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In the current COVID-19 pandemic scenario, it is still necessary to understand if differences exist between genders in terms of patients' characteristics and clinical outcomes. For this reason, we retrospectively analyzed data obtained from a local register-based dataset of all SARS-CoV-2 positive patients diagnosed in the province of Catania (Italy). The main aim of this analysis was to understand any differences between genders in the distribution of previous medical conditions, and to evaluate which of them posed individuals at higher risk of death. With this purpose, we analyzed data from 1424 patients with at least one underlying medical condition, who were tested positive for SARS-CoV-2 infection from February 2020 to December 2021. Overall, males were 59.5% of the total population and significantly younger than females (median ages: 68 years vs. 72 years; p = 0.011). The age distribution of cases by gender confirms that individuals from 70 to 79 years were the most affected in both genders. The comparison of underlying comorbidities by gender shows significant differences for diabetes (p < 0.001), other metabolic diseases (p = 0.006), and obesity (p = 0.019). Accordingly, multivariable logistic regression analysis confirmed that diabetes was more likely to be present in males than in females (p = 0.001), while other metabolic diseases and obesity were less likely to be present (p = 0.003 and p = 0.005, respectively). Although no difference in mortality was evident between genders (p = 0.141), both male and female COVID-19 patients had a significantly higher risk of death if they had comorbidities such as CVDs, kidney diseases, or chronic neurological diseases. Moreover, diabetes and chronic respiratory diseases were significant risk factors for COVID-19 mortality among men, whereas cancer was a significant contributor among women. Our findings confirm gender-differences in pre-existing medical conditions of COVID-19 patients, which may influence the risk of death. Further studies, however, are needed to understand physiological and pathological mechanisms underpinning these differences., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

During the COVID-19 pandemic, U.S. food assistance programs allowed the use of program benefits to order groceries online. We examined relationships between the food environment, food assistance, online grocery ordering, and diet quality among adults from one low-income, low food access community in Northeastern Connecticut during the pandemic. Via online survey, adults (n = 276) reported their perceived home and store food environments, food assistance participation, whether they ordered groceries online, and consumption frequency and liking of foods/beverages to calculate diet quality indices. Those who ordered groceries online (44.6%) were more likely to participate in food assistance programs and report greater diet quality. Perceived healthiness of store and home food environments was variable, with the ease of obtaining and selecting unhealthy foods in the neighborhood significantly greater than healthy foods. Healthier perceived home food environments were associated with significantly higher diet qualities, especially among individuals who participated in multiple food assistance programs. Ordering groceries online interacted with multiple measures of the food environment to influence diet quality. Generally, the poorest diet quality was observed among individuals who perceived their store and home food environments as least healthy and who did not order groceries online. Thus, ordering groceries online may support higher diet quality among adults who can use their food assistance for purchasing groceries online and who live in low-income, low-access food environments.

The conservation actions of endangered plant species require a clear knowledge of their habitats. Urtica rupestris Guss. (Urticaceae) is a rare endemic plant species occurring on shady cliffs in the southern-eastern part of Sicily. In the last century, the extreme anthropogenic alterations of Hyblaean plateau have caused the continuous and unrestrained fragmentation of natural habitats and consequently the reduction and disappearance of some plant species. A total of 52 vegetation plots, of which 34 are unpublished, were analyzed in order to characterize the floristic composition of the U. rupestris community. All the relevés were classified using classification and ordination methods. The species is mainly linked to shady and wet rock habitats, and only secondarily colonizes the undergrowth shrubs. According to IUCN criteria, we propose a new risk status for this species and the establishment of a new habitat (92/43CEE) for correct long-term conservation. Finally, a new association, Urtico rupestris-Adiantetum capilli-veneris , which falls within the Polysticho setiferi-Phyllitidion scolopendrii alliance ( Adiantetea capilli-veneris class), was described. This study can provide useful information for the management and conservation of U. rupestris .

There is a clear correlation between gut microbiota, diet, and metabolic outcomes. A diet high in fiber has been shown to decrease inflammation, increase insulin sensitivity, and reduce dyslipidemias whereas a diet high in fat and sugar leads to dyslipidemia, insulin resistance, and low-grade inflammation. There is recent evidence suggesting that the human gut microbiota has a significant role in the development or the resolution of metabolic syndrome (MetS) and associated conditions. Leading a stressful, sedentary lifestyle with limited or no physical activity and consuming an unhealthy diet high in saturated fat, simple carbohydrates, and sodium and low in dietary fiber and in high-quality protein are some of the contributing factors. Unhealthy diets have been shown to induce alterations in the gut microbiota and contribute to the pathogenesis of MetS by altering microbiota composition and disrupting the intestinal barrier, which leads to low-grade systemic inflammation. In contrast, healthy diets can lead to changes in microbiota that increase gut barrier function and increase the production of anti-inflammatory biomarkers. This review aims at providing a more in-depth discussion of diet-induced dysbiosis of the gut microbiota and its effect on MetS. Here, we discuss the possible mechanisms involved in the development of the metabolic biomarkers that define MetS, with an emphasis on the role of sugar and dietary fiber in microbiome-mediated changes in low-grade systemic inflammation and metabolic dysfunction.

