Azienda Ospedaliero-Universitaria Careggi Research Articles

Pre-pectoral breast reconstruction with tissue expander entirely covered by acellular dermal matrix: feasibility, safety and histological features resulting from the first 64 procedures.

Reconstructive options that can be used following conservative mastectomy, skin-, nipple-sparing and skin-reducing mastectomies, allow a remarkable variety of safe methods to restore the natural shape and aesthetics of the breast mound. In case of two-stage breast reconstruction, tissue expanders (TEs) are usually placed in a subpectoral position. The purpose of this retrospective cohort study is to evaluate the feasibility and safety of two-step reconstruction with TE in pre-pectoral position covered by acellular dermal matrix (ADM). Between March 2021 and May 2023, at the Azienda Ospedaliero Universitaria Careggi, University of Florence, 55 patients with BRCA 1/2 mutations or early breast cancer underwent conservative mastectomy with immediate pre-pectoral reconstruction using TE covered with ADM, followed by a second surgery with replacement of the expander with definitive prosthesis. Demographic, oncological, and histological data along with surgical complications were recorded. A total of 64 conservative mastectomies were performed. In 2 patients (3.1%) complications were found that required reintervention and, in both cases, the TE had to be removed. Two patients developed hematoma and one patient developed seroma. Two patients showed wound dehiscence, both healed after conservative treatment and without implant exposure. No case of necrosis of the skin or nipple-areola complex has been observed, neither of capsular contracture. Capsule formed around TE was populated with cells and blood vessels and showed a thin area of synovial metaplasia. In selected cases it may be more cautious to perform a two-stage breast reconstruction after radical breast surgery by means of TEs. The placement of TEs in pre-pectoral position combines the excellent aesthetic and functional results of the pre-pectoral philosophy with a quite safer and more prudent two-step approach. Our experience reports optimistic results: the ADM covering the TE is seen successfully integrating during tissue expansion and becoming a vascularised new self-tissue. Complications rates are low and such ADM-assisted two-stage pre-pectoral reconstructive technique is a safe, practical, and reproducible method.

Whole Exome Sequencing in Vaccine-Induced Thrombotic Thrombocytopenia (VITT).

Background: In February 2021, a few cases of unusual, severe thrombotic events associated with thrombocytopenia reported after vaccination with ChAdOx1 nCoV-19 (Vaxzevria) or with Johnson & Johnson's Janssen vaccine raise concern about safety. The vaccine-induced thrombotic thrombocytopenia (VITT) has been related to the presence of platelet-activating antibodies directed against platelet Factor 4. Objectives: We investigated VITT subject genetic background by a high-throughput whole exome sequencing (WES) approach in order to investigate VITT genetic predisposition. Methods: Six consecutive patients (females of Caucasian origin with a mean age of 64 years) were referred to the Atherothrombotic Diseases Center (Department of Experimental and Clinical Medicine, Azienda Ospedaliero-Universitaria Careggi, Florence) with a diagnosis of definite VITT underwent WES analysis. WES analysis was performed on the Illumina NextSeq500 platform. Results:WES analysis revealed a total of 140,563 genetic variants. Due to VITT's rare occurrence, we focused attention on rare variants. The global analysis of all high-quality rare variants did not reveal a significant enrichment of mutated genes in biological/functional pathways common to patients analyzed. Afterwards, we focused on rare variants in genes associated with blood coagulation and fibrinolysis, platelet activation and aggregation, integrin-mediated signaling pathway, and inflammation with particular attention to those involved in vascular damage, as well as autoimmune thrombocytopenia. According to ACMG criteria, 47/194 (24.2%) rare variants were classified as uncertain significance variants (VUS), whereas the remaining were likely benign/benign. Conclusion: WES analysis identifies rare variants possibly favoring the prothrombotic state triggered by the exposure to the vaccine. Functional studies and/or extensions to a larger number of patients might allow a more comprehensive definition of these molecular pathways.

The decision-making process in out-of-hospital cardiac arrest: from complexity to opportunities.

