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The SINODAR-ONE trial is a prospective noninferiority multicenter randomized study aimed at assessing the role of axillary lymph node dissection (ALND) in patients undergoing either breast-conserving surgery or mastectomy for T1-2 breast cancer (BC) and presenting one or two macrometastatic sentinel lymph nodes (SLNs). The endpoints were to evaluate whether SLN biopsy (SLNB) only was associated with worsening of the prognosis compared with ALND in terms of overall survival (OS) and relapse.Patients were randomly assigned (1:1 ratio) to either removal of ≥ 10 axillary level I/II non-SLNs followed by adjuvant therapy (standard arm) or no further axillary treatment (experimental arm).The trial started in April 2015 and ceased in April 2020, involving 889 patients. Median follow-up was 34.0 months. There were eight deaths (ALND, 4; SNLB only, 4), with 5-year cumulative mortality of 5.8% and 2.1% in the standard and experimental arm, respectively (p = 0.984). There were 26 recurrences (ALND 11; SNLB only, 15), with 5-year cumulative incidence of recurrence of 6.9% and 3.3% in the standard and experimental arm, respectively (p = 0.444). Only one axillary lymph node recurrence was observed in each arm. The 5-year OS rates were 98.9% and 98.8%, in the ALND and SNLB-only arm, respectively (p = 0.936).The 3-year survival and relapse rates of T1-2 BC patients with one or two macrometastatic SLNs treated with SLNB only, and adjuvant therapy, were not inferior to those of patients treated with ALND. These results do not support the use of routine ALND.

Inhalation of Calcium Phosphate nanoparticles (CaPs) has recently unmasked the potential of this nanomedicine for a respiratory lung-to-heart drug delivery targeting the myocardial cells. In this work, we investigated the development of a novel highly respirable dry powder embedding crystalline CaPs. Mannitol was selected as water soluble matrix excipient for constructing respirable dry microparticles by spray drying technique. A Quality by Design approach was applied for understanding the effect of the feed composition and spraying feed rate on typical quality attributes of inhalation powders. The in vitro aerodynamic behaviour of powders was evaluated using a medium resistance device. The inner structure and morphology of generated microparticles were also studied. The 1:4 ratio of CaPs/mannitol led to the generation of hollow microparticles, with the best aerodynamic performance. After microparticle dissolution, the released nanoparticles kept their original size. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

In the last decade 3D printing (3DP) technology has gained increasing interest in the pharmaceutical field addressing several novel challenges such as on-demand manufacturing at the point of need, customization of drug release profiles and patient-specific solutions as well as combinations of several APIs in one dosage form. Therefore, 3DP can become a new and promising path to drug product development and manufacturing, able to support specific therapies and improve compliance, safety and effectiveness. The aim of this work was to partially coat tablets with a glyceride, namely Precirol ATO 5 using a semi-solids 3D printer as an approach for tuning the release of two Active Pharmaceutical Ingredients (APIs), the hydrophilic methyl-levodopa hydrochloride (Melevodopa) and the lipophilic Acyclovir. Various parameters of the 3DP coating process were purposefully modified using experimental design techniques in order to customize the selected APIs release profile, without affecting the core composition of the formulation. The percentage of the tablet surface coated, the number of coating layers as well as the coated sides of the tablet where the parameters which controlled the release profile for both APIs. Different dissolution profiles have been achieved by tuning these simple parameters, which revealed a non-Fickian release mechanism regardless of the API. © 2020 Elsevier B.V.

From January 28th to February 10th, 2008 the Italian Society of Cardiac Rehabilitation and Prevention (GICR) conducted a national web-based survey aimed to provide specific and updated information on organization and core components of cardiac rehabilitation (CR) in Italy, and to describe, both in residential and out-patient settings, indications for CR, clinical characteristics of referred patients, risk profile, performed diagnostic procedures, exercise and educational programme, treatments and arrangements for the follow-up [1, 2]. The ISYDE-2008 is a multicenter, longitudinal, prospective observation study whose design was previously described [1, 2].