Plant-based (PB) diets are considered a healthy dietary pattern; however, eggs are not always included in this dietary regime. We hypothesized that the addition of two eggs per day would increase HDL cholesterol as well as plasma lutein, zeaxanthin and choline in individuals with metabolic syndrome (MetS). In this randomized controlled crossover intervention, we recruited 30 participants (49.3 ± 8 y) with MetS who followed a PB diet for 13 weeks. A registered dietitian advised all subjects on food selection and followed them through the intervention to ensure compliance. Participants underwent a 2-week washout with no eggs or spinach (a source of dietary lutein and zeaxanthin) and were randomly allocated to consume spinach (70 g) with either two eggs (EGG) or the equivalent amount of egg substitute (SUB) for breakfast for 4 weeks. After a 3-week washout, they were allocated the alternate breakfast. A total of 24 participants (13 women/11 men) finished the intervention. Plasma lipids, glucose, insulin, anthropometrics, plasma lutein, zeaxanthin, choline and trimethylamine oxide (TMAO) were assessed at baseline and the end of each intervention. When we compared individuals consuming the EGG versus the SUB breakfast, we observed a lower body weight (p < 0.02) and a higher HDL cholesterol (p < 0.025) after the EGG diet. There were no differences in plasma LDL cholesterol, triglycerides, glucose, insulin, or blood pressure. The number of large HDL particles measured by NMR was higher after EGG (p < 0.01) as compared to SUB. Plasma choline was higher in both treatments (p < 0.01) compared to baseline (8.3 ± 2.1 μmol/L). However, plasma choline values were higher in EGG (10.54 ± 2.8 μmol/L) compared to SUB (9.47 ± 2.7 μmol/L) p < 0.025. Both breakfasts increased plasma lutein compared to baseline (p < 0.01), while plasma zeaxanthin was only increased in the egg intervention (p < 0.01). These results indicate that consuming a plant-based diet in combination with whole eggs increases plasma HDL cholesterol, choline and zeaxanthin, important biomarkers in subjects with MetS.

Astrocytes have crucial functions in the central nervous system (CNS) and are major players in many CNS diseases. Research on astrocyte-centered diseases requires efficient and well-characterized gene transfer vectors. Vectors derived from the Adeno-associated virus serotype 9 (AAV9) target astrocytes in the brains of rodents and nonhuman primates. A recombinant (r) synthetic peptide-displaying AAV9 variant, rAAV9P1, that efficiently and selectively transduces cultured human astrocytes, has been described previously. Here, it is shown that rAAV9P1 retains astrocyte-targeting properties upon intravenous injection in mice. Detailed analysis of putative receptors on human astrocytes shows that rAAV9P1 utilizes integrin subunits αv, β8, and either β3 or β5 as well as the AAV receptor AAVR. This receptor pattern is distinct from that of vectors derived from wildtype AAV2 or AAV9. Furthermore, a CRISPR/Cas9 genome-wide knockout screening revealed the involvement of several astrocyte-associated intracellular signaling pathways in the transduction of human astrocytes by rAAV9P1. This study delineates the unique receptor and intracellular pathway signatures utilized by rAAV9P1 for targeting human astrocytes. These results enhance the understanding of the transduction biology of synthetic rAAV vectors for astrocytes and can promote the development of advanced astrocyte-selective gene delivery vehicles for research and clinical applications., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Low-income Americans tend to have poor diet quality and disease prevalence overall. Mobile food pantries aim to improve these outcomes, and have rarely been studied. This cross-sectional study aimed to evaluate the association between diet quality and health status in mobile food pantry users. Data were collected from two mobile food pantry sites in Northeastern Connecticut (n = 83). Sociodemographic food security and diet quality data were collected. Overall, diet quality was low among all participants with intakes of fruits, vegetables, and whole grains of concern. Participant adherence to the 2020−2025 US Dietary Guidelines were low, with no participants meeting recommendations for whole grains. Obesity, diabetes, and hypertension prevalence in this population exceeded national averages. After adjusting for covariates, hypertension was associated with higher dairy and added sugar intake, as well as a greater intake of added sugar from sugar-sweetened beverages (p < 0.05). Although results were not statistically significant, participants with obesity, diabetes, and hypertension showed a trend of having lower adherence to the guidelines than those without these chronic diseases. Questions assessing participant interest in changing their diets were also posed, indicating overall high interest in learning about current diet quality and weight improvement.

During adolescence, the summation of the "physiological" crisis to stressful or excessive demands from the environment can represent a source of significant discomfort and difficulties for the person. For mental health operators, and not only, it is always important to know how to distinguish, in the complexity that adolescence entails, the "typical" adolescence behaviours from risky behaviours or incipient signs of a mental disorder. Psychological distress can most frequently result when, together with difficulties in completing developmental tasks, individual vulnerabilities add up to inadequacy of an environmental system. To date, scientific evidence shows an earlier onset of many mental illnesses in the last decades. This explains the need and the usefulness of implementing interventions for promotion and prevention of mental health in this specific age group. The school, where teenagers spend most of their time, is the best place where provide information, skills and strategies to implement mental and physical well-being, resilience factors and identify fragilities. This article aims to make a survey of mental health promotion interventions carried out in schools nationally and internationally.

Background: To validate a novel trifecta for evaluating outcomes of partial nephrectomy (PN) on a multicentric dataset., Methods: Between 2007 and 2020, three renal cancer databases were queried for patients with solitary renal masses who underwent PN (n = 649). Trifecta was estimated for overall cohort and contributing centers. Overall survival (OS), cancer-specific survival (CSS) and end-stage renal disease (ESRD) probabilities were assessed by Kaplan-Meier. Cox regression was used to identify predictors of OS, CSS, ESRD. For all analyses, a p < 0.05 was considered significant., Results: At a median follow-up of 22.7 months (IQR 12.5-76.5) overall trifecta was 76.7% [Centre A; (n = 230; 68.6%), B (n = 68; 77.3%), C (n = 200; 88.4%); p = 0.001). On Kaplan-Meier, patients achieving trifecta exhibited higher OS ( p = 0.024), higher CSS ( p = 0.015) and lower ESRD rates ( p = 0.024). On multivariable analysis, age (HR 1.04; 95% CI 1.01-1.08) and trifecta (HR 0.34; 95% CI 0.15-0.76) were independent predictors of OS while pT stage (HR 1.95; 95% CI 0.45-8.43) and trifecta (HR 0.33; 95% CI 0.16-0.67) were predictors of CSS (each p < 0.01). Preoperative CKD stage ≥ 3a (HR 13.1; 95% CI 4.07-42.6) and trifecta (HR 0.41; 95% CI 0.19-0.87) were independent predictors of ESRD (each p < 0.05)., Conclusions: On external validation, trifecta was an independent predictor of all PN endpoints, regardless of hilar control and ischemia duration.

