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Fuchs C.S.,Dana-Farber Cancer Institute | Tomasek J.,Masaryk Memorial Cancer Institute | Yong C.J.,Yonsei University | Dumitru F.,Emergency County Hospital Dr Constantin Opris | And 21 more authors.
The Lancet | Year: 2014

Background Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. Methods We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24-87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384. Findings 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3-9·9) in patients in the ramucirumab group and 3·8 months (1·7-7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603-0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605-0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. Interpretation Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer.


Radaelli F.,Valduce Hospital | Paggi S.,Valduce Hospital | Hassan C.,Nuovo Regina Margherita Hospital | Senore C.,Centro Of Prevenzione Oncologica Cpo Piemonte | And 7 more authors.
Gut | Year: 2015

Objective Although a split regimen of bowel preparation has been associated with higher levels of bowel cleansing, it is still uncertain whether it has a favourable effect on the adenoma detection rate (ADR). The present study was aimed at evaluating whether a split regimen was superior to the traditional 'full-dose, day-before' regimen in terms of ADR. Design In a multicentre, randomised, endoscopistblinded study, 50-69-year-old subjects undergoing first colonoscopy after positive-faecal immunochemical test within an organised colorectal cancer organised screening programmes were 1:1 randomised to receive low-volume 2-L polyethylene glycol (PEG)-ascorbate solution in a 'split-dose' (Split-Dose Group, SDG) or 'day-before' regimen (Day-Before Group, DBG). The primary endpoint was the proportion of subjects with at least one adenoma. Secondary endpoints were the detection rates of advanced adenomas and serrated lesions at per-patient analysis and the total number of lesions. Results 690 subjects were included in the study. At per-patient analysis, the proportion of subjects with at least one adenoma was significantly higher in the SDG than in the DBG (183/345, 53.0% vs 141/345, 40.9%, relative risk (RR) 1.22, 95% CI 1.03 to 1.46); corresponding figures for advanced adenomas were 26.4% (91/345) versus 20.0% (69/345, RR 1.35, 95% CI 1.06 to 1.73). At per-polyp analysis, the total numbers of both adenomas and advanced adenomas per subject were significantly higher in the SDG (1.15 vs 0.8, p <0.001; 0.36 vs 0.22, p<0.001). Conclusions In an organised screening setting, the adoption of a split regimen resulted into a higher detection rate of clinically relevant neoplastic lesions, thus improving the effectiveness of colonoscopy. Based on such evidence, the adoption of a split regimen for colonoscopy should be strongly recommended. Clinical trial registration number NCT02178033. © 2015 BMJ Publishing Group Ltd & British Society of Gastroenterology.


Kalinka-Warzocha E.,University of Lodz | Plazas J.G.,Hospital General Universitario Of Elche | Mineur L.,Sainte Catherine Institute | Salek T.,Narodny Onkologicky Ustav | And 4 more authors.
Gastric Cancer | Year: 2015

Background: Potentially myelosuppressive doublet and triplet chemotherapy combination regimens are considered the most active treatments in gastric cancer. This multicenter prospective observational study was designed to gain insight into the chemotherapy regimens being used in Europe and to evaluate neutropenia management in patients identified as at high risk for febrile neutropenia (FN).Methods: Eligible patients had gastric cancer, were scheduled for ≥ 3 cycles of myelosuppressive chemotherapy, and had an investigator-assessed overall FN risk ≥ 20 %. Data were collected for up to ten cycles. The primary endpoint was the proportion of patients who received granulocyte colony stimulating factor (G-CSF) primary prophylaxis (defined as G-CSF initiated on days 1–7 of cycle 1). Secondary endpoints included FN incidence, chemotherapy administration, and G-CSF use.Results: Of 199 patients who met the eligibility criteria and started at least one cycle of chemotherapy, mean age was 63 years, 76 % were men, 83 % had an ECOG score of 0 or 1, 54 % had metastatic disease, and 24 % had received prior chemotherapy. A total of 27 different backbone regimens were given; the most common regimen was modified docetaxel, cisplatin, and 5-fluorouracil (DCF). Despite all patients having been identified as having a ≥ 20 % FN risk, only 70 (35 %) received G-CSF primary prophylaxis. FN occurred in 14 patients overall (7 %). Most FN events occurred in patients who received DCF/modified DCF (9/14 events, 64 %).Conclusions: The results of this study reveal a high use of myelotoxic treatment regimens in gastric cancer in Europe and low adherence to clinical practice guidelines for the use of primary and secondary G-CSF prophylaxis for FN. © 2014, The International Gastric Cancer Association and The Japanese Gastric Cancer Association.


