San Raffaele Cimena, Italy
San Raffaele Cimena, Italy

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Bernardi R.,San Raffaele Scientific Institute | Gianni L.,San Raffaele Hospital
Cell Research | Year: 2014

Triple negative breast cancers (TNBC) are clinically heterogeneous but mostly aggressive malignancies devoid of expression of the estrogen, progesterone and HER2 (ERBB2 or NEU) receptors. Recent evidence shows that basal endoplasmic reticulum stress (ERS) is typically activated in TNBC and cooperates with hypoxia signaling to promote tumor progression and relapse; ERS and hypoxia response may therefore be among the long-searched hallmarks of TNBC. © 2014 IBCB, SIBS, CAS.

John Camm A.,St George's, University of London | Colombo A.,San Raffaele Hospital | Corbucci G.,Boston Scientific Italy | Padeletti L.,University of Florence
Heart Rhythm | Year: 2014

Background/Objective Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. It is associated with increased risk for stroke mainly due to cardiac embolism from the left atrial appendage (LAA). Occlusion of the LAA by means of a device represents a valid alternative to oral anticoagulation, mainly in patients who cannot tolerate this therapy because of a high bleeding risk. Recent data on the endocardial device WATCHMAN show encouraging results for this patient population in terms of stroke risk reduction compared to the expected rate as well as in terms of implant success. This article reviews all relevant publications related to the main surgical and transcatheter devices used for LAA closure (LAAC). Methods/Results PROTECT-AF, the first prospective randomized trial conducted on this technique, showed that LAA occlusion using the WATCHMAN was noninferior to warfarin for a combined end-point in patients with nonvalvular AF. There is a lack of large-scale randomized trials on long-term stroke risk in patients submitted to LAAC. Most studies are relatively small and focus on the comparison of different surgical techniques with regard to complete/incomplete closure success. More recently, PROTECT-AF long-term results (4-year follow-up) demonstrated that LAAC was statistically superior to warfarin in terms of efficacy. Conclusion This review concludes that it is now appropriate to consider these techniques for patients with AF who are at high risk for stroke for whom effective conventional or novel anticoagulant therapy is not available or who present problems in managing drug treatment. © 2014 Heart Rhythm Society.

Solini A.,University of Pisa | Usuelli V.,San Raffaele Hospital | Fiorina P.,San Raffaele Hospital | Fiorina P.,Harvard University
Journal of the American Society of Nephrology | Year: 2015

Intracellular ATP is the most vital source of cellular energy for biologic systems, whereas extracellular ATP is a multifaceted mediator of several cell functions via its interaction, in an autocrine or paracrine manner, with P2 purinergic receptors expressed on the cell surface. These ionotropic and metabotropic P2 purinergic receptors modulate a variety of physiologic events upon the maintenance of a highly sensitive "set point," the derangement of which may lead to the development of key pathogenic mechanisms during acute and chronic diseases. Growing evidence suggests that extracellular ATP signaling via P2 purinergic receptors may be involved in different renal pathologic conditions. For these reasons, investigators and pharmaceutical companies are actively exploring novel strategies to antagonize or block these receptors with the goal of reducing extracellular ATP production or accelerating extracellular ATP clearance. Targeting extracellular ATP signaling, particularly through the P2X7 receptor, has considerable translational potential, given that novel P2X7-receptor inhibitors are already available for clinical use (e.g., CE224,535, AZD9056, and GSK1482160). This review summarizes the current evidence regarding the involvement of extracellular ATP and its P2 purinergic receptor-mediated signaling in physiologic and pathologic processes in the kidney; potential therapeutic options targeting extracellular ATP purinergic receptors are analyzed as well. Copyright © 2015 by the American Society of Nephrology.