To assess the feasibility and operative outcomes of RARP following colo-rectal surgery. A prospective database of patients undergoing RARP is maintained at our Institution since January 2015. We reviewed all patients undergoing RARP after previous colo-rectal surgery. Overall, 49 (7.4%) of 658 RARPs were performed after previous pelvic surgery, 14 (2.1%) of which following colo-rectal surgery after an interval of 5 years. (a) Colo-rectal surgery. Previous colo-rectal surgery included resection of the left colon (n = 6), and right colon (n = 4), and rectum (n = 4). Histopathology showed pT0-T2N0 in 5, pT3N0-1 in 3, and benign conditions in 4. Prostate-specific antigen (PSA) was elevated (4 ng/ml or greater) or slightly elevated (3.5-4 ng/ml) in 9 (65%) of 14 cases at the time of colo-rectal surgery. (b) Prostatectomy. Overall prostatectomy and adhesiolysis median operative times were 235 and 42 min, respectively. A robotic approach was accomplished in 11 cases with previous uncomplicated colo-rectal surgery; open conversion occurred in 3 cases. Risk factors for open conversion during RARP were: history of multiple or complicated abdominal surgery, previous open conversion, and hospital stay > 10 days. Postoperative complications included: anemization (n = 2), persistent drain output (n = 1), and urinary tract infection (n = 1). The robotic approach was successful in the case of previous uncomplicated colo-rectal surgery. The risk of intestinal injury during conversion might suggest a direct retropubic approach in case of previous multiple or complicated abdominal surgery. A planned elective colo-rectal surgery should include a thorough urologic evaluation, considering the risk of a subsequent prostate surgery., (© 2021. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Objective: This pilot study assessed the effectiveness and acceptability of personalized nutrition intervention for mobile food pantry users., Methods: The 8-week intervention recruited 25 participants in the control ( n = 13) and in the treatment ( n = 12) groups (60% obese). Personalized nutrition and health reports were generated based on baseline dietary intake and health status. The treatment group received weekly phone counseling and nutrition education, while the control group was only contacted to ensure compliance. The primary outcomes were 8-week changes in weight and diet quality score, assessed by the Healthy Eating Index., Results: The acceptability of the intervention was assessed by the eligibility rate, recruitment rate (62.5%), and drop-out rate (36%). Following the intervention, there was a significant decrease in weight (mean ± standard deviation, -2.3% ± 2.4%) among all participants ( p < 0.05). Diet-quality improved (4.54% in treatment vs. 0.18% in control), but was ultimately non-significant ( p = 0.284)., Conclusions and Implications: A personalized nutrition education intervention in mobile food pantry users may be an acceptable and effective intervention to encourage weight loss through dietary improvements.

Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m 2  day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov).

Purpose: The aim of this study was to compare the effect of combined oral administration and intralesional injection of hyaluronic acid (HA) with intralesional injections alone, in patients with early onset of Peyronie's disease (PD)., Materials and Methods: For this prospective, randomized phase III clinical trial we included patients with recent diagnosis of PD. Eighty-one patients were randomized into two groups. Group A consisted of 41 patients receiving oral administration of HA in combination with weekly intralesional injection of HA for 6 weeks. Group B consisted of 40 patients group B who received weekly intralesional injections of HA for 6 weeks, only. The main outcome measures were the changes from baseline to the end of therapy after three months in penile curvature (°) and changes in the international index of erectile function (IIEF-5) score and patient's global impressions of improvement (PGI-I) score., Results: Group A had a significantly larger reduction in penile curvature as compared with group B (Group A: -7.8°, Group B: -4.1° [p<0.001]). Group A also showed a higher improvement in IIEF-5 and PGI-I scores in comparison with Group B (Group A: +4 IIEF-5, Group B: +2 IIEF-5 [p<0.001]; Group A: 3 PGI-I, Group B: 1 PGI-I, [p<0.001]). At three months both groups had a significant reduction of penile curvature from baseline (p<0.001)., Conclusions: Oral administration combined with intralesional treatment with HA shows greater efficacy to improve penile curvature and overall sexual satisfaction in comparison with intralesional HA treatment alone., Competing Interests: Dr. Tommaso Cai, Dr. Alessandro Zucchi, and Dr. Alessandro Palmieri received speaker grants by IBSA, Italy, during national and international meetings but he made no influence on this work in relation with the company or its products. Other authors have no potential conflicts of interest to disclose., (Copyright © 2021 Korean Society for Sexual Medicine and Andrology.)

Objective: The aim of this study is to evaluate the efficacy of a food supplement containing Phyllanthus niruri and Chrysanthellum americanum in association with potassium and magnesium citrates in the treatment and prophylaxis of urinary stones., Materials and Methods: Eighty-two patients (mean age 49.7 ± 11.2) with history of urinary stones received this food supplement, one capsule a day for 6 months. Each administration contained a combination of the following ingredients: 244 mg Potassium citrate, 735 mg Magnesium citrate, Phyllanthus (Phyllantus niruri) herb d.e. 15% mg Tannins 220 mg, Chrysanthellum (Chrysanthellum americanum Vatke) plant d.e. ¼ 55 mg. After 6 months, all patients underwent urologic visit, urinalysis, imaging and quality of life (QoL) questionnaires evaluation. Each patient was also evaluated by computed tomography (CT) scan at baseline and at 6 months., Result: From January 2018 to March 2019, 82 patients (mean age 49.7 ± 11.2) completed the follow-up period and were analyzed. Fifty patients showed lower stone dimensions (60.9%). The average stone size was 0.9 mm, with a significant reduction in comparison with the baseline (-6.7 mm ± 3 mm) (p < 0.001). Forty-nine patients (59.7%) did not show any symptomatic episode with an improving in QoL (+0.4 ± 0.1) (p < 0.001) in comparison with the baseline. At the end of the follow-up period, 27 patients out of 82 were stone-free (32.9%). Moreover, we report a significant reduction of patients with asymptomatic bacteriuria (ABU) between the baseline and the end of the follow-up evaluation (p < 0.001)., Conclusions: In conclusion, this food supplement is able to improve quality of life in patients with urinary stones, reducing symptomatic episodes and the prevalence of ABU.

