Additional value of integrated 18F-choline PET/4D contrast-enhanced CT in the localization of hyperfunctioning parathyroid glands and correlation with molecular profile.

PURPOSE: The localization of hyperfunctioning parathyroid gland(s) (HPTG) in patients with primary hyperparathyroidism (PHPT) with negative or inconclusive first-line imaging is a significant challenge. This study aimed to evaluate the role of integrated 18F-choline PET/4D contrast-enhanced computed tomography (4DCeCT) in these patients, compare its detection rate and sensitivity with those of 18F-choline PET/CT and (4DCeCT), and analyse the association between choline metabolism and morphological, biochemical and molecular parameters of HPTG. METHODS: We prospectively enrolled 44 PHPT patients with negative or inconclusive first-line imaging. 18F-Choline PET/CT and 4DCeCT were performed at the same time, and integrated 18F-choline PET/4DCeCT images were obtained after coregistration. Experienced physicians examined the images. The SUVratio and degree of contrast enhancement were recorded for each positive finding. Histopathology, laboratory and multidisciplinary follow-up were used as the standard of reference. Both the detection rates and sensitivities of the three imaging modalities were calculated retrospectively. Immunohistochemistry was performed to evaluate the molecular profile of HPTGs. RESULTS: 18F-Choline PET/4DCeCT was positive in 32 of 44 patients with PHPT (detection rate 72.7%), and 31 of 31 surgically treated patients (sensitivity 100%). These results were significantly (p < 0.05) better than those of 18F-choline PET/CT (56.8% and 80%, respectively) and those of 4DCeCT (54.5 and 74%, respectively). A significant correlation between SUV and calcium level was found. In a multivariate analysis, only calcium level was significantly associated with 18F-choline PET/4DCeCT findings. SUVratio and Ki67 expression were significantly correlated. CONCLUSION: Integrated 18F-choline PET/4DCeCT should be considered as an effective tool to detect PHPT in patients with negative or inconclusive first-line imaging. Choline metabolism is correlated with both calcium level and Ki67 expression in HPTG.

Sequential use of vinorelbine followed by gefitinib enhances the antitumor effect in NSCLC cell lines poorly responsive to reversible EGFR tyrosine kinase inhibitors.

Preclinical studies have suggested that combining cytotoxic agents with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to treat EGFR-mutated tumors may increase their inhibitory effect depending on the order of drug administration. The antitumor efficacy of different treatment sequences using vinorelbine (VNB) and gefitinib (GEF) was investigated both in vitro and in vivo in non-small cell lung cancer (NSCLC) cell lines with the rationale of potentially translating these findings into the clinical setting. The EGFR-wild-type A549 and the EGFR-mutated (exon 21 L858R/exon 20 T790M) H1975 cell lines were treated as follows: GEF followed by VNB, VNB followed by GEF and the two drugs applied individually or concurrently. Results in vitro demonstrated that the sequence of VNB followed by GEF was significantly more active than single-agent treatments. The expression of activated EGFR and its downstream pathway genes indicated that the increased cytotoxic effect of the VNB and GEF treatment sequence was accompanied by inhibition of EGFR, AKT and ERK1/2. Moreover, the increased inhibition of tumor growth after treatment with VNB followed by GEF was also confirmed in CD1-nude mice that were xenotransplanted with H1975 cells (p < 0.0001). This effect was paralleled by a corresponding decrease in cancer glucose consumption, as assessed by micro-positron emission tomography scans (p < 0.05). These preclinical findings in NSCLC cell lines, which are poorly responsive to EGFR-TKIs, demonstrated that the sequential treatment of VNB followed by GEF induced a significant antitumor effect, which supports the translation of this treatment schedule into a clinical setting.

Cardiometabolic and immune factors associated with increased common carotid artery intima-media thickness and cardiovascular disease in patients with systemic lupus erythematosus.

