One-Lung Ventilation and Postoperative Pulmonary Complications After Major Lung Resection Surgery. A Multicenter Randomized Controlled Trial.

OBJECTIVES: The effect of one-lung ventilation (OLV) strategy based on low tidal volume (TV), application of positive end-expiratory pressure (PEEP), and alveolar recruitment maneuvers (ARM) to reduce postoperative acute respiratory distress syndrome (ARDS) and pulmonary complications (PPCs) compared with higher TV without PEEP and ARM strategy in adult patients undergoing lobectomy or pneumonectomy has not been well established. DESIGN: Multicenter, randomized, single-blind, controlled trial. SETTING: Sixteen Italian hospitals. PARTICIPANTS: A total of 880 patients undergoing elective major lung resection. INTERVENTIONS: Patients were randomized to receive lower tidal volume (LTV group: 4 mL/kg predicted body weight, PEEP of 5 cmH2O, and ARMs) or higher tidal volume (HTL group: 6 mL/kg predicted body weight, no PEEP, and no ARMs). After OLV, until extubation, both groups were ventilated using a tidal volume of 8 mL/kg and a PEEP value of 5 cmH2O. The primary outcome was the incidence of in-hospital ARDS. Secondary outcomes were the in-hospital rate of PPCs, major cardiovascular events, unplanned intensive care unit (ICU) admission, in-hospital mortality, ICU length of stay, and in-hospital length of stay. MEASUREMENTS AND MAIN RESULTS: ARDS occurred in 3 of 438 patients (0.7%, 95% CI 0.1-2.0) and in 1 of 442 patients (0.2%, 95% CI 0-1.4) in the LTV and HTV group, respectively (Risk ratio: 3.03 95% CI 0.32-29, p = 0.372). Pulmonary complications occurred in 125 of 438 patients (28.5%, 95% CI 24.5-32.9) and in 136 of 442 patients (30.8%, 95% CI 26.6-35.2) in the LTV and HTV group, respectively (risk ratio: 0.93, 95% CI 0.76-1.14, p = 0.507). The incidence of major complications, in-hospital mortality, and unplanned ICU admission, ICU and in-hospital length of stay were comparable in both groups. CONCLUSIONS: In conclusion, among adult patients undergoing elective lung resection, an OLV with lower tidal volume, PEEP 5 cmH2O, and ARMs and a higher tidal volume strategy resulted in low ARDS incidence and comparable postoperative complications, in-hospital length of stay, and mortality.

Postoperative pulmonary complications and mortality after major abdominal surgery. An observational multicenter prospective study.

BACKGROUND: Postoperative pulmonary complications (PPCs) significantly contribute to postoperative morbidity and mortality. We conducted a study to determine the incidence of PPCs after major elective abdominal surgery and their association with early and 1-year mortality in patient without pre-existing respiratory disease. METHODS: We conducted a multicenter observational prospective clinical study in 40 Italian centers. 1542 patients undergoing elective major abdominal surgery were recruited in a time period of 14 days and clinically managed according to local protocol. The primary outcome was to determine the incidence of PPCs. Further, we aimed to identify independent predictors for PPCs and examine the association between PPCs and mortality. RESULTS: PPCs occurred in 12.6% (95% CI 11.1-14.4%) of patients with significant differences among general (18.3%, 95% CI 15.7-21.0%), gynecological (3.7%, 95% CI 2.1-6.0%) and urological surgery (9.0%, 95% CI 6.0-12.8%). PPCs development was associated with known pre- and intraoperative risk factors. Patients who developed PPCs had longer length of hospital stay, higher risk of 30-days hospital readmission, and increased in-hospital and one-year mortality (OR 3.078, 95% CI 1.825-5.191; P<0.001). CONCLUSIONS: The incidence of PPCs in patients without pre-existing respiratory disease undergoing elective abdominal surgery is high and associated with worse clinical outcome at one year after surgery. General surgery is associated with higher incidence of PPCs and mortality compared to gynecological and urological surgery.

Synthesis and biological evaluation of new camptothecin derivatives obtained by modification of position 20.

The preparation and biological evaluation of a novel series of dimeric camptothecin derivatives are described. All the new compounds showed a significant ability to inhibit human tumor cell growth with IC(50) values ranging from 0.03 to 12.2 µM. The interference with the activity of the nuclear enzymes topoisomerases has been demonstrated, highlighting the poison effect of one of the obtained byproducts toward topoisomerase I. A moderate antiangiogenic activity has been demonstrated for one of the obtained compounds. Moreover, the effects of four new compounds on caspases activity and ROS generation have been studied on transgenic mouse cell.

Histone deacetylase and microtubules as targets for the synthesis of releasable conjugate compounds.

Design and synthesis of an HDAC inhibitor and its merger with three tubulin binders to create releasable conjugate compounds is described. The biological evaluation includes: (a) in vitro reactivity with glutathione, (b) antiproliferative activity, (c) cell cycle analysis and (d) quantification of protein acetylation. The cellular pharmacology study indicated that the HDAC-inhibitor-drug conjugates retained antimitotic and proapoptotic activity with a reduced potency.