Poor diet quality among low-income populations is a major contributing factor to their poor health and wellbeing, and thus is a focus of many government aid programs. Mobile food pantries are an increasingly popular method of emergency food assistance, targeting the communities most affected by food insecurity; however, little is known about the dietary characteristics of mobile food pantry users. This study aims to characterize the diet quality and nutrient adequacy level and examine its association with sociodemographic characteristics among mobile food pantry users in Windham County, Connecticut. Surveys to assess food insecurity, diet composition, and sociodemographic characteristics were administered to 83 adult food pantry users. Participants ( n = 40) completed a three-day dietary record for analysis of diet quality, and were found to have inadequate intakes of fruits, vegetables, whole grains and dairy, as well as some related micronutrients. At least 30% of participants had intakes below the Estimated Average Requirement (EAR) for vitamins A, C, E, calcium, zinc, magnesium, and folate. Intakes of added sugar, sugar sweetened beverages, and saturated fat were also above recommendations according to the United States Dietary Guidelines. Certain sociodemographic factors affected diet quality among this sample. For example, being male was associated with increased sugar-sweetened beverage and added sugar intake. This characterization of mobile pantry users will serve as a reference for developing nutrition education and determining the effectiveness of future interventions.

Invasive alien plants are a major threat to biodiversity and they contribute to the unfavourable conservation status of habitats of interest to the European Community. In order to favour implementation of European Union Regulation no. 1143/2014 on invasive alien species, the Italian Society of Vegetation Science carried out a large survey led by a task force of 49 contributors with expertise in vegetation across all the Italian administrative regions. The survey summed up the knowledge on impact mechanisms of invasive alien plants in Italy and their outcomes on plant communities and the EU habitats of Community Interest, in accordance with Directive no. 92/43/EEC. The survey covered 241 alien plant species reported as having deleterious ecological impacts. The data collected illustrate the current state of the art, highlight the main gaps in knowledge, and suggest topics to be further investigated. In particular, the survey underlined competition as being the main mechanism of ecological impact on plant communities and Natura 2000 habitats. Of the 241 species, only Ailanthus altissima was found to exert an ecological impact on plant communities and Natura 2000 habitats in all Italian regions; while a further 20 species impact up to ten out of the 20 Italian administrative regions. Our data indicate that 84 out of 132 Natura 2000 Habitats (64%) are subjected to some degree of impact by invasive alien plants. Freshwater habitats and natural and semi-natural grassland formations were impacted by the highest number of alien species, followed by coastal sand dunes and inland dunes, and forests. Although not exhaustive, this research is the first example of nationwide evaluation of the ecological impacts of invasive alien plants on plant communities and Natura 2000 Habitats., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: To evaluate the intermediate perioperative outcomes, rate of complications and functional data after XPS 180-W Greenlight photoselective laser vaporization (PVP) compared with transurethral resection of the prostate (TURP) in a prospective non-randomized single centre study., Methods: We analyzed a prospectively-maintained database collecting data on 100 patients undergoing surgical treatment of BPH (50 consecutive PVP and 50 consecutive TURP). All complications, recorded and graduated according to the Clavien Dindo system and the clinical, operative, perioperative variables were compared. The functional outcomes, International Prostate Symptom Score (IPSS), max flow rate (Qmax) and Prostate Specific Antigen (PSA), were recorded preoperatively and at 1 year of follow up., Results: Age, prostate volume, use of anticoagulants or antiplatelets, ASA score and operative time were comparable in the two groups. The reduction in the hemoglobin levels (0.46 vs 1.8 g/dL), the catheterization time (1.2 vs 3.2 days), the hospital stay (1.7 vs 3.8 days) and rate of transfused patients (0 vs 8%), were significantly lower for PVP. Transient re-catherization (6 vs 26%) was significantly lower for PVP. The IPSS and Qmax at 1 year showed no significant difference. The rate of repeat TURP/PVP was higher in the TURP group (0 vs 10%). Reduction of PSA, that reflects the major reduction of prostate volume, was statistically greater in PVP group respect TURP group (p = 0.001)., Conclusions: PVP has advantages in terms of perioperative safety and major complications than TURP. Functional outcomes at 1 year of follow-up were comparable.

Background: Limited evidence-based guidance is available to parents regarding optimal child feeding practices to prevent early childhood obesity from birth to 24 months of age (B-24). The objective of this qualitative study was to determine current child feeding practices, barriers to implementation, and educational needs of parents of varying socioeconomic backgrounds as it relates to responsive feeding to prevent early obesity in children of ages B-24. Methods: One-on-one interviews were conducted with parents ( n  = 66) of children ages B-24 from both low-and non-low-income households. Interviews were audiorecorded, transcribed verbatim, and analyzed with NVivo using classical qualitative analysis. Results: Participants were primarily female (91%), married (53%), low-income (59%), and were not first-time parents (72%). The results revealed overarching themes, including parents' reported need for information on preparing child meals, optimal dietary intake, affordable healthy foods, promoting child self-feeding, and food and nutrition knowledge. Low-income parents more frequently requested guidance about identifying affordable healthy options and overfeeding while non-low-income parents requested information about food allergens, transitioning to solids, and creating structured mealtimes. Conclusions: Additional and focused outreach to parents of children ages B-24 regarding optimal feeding practices is needed especially on topics related to complementary feeding during the transition to solid food.