Danelli G.,Istituti Ospitalieri di Cremona | Bonarelli S.,Instituto Ortopedico Rizzoli | Togn A.,Instituto Ortopedico Rizzoli | Ghisi D.,Istituti Ospitalieri di Cremona | And 4 more authors.
British Journal of Anaesthesia | Year: 2012

BackgroundTh. ere are few data comparing the onset time of interscalene brachial plexus block performed using ultrasound (US) guidance or nerve stimulation (NS) technique for elective coracoacromial ligament repair. Methods. Fifty ASA IIII patients were randomly allocated to receive a continuous interscalene brachial plexus block with 20 ml of 1% ropivacaine with either NS or US guidance. The time of block performance, number of skin punctures and needle redirections, inadvertent vascular punctures, and procedure-related pain scores were recorded. The onsets of sensory and motor blocks in the distribution of radial, axillary, and musculocutaneous nerves were blindly assessed every 5 min until 30 min from the end of local anaesthetic (LA) injection. Intraoperative fentanyl, general anaesthesia (GA) requirements, postoperative pain scores, LA consumption, and patients requirements for subcutaneous morphine during the first 24 h were compared. Results. Block onset times were similar. The time to complete the block and the number of skin punctures and vascular punctures were significantly lower in Group US. There were no differences in needle redirections, incidence of paraesthesiae, intraoperative fentanyl consumption, and requirements for GA or postoperative morphine. The US group required significantly less LA only at 16 h after surgery and had lower pain scores at rest at 24 h after surgery. Conclusions. Block onset times and success rate were similar whether NS or US was used, although US guidance allowed shorter procedural times, fewer needle punctures, and fewer vascular punctures. © 2012 The Author. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.


Buti S.,Istituti Ospitalieri di Cremona | Rovere R.K.,Hospital Santo Antonio Blumenau
Recent Patents on Anti-Cancer Drug Discovery | Year: 2010

Renal cell cancer is fastly growing in incidence worldwide. No adjuvant therapy has been unarguably proven feasible so far, although an autologous vaccine has achieved a significant benefit. An effective agent in adjuvant therapy against renal cell cancer must achieve several goals. It should be relatively non toxic, have estabilished efficacy in the metastatic setting, and have demonstrated efficacy against the standard of care in randomized phase III trials. The development of adjuvant therapy requires the properly identification of patients at highest risk of relapse, as potential benefactors of adjuvant therapy development. Our ability to predict when and where patients will recur has much room for improvement. Therefore several models and nomograms including the most important prognostic and predictive factors have been developed. Nevertheless, during the past few years, major advances have been made concerning the metastatic setting of the disease with the arrival of new drug classes such as tyrosine kinase inhibitors and monoclonal antibodies, strongly improving overall and progression free survivals, renewing hopes on activity regarding the adjuvant therapy. Several trials are today in progress to evaluate the effectiveness of antiangiogenic agents in this area. An overall review of the completed and upcoming trials and patents shall be discussed here. © 2010 Bentham Science Publishers Ltd.


