Luigi Ferri

A systems medicine clinical platform for understanding and managing non- communicable diseases

Non-Communicable Diseases (NCDs) are among the most pressing global health problems of the twenty-first century. Their rising incidence and prevalence is linked to severe morbidity and mortality, and they are putting economic and managerial pressure on healthcare systems around the world. Moreover, NCDs are impeding healthy aging by negatively affecting the quality of life of a growing number of the global population. NCDs result from the interaction of various genetic, environmental and habitual factors, and cluster in complex ways, making the complex identification of resulting phenotypes not only difficult, but also a top research priority. The degree of complexity required to interpret large patient datasets generated by advanced high-throughput functional genomics assays has now increased to the point that novel computational biology approaches are essential to extract information that is relevant to the clinical decision-making process. Consequently, system-level models that interpret the interactions between extensive tissues, cellular and molecular measurements and clinical features are also being created to identify new disease phenotypes, so that disease definition and treatment are optimized, and novel therapeutic targets discovered. Likewise, Systems Medicine (SM) platforms applied to extensively-characterized patients provide a basis for more targeted clinical trials, and represent a promising tool to achieve better prevention and patient care, thereby promoting healthy aging globally. The present paper: (1) reviews the novel systems approaches to NCDs; (2) discusses how to move efficiently from Systems Biology to Systems Medicine; and (3) presents the scientific and clinical background of the San Raffaele Systems Medicine Platform.

Tumor Necrosis Factor Enhances SN38-Mediated Apoptosis in Mesothelioma Cells: The Role of Nuclear Factor-κB Pathway Activation

In the April 1, 2005, issue of Cancer, an article entitled “Tumor necrosis factor enhances SN38‐mediated apoptosis in mesothelioma cells: The role of nuclear factor‐κB pathway activation” was published by Dr. Russo and colleagues. On October 6, 2009, we were alerted to concerns about the integrity of the data in the article. A formal investigation was conducted by the Institutional Office for Research Integrity (UIR) at the National Institute for Cancer Research (IST) in Genoa, Italy. The investigation report from the UIR President, dated November 4, 2009, stated the following:

Use of functional independence measure in rehabilitation of inpatients with respiratory failure

Most outcomes do not deeply express the degree of disability in patients with respiratory failure (RF) following inpatient pulmonary rehabilitation (IPR). The aim of our study was to evaluate the efficacy of an IPR in patients with confirmed COPD and RF using functional independence measure (FIM) that determines the degree of disability experienced by patients and the progress they make during rehabilitation. This scale includes several items: self care, mobility, locomotion, communication and social recognition. Twenty-two patients (age 70+/-2 years, PO(2) 58.18+/-7.63mmHg, PCO(2) 46.82+/-9.11mmHg) were prospectively observed and studied. IPR included respiratory and peripheral muscle training, mucus evacuation techniques, and energy conservation techniques. FIM, Medical Research Council dyspnoea scale (MRC), St. Georges Respiratory Questionnaire (SGRQ), and 6-min walking distance (6-MWD) were assessed on admission (pre) and discharge (post) from IPR. After IPR there was a statistically significant improvement (p<0.01) in all the FIM items (total score in self care, mobility, locomotion, social recognition) except for communication. Changes of MRC (pre 4.32+/-0.84; post 3.00+/-1.15, p<0.001), SGRQ (%) (pre 69.86+/-4.62; post 46.50+/-11.94, p<0.001), and 6-MWD (pre 164.54+/-98.63; post 214.32+/-97.64, p<0.001) paralleled those improvements. An inverse correlation between MRC and FIM (r=-0.5042, p=0.016) was observed. Our preliminary study has shown that the benefits of IPR in COPD with RF do not only translate in dyspnoea, exercise capacity and quality of life but also within neuromotor disabilities as assessed by FIM. Our results warrant future studies in pulmonary rehabilitation using FIM as an outcome measure.

Use of 6-min and 12-min walking test for assessing the efficacy of formoterol in COPD.

Exercise tolerance is an important outcome measure in patients with COPD, mostly because there is evidence that exercise testing is superior to other functional measurements obtained at rest in demonstrating the positive effect of a specific intervention. We assessed the effect of a 5-day treatment with formoterol 12 microg twice daily on lung function, exercise capacity and dyspnea in 22 stable COPD patients, and compared 6-MWT with 12-MWT in evaluating formoterol efficacy. All subjects entered a crossover design. They underwent 6-MWT or 12-MWT in a randomised order and soon after started the 5-day treatment. After a 3-day washout, patients who had first performed 6-MWT, underwent 12-MWT, and the contrary. Formoterol induced a progressively significant increase in pre-drug FEV1 and IC and also significant changes in these parameters 2 h after its inhalation at each test day. Moreover, it increased the walked distance by 53.6 m at the end of 6-MWT and 59.9 m at the end of 12-MWT. Formoterol also induced a significant change in Borg score for dyspnea caused by the 6-MWT when compared with the pre-treatment values, whereas it significantly changed dyspnea induced by 12-MWT only after the first dose. Our study not only strengthens the importance of walking tests as a useful tool for evaluating the impact of a bronchodilator on some COPD patient-centred outcomes, but also indicates that 6-MWT seems to be a more appropriate instrument than 12-MWT for assessing the exercise response to a bronchodilator in COPD.