News Article | November 18, 2015

Descriptions of a drug as revolutionary, transformative or a home run are usually reserved for press releases or presentations to investors. But oncologists are embracing such language to describe two drugs that allow them to offer some people with breast cancer a cure rather than a consolation. The drugs are trastuzumab (Herceptin) and pertuzumab (Perjeta). Both are antibody-based agents that target the signalling protein HER2, which is produced in abundance in 20–25% of breast tumours. The high levels result in poorly controlled cell growth and proliferation. For decades, the protein has been regarded as the hallmark of a dire prognosis, says oncologist Luca Gianni, at the San Raffaele Hospital Scientific Institute in Milan, Italy. Today, many patients with HER2-positive tumours are essentially having their cancer eradicated by receiving a double-hit of targeted therapy before surgery. Even patients diagnosed with late-stage, metastatic disease — once seen as an imminent death sentence — are living much longer than ever before. In a few exceptional cases, the duration of these benefits can be remarkable. “We never use the 'c-word' with metastatic disease, but I have one patient in my practice who has been in complete remission for 13 years,” says Shanu Modi, a medical oncologist at New York's Memorial Sloan Kettering Cancer Center. “I think of her as a cured person who just comes by my clinic to visit every three months.” These two agents exemplify the modern model of targeted therapy in oncology — give patients personalized treatments that selectively hit tumours based on their specific set of mutations, rather than conventional chemotherapy, which is broadly toxic to healthy as well as dangerous cells. Nevertheless, cancers will return in many people who receive prompt treatment. “I still don't think we're curing the vast majority of patients,” says Modi. New agents in the clinical pipeline could improve the effectiveness of these targeted agents and help doctors and patients to achieve more and longer-lasting victories, although some worry that soaring costs (see 'Crippling costs') will limit the reach of these next-generation therapeutics. Trastuzumab was the first HER2-targeting drug to reach the market, following a phase 3 clinical trial that showed that the drug improved the odds of survival by 20% in women with metastatic HER2-positive breast cancer1. Subsequent data showed that giving people the drug after the surgical removal of early-stage tumours cut the risk of the cancer returning in half2. “That's an absolute home run,” says Elizabeth Mittendorf, a surgical oncologist at Houston's MD Anderson Cancer Center. “We don't see numbers like that often in oncology.” In 2012, data from the CLEOPATRA clinical trial showed that oncologists could expect an even better return by pairing trastuzumab with pertuzumab3. Both drugs are antibodies that specifically bind HER2, but each recognizes a different site on the protein, and their combined effects (along with conventional chemotherapy) resulted in even greater tumour shrinkage and further improvements in prognosis for people with metastatic breast cancer. The combination prolonged median survival by well over a year relative to trastuzumab alone. “We give that combination to all of our metastatic patients as first-line treatment if we can,” says Modi, “and they're being treated for three or four years on average.” In two further trials4, 5, by using the trastuzumab–pertuzumab combination to shrink tumours before surgery — an approach known as neoadjuvant therapy — clinicians discovered that they could eradicate all traces of cancer from the breast and lymph nodes (known as a pathological complete response) in roughly half of patients. That is not the same as a cure, however, and these trials are too recent to confirm how durable the benefits are. Still, physicians are already seeing clear benefits in other domains. Mittendorf says she can now perform less-invasive operations that leave the breast largely intact, and neoadjuvant treatment can eliminate lymph node growths that previously required surgical removal. Oncologists are now eagerly awaiting the results from the recently concluded APHINITY trial, which measured survival and recurrence in patients given the combined therapy after surgery. Other HER2-targeted therapies have reached the clinic, but without offering such a clear patient benefit. Lapatinib, for example, delays tumour progression by interfering with HER2 signalling, but also exhibits more toxicity and is generally less effective as a first line of treatment than its antibody-based counterparts. As a result, lapatinib is generally reserved for late-stage treatment of patients whose tumours acquire resistance to trastuzumab or pertuzumab. Importantly, this treatment may also be effective at limiting metastatic growth in the brain — a particular threat to patients who are HER2-positive (see 'Staving off a deadly invasion'). Another HER2-targeted drug called T-DM1 (Kadcyla) mitigates the severe toxicity associated with conventional chemotherapy agents by physically tethering the chemotherapeutic agent DM1 to trastuzumab. This restricts the toxic effect to HER2-expressing cells. “There's no hair loss and very little neuropathy,” says Modi. “I think patients are enjoying a much better quality of life on T-DM1.” As one of the first antibody–drug conjugates to reach the clinic, T-DM1 extends median survival by more than five months in patients with recurrent HER2-positive breast cancer relative to lapatinib. A recently concluded trial called MARIANNE examined whether T-DM1 could replace trastuzumab and chemotherapy as the first line of treatment. Although less toxic than the standard drug combination, T-DM1 proved no more effective at delaying disease progression, and