Malberti F.,Istituti Ospitalieri di Cremona
Drugs | Year: 2013

Hyperphosphataemia can be induced by three main conditions: a massive acute phosphate load, a primary increase in renal phosphate reabsorption, and an impaired renal phosphate excretion due to acute or chronic renal insufficiency. Renal excretion is so efficient in normal subjects that balance can be maintained with only a minimal rise in serum phosphorus concentration even for a large phosphorus load. Therefore, acute hyperphosphataemia usually resolves within few hours if renal function is intact. The most frequent cause of chronic hyperphosphataemia is chronic renal failure. Hyperphosphataemia in chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Lowering the phosphate load and maintaining serum phosphorus levels within the normal range are considered important therapeutic goals to improve clinical outcomes in CKD patients. Treatment consists of diminishing intestinal phosphate absorption by a low phosphate diet and phosphate binders. In CKD patients on dialysis an efficient dialysis removal of phosphate should be ensured. Dietary restriction of phosphorus while maintaining adequate protein intake is not sufficient to control serum phosphate levels in most CKD patients; therefore, the prescription of a phosphate binder is required. Aluminium-containing agents are efficient but no longer widely used because of their toxicity. Calcium-based salts are inexpensive, effective and most widely used, but there is now concern about their association with hypercalcaemia, parathyroid gland suppression, adynamic bone disease, and vascular and extraosseous calcification. The average daily dose of calcium acetate or carbonate prescribed in the randomised controlled trials to control hyperphosphataemia in dialysis patients ranges between 1.2 and 2.3 g of elemental calcium. Such doses are greater than the recommended dietary calcium intake and can lead to a positive calcium balance. Although large amounts of calcium salts should probably be avoided, modest doses (<1 g of elemental calcium) may represent a reasonable initial approach to reduced serum phosphorus levels. A non-calcium-based binder can then be added when large doses of binder are required. At present, there are three types of non-calcium-based phosphate binders available: sevelamer, lanthanum carbonate and magnesium salts. Each of these compounds is as effective as calcium salts in lowering serum phosphorus levels depending on an adequate prescribed dose and adherence of the patient to treatment. Sevelamer is the only non-calcium-containing phosphate binder that does not have potential for systemic accumulation and presents pleiotropic effects that may impact on cardiovascular disease. In contrast, lanthanum carbonate and magnesium salts are absorbed in the gut and their route of excretion is biliary for lanthanum and urinary for magnesium. There are insufficient data to establish the comparative superiority of non-calcium binding agents over calcium salts for such important patient-level outcomes as all-cause mortality and cardiovascular end points. Moreover, full adoption of sevelamer and lanthanum by government drug reimbursement agencies in place of calcium salts would lead to a large increase in health-care expenditure. Therefore, the choice of phosphate binder should be individualised, considering the clinical context, the costs, and the individual tolerability the concomitant effects on other parameters of mineral metabolism, such as serum calcium and parathyroid hormone, besides those on serum phosphorus. © 2013 Springer International Publishing Switzerland.


Caretta G.,Istituti Ospitalieri di Cremona | Passamonti E.,Istituti Ospitalieri di Cremona | Pedroni P.N.,Istituti Ospitalieri di Cremona | Fadin B.M.,Istituti Ospitalieri di Cremona | And 2 more authors.
Clinical Cardiology | Year: 2014

Background: Elderly patients are at high risk of mortality when they present with ST-elevation myocardial infarction (STEMI). However, few data exist about prognostic factors in this sub-group when treated with primary percutaneous coronary intervention (pPCI). Hypothesis: To assess outcome and predictors of mortality among patients aged >80 years treated with pPCI. Methods: We evaluated 139 consecutive patients (age 85.1 ± 3.9 years, 43.2% males) who underwent pPCI for STEMI. Results: Male patients were younger and were more likely to have a history of coronary artery disease. Overall 30-day and 1-year mortality rates were 20.9% and 28.1%, respectively. Thrombolysis in Myocardial Infarction (TIMI) flow 3 was achieved in 82% of patients. There was a pPCI success rate in male patients. At univariable analysis, older age, diabetes mellitus, Killip class >III, left ventricular ejection fraction (LVEF) <40%, no use of stent, failure of pPCI, systolic blood pressure (SBP) <100 mm Hg, and infarct-related artery (left anterior descending vs others) were associated with higher 1-year mortality. Multivariate analysis identified LVEF <40% (hazard ratio: [HR] = 3.70; 95% confidence interval [CI]: 1.30-7.87; P = 0.0001), age (1-year step, HR: 1.13; 95% CI: 1.04-1.23; P = 0.007), failure of pPCI (HR: 2.93; 95% CI: 1.44-5.98; P = 0.0001), Killip class ≥III (HR: 2.29; 95% CI: 1.03-5.4; P = 0.04) and SBP <100 mm Hg (HR: 2.64; 95% CI: 1.22-5.19; P = 0.01) to be independently associated with increased 1-year mortality. Conclusions: Our data show that elderly patients with STEMI have a high risk of mortality, which is particularly high in the first 30 days. Older age, LVEF <40% at admission, hemodynamic instability (higher Killip class or low SBP), and postinterventional TIMI flow <3 were independent predictors of mortality in our population. © 2014 Wiley Periodicals, Inc.