© 2017 Elsevier B.V. Coenzyme Q10 (CoQ10) is an antioxidant substance indicated as a dietary supplement which has been proposed as adjuvant in the treatment of cardiovascular disorders and cancer for its protective and immunostimulating activities. The aim of this work was the production by high-pressure homogenization, characterization and stability investigation of three different CoQ10 nanosuspensions designed to be administered to the lungs by nebulization. Three surfactants, i.e. lecithin, PEG32 stearate and vitamin-E TPGS, were selected to stabilize CoQ10 formulations. Preparations were identified as nanosuspensions (particle size in the range 35–60 nm): the smallest particles were obtained with vitamin-E TPGS and denoted a core-shell structure. The CoQ10 delivered from a commercial air-jet nebulizer was in all the cases around 30% of the loaded dose. The nanosuspension containing PEG32 stearate presented the highest respirable fraction (70.6%) and smallest MMAD (3.02 μm). Stability tests showed that the most stable formulation, after 90 days, was the one containing vitamin-E TPGS, followed by the CoQ10-lecithin formulation. Interestingly, those formulations were demonstrated to be suitable also for nebulizers using other mechanisms of aerosol production such as ultrasound and vibrating mesh nebulizers. Studies focused on in vitro cellular toxicity of the formulations and their single components using A549 human lung cells showed no obvious cytotoxicity for the formulations containing lecithin and PEG 32 stearate. Vitamin-E TPGS alone was shown to be able to damage the plasma membrane, nevertheless, cell damage was decreased when vitamin-E TPGS was present in the formulation with CoQ10.

A Central Composite Design (CCD) was applied in order to identify positive combinations of the production parameters of amikacin sulphate spray-dried powders for inhalation, with the intent to expand the experimental space defined in a previous half-fractional factorial design. Three factors, namely drying temperature, feed rate and ethanol proportion, have been selected out of the initial five. In addition, the levels of these factors were increased from two to three and their effect on amikacin respirability was evaluated. In particular, focus was given on the role of ethanol presence on the formation of the microparticles for inhalation. The overall outcome of the CCD was that amikacin respirability was not substantially improved, as the optimum region coincided with areas already explored with the fractional factorial design. However, expanding the design space towards smaller ethanol levels, including its complete absence, revealed the crucial role of this solvent on the morphology of the produced particles. Peclet number and drug solubility in the spraying solution helped to understand the formation mechanism of these amikacin sulphate spray-dried particles. © 2015 Elsevier B.V. All rights reserved.

An amikacin product for convenient and compliant inhalation in cystic fibrosis patients was constructed by spray-drying in order to produce powders of pure drug having high respirability and flowability. An experimental design was applied as a statistical tool for the characterization of amikacin spray drying process, through the establishment of mathematical relationships between six Critical Quality Attributes (CQAs) of the finished product and five Critical Process Parameters (CPPs). The surface-active excipient, PEG-32 stearate, studied for particle engineering, in general did not benefit the CQAs of the spray dried powders for inhalation. The spray drying feed solution required the inclusion of 10% (v/v) ethanol in order to reach the desired aerodynamic performance of powders. All desirable function solutions indicated that the favourable concentration of amikacin in the feed solution had to be kept at 1% w/v level. It was found that when the feed rate of the sprayed solution was raised, an increase in the drying temperature to the maximum value (160 °C) was required to maintain good powder respirability. Finally, the increase in drying temperature always led to an evident increase in emitted dose (ED) without affecting the desirable fine particle dose (FPD) values. The application of the experimental design enabled us to obtain amikacin powders with both ED and FPD, well above the regulatory and scientific references. The finished product contained only the active ingredient, which keeps low the mass to inhale for dose requirement. © 2014 Elsevier B.V.

Endocrine pancreatic tumors are rare and their surgical treatment is often debated. This review analyzes the management and the different indications in functioning and non-functioning neoplasms. The choice among different procedures is described as well as the role of intra operative ultrasound. Moreover, the different patterns of tumor spread are considered (local, loco-regional and metastatic) along with the indications according to the main controversies relating to cytoreductive surgery, transplantation and multiple endocrine neoplasia type 1 patients.