so will probably remain a second-line option. Gianni hopes that these results will not prevent clinicians from finding smart ways to incorporate this safe and generally effective drug into their regimens. “T-DM1 was presented as the solution to all of our problems, and now it's being demonized as an expensive failure — but this is not so,” he says. “It is simply a drug that requires some better thinking and a different approach.” The ability to target HER2 has been a life saver for many patients, but it is far from a complete victory. Many people who receive neoadjuvant treatment will not have their cancer eradicated. And although oncologists can keep cancer in people with metastatic disease at bay for years, this requires multiple rounds of therapeutic attack with a shifting arsenal of drugs. “The chance of having a durable response is much higher, and we're seeing patients with metastatic disease go through five, six or seven lines of treatment,” says Nancy Lin, an oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts. “But the disease is generally not curable.” The mechanisms by which HER2-positive tumours acquire resistance to the drugs that once laid them low are poorly understood. Gianni sees the tumour environment, which contains a diverse mixture of cells with distinct mutational profiles, as part of the problem. “If 30% of the cells in a tumour overexpress HER2, that's a HER2-positive tumour,” he says, “but many cells still do not express that target.” Thus, killing off trastuzumab-vulnerable cells will still leave a large cancerous community. This highlights the value of generalized chemotherapy, and Francisco Esteva at New York University's Langone Medical Center suggests that this phenomenon may also be to blame for T-DM1's modest performance in MARIANNE. “If you target too much, the other clones can escape,” he says. However, Thomas Bachelot, a medical oncologist at the Centre Léon Bérard, in Lyon, France, does not believe that this is the only mechanism by which tumours can recur after an initial therapeutic victory. “I do a lot of biopsies, and they always remain HER2-positive — they don't lose it,” he says, adding that even if the tumour rebounds while patients are taking trastuzumab or pertuzumab, they still draw some benefit from those drugs. If HER2-targeted therapies are halted, he says, patients tend to fare even worse than if they had stayed the course. This outcome hints at other cellular pathways and processes that amplify or mitigate the effects of HER2-targeted treatment. These pathways might therefore serve as useful biomarkers to guide therapy. The trial data point to sub-populations with strong responses in both directions — one neoadjuvant trial4 found that nearly 17% of patients had a pathological complete response from targeted drugs without any chemotherapy, a result that suggests that some patients could skip the most toxic components of treatment. Other tumours remain stubbornly unresponsive. “About 10% of our HER2-positive patients do not respond at all to trastuzumab and pertuzumab,” says Bachelot. “There is this huge primary resistance, and we don't know why.” Another apparent pathway to resistance arises from hyperactivation of a signalling cascade known as the phosphoinositide 3-kinase (PI3K) pathway. Preliminary clinical studies suggested that everolimus, a drug that interferes with PI3K signalling, might increase the effectiveness of trastuzumab against metastatic breast cancer. Although results from two phase 3 trials proved disappointing, subsequent examination of the data revealed that everolimus may delay progression in patients with mutations that affect PI3K activity6. However, Modi believes that future studies should hit this pathway through alternate means. “You can get a few weeks improvement from everolimus, but with a lot of toxicity,” she says. “There have got to be better drugs for targeting PI3K.” Her team is evaluating one such drug, BYL719, and has also seen promising results from another approach to bolstering HER2-targeted treatment. Tumour cells rely on a molecule called heat-shock protein 90 (HSP90) to manage the production of HER2, and Modi and colleagues have found that chemical inhibition of HSP90 can stall HER2-dependent tumour growth7. “In our first phase 2 trial, we combined an HSP90 inhibitor with Herceptin and saw a nearly 25% response rate from just these two agents, without any chemo,” she says. Her team is working with two different HSP90 inhibitors, including a compound that can be isotopically labelled so that the extent to which tumours are taking up the drug can be directly monitored. Most breast tumours also show excessive activity by the receptors that respond to the reproductive hormones oestrogen and progesterone, and numerous studies suggest that these hormone receptors influence the response to HER2-targeted drugs. Data from dual-therapy neoadjuvant trials indicate that the pathological complete response rate jumps from around 50% to more than 80% in patients with hormone receptor-negative tumours5. A growing body of data demonstrate that these two signalling pathways collaborate to promote growth8, suggesting that multiple hits may be necessary to limit the tumour's escape routes. Ultimately, combinations of highly targeted treatments with more broadly active therapy regimens may hold the key to ensuring that no patient with cancer gets left behind, Gianni says. “We now have plenty of drugs that exploit different mechanisms of action,” he says. “The challenge is to use them in the optimal way.” For now, these targeted therapies are giving some patients the opportunity to live cancer-free, and giving many others the prospect of additional years of life — and a chance to think differently about their futures. “It's completely changed the conversation in my office,” Mittendorf says.