Ratti M.,Istituti Ospitalieri di Cremona | Tomasello G.,Istituti Ospitalieri di Cremona
Expert Review of Clinical Pharmacology | Year: 2014

Chemotherapy is frequently associated with hematologic toxicity. Neutropenia with or without fever is a relevant cause of morbidity, mortality and costs, compromising treatment administration and clinical outcomes. The development of granulocyte colony-stimulating factors has had a positive impact on the clinician's approach to neutropenia. Such agents, currently used for primary and secondary prophylaxis of chemotherapy-induced neutropenia and febrile neutropenia (FN), are effective in limiting hematologic toxicities and consequently allow the administration of intensive dose-dense regimens. Several biosimilar products of filgrastim have been developed over the years, showing effects similar to the originator drug. Until now, pegfilgrastim has been the only available long-acting factor, requiring just a single administration per chemotherapy cycle. The recent approval of the novel granulocyte colony-stimulating factors, lipegfilgrastim, offers interesting therapeutic alternatives. In fact, similar to pegfilgrastim, it has been demonstrated to reduce the duration of neutropenia and the occurrence of FN during chemotherapy safely. © 2015 Informa UK, Ltd.


Fanelli A.,Istituti Ospitalieri di Cremona | Ghisi D.,Istituti Ospitalieri di Cremona | Allegri M.,University of Pavia
Acta Biomedica | Year: 2013

Spinal anaesthesia is an easy and reliable technique. Factors limiting its use in the ambulatory setting include delayed ambulation, risk of urinary retention and pain after block regression. On the contrary, general anaesthesia with fast-acting drugs provides a fast recovery that facilitates an early discharge. Although recovery after spinal anaesthesia has been improved by reducing the dose of the commonly used longacting local anaesthetics, discharge times are still prolonged compared with general anaesthesia. 2-Chloroprocaine is an amino-ester local anaesthetic with a very short half-life and a favourable evolution of spinal block for ultra-short outpatient procedures. Moreover, the preservative free 2-chloroprocaine solution showed a very low risk of urinary retention and transient neurological symptoms when compared with bupivacaine and lidocaine. The aim of this article is to evaluate if the neuraxial administration of short-acting local anaesthetics renders spinal anaesthesia a suitable technique for ultra-short surgical procedures. © Mattioli 1885.


Liguigli W.,Istituti Ospitalieri di Cremona | Tomasello G.,Istituti Ospitalieri di Cremona | Toppo L.,Istituti Ospitalieri di Cremona | Ratti M.,Istituti Ospitalieri di Cremona | Passalacqua R.,Istituti Ospitalieri di Cremona
Future Oncology | Year: 2014

Gastric cancer is a highly aggressive disease. In metastatic setting, median overall survival, even with modern chemotherapy regimens, generally does not exceed 1 year and toxicity is a major concern. Angiogenesis plays a crucial role in cancer development and progression, and VEGF is one of the most important mediators of this process. Ramucirumab, an anti-VEGFR-2 antibody, has been recently evaluated in the large Phase Iii REGARD trial, demonstrating a significant survival benefit in second-line treatment of patients with advanced gastric or gastro-eosophageal junction adenocarcinoma. Unlike traditional chemotherapy, treatment with ramucirumab was associated with very few toxic effects. This article will review the main findings of the REGARD trial and discuss their potential impact on future treatment of metastatic gastric cancer. © 2014 Future Medicine Ltd.

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