The present study investigated the psychometric properties of the Raven's Colored Progressive Matrices (CPM) test in a sample of preschoolers from Brazil ( n = 582; age: mean = 57 months, SD = 7 months; 46% female). We investigated the plausibility of unidimensionality of the items (confirmatory factor analysis) and differential item functioning (DIF) for sex and age (multiple indicators multiple causes method). We tested four unidimensional models and the one with the best-fit index was a reduced form of the Raven's CPM. The DIF analysis was carried out with the reduced form of the test. A few items presented DIF (two for sex and one for age), confirming that the Raven's CPM items are mostly measurement invariant. There was no effect of sex on the general factor, but increasing age was associated with higher values of the g factor. Future research should indicate if the reduced form is suitable for evaluating the general ability of preschoolers.

To compare the functional and operative outcomes of robot-assisted partial nephrectomy with selective arterial clamping guided by near infrared fluorescence imaging (NIRF-RAPN) versus a cohort of patients who underwent standard RAPN without selective arterial clamping (S-RAPN). 62 consecutive patients underwent RAPN from January 2016 to May 2017: the last 20 patients underwent NIRF-RAPN. Preoperative and postoperative renal scan at 1 month were performed to evaluate the glomerular filtration rate (GFR) of the operated renal unit and total function. Functional and operative outcomes of cases were compared with a cohort of 42 patients undergoing S-RAPN. Selective clamping was performed in 15 patients (75%), whereas five (25%) cases were converted to S-RAPN, due to incomplete ischemic appearance of the tumor after selective clamping. Median tumor diameter was 40 mm in both groups. Median selective clamping was 24 min in both groups. Operative time (206' vs 190') and blood loss (200 vs 170 cc) were comparable. No major complications have been reported in the NIRF-RAPN group, whereas three acute hemorrhages with embolization were found in the S-RAPN group. The analysis of renal scan data revealed that a greater loss of GFR in the operated renal unit was observed after S-RAPN compared to NIRF-RAPN [21.5% vs. 5.5%; p = 0.046], as well as total GFR loss [8% vs 0%; p = 0.007]. The use of NIRF imaging was associated with improved short-term renal functional outcomes compared to RAPN without selective arterial clamping. To our knowledge, this is the first comparative study analyzing the GFR obtained from renal scan.

Insufficient 25-hydroxyvitamin D [25(OH)D] levels are associated with high resting blood pressure (BP). However, the relationship between 25(OH)D and the peak systolic BP (SBP) response to exercise, a predictor of future hypertension, has yet to be investigated. We sought to examine the relationship among serum 25(OH)D and the peak SBP response to a graded exercise stress test (GEST) among a large sample ( n  = 417) of healthy men (49%) and women (51%) over a broad age range (20-76 years; mean age: 44.1 ± 0.8 years). We hypothesized that individuals with clinically insufficient 25(OH)D would have a greater peak SBP response to a GEST compared to individuals with sufficient 25(OH)D levels. Fasting serum 25(OH)D, anthropometrics, resting BP, and peak exercise SBP were obtained at the baseline visit of a larger clinical trial (STOMP; NCT01140308). Mean 25(OH)D levels were 36.1 ± 0.7 ng/ml, with ∼35% of individuals classified as insufficient (<30 ng/ml). Average resting BP was 119 ± 13 mmHg/75 ± 10 mmHg, with 52.3% considered to have normal BP, while 25.2% had elevated BP and 22.5% had established hypertension. The peak SBP response to a GEST was similar between individuals with sufficient (48 ± 19 mmHg) versus insufficient (48 ± 18 mmHg) 25(OH)D ( p  = 1.000). One unexpected finding emerged such that individuals with sufficient 25(OH)D had higher resting SBP (120 ± 14 mmHg vs. 117 ± 13 mmHg; p  = .020) than individuals with insufficient 25(OH)D. In contrast to our hypothesis, 25(OH)D levels were not associated with the peak SBP response to a GEST. Baseline 25(OH)D levels were positively correlated with resting SBP; however, the magnitude of this effect is likely not clinically meaningful.

Objectives: We evaluated the efficacy of sutureless laparoscopic partial nephrectomy (LPN), using a fibrin gel in order to minimize renal ischemia time and preserve kidney function., Materials and Methods: Nineteen patients (mean age 58.3 ± 7.1) undergoing sutureless LPN using a fbrin gel were compared with a control group consisting of 21 patients (mean age 57.9 ± 7.5) subjected to LPN with standard suturing. Intraand post-operative data for the two groups were compared. The following parameters were recorded: patient demographics, Charlson Comorbidity Index, tumor characteristics according to the RENAL score, warm ischemia and operative times, estimated blood loss, mean hospital stay, post-operative complications referring to the Clavien-Dindo classification, renal function parameters pathologic and follow-up data. The main outcome measure was renal ischemia time and maintenance of kidney function., Results: Median warm ischemia time was 13 minutes (range 11-19) in the group treated with fibrin gel and 19 (range 17- 29) in the control group, with a statistically significant difference (p < 0.001). The two groups were homogeneous in terms of the Charlson Comorbidity Index (4.6 vs 4.8) and RENAL score (9.6 vs 9.4). Median operative time differed significantly in the two groups, 183 minutes (range 145-218) in the group treated with fibrin gel and 201 (range 197-231) in the control group (p < 0.001). A negative surgical margin was reported in 18 patients (94.7%) in the group treated with fibrin gel and in 21 patients (100%) in the control group. No difference in renal function was found between the two groups., Conclusions: Sutureless LPN with fibrin gel can reduce warm ischemia and total operative time while preserving kidney function.