Benedetti S.,University College London | Hoshiya H.,University College London | Tedesco F.S.,University College London | Tedesco F.S.,San Raffaele Hospital
FEBS Journal | Year: 2013

Muscular dystrophies are genetic disorders characterized by skeletal muscle wasting and weakness. Although there is no effective therapy, a number of experimental strategies have been developed over recent years and some of them are undergoing clinical investigation. In this review, we highlight recent developments and key challenges for strategies based upon gene replacement and gene/expression repair, including exon-skipping, vector-mediated gene therapy and cell therapy. Therapeutic strategies for different forms of muscular dystrophy are discussed, with an emphasis on Duchenne muscular dystrophy, given the severity and the relatively advanced status of clinical studies for this disease. Muscular dystrophies are severe genetic disorders characterized by muscle wasting. Although there is no effective therapy, different experimental strategies have been developed. Here, we highlight recent experimental therapies based upon gene replacement and gene/expression repair, including exon-skipping, vector-mediated gene therapy and cell therapy. Different forms of muscular dystrophy will be discussed, with an emphasis on Duchenne muscular dystrophy. © 2013 The Authors Journal compilation © 2013 FEBS.

Gianni L.,San Raffaele Hospital
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

PURPOSE The AVEREL trial [A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab)/Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer] evaluated first-line bevacizumab-containing therapy for human epidermal growth factor receptor 2 (HER2) -positive locally recurrent/metastatic breast cancer (LR/MBC). PATIENTS AND METHODS Patients with measurable/evaluable HER2-positive LR/MBC who had not received trastuzumab or chemotherapy for LR/MBC were stratified by prior adjuvant trastuzumab, prior (neo)adjuvant taxane, hormone receptor status, and measurable disease and were randomly assigned to receive docetaxel 100 mg/m(2) plus trastuzumab 8 mg/kg loading dose followed by 6 mg/kg either with bevacizumab 15 mg/kg or without bevacizumab, all administered every 3 weeks. The primary end point was progression-free survival (PFS). Additional end points included overall survival, response rate (RR), safety, quality of life, and translational research. Results Baseline characteristics of the 424 patients were balanced between treatment arms. Most patients had visceral metastases, 43% had a disease-free interval less than 12 months, and 85% had measurable disease. Median follow-up was 26 months. The hazard ratio for investigator-assessed PFS was 0.82 (95% CI, 0.65 to 1.02; P = .0775; median PFS, 13.7 v 16.5 months in the non-bevacizumab and bevacizumab arms, respectively; PFS events in 72%). The Independent Review Committee-assessed PFS hazard ratio was 0.72 (95% CI, 0.54 to 0.94; P = .0162; median PFS, 13.9 v 16.8 months, respectively; PFS events in 53%). The RR was 70% versus 74%, respectively (P = .3492). Grade ≥ 3 febrile neutropenia and hypertension were more common with bevacizumab-containing therapy. High baseline plasma vascular endothelial growth factor A (VEGF-A) concentrations were associated with greater bevacizumab benefit (not statistically significant). CONCLUSION Combining bevacizumab with docetaxel and trastuzumab did not significantly improve investigator-assessed PFS. The potential predictive value of plasma VEGF-A is consistent with findings in HER2-negative LR/MBC, warranting prospective evaluation.

Maisano F.,San Raffaele Hospital | La Canna G.,San Raffaele Hospital | Colombo A.,San Raffaele Hospital | Alfieri O.,San Raffaele Hospital
Journal of the American College of Cardiology | Year: 2011

The edge-to-edge technique is a versatile procedure for mitral valve repair. Its technical simplicity has been the prerequisite for the development of a number of transcatheter technologies to perform percutaneous mitral valve repair. The evolution from a standard open heart surgical to percutaneous procedure involved the application of the technique in minimally invasive robotic surgery and direct access (transatrial) off-pump suture-based repair and finally in the fully percutaneous approach with either suture-based or device (clip)-based approach. The MitraClip (Abbott Vascular, Menlo Park, California) is currently available for clinical use in Europe, and it is mainly applied to treat high-risk patients with functional mitral regurgitation. A critical review of the surgical as well as the early percutaneous repair data is necessary to elucidate the clinical role and the potential for future developments of the edge-to-edge repair in the treatment of mitral regurgitation. © 2011 American College of Cardiology Foundation.

