Athanassios Zissimopoulos

A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis

IntroductionRegenerative medicine and particular adult stem cells represent an alternative option with several fruitful therapeutic applications in patients suffering from chronic lung diseases including idiopathic pulmonary fibrosis (IPF). Nevertheless, lack of knowledge regarding the origin and the potential of mesenchymal stem cells (MSCs) to differentiate into fibroblasts has limited their use for the treatment of this dismal disease.Patients and methodsTo this end, we conducted a phase Ib, non-randomized, clinical trial to study the safety of three endobronchial infusions of autologous adipose derived stromal cells (ADSCs)-stromal vascular fraction (SVF) (0.5 million cells per kgr of body weight per infusion) in patients with IPF (n=14) of mild to moderate disease severity (forced vital capacity –FVC>50% predicted value and diffusion lung capacity for carbon monoxide-DLCO>35% of predicted value). Our primary end-point was incidence of treatment emergent adverse events within 12 months. Alterations of functional, exercise capacity and quality of life parameters at serial time points (baseline, 6 and 12 months after first infusion) were exploratory secondary end-points.ResultsNo cases of serious or clinically meaningful adverse events including short-term infusional toxicities as well as long-term ectopic tissue formation were recorded in all patients. Detailed safety monitoring through several time-points indicated that cell-treated patients did not deteriorate in both functional parameters and indicators of quality of life.ConclusionsThe clinical trial met its primary objective demonstrating an acceptable safety profile of endobronchially administered autologous ADSCs-SVF. Our findings accelerate the rapidly expanded scientific knowledge and indicate a way towards future efficacy trials.

Stem cell therapy for idiopathic pulmonary fibrosis: a protocol proposal

BackgroundIdiopathic pulmonary fibrosis represents a lethal form of progressive fibrotic lung disorder with gradually increasing incidence worldwide. Despite intense research efforts its pathogenesis is still elusive and controversial reflecting in the current disappointing status regarding its treatment. Patients and Methods: We report the first protocol proposal of a prospective, unicentric, non-randomized, phase Ib clinical trial to study the safety and tolerability of the adipose-derived stem cells (ADSCs) stromal vascular fraction (SVF) as a therapeutic agent in IPF. After careful patient selection based on functional criteria (forced vital capacity-FVC > 50%, diffuse lung capacity for carbon monoxide-DLCO > 35% of the predicted values) all eligible subjects will be subjected to lipoaspiration resulting in the isolation of approximately 100- 500 gr of adipose tissue. After preparation, isolation and labelling ADSCs-SVF will be endobronchially infused to both lower lobes of the fibrotic lungs. Procedure will be repeated thrice at monthly intervals. Primary end-point represent safety and tolerability data, while exploratory secondary end-points include assessment of clinical functional and radiological status. Results: Preliminary results recently presented in the form of an abstract seem promising and tantalizing since there were no cases of clinically significant allergic reactions, infections, disease acute exacerbations or ectopic tissue formation. In addition 6 months follow-up data revealed a marginal improvement at 6-minute walking distance and forced vital capacity.ConclusionsAdipose tissue represents an abundant, safe, ethically uncontested and potentially beneficial source of stem cells for patients with IPF. Larger multicenter phase II and III placebo-controlled clinical trials are sorely needed in order to prove efficacy. However, pilot safety studies are of major importance and represent the first hamper that should be overcome to establish a rigid basis for larger clinical trials.

Comparative Efficacies of Procalcitonin and Conventional Inflammatory Markers for Prediction of Renal Parenchymal Inflammation in Pediatric First Urinary Tract Infection

OBJECTIVES To compare the reliability of procalcitonin (PCT) with conventional laboratory parameters in predicting for renal parenchymal inflammation (RPI). METHODS The study cohort consisted of 57 children who were admitted for a first-episode urinary tract infection. All patients underwent measurement of the leukocyte count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum PCT. RPI was evaluated by technetium-99m dimercaptosuccinic acid (DMSA) scintigraphy within 7 days of admission. If the first DMSA findings were abnormal, another analysis was performed 6 months later. The cutoff points for ESR, CRP, and PCT were established by comparing the areas under their receiver operating characteristic curves. Statistical analysis was performed using 1-way analysis of variance. RESULTS Of the 57 children, 27 were diagnosed with RPI on the basis of positive DMSA results. The ESR, CRP, and PCT levels were significantly greater (P < .001) in the patients with RPI than in those without RPI. In contrast, the leukocyte count was the same in both groups (P > .05). PCT was a more sensitive and specific marker for differentiating upper and lower urinary tract infection than ESR and CRP. Persistent lesions at the site of previous RPI were found in 12 patients in the follow-up DMSA analysis, with total regression evident in the remaining 15. The PCT levels were significantly greater in those with persistent renal lesions than in those with total regression (P = .005). CONCLUSIONS Serum PCT is a more reliable biologic marker than the ESR, CRP, or leukocyte count for the early prediction of RPI in children with a first episode of urinary tract infection. In addition, the greater the elevation of PCT at admission, the more positive the correlation for subsequent permanent renal damage.