Objective: To evaluate the efficacy of a combination of Hibiscus extract, vegetable proteases and Commiphora myrrha extract in the prophylaxis of symptomatic episode in women affected by recurrent urinary tract infections (rUTIs)., Materials and Methods: In this phase II clinical trial, all patients with history and diagnosis of rUTI were enrolled. All patients underwent the following treatment schedule: 1 tablet in the morning and 1 tablet in the evening for 7 days and, then, 1 tablet in the evening for 10 days (1 cycle every each month, for 6 months) of a combination of Hibiscus extract, vegetable proteases and Commiphora myrrha extract. At the baseline, all patients underwent urologic visit with quality of life (QoL) questionnaires and mid-stream urine culture. After 3 and 6 months, all patients underwent urologic visit, urine culture and QoL questionnaires evaluation., Results: Fifty-five women were enrolled (mean age 49.3; range: 28-61). At the enrollment time, the most common pathogen was Escherichia coli (63.7%). The median number of UTI per 6 months was 5 (IQR: 4-9). At the end of the second follow-up evaluation, 25 women did not reported any symptomatic episode of UTI (49%), 18 reported less than 2 episodes (35.3%), while 8 reported more than 2 episodes (15.7%). However, at the first and second follow-up evaluation the clinical statistically significant improvement (QoL) was reported by 38/51 (74.5%) (p < 0.001 from baseline) and 43/51 (84.3%) (p < 0.001 from baseline) women, respectively. The median number of UTI decreased to 2 (IQR: 0-3). At the end of the follow-up period, 30/51 had sterile urine (58.8%), while 21/51 (41.2%) reported a transition from symptomatic UTI to asymptomatic bacteriuria., Conclusions: In conclusion, this treatment, in motivated patients, is able to prevent symptomatic UTI symptomatic episode and improve patient's QoL.

Objective: To evaluate the efficacy of a phytotherapic combination of L-Methionine associated with Hibiscus sabdariffa and Boswellia serrata for treatment of acute episodes of uncomplicated urinary tract infections (UTI) in women affected by recurrent UTIs., Materials and Methods: In this randomized phase III clinical trial, adult females with uncomplicated UTI were enrolled into one of the following treatment groups: Group A: phytotherapic combination 1 tablet in the morning and 1 tablet in the evening for 7 days; Group B: Short term antibiotic treatment according to international guidelines recommendations. At baseline, all patients were evaluated by a urologist and quality of life (QoL) questionnaires and mid-stream urine culture. Same clinical and laboratory investigations were repeated at each follow-up visit., Results: Forty-six patients were enrolled in Group A and 47 in Group B. At the first follow-up (30 days), both groups showed a statistically significant improvement in quality of life scores as compared with baseline assessment [Group A: (QoL 94.3 VS 98.5 p < 0.001); Group B: (QoL 94.5 VS 98.7 p < 0.001)]. An improvement from baseline was also seen at the second followup evaluation after 3 months [Group A: (QoL 94.3 VS 99.1 p < 0.001); Group B: (QoL 94.5 VS 98.1 p < 0.001)]. At the second follow-up visit, a statistically significant difference in QoL was reported between the two groups (99.1 VS 98.1; p < 0.003) and a transition from UTI to asymptomatic bacteriuria (ABU) was observed 12 of 46 (26%) patients in Group A, while no patients in Group B demonstrated ABU (p = 0.007)., Conclusions: Here, we demonstrated that this phytotherapic combination is able, in comparison to antibiotic treatment, to improve patients quality of life, reducing symptoms in acute setting and preventing the recurrences. Interestingly, a significantly higher proportion of patients in the phytotherapy group had ABU after three months. Our findings are of great interest in an antibiotic stewardship perspective.

This study aimed at reporting our first experience with robotic laparoendoscopic single-site radical prostatectomy (R-LESS-RP) with single-site VesPa platform (Intuitive Surgical Inc.). A 68-year-old-man presenting with a cT1c adenocarcinoma Gleason Score 3 + 4 = 7 in 4/12 bilateral cores underwent a transperitoneal robotic LESS-RP with a single-site Vespa platform. Initial PSA, prostate weight, and body mass index (BMI) were 4.4 ng/ml, 45 g, and 25, respectively. Instruments and camera cross within the Single-Site port; the da Vinci System software detects and reassigns the user's hands with the instruments position. The single-site port is inserted through a 2-cm intraumbilical incision. The robotic 8.5 mm scope and two surgical curved instruments (fenestrated bipolar forceps and cautery hook) are introduced through the ports and used for most of the procedure, whereas a wristed needle driver on the right hand is used for the reconstructive steps. An additional 12 mm port (Air Seal, SurgiQuest) is placed in a midline between the umbilicus and the right iliac spine in order to facilitate table assistance during surgery and to place a drain at the end of the procedure.Operative time and blood loss were 300 min and 400 mL, respectively. The postoperative course was uneventful. The drain and the catheter were removed on days 1 and 6, respectively. The patient experienced a temporary mild stress incontinence (one pad at sixth month) and erectile dysfunction.Our first robotic laparoendoscopic single-site radical prostatectomy (R-LESS-RP) with the single-site VesPa platform was associated with acceptable operative times and perioperative outcome. This procedure is feasible without complications, provided that a proper patient selection has occurred. Limited movements together with the lack of the fourth robotic arm require a considerable expertise in robotic surgery. Some tricks can help overcome technical limitations. The Robotic LESS-RP reduces in some measure the limitations of conventional LESS RP, although further refinement of the robotic instruments is necessary.