BACKGROUND AND AIM: Patients with systemic lupus erythematosus (SLE) have a higher prevalence of subclinical atherosclerosis and higher risk of cardiovascular (CV) events compared to the general population. The relative contribution of CV-, immune- and disease-related risk factors to accelerated atherogenesis in SLE is unclear. METHODS AND RESULTS: Fifty SLE patients with long-lasting disease (mean age 44 ± 10 years, 86% female) and 50 sex- and age-matched control subjects were studied. Common carotid artery intima-media thickness (CCA-IMT) was used as a surrogate marker of atherosclerosis. We evaluated traditional and immune- and disease-related factors, assessed multiple T-cell subsets by 10-parameter-eight-colour polychromatic flow cytometry and addressed the effect of pharmacological therapies on CCA-IMT. In SLE patients, among several cardiometabolic risk factors, only high-density lipoprotein levels (HDL) and their adenosine triphosphate-binding cassette transporter 1 (ABCA-1)-dependent cholesterol efflux capacity were markedly reduced (p < 0.01), whereas the CCA-IMT was significantly increased (p = 0.03) compared to controls. CCA-IMT correlated with systolic blood pressure, low-density lipoprotein (LDL) cholesterol and body mass index (BMI), but not with disease activity and duration. The activated CD4(+)HLA-DR(+) and CCR5(+) T-cell subsets were expanded in SLE patients. Patients under hydroxychloroquine (HCQ) therapy showed lower CCA-IMT (0.62 ± 0.08 vs. 0.68 ± 0.10 mm; p = 0.03) and better risk-factor profile and presented reduced circulating pro-atherogenic effector memory T-cell subsets and a parallel increased percentage of naïve T-cell subsets. CONCLUSION: HDL represents the main metabolic parameter altered in SLE patients. The increased CCA-IMT in SLE patients may represent the net result of a process in which 'classic' CV risk factors give a continuous contribution, together with immunological factors (CD4(+)HLA-DR(+) T cells) which, on the contrary, could contribute through flares of activity of various degrees over time. Patients under HCQ therapy present a modified metabolic profile, a reduced T-cell activation associated with decreased subclinical atherosclerosis.

The effect of knee brace and knee sleeve on the proprioception of the knee in young non-professional healthy sportsmen.

BACKGROUND: Proprioception has been defined as the capacity to feel the position of a joint in space as sensed by the central nervous system. Prophylactic knee braces are supposed to help in knee injury prevention not just with a mechanical support of the joint but also improving proprioception. The main aim of this study was to determine the effects of a knee brace and a knee sleeve on knee proprioception. The secondary aim was to determine if different starting angles of the knee and different movement directions influence knee proprioception. METHODS: We tested a group of twenty healthy male sport students without knee injuries. They were tested with the brace, with the sleeve and without support. The threshold of detection of passive knee movement with a starting knee angle of 30° and 60°, both in flexion and extension was determined. RESULTS: We did not find any statistically significant change in the threshold of detection of passive knee movement wearing the brace or the sleeve compared to the unsupported condition (p=0.462, α=0.05). We found a significantly lower proprioceptive sensitivity starting at the more flexed knee angle (p=0.005, α=0.05) and moving in extension than in the other test situations (p=0.001, α=0.05). CONCLUSION: Movement direction and starting position appear to influence the threshold of detection of passive knee movement. The results of this study also suggest that knee supports do not influence either positively or negatively knee proprioception of uninjured active subjects.

[Bioadhesives: rationale, state of the art and therapeutic potential]. / Bioadesione: razionale, stato dell'arte e potenzialità terapeutiche.

Pharmaceutical research is going on the way to formulate drugs in dosage forms and delivery systems able to improve their biopharmaceutical properties. For some routes of administration, among them the transmucosal ones, such improvements may be reached by increasing the time and the nature of the contact between mucosal tissues and drug dosage forms via chemical or physical bioadhesive links. Biopharmaceutical AFI Study Group efforts were oriented in analyzing the actual state of the art in the field of bioadhesive drug delivery. Rationals of use of drug dosage forms with bioadhesive properties, analytical method of control of bioadhesion (both in vitro and in vivo) and therapeutical potentialities are the matter of this review.

Nasal formulations of ketorolac tromethamine: technological evaluation--bioavailability and tolerability in rabbits.

This paper describes the development of a novel formulation of the powerful non narcotic analgesic ketorolac tromethamine. This drug is given orally three to four times/day to deliver a total of 30 to 60 mg of drug. Higher doses cannot be given orally because of gastrointestinal side effects and intramuscular injections, three times/day must then be used. The need for injections limits the drug to a clinical setting. Nasal delivery offers a method of achieving the high blood levels of repeated intramuscular injections in a formulation that can be easily applied by the patients. Four formulations were evaluated in "in vitro" and "in vivo" rabbit tests. The best formulation consisted of a 5% solution of ketorolac tromethamine containing 0.3% sodium glycocolate as a known mucosal drug absorption enhancer. Ketorolac applied in this way had a bioavailability greater than 80%. The controlled release nature of nasal delivery also doubled the drug's apparent half life. The drug formulation was stable in three-months stability tests and produced minimal nasal irritation.