Synthesis and biological evaluation of epothilone A dimeric compounds.

The preparation and biological evaluation of a novel series of dimeric epothilone A derivatives (1-6) are described. Two types of diacyl spacers were introduced to establish the various dimeric epothilone A constructs. The effect of these compounds on tubulin polymerization and their cytotoxicity against four different cancer cell lines are reported. Several of the newly synthesized compounds inhibit endothelial cell differentiation and endothelial cell migration that are key steps of the angiogenic process.

Effectiveness and Tolerability of Repeated Courses of Viscosupplementation in Symptomatic Hip Osteoarthritis: A Retrospective Observational Cohort Study of High Molecular Weight vs. Medium Molecular Weight Hyaluronic Acid vs. No Viscosupplementation.

Background: Nonsurgical management of symptomatic hip osteoarthritis needs real-world evidence. We evaluated the effectiveness and tolerability of US-guided intra-articular treatment of two hyaluronic acids (HAs) commercially available in Italy and investigated predictors of response. Methods: Outpatient records including three cohorts: 122 subjects treated with medium (1,500-3,200 kDa; Hyalubrix®) molecular weight (MW) or high (hylan G-F20; Synvisc®) MW HAs and 20 controls taking NSAIDs/analgesics on demand were retrospectively analyzed. Pain VAS score, WOMAC, NSAID/analgesic consumption, and causes of suspension were available at 1, 6, 12, and 24 months after first administration. As selection bias usually affects observational retrospective studies, a quasi-randomization process was attained by performing propensity score approach. Results: Propensity score adjustment successfully allowed comparisons among balanced groups of treatments. VAS and WOMAC considerably decreased over time in treated groups independently of the radiological grade (p<0.001). On the other hand, the control group showed only a slight and rather uneven variation in VAS. Mean score changes were comparable in both HA cohorts from the earliest stages (ΔVAS(HA1,500-3,200kDa)T1vsT0 = -20%; ΔVAS(hylan G-F20)T1vsT0 = -23%/ΔWOMAC(HA1,500-3,200kDa)T1vsT0 = -17%; ΔWOMAC(hylan G-F20)T1vsT0 = -19%), reaching a further substantial reduction after 12 months (ΔVAS(HA1,500-3,200kDa)T12vsT0 = -52%; ΔVAS(hylan G-F20)T12vsT0 = -53%/ΔWOMAC(HA1,500-3,200kDa)T12vsT0 = -45%; and ΔWOMAC(hylan G-F20)T12vsT0 = -47%). Almost 11% (=13/122) of ineffectiveness and few moderate local side effects 3% (=4/122) were detected. Conclusions: Viscosupplementation in a real-life setting seems to provide a sound alternative in pain management in comparison to oral NSAIDs/analgesics, guaranteeing a reduced intake of pain killer medications. Analgesic effectiveness, functional recovery, and reduced joint stiffness extend and improve over 12 and 24 months, suggesting that repeated administrations achieve an additive effect.

Reliability and validity of the Italian version of the hand functional disability scale in patients with systemic sclerosis.

The English version of hand functional disability scale is a validated instrument for measuring hand involvement in patients with systemic sclerosis (SSc). Because validation of multiple-language versions of existing validated questionnaires plays a key role in standardizing the outcome measurement and increasing the statistical power of clinical studies, this study aims to validate a translated Italian version of hand functional disability scale which is not available at the moment. The Italian version of hand functional disability scale was tested on 50 patients with SSc. To determine test-retest reliability, 40 SSc patients were asked to complete the questionnaire a second time within 2 weeks of the initial testing session. The test-retest reliability and internal consistency were determined by intra-class correlation coefficient (ICC) and Cronbach's alpha. External consistency was measured by comparing with an already validated test, the Health Assessment Questionnaire (HAQ), and clinical measurements. To explore the relationships among these variables, multiple correspondence analysis (MCA) was adopted. The statistical analysis of each domain and the total score revealed a good test-retest reliability (ICCs > 0.75) and internal consistency (Cronbach's alpha > 0.7). Furthermore, a good external consistency was confirmed by evaluating the differences between the distributions of hand functional disability scale score for SSc patients with or without hand involvement (arthralgias, arthritis, flexion contractures, and digital ulcers) and comparing results with those obtained for HAQ. Finally, MCA demonstrates a strong correlation among functional disability scale areas and HAQ scores. The hand functional disability scale is a self-administered questionnaire and it has been specially developed to measure hand impairment in patients with hand disorders. Our data support its validity and reliability in Italian SSc patients.

Camptothecin-7-yl-methanthiole: semisynthesis and biological evaluation.

The introduction of a methylenthiol group at position 7 of camptothecin was carried out in four steps. This preparation also yielded the corresponding disulfide, which behaves as a prodrug due to its reactivity with glutathione. Assessment of their antiproliferative activities, investigations of their mechanism of action, and molecular modeling analysis indicated that the 7-modified camptothecin derivatives described herein maintain the biological activity and drug-target interactions of the parent compound.