4 cells is widely used as a marker to identify regulatory T cells (T(R)), although cells with regulatory properties are also found in the CD4+CD25- subset. By using in vivo functional assays and Foxp3 expression as a faithful marker of T(R) differentiation, we have evaluated the requirements for CD25 expression by peripheral T(R). We first show that in vivo depletion of CD25+ cells prevents the development of spontaneous encephalomyelitis in recombination-activating gene (RAG)-deficient anti-myelin basic protein T cell antigen receptor (TCR) transgenic mice, and allows disease induction in otherwise healthy RAG-competent transgenic mice. Similar treatment in normal thymectomized animals is followed by the fast recovery of a normal number of CD25+ T(R). Consistently, Foxp3-expressing T(R) encompassed in the CD25- cell population convert to CD25+ after homeostatic expansion and are selectable by IL-2 in vitro. Surface expression of CD25 on T(R) is controlled by the activity of conventional CD4 cells and is fully labile because it can be lost and regained without affecting the functional potential of the cells. These findings reveal that Foxp3-expressing CD25- cells constitute a peripheral reservoir of differentiated T(R), recruited to the CD25+ pool upon homeostatic expansion and/or activation. This analysis, together with the notion that physiological commitment of T(R) takes place exclusively in the thymus should help for the interpretation of experiments assessing peripheral T(R) differentiation from naive CD4 T cells, defined as CD25-.     

Long-term efficacy of therapy in patients with fibromyalgia: a physical exercise-based program and a cognitive-behavioral approach

OBJECTIVE: To analyze the long-term efficacy of 2 interventions for female fibromyalgia (FM) patients: 1) cognitive-behavioral therapy (CBT), and 2) a physical exercise (PE)-based strategy. METHODS: We conducted a prospective, long-term, randomized, parallel clinical trial. The outcome variables are physical activity, aerobic capacity, and results of the Fibromyalgia Impact Questionnaire (FIQ), Short Form 36, Beck Anxiety and Depression Inventory, Chronic Pain Self-Efficacy Scale, and Chronic Pain Coping Inventory. All were measured at baseline, posttreatment, 6 months, and 1 year. The duration of both treatments was 8 weeks. RESULTS: Some items of the FIQ and some strategies to cope with pain improved significantly in both groups after treatment. All variables measuring functional capacity improved significantly in the PE group, whereas only physical activity of the vertebral column improved in the CBT group. There were no differences in anxiety, depression, and self efficacy after treatment in either group. After 1 year of followup, most of the parameters had returned to baseline values in both groups. However, in the PE group, functional capacity remained significantly better. CONCLUSIONS: PE and CBT improve clinical manifestations in FM patients only for short periods of time. Improvement in self efficacy and physical fitness are not associated with improvement in clinical manifestations.     

Molecular analysis of pancreatic cystic neoplasm in routine clinical practice

BACKGROUNDCystic pancreatic lesions consist of a wide variety of lesions that are becoming increasingly diagnosed with the growing use of imaging techniques. Of these, mucinous cysts are especially relevant due to their risk of malignancy. However, morphological findings are often suboptimal for their differentiation. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) with molecular analysis has been suggested to improve the diagnosis of pancreatic cysts.AIMTo determine the impact of molecular analysis on the detection of mucinous cysts and malignancy.METHODSAn 18-month prospective observational study of consecutive patients with pancreatic cystic lesions and an indication for EUS-FNA following European clinical practice guidelines was conducted. These cysts included those > 15 mm with unclear diagnosis, and a change in follow-up or with concerning features in which results might change clinical management. EUS-FNA with cytological, biochemical and glucose and molecular analyses with next-generation sequencing were performed in 36 pancreatic cysts. The cysts were classified as mucinous and non-mucinous by the combination of morphological, cytological and biochemical analyses when surgery was not performed. Malignancy was defined as cytology positive for malignancy, high-grade dysplasia or invasive carcinoma on surgical specimen, clinical or morphological progression, metastasis or death related to neoplastic complications during the 6-mo follow-up period. Next-generation sequencing results were compared for cyst type and malignancy.RESULTSOf the 36 lesions included, 28 (82.4%) were classified as mucinous and 6 (17.6%) as non-mucinous. Furthermore, 5 (13.9%) lesions were classified as malignant. The amount of deoxyribonucleic acid obtained was sufficient for molecular analysis in 25 (69.4%) pancreatic cysts. The amount of intracystic deoxyribonucleic acid was not statistically related to the cyst fluid volume obtained from the lesions. Analysis of KRAS and/or GNAS showed 83.33% [95% confidence interval (CI): 63.34-100] sensitivity, 60% (95%CI: 7.06-100) specificity, 88.24% (95%CI: 69.98-100) positive predictive value and 50% (95%CI: 1.66-98.34) negative predictive value (P = 0.086) for the diagnosis of mucinous cystic lesions. Mutations in KRAS and GNAS were found in 2/5 (40%) of the lesions classified as non-mucinous, thus recategorizing those lesions as mucinous neoplasms, which would have led to a modification of the follow-up plan in 8% of the cysts in which molecular analysis was successfully performed. All 4 (100%) malignant cysts in which molecular analysis could be performed had mutations in KRAS and/or GNAS, although they were not related to malignancy (P > 0.05). None of the other mutations analyzed could detect mucinous or malignant cysts with statistical significance (P > 0.05). CONCLUSIONMolecular analysis can improve the classification of pancreatic cysts as mucinous or non-mucinous. Mutations were not able to detect malignant lesions.