Background Secondary prevention is not adequately implemented after myocardial infarction (MI). We assessed the effect on quality of care and prognosis of a long-term, relatively intensive rehabilitation strategy after MI. Methods We conducted a multicenter, randomized controlled trial in patients following standard post-MI cardiac rehabilitation, comparing a long-term, reinforced, multifactorial educational and behavioral intervention with usual care. A total of 3241 patients with recent MI were randomized to a 3-year multifactorial continued educational and behavioral program (intervention group; n = 1620) or usual care (control group; n = 1621). The combination of cardiovascular (CV) mortality, nonfatal MI, nonfatal stroke, and hospitalization for angina pectoris, heart failure, or urgent revascularization procedure was the primary end point. Other end points were major CV events, major cardiac and cerebrovascular events, lifestyle habits, and drug prescriptions. Results End point events occurred in 556 patients (17.2%). Compared with usual care, the intensive intervention did not decrease the primary end point significantly (16.1% vs 18.2%; hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.74-1.04). However, the intensive intervention decreased several secondary end points: CV mortality plus nonfatal MI and stroke (3.2% vs 4.8%; HR, 0.67; 95% CI, 0.47-0.95), cardiac death plus nonfatal myocardial infarction (2.5% vs 4.0%; HR, 0.64; 95% CI, 0.43-0.94), and nonfatal MI (1.4% vs 2.7%; HR, 0.52; 95% CI, 0.31-0.86). A marked improvement in lifestyle habits (ie, exercise, diet, psychosocial stress, less deterioration of body weight control) and in prescription of drugs for secondary prevention was seen in the intervention group. Conclusion The GOSPEL Study is the first trial to our knowledge to demonstrate that a multifactorial, continued reinforced intervention up to 3 years after rehabilitation following MI is effective in decreasing the risk of several important CV outcomes, particularly nonfatal MI, although the overall effect is small. Trial Registration ClinicalTrials.gov Identifier:NCT00421876

Long-term survival for patients with pancreatic carcinoma is low, even following resection. Most patients who undergo curative treatment, develop recurrence usually at the same site of resection or in the liver. Failure seals the fate of the patient. Local recurrence occurs frequently; however, it is rarely a direct cause of death. In fact, most patients die from distant metastases. From a clinical point of view, it is important to distinguish recurrence from relapse. In fact, recurrence can be recognized as the reappearance of the disease in the surgical bed, often due to inadequate surgical clearance. On the other hand, the concept of relapse should be much more related to the appearance of the disease in a distant site. Both underestimated staging of the diagnosis and the biological features of the tumor can cause relapse. Up to now, there have only been a few reviews on the incidence and pattern of failure following resection. Detailed knowledge of the recurring sites of pancreatic carcinoma and study of the factors influencing disease-free survival are significant in developing neoadjuvant, surgical and adjuvant treatment. The aim of this review is to point out the major factors most commonly identified as determinants of both recurrence and relapse.

One hundred and twenty adult patients with high temperatures (≥38°C) brought about by influenza viruses or other conditions were randomly treated with two different antipyretics: a) a 25 mg sodium diclofenac tablet (Novapirina) every 12 hours for 2 consecutive days; b) a 500 mg tablet of acetylsalicylic acid (Aspirin) every 8 hours for 2 consecutive days. Antipyretic action (assessed at 6 hours following the first administration) was found to be equally rapid and consistent in both cases but significantly longer-lasting in the Novapirina-treated group than the Aspirin-treated group (p < 0·01). Mean temperature changes over the 48 hours of observation and the over-all judgement on the antipyretic effect expressed at the end of each day of treatment were similar for both groups and good in all cases. The antiphlogistic-painkilling properties of both drugs were found to be effective in improving the symptomatology accompanying the high temperature during the course of the bout of influenza. The effectiveness/tolerability ratio was found to be satisfactory for both groups: only one case of gastric intolerance to Novapirina was recorded and five cases of gastric intolerance to Aspirin.

Sudden death has been reported to occurr in 1,4% of patients suffering from mitral valve prolapse (MVP). Ventricular hyperkinetic arrhythmias (VHA), also potentially malignant, are found in a substantial number of patients suffering from this syndrome. Thus effective antiarrhythmic treatment is necessary.

