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Early detection and treatment of cancers can significantly increase patient prognosis and enhance the quality of life of affected patients. The emerging significance of the tumor microenvironment (TME) as a new frontier for cancer diagnosis and therapy may be exploited by radiolabeled tracers for diagnostic imaging techniques such as positron emission tomography (PET). Cancer-associated fibroblasts (CAFs) within the TME are identified by biomarkers such as fibroblast activation protein alpha (FAPα), which are expressed on their surfaces. Targeting FAPα using small-molecule 18 F-labeled inhibitors (FAPIs) has recently garnered significant attention for non-invasive tumor visualization using PET. Herein, two potent aryl-fluorosulfate-based FAPIs, 12 and 13, were synthetically prepared, and their inhibition potency was determined using a fluorimetric FAP assay to be IC 50 9.63 and 4.17 nM, respectively. Radiofluorination was performed via the sulfur [ 18 F]fluoride exchange ([ 18 F]SuFEx) reaction to furnish [ 18 F] 12 and [ 18 F] 13 in high activity yields (AY) of 39-56% and molar activities (A m ) between 20-55 GBq/µmol. In vitro experiments focused on the stability of the radiolabeled FAPIs after incubation with human serum, liver microsomes and liver cytosol. Preliminary PET studies of the radioligands were performed in healthy mice to investigate the in vivo biodistribution and 18 F defluorination rate. Fast pharmacokinetics for the FAP-targeting tracers were retained and considerable bone uptake, caused by either 18 F defluorination or radioligand accumulation, was observed. In summary, our findings demonstrate the efficiency of [ 18 F]SuFEx as a radiolabeling method as well as its advantages and limitations with respect to PET tracer development. more...

Fibroblast activation protein (FAP) has emerged as an interesting molecular target used in the imaging and therapy of various types of cancers. 68 Ga-labeled chelator-linked FAP inhibitors (FAPIs) have been successfully applied to PET imaging of various tumor types. To broaden the spectrum of applicable PET tracers for extended imaging studies of FAP-dependent diseases, we herein report the radiosynthesis and preclinical evaluation of an 18 F-labeled glycosylated FAPI ([ 18 F]FGlc-FAPI). Methods: An alkyne-bearing precursor was synthesized and subjected to click chemistry-based radiosynthesis of [ 18 F]FGlc-FAPI by 2-step 18 F-fluoroglycosylation. FAP-expressing HT1080hFAP cells were used to study competitive binding to FAP, cellular uptake, internalization, and efflux of [ 18 F]FGlc-FAPI in vitro. Biodistribution studies and in vivo small-animal PET studies of [ 18 F]FGlc-FAPI compared with [ 68 Ga]Ga-FAPI-04 were conducted in nude mice bearing HT1080hFAP tumors or U87MG xenografts. Results: [ 18 F]FGlc-FAPI was synthesized with a 15% radioactivity yield and a high radiochemical purity of more than 99%. In HT1080hFAP cells, [ 18 F]FGlc-FAPI showed specific uptake, a high internalized fraction, and low cellular efflux. Compared with FAPI-04 (half maximal inhibitory concentration [IC 50 ] = 32 nM), the glycoconjugate, FGlc-FAPI (IC 50 = 167 nM), showed slightly lower affinity for FAP in vitro, whereas plasma protein binding was higher for [ 18 F]FGlc-FAPI. Biodistribution studies revealed significant hepatobiliary excretion of [ 18 F]FGlc-FAPI; however, small-animal PET studies in HT1080hFAP xenografts showed higher specific tumor uptake of [ 18 F]FGlc-FAPI (4.5 percentage injected dose per gram of tissue [%ID/g]) than of [ 68 Ga]Ga-FAPI-04 (2 %ID/g). In U87MG tumor-bearing mice, both tracers showed similar tumor uptake, but [ 18 F]FGlc-FAPI showed a higher tumor retention. Interestingly, [ 18 F]FGlc-FAPI demonstrated high specific uptake in bone structures and joints. Conclusion: [ 18 F]FGlc-FAPI is an interesting candidate for translation to the clinic, taking advantage of the longer half-life and physical imaging properties of 18 F. The availability of [ 18 F]FGlc-FAPI may allow extended PET studies of FAP-related diseases, such as cancer, but also arthritis, heart diseases, or pulmonary fibrosis., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.) more...