Background: To compare the surgical outcomes of radical prostatectomy (RP) performed via 3 different approaches: retropubic (RRP), laparoscopic-assisted (LRP), and robot-assisted (RARP), in a single non-academic regional center by a single surgeon., Materials and Methods: The data of patients undergoing RP from 2005 to 2014 were reviewed. The standard approach changed through the years: RRP (n = 380, years 2005 to 2008), LRP (n = 240, years 2009 to 2011), and RARP (n = 262, years 2012 to 2014). Our analysis included the last consecutive 100 RP for each surgical technique by a single surgeon. A logistic regression model adjusted for pre-and postoperative variables was done to evaluate whether transfusion, conversion, and post-operative complication rates were influenced by the approach., Results: RARP was associated with significantly lower blood loss (400 vs. 600 and 600 ml, respectively), transfusion (6 vs. 21 and 21%, respectively), and shorter hospital stay (6 vs. 7 and 8 days, respectively), compared to LRP and RRP, and a lower conversion rate (1 vs. 12%) compared to LRP. Multivariate analysis adjusted for confounders confirmed that the risk of transfusion and conversion was significantly lower in the RARP group compared to the LRP and RRP groups. The RARP group was also associated with a significantly lower risk of complications compared to the RRP group and with a trend in favor of the RARP group compared to the LRP group. The 1-year continence rate was significantly higher in the RARP group compared to the RRP and LRP groups (80 vs. 72 and 68%, respectively)., Conclusion: The surgical approach affected the operative outcomes in a regional setting. The advantages of RARP over RRP (complications, transfusion, conversion, hospital stay, 1-year continence) were over LRP as well, with the only exception being complications.

Background: New therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma., Methods: DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374., Findings: Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7·7 months (95% CI 6·8-8·9) in the tremelimumab group and 7·3 months (5·9-8·7) in the placebo group (hazard ratio 0·92 [95% CI 0·76-1·12], p=0·41). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient., Interpretation: Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing., Funding: AstraZeneca., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The objective of this is to compare the surgical outcomes of partial nephrectomy (PN), performed via three different approaches: robot-assisted (RAPN), laparoscopic (LPN), and open (OPN), in a single non-academic regional center. The data of patients undergoing PN at our Department from 2005 to 2016 were prospectively collected. A logistic regression model adjusted for preoperative variables (age, tumor size, creatinine and hemoglobin, ASA and Padua scores) was performed to evaluate whether transfusion, conversion, and postoperative complication rate were influenced by the surgical approach. Overall 270 patients underwent PN: analysis included 253 cases (RAPN = 110, LPN = 70, OPN = 73). Preoperative variables did not differ significantly among the three groups. Shorter operative (130 vs 180 and 200') and ischaemia (12 vs 23 and 22') times and longer hospital stay (8 vs 7 and 6 days) were found in the OPN group as compared to LPN and RAPN, respectively. The RAPN group included a higher rate of pT1b (31.8 vs 14.2 and 15%) and malignant histotype (90 vs 82.9 and 68.5%) as compared to LPN and OPN, respectively. Clavien Grade III-IV complications were lower in the RAPN (7.2%) as compared to OPN (12.3%) and LPN (17.1%) groups. Multivariate analysis showed a lower risk for conversion, transfusion and overall complications in the RAPN group versus LPN and OPN. The surgical approach affects the perioperative outcomes in a regional setting. The advantages of RAPN over OPN (lower risk of conversion, transfusion, and overall complications) are extended over LPN as well, although OPN offered faster operative and ischemia times at the expense of greater blood loss and hospital stay.

Background: To better inform clinical practice, this study was aimed at capturing patients' motivations for enrolling in phase 1 trials and at quantifying their expectations of the benefits, risks, and commitment associated with clinical trials and the impact of the initial consultation on their expectations., Methods: This was a single-center, prospective, quantitative study of newly referred adult patients considering their first phase 1 oncology trial. Participants completed questionnaires before they were seen and an abbreviated follow-up version after their consultation., Results: Questionnaires were completed by 396 (99%) and 301 (76%) before and after the clinic, respectively. Participants ranked the possibility of tumor shrinkage (84%) as the most important motivation for considering a phase 1 trial; this was followed by no alternative treatments (56%), their physician's recommendation (44%), and the fact that the research might benefit others (38%). When they were asked about the potential personal benefit, 43% predicted tumor shrinkage initially. After the consultation, this increased to 47%. Fourteen percent of patients expected a cure. When asked about risks, 71% of the participants expected moderate side effects. When asked about expectations of time commitments, a majority of patients did not anticipate weekly visits, although this was understood by 93% of patients after the consultation. Overall, patients were keen to consider trials and when asked before and after the consultation 72% and 84% were willing to enroll in studies, respectively., Conclusions: This study reports that more than 80% of patients enroll in early-phase clinical oncology trials motivated by the potential of a clinical benefit, with approximately half expecting tumor shrinkage and approximately a tenth anticipating a cure. The typical phase 1 response rate is 4% to 20%, and this discrepancy exemplifies the challenges faced by patients and healthcare professionals during their interactions for phase 1 studies. Cancer 2016;122:3501-3508. © 2016 American Cancer Society., (© 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Objective: To evaluate contemporary international trends in the implementation of minimally invasive adrenalectomy and to assess contemporary outcomes of different minimally invasive techniques performed at urologic centers worldwide., Methods: A retrospective multinational multicenter study of patients who underwent minimally invasive adrenalectomy from 2008 to 2013 at 14 urology institutions worldwide was included in the analysis. Cases were categorized based on the minimally invasive adrenalectomy technique: conventional laparoscopy (CL), robot-assisted laparoscopy (RAL), laparoendoscopic single-site surgery (LESS), and mini-laparoscopy (ML). The rates of the four treatment modalities were determined according to the year of surgery, and a regression analysis was performed for trends in all surgical modalities., Results: Overall, a total of 737 adrenalectomies were performed across participating institutions and included in this analysis: 337 CL (46 % of cases), 57 ML (8 %), 263 LESS (36 %), and 80 RA (11 %). Overall, 204 (28 %) operations were performed with a retroperitoneal approach. The overall number of adrenalectomies increased from 2008 to 2013 (p = 0.05). A transperitoneal approach was preferred in all but the ML group (p < 0.001). European centers mostly adopted CL and ML techniques, whereas those from Asia and South America reported the highest rate in LESS procedures, and RAL was adopted to larger extent in the USA. LESS had the fastest increase in utilization at 6 %/year. The rate of RAL procedures increased at slower rates (2.2 %/year), similar to ML (1.7 %/year). Limitations of this study are the retrospective design and the lack of a cost analysis., Conclusions: Several minimally invasive surgical techniques for the management of adrenal masses are successfully implemented in urology institutions worldwide. CL and LESS seem to represent the most commonly adopted techniques, whereas ML and RAL are growing at a slower rate. All the MIS techniques can be safely and effectively performed for a variety of adrenal disease.