Intensive Care Unit and Regional ECMO Referral Centre, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy Received 1 May 2023 Accepted 3 May 2023. Correspondence to Chiara Lazzeri, MD, Intensive Care Unit and Regional ECMO Referral Centre Emergency Department, Largo Brambilla 3, 50134, Florence, Italy, Tel: +39 55 7947823; fax: +39 55 7947821; e-mail: [email protected]

310 CLINICAL COURSE AND CHARACTERISTICS OF ADVANCED HEART FAILURE ASSOCIATED WITH ARRHYTHMOGENIC CARDIOMYOPATHY

Abstract Background The prevalence and course of heart failure (HF) in arrhythmogenic cardiomyopathy (ACM) is unresolved, and previous studies have mostly focused on the right-dominant variant of the disease, less prone to HF. Conversely, ACM variants with left ventricular (LV) involvement are now increasingly recognized, often initially ‘mis-diagnosed’ as dilated cardiomyopathy. Aim of this study was therefore to describe the prevalence and clinical course of advance HF in the full clinical spectrum of ACM. Methods We retrospectively reviewed records of all ACM patients diagnosed before 2021 from 3 Italian Cardiomyopathy Referral Centres (Azienda Ospedaliero Universitaria Careggi; Policlinico Sant’Orsola; Azienda Ospedaliero Universitaria Sant’Andrea). LV involvement was diagnosed in the presence of subepicardial late gadolinium enhancement (LGE) in at least 3 contiguous segments in the same short-axis slice at cardiac magnetic resonance, independent of whether it fulfilled the 2010 Task Force criteria for right-dominant ACM (biventricular ACM) or not (left-dominant ACM); in this latter case, diagnosis was reached after careful exclusion of other differential diagnosis, and only when at least one of the following features was present: likely pathogenic/pathogenic genetic variant associated with ACM; familial history of ACM; electrocardiographic abnormalities suggestive of ACM with LV involvement. Advanced HF was defined as NYHA functional class III/IV and/or referral for heart transplantation. Median follow-up was 6 years. Results Forty-four out of 174 ACM patients (25%) developed advanced HF: 10 right-dominant ACM and 34 with LV involvement. Twenty ACM patients were initially diagnosed with dilated cardiomyopathy; as such, development of advanced HF in 17 cases preceded the diagnosis of ACM. Five patients were diagnosed with ACM after heart transplantation, by histological examination. In the other 22, median time from ACM diagnosis to advanced HF development was 4 years. As compared to those without, advanced HF patients were more likely to present LV involvement. During clinical course, 20 (46%) advanced HF patients received at least one appropriate ICD intervention, with 13 experiencing an electrical storm. Twenty-six (59%) patients required HF-related hospitalization, and 32 (72%) were referred for heart transplantation with 25 ultimately receiving it. ACM patients with advanced HF, compared to those without, experienced a higher rate of mortality (36% vs. 6%; OR 3.5 [95%CI: 1.4-8.7], p=0.01) and ventricular arrhythmic events (41% vs. 11%; OR 2.4 [95%CI: 1.1-5.0], p=0.02). Conclusions Advanced HF progression in ACM is not rare, and occurs more frequently in variants with LV involvement. Advanced HF is associated with increased mortality and arrhythmic risk.

P2731Genetic ancestry analysis of the Italian founder population carrying the cardiac amyloidosis-causing variant Val122Ile in the transthyretin gene