Is pulmonary function damaged by neoadjuvant lung cancer therapy? A comprehensive serial time-trend analysis of pulmonary function after induction radiochemotherapy plus surgery

OBJECTIVE We have analyzed short- and long-term variations of pulmonary function in locally advanced non-small cell lung cancer after induction chemoradiotherapy. METHODS Twenty-seven patients with stage IIIA (N2) non-small cell lung cancer underwent resection with radical intent after induction chemoradiotherapy in the period 2003 to 2006. Pulmonary function has been evaluated by spirometry, diffusing capacity of the lung for carbon monoxide, and blood gas analysis before induction chemoradiotherapy (T0), 4 weeks after induction chemoradiotherapy and before surgery (T1), and 1 (T2), 3 (T3), 6 (T4), and 12 months (T5) after surgery. RESULTS A 22.80% decrease of diffusing capacity of the lung for carbon monoxide (P < .001) was observed at T1. At T2 significant decreases in the following were present: vital capacity, -20.50% (P < .001); forced vital capacity, -22.50% (P < .001); forced expiratory volume in 1 second, -23.00% (P < .001); peak expiratory flow, -29.0 (P < .001); forced expiratory flow 25% to 75%, -13.7% (P = .005); and diffusing capacity of the lung for carbon monoxide, 43.6% (P < .001). However, in the interval between T2 and T5, a progressive improvement of lung function in most parameters was observed, but only diffusing capacity of the lung for carbon monoxide presented a significant increase (P < .001). Within the same time gap (T2 to T5), subjects 65 years of age or younger showed an increasing trend for vital capacity, forced expiratory volume in 1 second, total lung capacity, and residual volume significantly different from that of elderly patients, in whom a decrease in these parameters is reported. CONCLUSIONS An impairment of respiratory function is evident in the immediate postoperative setting in patients with non-small cell lung cancer receiving induction chemoradiotherapy. In the long-term period, a general recovery in diffusing capacity of the lung for carbon monoxide was found, whereas an improvement of forced expiratory volume in 1 second, vital capacity, total lung capacity, and residual volume was detected in the younger population only.

Rapid onset of bronchodilation with formoterol/beclomethasone Modulite and formoterol/budesonide Turbuhaler as compared to formoterol alone in patients with COPD.

In the present study, we examined whether there is a difference in the onset of bronchodilatation between formoterol/beclomethasone 12/200 μg Modulite and formoterol/budesonide 9/320 μg Turbuhaler in patients with COPD. We enrolled 28 patients with stable COPD. Both formoterol/beclomethasone and formoterol/budesonide elicited a larger mean FEV₁-AUC₀₋₁₅min than formoterol alone, whereas there was no significant difference between their FEV₁-AUC₀₋₁₅min. Also the change in FEV₁ 15 min after inhalation of formoterol/beclomethasone combination or formoterol/budesonide combination was greater than that induced by formoterol alone. This study confirms the rapid effect of the inhaled corticosteroid component when combined with formoterol and indicates that the onset of bronchodilation of formoterol/beclomethasone Modulite and formoterol/budesonide Turbuhaler are similar and greater than formoterol alone in patients with COPD.

BODE index and pulmonary rehabilitation in chronic respiratory failure.

To the Editors: We read with interest the article by Cote and Celli 1 regarding the beneficial effects induced by pulmonary rehabilitation (PR) on the BODE (body mass index (BMI), degree of airway obstruction, dyspnoea, exercise capacity) index (BI) in patients with chronic obstructive pulmonary disease (COPD). In an observational study, Cote and Celli 1 showed that the response to outpatient PR can be objectively measured using the BI, whose change provides information regarding ultimate survival, and that participation in a PR is associated with a decrease in the number of hospitalisations. This multidimensional 10-point scale has been previously shown to predict the death risk in COPD patients 2 …