Aim: To correlate clinical and radiological outcome following one- and two-level anterior cervical discectomy and fusion (ACDF) with stand-alone polyetheretherketone (PEEK) cages filled with demineralized bone matrix (DBM)., Methods: We performed a retrospective review of a consecutive patient cohort with degenerative disc disease that underwent ACDF with stand-alone PEEK cages filled with demineralized bone matrix (DBM) between 2010 and 2013 with a minimum follow-up of 12 months. Changes in the operated segments were measured and compared to radiographs directly after surgery. Clinical outcome was evaluated by a physical examination, pain by visual analog scale (VAS) for arm and neck. Health-related quality of life was measured using the EuroQOL questionnaire (EQ-5D)., Results: Of 282 consecutive cases, follow-up data were obtained from 194 (69%) cases. The median age at presentation was 54 years and 91 patients were male (46%). Ninety-eight and 96 patients had one- and two-level surgeries, respectively. Mean VAS pain was reduced from 5.2 ± 3.6 to 2.6 ± 2.4 (p < 0.001) and from 5.8 ± 3.3 to 2.1 ± 2.7 (p < 0.001) in the myelopathy and radiculopathy group, respectively. Fusion was achieved in 79 and 82% of segments in one- and two-level surgeries, respectively. Cervical alignment was better in 10 and 1%, similar in 68 and 76%, worse in 23 and 23% in one- and two-level surgeries, respectively. Subsidence was observed in 44 and 34% of segments in one- and two-level surgeries, respectively. Follow-up operations due to symptomatic adjacent disc disease or implant failure were needed in 13 (7%) and 15 (8%) of cases, respectively. Subsidence, adjacent disc disease, and cervical alignment all had no influence on the clinical outcome., Conclusions: The clinical outcome after ACDF with PEEK cages filled with demineralized bone matrix is highly satisfactory. Radiological signs of non-fusion, subsidence, and cervical alignment have no influence on clinical outcome. more...

Aim: To investigate whether the fluid volume administered during esophageal cancer surgery affects pulmonary gas exchange and tissue perfusion., Methods: An exploratory single-center randomized clinical trial was performed. Patients with esophageal cancer who underwent Lewis-Tanner procedure between June 2011 and August 2012 at the Department of Thoracic surgery "Jordanovac", Zagreb were analyzed. Patients were randomized (1:1) to receive a restrictive volume of intraoperative fluid (≤8 mL/kg/h) or a liberal volume (>8 mL/kg/h). Changes in oxygen partial pressure (Pao2), inspired oxygen fraction (FiO2), creatinine, and lactate were measured during and after surgery., Results: Overall 16 patients were randomized and they all were analyzed (restrictive group n=8, liberal group n=8). The baseline value Pao2/FiO2 ratio (restrictive) was 345.01±35.31 and the value six hours after extubation was 315.51±32.91; the baseline Pao2/FiO2 ratio (liberal) was 330.11±34.71 and the value six hours after extubation was 307.11±30.31. The baseline creatinine value (restrictive) was 91.91±12.67 and the value six hours after extubation was 100.88±18.33; the baseline creatinine value (liberal) was 90.88±14.99 and the value six hours after extubation was 93.51±16.37. The baseline lactate value (restrictive) was 3.93±1.33 and the value six hours after extubation was 2.69±0.91. The baseline lactate value (liberal) was 3.26±1.25 and the value six hours after extubation was 2.40±1.08. The two groups showed no significant differences in Pao2/FiO2 ratio (P=0.410), creatinine (P=0.410), or lactate (P=0.574)., Conclusions: Restriction of intraoperative applied volume does not significantly affect pulmonary exchange function or tissue perfusion in patients undergoing surgical treatment for esophageal cancer. more...