Isolated blunt duodenal injury is a rare finding associated with high morbidity and significant mortality. The early identification of a duodenal injury is usually difficult, considering the anatomical location of the duodenum and lack of peritoneal signs and diagnostic delay is part of the clinical picture in most cases.A 43-year-old man was admitted to our hospital after a motor vehicle collision. At admission he underwent emergency surgery because of lower extremities fractures. Twelve hours later he started to complain an increasing abdominal pain; blood tests showed serum amylase up to 180 U/L and a CT scan demonstrated a perforation of the third duodenal portion. At laparotomy a Grade III injury of the duodenum was evident. The laceration was sutured and a "quadruple-tube" decompression was performed. The postoperative course was uneventful. One year after surgery he is well without any long-term complication.A high degree of suspicion is necessary for early diagnosis of blunt duodenal trauma and CT scan should be performed in case of all significant epigastric trauma. In most cases primary direct repair of duodenal wounds can be safely achieved and duodenal decompression via triple or quadriple tube technique is required to decrease the risk of duodenal fistula.

The swelling behavior of novel Dome Matrix drug delivery modules was investigated using high-resolution X-ray computed tomography studies. The technique was exploited to investigate the swelling front position and the conditions of the interacting surfaces in situ without removing the sample from the medium during swelling. Surface and volume evolution of the glassy core under the gel layer were precisely described. Within the gel formed on the glassy core there were several particles not completely dissolved or swollen, transported from the core by the stresses due to the polymer swelling. The gel portion defined as partially swollen gel was evidenced on the convex and flat surfaces of tablets, where a line of fracture in the gel could be observed near the glassy core. In addition, the presence of solid particles in the gel layer confirmed that the translocation of particles in the swellable system affected the drug and polymer gradient within the system.

Non-segregating ordered powder mixtures constituted by a coarse carrier fraction and finer components are at the basis of dry powders for inhalation pharmaceuticas. The estimation of the loading capacity, i.e. how many fines can be hosted on each carrier particle, is crucial to grant the product quality through a reproducible and affordable manufacturing process. We propose an approach based on the combination of sieve analysis, optical microscopy and powder bed permeability to quantify the loading capacity and understand the fines behavior, the impact of the mixing process was also investigated. We tested the method on model binary mixtures composed only of a coarse lactose carrier and micronized lactose fines as a surrogate of a real active pharmaceutical ingredient. The results provided by the different methods are consistent, the approach proved to be accurate and reproducible. The effect of different mixing parameters and equipment on the loading capacity is also discussed.

The combination of a chitosan 3D-printed scaffold with a hydrogel matrix containing an elastin-like polypeptide functionalized with the epidermal growth factor (HEGF) was evaluated as a possible strategy to obtain a bioactive platform with stimuli-responsive properties. We designed a chitosan/HEGF hybrid scaffold and examined the physico-chemical properties and the in vitro behavior when in contact with simulated biological fluids. Primary human dermal fibroblasts (hDFs) were used to test the in vitro cytocompatibility. Overall, these data provide first insights into the integration of HEGF-based hydrogel with 3D-printed scaffolds, contributing towards the rational design of a new smart functional wound dressing. Graphical Abstract: [Figure not available: see fulltext.].

The purpose of this work was to study a new dry powder inhaler (DPI) of tobramycin capable to simplify the dose administration maneuvers to maximize the cystic fibrosis (CF) patient care in antibiotic inhalation therapy. For the purpose, tobramycin/sodium stearate powder (TobraPS) having a high drug content, was produced by spray drying, characterized and the aerodynamic behavior was investigated in vitro using different RS01 DPI inhalers. The aerosols produced with 28, 56 or 112 mg of tobramycin in TobraPS powder using capsules size #3, #2 or #0 showed that there was quasi linear relationship between the amount loaded in the device and the FPD. An in vivo study in healthy human volunteers showed that 3–6 inhalation acts were requested by the volunteers to inhale 120 mg of TobraPS powder loaded in a size #0 capsule aerosolized with a prototype RS01 device, according to their capability to inhale. The amount of powder emitted at 4 kPa pressure drop at constant air flow well correlated with the in vivo emission at dynamic flow, when the same volume of air passed through the device. The novel approach for the administration of 112 mg of tobramycin in one capsule could improve the convenience and adherence of the CF patient to the antibiotic therapy.