Sessa C.,San Giovanni Hospital | Sessa C.,San Raffaele Hospital
Annals of Oncology | Year: 2011

The clinical development of PARP inhibitors for the treatment of tumors deficient in BRCA1 or BRCA2 is based on the concept of synthetic lethality. From the initial proof of concept study with the PARP1 inhibitor olaparib (AZD2281) in BRCA mutation carriers, in which 28% of ovarian cancer patients achieved an objective response, the target population of ovarian patients potentially sensitive to treatment with PARP inhibitors has greatly increased. Objective responses have been observed in both platinum-sensitive and platinum-resistant BRCA mutation carriers but, more recently, also in BRCA negative 'BRCAness' patients, those with no BRCA mutations but with a dysfunction of the homologous recombination (HR) system, which makes them more sensitive to the antitumor agents which cause double strand breaks of DNA. The recent results achieved with olaparib, given as maintenance in platinum sensitive recurrent high grade serous ovarian cancer, in response after reinduction with platinum, confirm the antitumor effect of single agent olaparib in BRCAness patients. Main topics of investigations in this field are the identification of BRCAness phenotype and the definition of tests to identify BRCAness patients. More in general, additional preclinical studies are needed to further improve clinical results in order to define the optimal regimen of combination with PARP1 inhibitor and cytotoxics or molecular targeted agents (sequence of administration, interval between dosing of the agents, duration of treatment). © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Braga M.,San Raffaele Hospital
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2012

PURPOSE OF REVIEW: In the last year, several meta-analyses focused on the potential clinical benefits of perioperative immunonutrition in surgical patients. Purpose of this review is to summarize their results and to draw recommendations about the current indication of immunonutrition in surgery. RECENT FINDINGS: Standard enteral preparations have been modified by adding specific nutrients, such as arginine, omega-3 fatty acids and others, which have been shown to upregulate immune response, to control inflammatory response, and to improve gut function after surgery. The majority of the randomized trials found that perioperative immunonutrition improved short-term outcome in patients, who underwent elective major gastrointestinal (GI) surgery. Four meta-analyses including a large number of randomized clinical trials reported that perioperative immunonutrition is associated with a substantial reduction in both infection rate and length of hospital stay. These results have been found in both upper and lower GI patients, regardless of their baseline nutritional status. Promising results have been found also in head and neck surgery. SUMMARY: In the light of these findings the use of perioperative immunonutrition should be implemented in patients undergoing elective major GI surgery. This should result in a considerable reduction in both postoperative morbidity and costs for healthcare systems.Larger trials are required before recommending immunonutrition as a routine practice in head and neck surgery. © 2012 Wolters Kluwer Health.

Buzzatti N.,San Raffaele Hospital
European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery | Year: 2013

Computed tomography (CT) is an increasingly utilized method for the evaluation of patient suitability for transcatheter aortic valve implantation (TAVI). The aim of this study was to analyse the role of CT in the choice of prosthesis and the prevention of residual aortic regurgitation (RAR). From November 2007 to September 2010, 115 patients (median age 81 years, inter-quantile range (IQR) 76-85; median ejection fraction 55%, IQR 45-60; median logistic EuroSCORE 19.7, IQR 11.0-32.1) undergoing TAVI were evaluated with a pre-procedural CT. An aortic complex was evaluated with multi-planar reconstructions, and we defined significant early RAR as RAR ≥ 2, and prosthesis/annulus mismatch (PAM) as the ratio between prosthesis size and mean annular size. All analyses were conducted for the whole sample and then separately for the two types of prosthesis implanted. An Edwards-SAPIEN(®) prosthesis was implanted in 62 patients (54.7%), and a Medtronic CoreValve(®) in 52 (45.2%). Aortic annulus minimum and maximum diameters were 22.6 ± 2.1 and 26.0 ± 2.3 mm, respectively. The aortic annulus diameter and the length of the free edge of the aortic cusps were linearly related to a 1:1 ratio (P < 0.0001). Significant RAR (34 patients, 30%) appeared directly related to the annulus diameters (particularly maximum and medium diameters, P = 0.0003 and P = 0.0010, respectively) and cusp length (P = 0.0007) but inversely correlated with PAM (P = 0.0006). Prosthesis/annulus oversizing was associated with a reduction in RAR, with a cut-off of 7% as the limit below which RAR increases; moreover, we observed different cut-off values for the Edwards and CoreValve prostheses, although statistical significance was not reached for the CoreValve (respectively, 2% with P < 0.0001, 11% with P = 0.16). No association was found between PAM and possible PAM-related complications. CT evaluation prior to TAVI showed that RAR was directly correlated with aortic root dimensions (particularly maximum and medium annulus diameters and cusp lengths) and inversely correlated with PAM. Oversizing the prosthesis by at least 7% reduces the risk of RAR. CT is an essential and invaluable tool in the assessment of patients undergoing TAVI.

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