SUMMARY - Post-intubation tracheal injury is a rare and potentially fatal complication. The most common causes are overinflation ofendotracheal tube cuffs and multiple intubation attempts in emergency cases. The diagnosis is based on clinical and radiological suspicion of tracheal injury confirmed by fiberoptic bronchoscopy. Decision between conservative and surgical management of the injury depends on clinical presentation (respiratory instability, concomitant diseases), lesion characteristics (lesion site, size, and number), and time elapsed from injury to diagnosis. We present three cases ofpost-intubation tracheal injury. In two cases, the patients were treated conservatively; in the third case, the patient died from asphyxia caused by thrombus occlusion of the trachea after a longitudinal tracheal lesion. Pre-anesthetic examination did not indicate any possibility of difficult intubation in any of the patients; however, in one of the patients admitted through the emergency department, emergency intubation was performed. more...

Magnesium can act as an adjuvant in analgesia due to its properties of calcium channel blocker and N-methyl-D-aspartate antagonist. The aim of our study was to determine if magnesium sulfate reduces perioperative analgesic requirements in patients undergoing thoracotomy procedure. Our study included 68 patients undergoing elective thoracotomy that received a bolus of 30-50 mg/kg MgSO4 followed by continuous infusion of 500 mg/h intraoperatively and 500 mg/h during the first 24 hours after the operation, or the same volume of isotonic solution (control group). Intraoperative analgesia was achieved with fentanyl and postoperative analgesia with a mixture of fentanyl and bupivacaine through epidural catheter. The level of pain was estimated using Visual Analog Scale (VAS) and TORDA pain scales. Fentanyl consumption during the operation was significantly lower in the magnesium treated group compared to control group. There was no statistically significant difference in epidural bupivacaine and fentanyl consumption during 48 hours postoperatively between the magnesium treated and control group. The measured VAS score at all intervals was similar in both groups. Postoperative TORDA scores were similar in both groups during the first 24 hours; however, a statistically significant difference was recorded in 40-48 h measurements. Results of our study revealed that magnesium reduced intraoperative analgesic requirements and also contributed to effective control of the static component of postthoracotomy pain. more...

A 70-year old female patient was admitted to the hospital because of scheduled thoracotomy and biopsy of posterior mediastinal retrocardiac tumor of unrecognized etiology. The patient had no complaints regarding the tumor. Routine anesthesiological preoperative examination revealed status ASA III. Induction in anesthesia was usually stable. At the moment when the surgeon intraoperatively touched the tumor, hemodinamic instability started and arterial blood pressure and heart rate dramatically increased. Our first reaction was to deepen the anesthesia. Very soon it was obvious that blood pressure increased by the surgeon's manipulation of the tumor and we started to doubt on catecholamine-secreting tumor. During the course of the operation there were several hypertensive episodes and we managed them by alternately using atenolol, glyceroltrinitrate and anesthetic drug. The patient was extubated 5 hours after transfer to the intensive care unit. Postoperative period was hemodynamically stable. The level of catecholamines in 24-hour urine collection was significantly increased. Pathohistologic diagnosis was mediastinal paraganglioma. more...