Abstract Background Transthyretin amyloidosis is a life-threatening disorder caused by the deposition of TTR amyloid in various tissues and organs. The most common worldwide pathogenic variant with almost exclusive cardiac involvement is Val122Ile (rs76992529), with an allele frequency of 3.5% in the U.S. African-American population, but rare in Caucasians. Unexpectedly, we identified 23 Caucasian individuals with Val122Ile in our amyloidosis referral center (9 affected patients, 14 carriers), belonging to 9 unrelated families. Purpose To determine the ancestral origin of the Tuscan founder population of TTR Val122Ile carriers. Methods A total of 24 individuals were included in the analysis (our 23 probands and relatives from Val122Ile families and the Caucasian reference sample NA10851 (CEU – Utah resident with European ancestry). All samples were genotyped using the EUROFORGEN Global AIM-SNP array1, inclusive of 127 highly informative SNPs to infer genetic ancestry. We have performed a principal component analysis (PCA) of the 9 unrelated probands and NA10851, compared with the Phase 3 of the 1000 Genomes Project data, comprising 2504 unrelated individuals from >20 distinct populations.(Figure 1). Results As shown in Figure 1, all our samples but one (from Argentina) cluster very close to the super-cluster of European populations, and distant from the populations of African ancestry. The proband from Argentina and the Caucasian reference sample NA10851 cluster close to Mexicans and Peruvians, and the super-cluster of European populations, respectively, confirming the robustness of the analysis. Conclusion Based on this result, we can confidently conclude that our samples from Tuscan families in which the TTR Val122Ile variant segregates are of ancestral European origin, with no mixed African ancestry, implying that the same variant originated in Africans and Europeans independently and not as result of genetic admixture. These findings suggest the presence of a mutational hot spots in TTR, with potential impact on the epidemiology of amyloidosis worldwide. Acknowledgement/Funding The present study was supported by an Investigator-Initiated Research to Azienda Ospedaliero Universitaria Careggi from Pfizer Srl.

Reperfusion Injury after ischemic Stroke Study (RISKS): single-centre (Florence, Italy), prospective observational protocol study

IntroductionTreatments aiming at reperfusion of the acutely ischaemic brain tissue may result futile or even detrimental because of the so-called reperfusion injury. The processes contributing to reperfusion injury involve a...

Spectrum and burden of neglected tropical diseases observed in an infectious and tropical diseases unit in Florence, Italy (2000-2015).

Neglected tropical diseases (NTDs) are a diverse group of acute and chronic conditions with distinct characteristics that thrive mainly among the poorest populations, almost exclusively in tropical countries. To evaluate the relevance and impact of NTDs in a temperate area, the number and features of patients diagnosed with NTDs at the Infectious and Tropical Diseases Unit (ITDU), Azienda Ospedaliero-Universitaria Careggi, Florence, Italy between 2000 and 2015 were retrospectively reviewed. Overall 289 NTD cases were diagnosed in 283 subjects accounting for 2.4% of all patients accessing the center: 96 dengue, 62 schistosomiasis, 36 strongyloidiasis, 22 cystic echinococcosis, 19 Chagas disease, 14 leishmaniasis, 11 chikungunya, 10 cysticercosis, 6 soil-transmitted helminthiasis, 6 lymphatic filariasis, 3 trachoma, 2 onchocerciasis, and 2 leprosy. There was one fatal case of disseminated strongyloidiasis. According to the type of exposure, 145 (50.2%) NTDs were diagnosed in immigrants, 121 (41.9%) in travelers, 18 (6.3%) were autochthonous infections, while in 5 cases (1.7%), the type of exposure was unknown. The number of patients seen at the ITDU with a diagnosis of NTD increased over time (from 29 in 2000-2005 to 81 in 2006-2010, to 173 in 2011-2015). Late diagnosis and mismanagement before coming to the center were common features in several cases. Considering the increasing incidence and possible misdiagnosis of NTDs in non-endemic countries, to raise awareness about NTDs among health care providers seems to be of primary concern.

Cardiovascular risk stratification in patients with non-valvular atrial fibrillation: the 2MACE score.

Recent findings suggest that patients with non-valvular atrial fibrillation (AF), in addition to having a high risk for ischemic stroke, are also at risk for myocardial infarction (MI). The aim of the study was to combine factors predicting Major Adverse Cardiovascular Events (MACE) in AF patients, including fatal/nonfatal MI, cardiac revascularization, and cardiovascular death, into a simple risk score. Predictors of MACE were obtained from a prospective observational cohort study, including 1019 AF patients taking vitamin K antagonists from the Atherothrombosis Center, of Sapienza University of Rome. Thus, we derived the 2MACE score [2 points for Metabolic Syndrome and Age ≥75, 1 point for MI/revascularization, Congestive heart failure (ejection fraction ≤40%), thrombo-Embolism (stroke/transient ischemic attack)], ranging from 0 to 7 points. To evaluate the 2MACE score, we included an external validation cohort of 1089 anticoagulated AF patients from the Thrombosis Centre of Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy. At follow-up, 111 AF patients in the internal and 68 in the external cohort experienced a MACE. The 2MACE score showed a good ability in discriminating AF patients experiencing MACE both in the internal derivation cohort, with a c-index of 0.79 [95% Confidence Interval (CI) 0.71-0.90, p<0.001] and in the external validation cohort (c-index 0.66, 95% CI 0.60-0.73, p<0.001). The overall Hazard Ratio (HR) was 1.61 (95% CI 1.40-1.85, p<0.001) for each additional point. A 2MACE score ≥3 had the best combination of specificity and sensitivity, with an HR of 3.92 (95% CI 2.41-6.40, p<0.001). The new simple 2MACE score may help identifying AF patients at risk for cardiovascular events.