The aim of the present study is to assess whether or not there has been improvement in the therapeutic strategy for body-tail pancreatic carcinoma over the past decade.A total of 215 patients suffering from cytologically and histologically documented ductal carcinoma in the pancreatic body-tail, observed from 1990 to 1999, were analysed. Changes in tumour stage at diagnosis, in the percentage of patients treated surgically, in resectability rates and in the use of anticancer therapies over the years were sought. Survival curves were evaluated in relation to the treatments adopted.Over the 10-year period, no significant differences were observed with respect to the stage at diagnosis, resectability or type of surgery adopted. There was a significant increase in the percentage of unoperated patients (p < 0.0001) and, as expected, in the percentages of patients submitted to chemo- and/or radiotherapy (p < 0.0001). With the sole exception of tumour stage in the case of patients undergoing radiotherapy, a comparison between groups revealed no element of patient selection bias other than time. The survival of patients undergoing chemotherapy is significantly better, also at multivariate analysis, than that of patients not undergoing such therapy (13 vs. 5.8 months; p < 0.0001).There has been no change over the years in the direction of earlier diagnosis and the prognosis remains distinctly poor. More extensive use of anticancer therapies, however, has led to a significant increase in median survival. Radical resection, when possible, assures the longest survival.

INTRODUCTION: Malignant pancreatic neuroendocrine tumours (PNENs) are generally associated with a good prognosis after radical resection. In other pancreatic malignancies predictors of recurrence and the role of lymph node ratio (LNR) are well known, but both have been scarcely investigated for malignant PNETs. METHODS: The prospective database from the surgical Department of Verona University was queried. Clinical and pathological data of all patients with resected malignant PNET between 1990 and 2008 were reviewed. Univariate and multivariate analysis were performed. RESULTS: Fifty-seven patients (male/female ratio=1) with a median age of 58years (33-78) entered in the study. Twenty-nine (51\%) patients underwent pancreaticoduodenectomy and 28 (49\%) distal pancreatectomy. Postoperative mortality was nil with a 37\% morbidity rate. There were 36 (63\%) patients with lymph node metastases (N1). Of these, 23 (64\%) had a lymph node ratio (LNR) >0 and ⩽0.20 and 13 (36\%) had a LNR >0.20. The median overall survival and the median disease free survival (DFS) were 190 and 80months, respectively. Recurrent disease was identified in 24 patients (42\%) with a 2 and 5-year DFS rate of 82\% and 49\%, respectively. On multivariate analysis, LNR >0.20 (HR=2.75) and a value of Ki67 >5\% (HR=3.39) were significant predictors of recurrence (P5\% are the most powerful predictors of recurrence. The presence of these factors should be considered for addressing patients to adjuvant treatment in future clinical trials.

BACKGROUND:Tumor size is a criterion of staging in nonfunctioning pancreatic endocrine tumors as well as a predictor of outcome after curative resection. This study analyzes the correlation between tumor size and malignancy in patients with nonfunctioning pancreatic endocrine tumors.METHODS:All patients with nonfunctioning pancreatic endocrine tumors who underwent curative resection (R0) at our institution between 1990 and 2008 were considered. Their clinicopathologic characteristics were compared among 3 different groups according to tumor size. Univariate and multivariable analyses were performed.RESULTS:Over the study period, 177 patients were identified. Overall, 90 patients (51%) had a tumor size ≤2 cm (group 1), 46 (26%) had tumor size between >2 cm and ≤4 cm (group 2), and 41 (23%) had tumor size >4 cm (group 3). Tumors ≤2 cm were more frequently incidentally discovered (group 1, 57% vs group 2, 51% vs group 3, 32%; P = .014) and benign (group 1, 81% vs group 2, 65% vs group 3, 5%; P < .0001). The presence of a nonfunctioning pancreatic endocrine tumor >2 cm and a nonincidental diagnosis of the tumor were independent predictors of malignancy at multivariable analysis. None of the 51 patients (29%) with a pancreatic endocrine tumor ≤2 cm that was incidentally diagnosed died of disease.CONCLUSION:A strict correlation between tumor size and malignancy in nonfunctioning pancreatic endocrine tumors was demonstrated. A nonoperative management could be advocated for tumors ≤2 cm when discovered incidentally.