Background and Objective: It is not precisely defined which group of non-cardiac surgery patients should undergo transthoracic echocardiography in preoperative preparation. This study was prospectively performed to find out whether the routine use of echocardiography is justified in patients scheduled for lung resection, and to assess its role in cardiac risk evaluation., Methods: Patients classified as ASA III who were identified as having minor or intermediate predictors of cardiac risk were included in the study. Based on this triage, 130 patients underwent transthoracic echocardiography., Results: Intermediate index of increased perioperative cardiovascular risk was recorded in 36.2% and low index in 63.8% of patients. Preoperative anesthesiologic examination revealed some form of cardiac arrhythmia in 28.5%, symptoms of coronary disease in 25.4%; hypertension in 52.3%, and chronic obstructive pulmonary disease in 16.9% of patients. Transthoracic echocardiography showed the ejection fraction of 60% in 86.9% and of 40%-49% in only one patient. Left ventricular contractility was preserved in 96.2% of patients. Diastolic relaxation was weakened in 42.3% of patients. Mild mitral insufficiency was found in 29.2%; aortic stenosis in 1.5%, mild aortic insufficiency in 2.3%, mild pulmonary hypertension in 70.8%, and severe pulmonary hypertension in only 1.5% of patients. Pulmonectomy was performed in 26.9%, lobectomy in 62.3% and segmental tumor resection in 10.8% of patients. Only 26.2% of patients had peri- and postoperative complications: tachyarrhythmia and atrial fibrillation with rapid ventricular answer in 16.2%, hypotension 1.5%; hypertension in 2.3% and hypertension and arrhythmia in 1.5% of patients. Three (2.3%) patients died. None of our patients had Goldman's score higher than 25; according to Detsky index our patients belonged to 0-15 point group, class I, with the foreseen risk %., Conclusions: Transthoracic echocardiography is not justified in the routine preoperative preparation of thoracosurgical patients classified as ASA III with clinically minor and intermediate indexes of increased cardiovascular risk. It should be done in selected patients, primarily those that have history data and clinical picture consistent with major indices of an increased cardiovascular risk. more...

The brain is an excitable media in which excitation waves propagate at several scales of time and space. "One-dimensional" action potentials (millisecond scale) along the axon membrane, and spreading depression waves (seconds to minutes) at the three dimensions of the gray matter neuropil (complex of interacting membranes) are examples of excitation waves. In the retina, excitation waves have a prominent intrinsic optical signal (IOS). This optical signal is created by light scatter and has different components at the red and blue end of the spectrum. We could observe the wave onset in the retina, and measure the optical changes at the critical transition from quiescence to propagating wave. The results demonstrated the presence of fluctuations preceding propagation and suggested a phase transition. We have interpreted these results based on an extrapolation from Tasaki's experiments with action potentials and volume phase transitions of polymers. Thus, the scatter of red light appeared to be a volume phase transition in the extracellular matrix that was caused by the interactions between the cellular membrane cell coat and the extracellular sugar and protein complexes. If this hypothesis were correct, then forcing extracellular current flow should create a similar signal in another tissue, provided that this tissue was also transparent to light and with a similarly narrow extracellular space. This control tissue exists and it is the crystalline lens. We performed the experiments and confirmed the optical changes. Phase transitions in the extracellular polymers could be an important part of the long-range correlations found during wave propagation in central nervous tissue. more...

This is a rare case of concomitant bihemispheric cerebral ganglioglioma and hemangioma in an 18-month-old child. There were two identical processes; a combination of ganglioglioma and hemangioma was located in the parieto-occipital region of both cerebral hemispheres. The child underwent diagnostic computed tomographic and magnetic resonance imaging examinations for seizures and right-sided facial palsy, which showed the bilateral presence of parieto-occipital, oval, well-demarcated, subcortically located processes. A biparieto-occipital craniotomy was carried out and two well-demarcated abnormalities were observed and both were removed in toto. Two years after the operation, the boy had normal psychomotor development and remained free from seizures with no therapy required. Repeat magnetic resonance imaging showed no tumor recurrence. Gangliogliomas are relatively uncommon tumors in childhood, located in the supratentorial compartment and usually associated with seizures. Histopathologic and immunohistochemical analysis of the two processes found in our patient showed them to be a ganglioglioma and a hemangioma, confirming the dysontogenetic origin of these alterations and the association between malformations and tumor growth. The combination of ganglioglioma and hemangioma, especially bilateral presentation of two such identical processes in a young child, is very rare and was not found in the recent literature. more...