Morbidly obese patients in emergency department

aEmergency Intensive Care Unit bEmergency Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy Correspondence to Stefano Bambi, RN, MSN, Emergency Intensive Care Unit, Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 1, 50132 Florence, Italy Tel: +39 055 797 473; fax: +39 055 794 7821; e-mail: [email protected];[email protected] Received February 3, 2013 Accepted March 21, 2013

Prothrombotic burden in a patient with recurrent thrombotic events: might an early assessment of thrombophilia be useful in the presence of a strong family history for vascular events?

A 55-year-old man (A. Z.) was admitted to Our Cardiac Step Down Unit of the tertiary center: Careggi Hospital, for an evaluation in the presence of a history of recurrent cardiovascular events. Classical cardiovascular risk factors: Hypertension on therapy with a good control, type 2 diabetes mellitus on metformin (3 g/day) with good glycemic control (glycated hemoglobin 5.6 %), high LDL cholesterol levels on statin treatment (rosuvastatin 20 mg/day) reaching a target of LDL 42 mg/dl; low HDL levels (24 mg/dl) on treatment, overweight (BMI 27.6). With regard to family history, almost all his relatives had suffered from a cardiovascular event (Fig. 1) at a young age. The first thrombotic event occurred at the age of 44 when he had an ischemic stroke without neurological sequelae treated with medical therapy. Aspirin therapy was spontaneously discontinued by the patient after about 4 years. At the age of 52, he had a STEMI treated with thrombolysis and subsequently underwent coronary angiography that demonstrated the presence of a critical stenosis in the right coronary artery (RCA) treated by angioplasty and drug-eluting stent (DES) implantation. One year later (on aspirin and clopidogrel), he suffered from an anterior STEMI initially treated with thrombolysis. A subsequent coronary angiography showed a critical stenosis of the left anterior descending artery (LAD), treated with balloon angioplasty and implantation of a DES on LAD and first and second diagonal branches. The course was complicated by acute intrastent thrombosis of the second diagonal branch, treated with the deployment of another DES. A few months later, a myocardial scintigraphy demonstrated signs of previous subendocardial necrosis in the mid-distal portion of the anterior wall and in the apex with mild inducible ischemia in the same area. At the age of 55—on dual antiplatelets—he had a recurrent inferior STEMI treated with thrombolysis, heparin and clopidogrel. After 1 day, a coronary angiography demonstrated a stenosis of LAD and circumflex artery and critical stenosis of RCA with image of complex plaque, which was treated with DES implantation. Previously implanted stents on first and second diagonal branches were patent. Echocardiography showed normal left chambers diameters and ventricular ejection fraction (EF 55 %) without valve diseases. The patient was then referred to our Cardiac Step Down Unit of Careggi Hospital. Because of his personal and family history, a thrombophilic screening was performed with these results: heterozygous mutations of both factor V Leiden and factor II G20210A; low levels of free protein S (52 %; n.v. \75 %); high levels of factor VIII (210 %; n.v. 60–150 %); elevated Lipoprotein(a) (893 mg/l; n.v.\300 mg/l) (Fig. 1). One month later, he was submitted to a myocardial perfusion stress test with dipyridamole, which was negative. A myocardial perfusion scintigraphy, a few months later, was positive for reversible uptake defects in LAD territory. Because of the presence of two stenoses on the LAD and the high estimated thrombotic risk, the patient was advised to undergo coronary artery bypass graft (CABG) but, after his refusal, a percutaneous coronary intervention (PCI) (triple DES implantation of the double stenosis on LAD II and on the critical stenosis of LAD III) was performed and E. Cecchi C. Giglioli Department of Heart and Vessels, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy

Liver Lesion Characterization: The Wrong Choice of Contrast Agent Can Mislead the Diagnosis of Hemangioma

AJR 2012; 199:W662 0361–803X/12/1995–W662 © American Roentgen Ray Society Liver Lesion Characterization: The Wrong Choice of Contrast Agent Can Mislead the Diagnosis of Hemangioma Over the past few years, abdominal radiology experts studying the liver have increased the usage of liver-specific gadolinium-chelate contrast agents. These agents are gadobenate dimeglumine (MultiHance, Bracco) and gadoxetate (Primovist, Bayer HealthCare), with different biliary rate excretion (5% and 50%) and liver-specific phase acquisition time (120 and 20 minutes), respectively. This great difference in biliary clearance requires the radiologist’s consideration, especially in the study of focal lesions. In fact, with Primovist, the equilibrium phase (180 seconds) is an early-uptake stage because of the quick accumulation of the contrast agent in hepatic cells. Therefore, we must consider a false washout at the equilibrium phase, in which Primovist is retained in the hemangioma, which nonetheless appears isoor hypointense on T1-weighted images because of the increasing signal intensity of the surrounding healthy hepatic parenchyma. This implies that hemangiomas may have a misleading contrast imaging pattern with Primovist, without the usual, well-demonstrable fill in, as assessed by Gupta et al. [1] who showed the different contrast imaging pattern of hemangiomas with Primovist and MultiHance. This nontypical pattern of hemangiomas with Primovist does not represent a significant problem in detecting large masses, which are already well recognizable on unenhanced acquisitions. However, it can be difficult to properly characterize small lesions that may not be benign [2]. In particular, it can be complicated when we observe small multiple hemangiomas—sometimes with a prevalent fibrous component and relatively low signal intensity in heavily T2-weighted acquisitions—that have not been documented in previous examinations or, as often occurs in daily practice, in patients lacking an accurate clinical history or previous examination (e.g., occasional hepatic lesion seen on an ultrasound examination) (Fig. 1). These problems can be amplified if, to optimize examination time, the radiologist chooses to apply the Primovist inverse study protocol, in which only the T1-weighted sequences are acquired before the dynamic phase, and T2weighted and diffusion-weighted sequences are acquired in the contrast-enhanced phase before the hepatobiliary phase is acquired. Such an inverse modality is based on studies that have highlighted that Primovist does not influence the T2-weighted and diffusionweighted sequences, and our experience confirms these data [3]. Of course, the saving in time is relevant, but the risk of selecting an unsuitable contrast agent is increased. On the basis of these considerations, to avoid the risk of making mistakes or at least to deal with divergent patterns in patients without a clinical history or with a suspicion of hemangioma, we prefer the use of MultiHance, which can act as a non–liver-specific gadolinium chelate (with an appropriate dynamic phase) and, if necessary, make it possible to acquire a hepatobiliary phase. Silvia Pradella Silvia Lucarini Stefano Colagrande Azienda Ospedaliero-Universitaria Careggi, Florence, Italy DOI:10.2214/AJR.12.8951 WEB—This is a Web exclusive article.

Association of Marfan syndrome and bicuspid aortic valve: Frequency and outcome

a Cardiology Service, CMSR Veneto Medica, Altavilla Vicentina, Italy b Department of Medical and Surgical Critical Care, University of Florence, Center of the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Disease to Develop Novel Therapies, University of Florence, Italy c Department of Heart and Vessels, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Italy d S. Maria agli Ulivi Center, Fondazione Don Carlo Gnocchi, Onlus, IRCCS, Florence, Italy

Letter to the Editor

Emergency Intensive Care Unit, Azienda Ospedaliero Universitaria Careggi, 50139 Florence, Italy, [email protected] The author has disclosed that he has no significant relationships with, or financial interest in any commercial companies pertaining to this article.

