Upgrading Monocytes Therapy for Critical Limb Ischemia Patient Treatment: Pre-Clinical and GMP-Validation Aspects

Advanced cell therapy medicinal products (ATMP) are at the forefront of a new range of biopharmaceuticals. The use of ATMP has evolved and increased in the last decades, representing a new approach to treating diseases that are not effectively managed with conventional treatments. The standard worldwide recognized for drug production is the Good Manufacturing Practices (GMP), widely used in the pharma production of synthesized drugs but applying also to ATMP. GMP guidelines are worldwide recognized standards to manufacture medicinal products to guarantee high quality, safety, and efficacy. In this report, we describe the pre-clinical and the GMP upgrade of peripheral blood mononuclear cell (PBMC) preparation, starting from peripheral blood and ending up with a GMP-grade clinical product ready to be used in patients with critical limb ischemia (CLI). We also evaluated production in hypoxic conditions to increase PBMC functional activity and angiogenic potential. Furthermore, we extensively analyzed the storage and transport conditions of the final product as required by the regulatory body for ATMPs. Altogether, results suggest that the whole manufacturing process can be performed for clinical application. Peripheral blood collected by a physician should be transported at room temperature, and PBMCs should be isolated in a clean room within 8 h of venipuncture. Frozen cells can be stored in nitrogen vapors and thawed for up to 12 months. PBMCs resuspended in 5% human albumin solution should be stored and transported at 4 degrees C before injection in patients within 24 h to thawing. Hypoxic conditioning of PBMCs should be implemented for clinical application, as it showed a significant enhancement of PBMC functional activity, in particular with increased adhesion, migration, and oxidative stress resistance. We demonstrated the feasibility and the quality of a GMP-enriched suspension of monocytes as an ATMP, tested in a clean room facility for all aspects related to production in respect of all the GMP criteria that allow its use as an ATMP. We think that these results could ease the way to the clinical application of ATMPs

Retrospective assessment of inguinal hernia repair in elderly outpatients

Background In the last ten years Day Surgery has significantly evolved, due to improvements in surgery and anaesthesia, and the need of reducing long term admission costs [1]. However, is Day Surgery suitable for elderly patients? The aim of this paper is to assess the risk of over 70 year-old outpatients who underwent inguinal hernia repair, and suggest an adequate preoperative pathway

Idiopathic Pulmonary Fibrosis (IPF) incidence and prevalence in Italy

Background: Studies of Idiopathic Pulmonary Fibrosis (IPF) epidemiology show regional variations of incidence and prevalence; no epidemiological studies have been carried out in Italy. Objective: To determine incidence and prevalence rates of IPF in the population of a large Italian region.Methods: in this cross-sectional study study data were collected on all patients of 18 years of age and older admitted as primary or secondary idiopathic fibrosing alveolitis (ICD9-CM 516.3) to Lazio hospitals, from 1/1/2005 to 31/12/2009, using regional hospital discharge, population and cause of death databases. Reporting accuracy was assessed on a random sample of hospital charts carrying the ICD9-CM 516.3, 516.8, 516.9 and 515 codes, by reviewing radiology and pathology findings to define cases as IPF “confident”, “possible” or “inconsistent”. Results: Annual prevalence and incidence of IPF were estimated at 25.6 per 100,000 and 7.5 per 100,000 using the ICD9-CM code 516.3 without chart audit while they were estimated at 31.6 per 100,000 and at 9,3 per 100,000 for the IPF “confident” definition after hospital chart audit. Conclusion: The data provide a first estimate of IPF incidence in Italy and indicate that incidence and prevalence in southern European regions may be similar to those observed in northern Europe and North America. (Sarcoidosis Vasc Diffuse Lung Dis 2014; 31: 191-197