Pancreatic endocrine tumors are rare diseases and devising a clinically effective prognostic stratification of patients is a major clinical challenge. This study aimed at assessing whether the tumor-node-metastasis (TNM)-based staging and proliferative activity-based grading recently proposed by the European NeuroEndocrine Tumors Society (ENETS) have clinical value. TNM was applied to 274 patients with histologically diagnosed pancreatic endocrine tumors operated from 1991 to 2005, with last follow-up at December 2007. According to World Health Organization (WHO) classification, 246 were well-differentiated neoplasms (51 benign, 56 uncertain behavior, 139 carcinomas) and 28 poorly differentiated carcinomas. Grading was based on Ki67 immunohistochemistry. Survival analysis not only ascertained the prognostic value of the TNM system but also highlighted that in the absence of nodal and distant metastasis, infiltration and tumor dimensions over 4 cm had prognostic significance. T parameters were then appropriately modified to reflect this weakness. The 5-year survival for modified TNM stages I, II, III and IV were 100, 93, 65 and 35%, respectively. Multivariate analysis identified TNM stages as independent predictors of death, in which stages II, III and IV showed a risk of death of 7, 29 and 58 times higher than stage I tumors (P

Pancreatic endocrine tumors (PETs) are heterogeneous tumors with increasing prevalence. Little is known about the molecular pathogenesis and risk factors for the occurrence of sporadic PETs. The aim of this study was to identify the risk factors associated with the occurrence of sporadic PETs.A case-control study comprising 162 sporadic PETs and 648 controls was undertaken. Subjects were interviewed using a specific questionnaire on demographics and potential risk factors, including smoking, alcohol, height, weight, medical history, and family history of cancer. A multiple hierarchical logistic regression analysis was performed with a stepwise variable- selection procedure.A first-degree family history of any cancer was a significant risk factor (odds ratio (OR) 2.2; 95% confidence interval (CI): 1.5-3.2). Among the different cancer sites, first-degree family history of pancreatic adenocarcinoma was more frequent in PETs than in controls (4.3 vs. 1.2%; P=0.01). A high alcohol intake (OR 4.8; 95% CI: 2.4-9.5), history of chronic pancreatitis (CP) (OR 8.6; 95% CI: 1.4-51), and recent-onset diabetes (OR 40.1; 95% CI: 4.8-328.9) were all independent risk factors. The history of diabetes was also associated with metastatic disease at the time of diagnosis.This case-control study identified family history of any cancer (and to a less extent of pancreatic adenocarcinoma), CP, high alcohol intake, and recent-onset diabetes as risk factors for PET, thus suggesting a possible partial overlap with risk factors for exocrine pancreatic carcinogenesis.

Nonfunctioning pancreatic endocrine tumors (NFPTs) are rare neoplasms that have been the object of few studies that have involved only small numbers of patients. This study was carried out to obtain a comprehensive and up-to-date clinical picture of these tumors.A total of 184 patients with NFPT admitted to three Italian hospitals in the last 15 yr were studied. The diagnosis of NFPT was confirmed histologically using conventional and immunohistochemical techniques. Data were obtained from the medical charts or directly from the patients.There were 85 men (46.2%) and 99 women (53.8%). The mean age at diagnosis was 55.2 yr (range 17-82 yr). The percentage of smokers and alcohol drinkers was similar to that in the general population. Seven patients (3.9%) had a family history of exocrine pancreatic carcinoma. In 120 cases (65.2%), the diagnosis was made after workup for pain or other symptoms, in the remaining 64 cases (34.8%), the tumor was discovered incidentally by ultrasound; in this group survival was significantly greater than it was for the symptomatic patients (p=0.0043). Survival was also found to be improved by tumor resection (p0.0001), absence of metastases (p0.0001), and small tumor size (or =3 cm) (p0.0007).NFPTs were slightly more frequent in women and were diagnosed most often in middle-aged individuals. No risk factors other than a family history of exocrine pancreatic carcinoma were found. Tumor discovery while patients were still asymptomatic, tumor resection, absence of metastases, and tumor sizeor =3 cm significantly prolonged survival.