Commentary on: Economic evaluation of human papilloma virus vaccination in the European Union: a critical review

The article by Koleva et al. [1] in current issue is unusual reading for the public of IEM. First, systematic reviews of economic evaluations are still uncommon in general medical journals. Second, this review on HPV vaccination deals with a very important public health topic, which, on the other hand, is not a typical theme for this journal. There are good reasons for the Clinical Evidence and HTA section of IEM to present such articles. Cost effectiveness reviews represent a methodological challenge and, as such, are relevant and intriguing regardless of their object. Furthermore, cost-issues are by their nature a general medical issue, because the cost of resources spent in one field of health care compete with the money spent in others. Finally, an economic publication on a vaccine in a general medical journal is a chance for readers to be challenged by the diverse methodological problems which are encountered in the complex area of screening and vaccines [2]. Coming to Koleva et al.’s message [1], we notice that the authors are critical regarding cost-effectiveness of HPV vaccination as measured in the reviewed studies, despite the fact that all but one concluded in favour of vaccination. However, they mention other reviews of economic evaluations which reach similar conservative conclusions [3, 4].They finally observe that vaccination cost-effectiveness was sensitive to the assumptions made in sensitivity analyses and that non-sponsored evaluations were somehow more cautious and restrictive. Koleva et al. [1] are particularly dubious about the validity of life-long modelling of the effects of screening vaccination campaigns, based on a few years follow-up of RCTs and on assumptions borrowed from current data. The comments raised by Koleva et al. [1] are reasonable. Nevertheless, we have to deal with the limits that we face in performing EEs. In particular, everybody would agree that, for clinical and health policy decisions, it would be desirable to have long term data to work on, rather than referring to assumptions in statistical models. Conditions under which decisions are made are very often different from the desired ones. Models allow to ‘‘rationalize future uncertainty’’, framing uncertainty within probabilistic models. This is an imperfect method, with large margins of subjectivity, but on the other hand it makes possible—based on more or less optimistic scenarios—to generate forecasts based on epidemiological and clinical data available today, using such predictions to inform decision making. Furthermore, the process is dynamic and it allows to update the estimates by including the evidence provided by new studies. Regarding the level of subjectivity associated with the selection of model components, if the hypotheses are not ‘‘specious’’, but ‘‘reasonable’’ and ‘‘standard/coherent’’ with the literature [5, 6], then the emerging scenario will present a few levels of ‘‘controlled and conscious subjectivity’’. In other words, the limits of the results and the G. Virgili (&) Department of Specialized Surgical Sciences, University of Florence and Azienda Ospedaliero-Universitaria Careggi, V.le Morgagni 85, 50134 Florence, Italy e-mail: gianni.virgili@unifi.it

Utilities and QALYs in health economic evaluations: glossary and introduction

Economics studies the optimal allocation of resources for the production of benefits to the society. By definition, resources are limited, and healthcare systems must face this condition every day. This may explain why economic evaluations are increasingly used as a key component of decision making. For instance, they represent a mainstay in any Health Technology Assessment (HTA) exercise and are subject to a guidelines’ development process [1]. After the assessment of the efficacy and safety of health interventions, economic evaluations enter to compare alternative options in terms of costs and consequences. Full economic evaluations consist of a comparison of both costs (resource use) and consequences (outcomes, effects) of alternative strategies [2]. If Cochrane reviews are intended to help providers, practitioners and patients in making informed decisions about health care interventions, they cannot afford to ignore their economic aspects. Cochrane reviews assemble, select, critique and combine reliable data from multiple research studies on the effectiveness and other issues related to healthcare interventions. The latest version of the Cochrane Handbook for Systematic Reviews of Interventions [3], freely accessible at http://www.cochrane-hand book.org, acknowledges that incorporating economic perspectives and evidence into Cochrane reviews can enhance their usefulness and applicability for healthcare decisionmaking. An entire chapter (‘‘Incorporating economics evidence’’), provides guidance on how authors of systematic reviews can collect the best evidence on the economic aspects of interventions in addition to the best evidence on their clinical effectiveness [4]. A leading point here is to expand our knowledge on efficiency (optimal use of resources) after having established effectiveness (whether treatments work) [5]. The main types of full economic evaluations (costeffectiveness, cost-utility and cost-benefit analyses) compare alternative interventions in terms of both costs (resource use) and consequences (effects) and can be included in Cochrane reviews, as well as studies that only focus on costs and resource use, without comparing health alternatives, i.e. partial economic evaluations [4]. Cost-effectiveness analyses measure the effects of an intervention and its comparators in identical units of outcome (e.g. mortality), thus comparing them in terms of ‘cost per unit of effect’ [5]. In a cost-benefit analysis both resource use and effects of alternative interventions are G. Virgili (&) Department of Specialised Surgical Sciences, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Florence, Italy e-mail: gianni.virgili@unifi.it