Cavernostomy x Resection for Pulmonary Aspergilloma: A 32-Year History

<p>Abstract</p> <p>Background</p> <p>The most adequate surgical technique for the treatment of pulmonary aspergilloma is still controversial. This study compared two groups of patients submitted to cavernostomy and pulmonary parenchyma resection.</p> <p>Methods</p> <p>Cases of pulmonary aspergilloma operated upon between 1979 and 2010 were analyzed retrospectively. Group 1 consisted of patients submitted to cavernostomy and group 2 of patients submitted to pulmonary parenchyma resection. The following variables were compared between groups: gender, age, number of hospitalizations, pre- and postoperative length of hospital stay, time of follow-up, location and type of aspergilloma, preoperative symptoms, underlying disease, type of fungus, preoperative pulmonary function, postoperative complications, patient progression, and associated diseases.</p> <p>Results</p> <p>A total of 208 patients with pulmonary aspergilloma were studied (111 in group 1 and 97 in group 2). Group 1 was older than group 2. The number of hospitalizations, length of hospital stay and time of follow-up were higher in group 1. Hemoptysis was the most frequent preoperative symptom in group 1. Preoperative respiratory malfunction was more severe in group 1. Hemorrhagic complications and recurrence were more frequent in group 1 and infectious complications and residual pleural space were more common in group 2. Postoperative dyspnea was more frequent in group 2. Patient progression was similar in the two groups. No difference in the other factors was observed between groups.</p> <p>Conclusions</p> <p>Older patients with severe preoperative respiratory malfunction and peripheral pulmonary aspergilloma should be submitted to cavernostomy. The remaining patients can be treated by pulmonary resection.</p

SPIRAL CT AND ENDOOSCOPIC FINDINGS IN A CASE OF TRACHEOBRONCHOPATIA OSTEOCHONDROPLASTICA

Impact factor: 1,32

Oral corticosteroids can improve nocturnal isolated hypoxemia in stable COPD patients with diurnal PaO2 > 60 mmHg

The aim of this study was to evaluate whether a short therapy cycle of oral methylprednisolone plus conventional therapy might improve isolated nocturnal hypoxemia evidenced through pulse-oxymetry in 28 patients (19 M/9 F; mean age 71 +/- 8.31) with stable moderate to severe COPD (average FEV1 of 43.33 +/- 9.38 of theoretical) and daytime PaO2 > 60 mmHg. All patients showed oxygen desaturation during the night and apnoea/hypoapnoea index <= 10, measured by means of a nocturnal polysomnography and were successfully on conventional treatment for COPD. The patients were randomly divided into two groups: 14 (steroid group) were administered methylprednisolone for three weeks at progressively decreasing doses (16 mg/die for the first 7 days, then 8 mg die for another 7 days, and finally 4 mg die for another 7 days) plus conventional therapy (bronchodilators and inhaled corticosteroids). The remaining 14 patients (control group) instead were on conventional therapy only. After 3 weeks for the steroid group, but no for the control group, was improved next parameters (p < 0.0001): VC (L) dropped from 2.53 +/- 0.85 measured at baseline to 2.82 +/- 0.84, FEV1 dropped from 1.07 +/- 0.31 L to 1.23 +/- 0.31 L, the IC dropped from 1.71 +/- 0.48 to 2 +/- 0.37L, the average nocturnal SPO2% from 90.4 +/- 1.79 to 92.3 +/- 1.72 and the Nocturnal Time % of SPO2 < 90% went from 31.19 +/- 18.12 to 10.88 +/- 11.56 after 3 weeks of therapy. Also dyspnoea, sleep duration and mean heart rate significantly improved (p < 0.0001). There was also a significant correlation between average increase in mean nocturnal SPO2% and in Lowest SPO2% and the variation in inspiratory capacity (IC) and in Sleep Duration % in the steroid group (p < 0.0001). In conclusion, methylprednisolone in combination with conventional medical therapy not only improved lung function values but also mean nocturnal oxyhemoglobin saturation and sleep duration in clinically stabilized COPD patients who experience nocturnal oxyhemoglobin desaturation