Lower eyelid laxity in functional acquired epiphora: evaluation with quantitative scintigraphy.

Purpose: The examination of lacrimal drainage is often based on qualitative criteria. This study uses quantitative scintigraphy to evaluate “functional” epiphora. Methods: Thirty-two patients with functional epiphora (no morphologic abnormalities of the conjunctiva and eyelids, a patent nasolacrimal duct on irrigation, and no anatomical stenosis on dacryocystography) were studied (study group, SG). Twenty-two individuals without epiphora were also examined (control group, CG). Fifty microliters of Technetium-99m was instilled into the conjunctival cul-de-sac. Time-activity curves were then constructed, and conjunctival lacrimal clearance (CLC) at 2.5, 5, 7.5, and 10 minutes was calculated. Differences in CLC between the SG and the CG and correlations between CLC and horizontal and median tendon laxity and eyelid length in the SG were examined. Results: The SG had significantly reduced CLC at 2.5 and 5 minutes, compared with the CG (p = 0.01 and p = 0.04, respectively), whereas respective differences at 7.5 and 10 minutes were not statistically significant. In the SG, CLC at 2.5 and 5 minutes was significantly correlated with horizontal and median tendon laxity. The respective correlation with eyelid length was not statistically significant. Furthermore, in the SG, CLC at 2.5 and 5 minutes was significantly correlated with patient age (p = 0.03 and p = 0.04, respectively). Differences in CLC between men and women were not statistically significant at all intervals. Conclusions: The correlation between eyelid laxity and CLC supports the role of the eyelid “pump” in lacrimal drainage. CLC at 2.5 and 5 minutes may be used to decide treatment methods for functional epiphora.

Lacrimal Outflow Mechanisms and the Role of Scintigraphy: Current Trends

Lacrimal outflow can be compromised by anatomical obstructions or stenoses (nonfunctional epiphora) or by defective lacrimal “pump” function (functional epiphora). Although classic imaging modalities, such as X-ray dacryocystography, computed tomography, or magnetic resonance imaging can effectively evaluate the former, their success is much less in the evaluation of the latter. This is largely due to the fact that forced diagnostic injection of fluid into the canalicular system can overcome partial obstruction sites. On the other hand, lacrimal scintigraphy mimicks “physiological” lacrimal outflow, being performed under pressure gradients present in everyday life. This is why it is considered more suitable for the study of functional epiphora. Furthermore, quantitative lacrimal scintigraphy (with time-activity curves) enables the accurate measurement of lacrimal clearance from the conjunctival fornices and may be used to study the physiology of the lacrimal “pump.” Data obtained from the scintigraphic study of lacrimal outflow may be used to design more effective procedures in the management of functional and nonfunctional epiphora. This is a review article, based on a literature search with emphasis on recent publications and on those supporting interdisciplinary cooperation between ophthalmology and nuclear medicine.

MEG evaluation of taste by gender difference

Magnetoencephalographic recordings were evaluated in five different states: normal condition, sweet, bitter, sour, and salt taste. Twenty-eight healthy volunteers, 14 male and 14 female, ranging from 12 to 50 years of age, were included in the study. The results showed that, in the normal condition, as well as in the sweet and the bitter taste, the male volunteers exhibited a higher count of low-frequency than high-frequency channels compared to the femal ones; in the case of the sour taste, there was no clear differentiation between the genders; with the salt taste, the female volunteers exhibited a higher count of low-frequency channels whereas there was no clear differentiation in the number of high frequencies between the gender. A discrimination in the spatial distribution of the frequencies provides novel insights into the identification of gender-related taste sensation.

A study on the age dependency of gustatory states: Low-frequency spectral component in the resting-state MEG

Magnetoencephalography (MEG) recordings were evaluated for 25 healthy female volunteers, in five different gustatory states: normal, sweet, bitter, sour and salty. The study population was divided in two groups according to age: group A (10-19 years old) and group B (20-30 years old). There was a higher count of low frequencies (2 Hz) and a lower count of high frequencies (7 Hz) with increasing age, in all studied states. We compared each state for the frequencies of 2 Hz and 7 Hz between the two groups. Statistically significant differences were found in the normal and sweet states for the frequencies of 2 Hz and 7 Hz and in the salty taste in the frequency of 7 Hz. We also intra-compared the five states in group A and the five states in group B for the 2 Hz and 7 Hz frequencies. The results were not statistically significant. A differentiation in the distribution of the frequencies with increasing age may provide new insights into the age-dependence of taste quality brain centers.