Targeted delivery of albumin bound paclitaxel in the treatment of advanced breast cancer

Taxanes are chemotherapeutic agents with a large spectrum of antitumor activity when used as monotherapy or in combination regimens. Paclitaxel and docetaxel have poor solubility and require a complex solvent system for their commercial formulation, Cremophor EL(R) (CrEL) and Tween 80(R) respectively. Both these biological surfactants have recently been implicated as contributing not only to the hypersensitivity reactions, but also to the degree of peripheral neurotoxicity and myelosuppression, and may antagonize the cytotoxicity. Nab-paclitaxel, or nanoparticle albumin-bound paclitaxel (ABI-007; Abraxane(R)), is a novel formulation of paclitaxel that does not employ the CrEL solvent system. Nab-paclitaxel demonstrates greater efficacy and a favorable safety profile compared with standard paclitaxel in patients with advanced disease (breast cancer, non-small cell lung cancer, melanoma, ovarian cancer). Clinical studies in breast cancer have shown that nab-paclitaxel is significantly more effective than standard paclitaxel in terms of overall objective response rate (ORR) and time to progression. Nab-paclitaxel in combination with gemcitabine, capecitabine or bevacizumab has been shown to be very active in patients with advanced breast cancer. An economic analysis showed that nab-paclitaxel would be an economically reasonable alternative to docetaxel or standard paclitaxel in metastatic breast cancer. Favorable tumor ORR and manageable toxicities have been reported for nab-paclitaxel as monotherapy or in combination treatment in advanced breast cancer.

The CHOLEGAS study: multicentric randomized, blinded, controlled trial of gastrectomy plus prophylactic cholecystectomy versus gastrectomy only, in adults submitted to Gastric cancer surgery with curative intent

BackgroundThe incidence of gallstones and gallbladder sludge is known to be higher in patients after gastrectomy than in general population. This higher incidence is probably related to surgical dissection of the vagus nerve branches and the anatomical gastrointestinal reconstruction. Therefore, some surgeons perform routine concomitant cholecystectomy during standard surgery for gastric malignancies. However, not all the patients who are diagnosed to have cholelithiasis after gastric cancer surgery will develop symptoms or require additional surgical treatments and a standard laparoscopic cholecystectomy is feasible even in those patients who underwent previous gastric surgery. At the present, no randomized study has been published and the decision of gallbladder management is left to each surgeon preference.DesignThe study is a randomized controlled investigation. The study will be performed in the General and Oncologic Surgery, Department of Oncology – Azienda Ospedaliero-Universitaria Careggi – Florence – Italy, a large teaching institution, with the participation of all surgeons who accept to be involved in, together with other Italian Surgical Centers, on behalf of the GIRCG (Italian Research Group for Gastric Cancer).The patients will be randomized into two groups: in the first group the patient will be submitted to prophylactic cholecystectomy during standard surgery for curable gastric cancer (subtotal or total gastrectomy), while in the second group he/she will be submitted to standard gastric surgery only.Trial RegistrationClinicalTrials.gov ID. NCT00757640

Prognostic Value of ECG Among Patients with Acute Pulmonary Embolism and Normal Blood Pressure