Pulmonary rehabilitation following radical chemo-radiation in locally advanced non surgical NSCLC: Preliminary evidences

pulmonary rehabilitation (PR) has been fully included in the trategy for treatment of lung cancer [1]. Evidences from ranomised controlled trials (RCTs) are scarce and limited to the ost-surgical setting [2] but a systematic review on the topic as recently concluded that “(rehabilitative) interventions preperatively or post-cancer treatment are associated with positive enefits on exercise capacity, symptoms and some domains of RQoL” [3]. We have a long-standing interest in this approach [4–6] nd the positive results in our everyday clinical practice, based n extensive multidisciplinary cooperation, have prompted us to xplore its further application beyond the strictly “peri-surgical” etting. We have therefore offered to patients with locally advanced SCLC who are not suitable for surgical treatment an inpatient Pulonary Rehabilitation protocol (iPR), comprehensively described n [4] and summarised below. According to oncological guideines, these patients undergo concurrent chemo-radiation (CTRT) dministered with radical intent where pulmonary toxicity is one f the most important adverse effect limiting the delivered radition dose (and plausibly the overall cure rate). We report here ur preliminary findings, in a setting not matched with a control roup, on the feasibility and efficacy of this approach. Following nformed consent and communication to the local ethical comittee, according to national guidelines and regulations the iPR s routinely prescribed and performed on the basis of the pulonary functionality of patients. Following the chemo-radiation

Pulmonary rehabilitation in patients undergoing resection for non-small cell lung cancer. A preoperative and postoperative added value

We read with interest the report from Bobbio et al. on preoperative pulmonary rehabilitation (Pre-PR) in COPD/ non-small cell lung cancer (NSCLC) patients who are candidates for surgery [1]. We have recently published our own experience based on early stage NSCLC patients where surgery could not be considered due to impaired pulmonary function [2]. The eight patients who accepted to enter the study could then be operated (necessary functional criteria for surgery were re-met). Interestingly a degree of functional amelioration was noticed: increases were observed in the FVC, both in terms of volume and percentage of that predicted (+0.44 l and +12.9%, respectively) and less significantly in FEV1. Apart from this, an amelioration of the exercise endurance (6 min walking test) was reported. We would like to invite the authors of [1] to discuss the possible reasons for this difference (no substantial change in function, as expressed by volumes, in their experience vs a significant change in ours) whereas, apart from the differences in the protocol (the length and the ‘inpatient’ condition may have helped situations like suspension of smoking habit/compliance to therapy along with a comprehensive psychological support to foster motivation), we could attest to the fact that only patients with a very impaired function were enrolled in our observation and this fact may have given a certain enhancement to the relative improvement of volumes (potential interpretation bias). Our group has a long lasting interest in pulmonary rehabilitation in NSCLC surgical patients. In fact we have recently published our experience in postoperative pulmonary rehabilitation (Post-PR) whereas most functional parameters among treated (rehabilitated) patients were improved and, on the contrary, global function in the control group (non-rehabilitated patients) was homogeneously decreased [3]. Despite the substantial difference at baseline in functional terms of the two groups (rehabilitated worse, non-rehabilitated better), the comparison of treated vs untreated patients 1 month after the operation did not show significant difference thus demonstrating a clinically significant amelioration in the treated ones. Both the PrePR and the PostPR approaches have proved to benefit NSCLC patients who are candidates for or who have undergone surgery. For this reason we have planned a more comprehensive clinical experimentation to addmore power to our preliminary results within properly controlled prospected trials (weareperfectly aware thatat least in thePrePR setting, recruitment canbequitedifficult).Moreoverwearepursuinga translational approach investigating, on the clinical side, the value of the BODE index [4] as a validated indicator of the effects of PR and, on the opposite side of the translational research loop, the possible validation of some molecular biomarkers (mostly related to oxidative stress) to verify any potential match and value in the monitoring of the effects of PR in COPD and NSCLC surgical patients. As well we would like the authors [1] to briefly comment on these approaches in the light of fostering a comprehensive and constructive discussion towards the full inclusion of PR into the treatment strategy for NSCLC.

Could pulmonary postoperative physiotherapy really change postoperative morbidity

It is correct that the bicuspid aortic valve is associated with aortic dilatation in a relevant proportion of individuals. It appears overly simplistic to relate the aortopathy to flow turbulence; genetic factors seem to play a more dominant role [2]. We do agree that aortic dilatation, if present, requires correction, as we have previously pointed out [3]. It seems very hypothetical that a very liberal use of vascular grafts results in improved event-free survival. This will have to be carefully studied first, weighing risks and benefits. Plication of prolapsing cusps is only one of several possible techniques [4]. On the other hand, we have found it to be simple, reproducible and durable [5]. In summary, we appreciate interest and comments in this new and growing area of cardiac surgery.