Objective To investigate the prognostic value of electrocardiography (ECG) alone or in combination with echocardiography in patients with acute pulmonary embolism and normal blood pressure. Methods Consecutive adult patients presenting to the emergency department at Azienda Ospedaliero-Universitaria Careggi with the first episode of pulmonary embolism were included. Patients with systolic blood pressure less than 100 mm Hg were excluded. ECG and echocardiography were performed within 1 hour from diagnosis and evaluated in a blinded fashion. Right ventricular strain was diagnosed in the presence of one or more of the following ECG findings: complete or incomplete right ventricular branch block, S1Q3T3, and negative T wave in V1-V4. The main outcome measurement was clinical deterioration or death during in-hospital stay. The association of variables with the main outcome was evaluated by multivariate Cox survival analysis. Results A total of 386 patients with proved pulmonary embolism were included in the study; 201 patients (52%) had right ventricular dysfunction according to echocardiography, and 130 patients (34%) showed right ventricular strain. Twenty-three patients (6%) had clinical deterioration or died. At multivariate survival analysis, right ventricular strain was associated with adverse outcome (hazard ratio 2.58; 95% confidence interval, 1.05-6.36) independently of echocardiographic findings. Patients with both right ventricular strain and right ventricular dysfunction (26%) showed an 8-fold elevated risk of adverse outcome (hazard ratio 8.47; 95% confidence interval, 2.43-29.47). Conclusion Right ventricular strain pattern on ECG is associated with adverse short-term outcome and adds incremental prognostic value to echocardiographic evidence of right ventricular dysfunction in patients with acute pulmonary embolism and normal blood pressure.

A 48-year-old woman with dyspnoea on exertion, anemia and thrombocytopenia

Dr. Micheli: A 48-year-old woman was admitted to our hospital after a 2-month history of dyspnoea on exertion. She did not report fever, sweats, chills, chest pain or recent weight loss. Twenty years before she had undergone mitral commissurotomy for rheumatic mitral stenosis. One week before current admission, the patient was seen in the emergency department (ED) because of paroxysmal atrial fibrillation. Synchronized electrical cardioversion was performed with recover of sinus rhythm. Echocardiography showed mitral stenosis with a valve area 1 cm and mild pulmonary hypertension. Results of routine laboratory tests were normal except for anemia and thrombocytopenia (platelet count 35,000/mm, hemoglobin 11.1 g/dl). Seven months before admission, these values were in the normal range. After discharge, the patient continued to experience dyspnoea while walking for a short distance and orthopnea. Eleven years before she had undergone excision of a right breast carcinoma, and had received a 6-month cycle of adjuvant chemotherapy. No local or systemic relapse had subsequently been documented. She worked as a pianist. There was no history of allergies. She did not report diabetes mellitus, illicit drug use, smoke history, alcohol use, hypertension, dyslipidemia or family history of heart disease or cancer. She did not consume medications except propafenone that had been prescribed in the ED a few days before. On physical examination, the patient was not in acute distress. Blood pressure was 115/70 mmHg, pulse rate 98 beats/min, respiratory rate16 breaths/min, temperature 36 C and SpO2 98% while she was breathing room air. Lungs fields were clear on auscultation. A low-frequency holodiastolic murmur and mitral valve opening snap were heard over the cardiac apex. There was neither peripheral oedema nor increased jugular venous pressure. Peripheral pulses were normal and symmetrical. Abdomen was soft and non-tender. No masses or enlarged organs were detectable. There were no petechiae, ecchymoses, skin rash or lymphadenopathy. Neurologic examination was unremarkable. An electrocardiogram showed sinus rhythm. A blood gas analysis was normal. Thrombocytopenia (38,000/mm) was confirmed and pseudo-thrombocytopenia was excluded. On second hospital day, the patient abruptly developed left hemiplegia and dizziness. A CT scan of the head excluded acute intracranial hemorrhage. NIHSS was 12. The hospital Stroke Team was alerted within 30 min after the onset of symptoms but thrombolytic therapy was not performed because of the low platelet count. The patient underwent cerebral angiography that revealed diffuse bilateral microemboli not suitable for mechanical revascularization. Transesophageal echocardiography showed left appendage thrombosis. Intravenous heparin therapy S. Del Pace C. Alderighi R. Rasoini (&) R. Alterini S. Micheli G. Santoro Clinica Medica Generale e Cardiologia, Department of Heart and Vessels, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Viale Morgagni 85, 50134 Florence, Italy e-mail: raffaele.rasoini@tiscali.it