Objectives: We hypothesised that it was possible to quantify phosphorylation of important nodes in the phosphatidylinositol 3-kinase (PI3K) pathway in cancer cells isolated from pleural effusions of patients with non-small cell lung cancer (NSCLC) and study their correlation to somatic mutations and clinical outcomes., Materials and Methods: Cells were immunomagnetically separated from samples of pleural effusion in patients with NSCLC. p-AKT, p-S6K and p-GSK3β levels were quantified by ELISA; targeted next-generation sequencing was used to characterise mutations in 26 genes., Results: It was possible to quantify phosphoproteins in cells isolated from 38/43 pleural effusions. There was a significant correlation between p-AKT and p-S6K levels [r = 0.85 (95% confidence interval 0.73-0.92), p < 0.0001], but not p-AKT and p-GSK3β levels [r = 0.19 (95% confidence interval -0.16 to 0.5), p = 0.3]. A wide range of mutations was described and p-S6K was higher in samples that harboured at least one mutation compared to those that did not (p = 0.03). On multivariate analysis, p-S6K levels were significantly associated with poor survival (p < 0.01)., Conclusion: Our study has shown a correlation between p-AKT levels and p-S6K, but not GSK3β, suggesting differences in regulation of the distal PI3K pathway by AKT. Higher p-S6K levels were associated with adverse survival, making it a critically important target in NSCLC., (© 2016 S. Karger AG, Basel.)

Purpose: AZD2014 is a novel, oral, m-TORC 1/2 inhibitor that has shown in vitro and in vivo efficacy across a range of preclinical human cancer models., Experimental Design: A rolling six-dose escalation was performed to define an MTD (part A), and at MTD a further cohort of patients was treated to further characterize toxicities and perform pre- and posttreatment biopsies (part B). AZD2014 was administered orally twice a day continuously. Flow cytometry, ELISA, and immunohistochemistry were used to quantify pharmacodynamic biomarkers. Pharmacokinetic analysis was carried out by mass spectrometry., Results: A total of 56 patients were treated across a dose range of 25 to 100 mg. The MTD was 50 mg twice daily. The dose-limiting toxicities were fatigue and mucositis. At the MTD, the most common adverse events (AE) were fatigue (78%), nausea (51%), and mucositis (49%), but these were equal to or greater than grade 3 in only 5% of patients. Drug levels achieved at the MTD (AUC SS: 6686 ng·h/mL, Cmax ss 1,664 ng/mL) were consistent with activity in preclinical models. A reduction in p-S6 levels and Ki67 staining was observed in 8 of 8 and 5 of 9 evaluable paired biopsy samples. Partial responses were seen in a patient with pancreatic cancer and a patient with breast cancer, who were found to have a PDGFR and ERBB2 mutation, respectively., Conclusions: The recommended phase II dose for further evaluation of AZD2014 is 50 mg twice daily, and at this dose it has been possible to demonstrate pharmacologically relevant plasma concentrations, target inhibition in tumor, and clinical responses., (©2015 American Association for Cancer Research.)

Background: Vitamin B12 and folic acid (referred to as vitamin supplementation) improves the toxicity profile of pemetrexed containing regimens. Low baseline vitamin B12 and folate levels are reflected in a raised total homocysteine level (HC). Studies have suggested that pretreatment HC levels predict neutropenia toxicity. We have tested supplementation with vitamin B12 and folate in non-pemetrexed platinum-based regimens to decrease treatment-related toxicity and looked for a correlation between toxicity and change in homocysteine levels., Patient and Method: Eighty-three patients with advanced lung cancer and malignant mesothelioma were randomly assigned to receive platinum-based chemotherapy with (arm A) or without (arm B) vitamin B12 and folic acid supplementation. The primary end point was grade 3/4 neutropenia and death within 30 days of treatment. Secondary end points included quality of life, overall survival (OS) and the relationship between baseline and post supplementation HC levels and toxicity., Results: In the intention-to-treat population, no significant difference was seen between the two groups with respect to chemotherapy-induced grade 3/4 neutropenia and death within 30 days of chemotherapy (36% vs 37%; p=0.966, emesis (2% vs 6%; p=0.9) or OS (12.3 months vs 7 months; p=0.41). There was no significant difference in survival rates by baseline HC level (p=0.9). Decrease in HC with vitamin supplementation was less frequent than expected. High baseline HC levels decreased with vitamin supplementation in only 9/36 (25%) patients (successful supplementation). Post hoc analysis showed that patients in arm A who were successfully supplemented (9/36=25%) had less neutropenic toxicity (0% vs 69%; p=0.02) compared to unsupplemented patients., Conclusions: The addition of vitamin B12 and folic acid to platinum-containing regimens did not overall improve the toxicity, quality of life or OS. Rates of grade 3/4 neutropenia at 36/37% was as predicted. Further studies to increase the rate of successful supplementation and to further test the biomarker potential of post supplementation HC levels in predicting chemotherapy-induced neutropenia in platinum-based chemotherapy are warranted., Trial Registration Number: EudracCT 2005-002736-10 ISRCTN8734355.

The terms "dyadic death" or "murder-suicide" refer to an incident where an individual commits homicide and then takes his or her own life. These events are generally committed by men within the family network, using firearms or sharp force instruments, and make up a relatively small proportion of homicides overall. Herein, we present the application of post-mortem multislice computed tomography (CT) and micro-CT analysis to an unusual case of dyadic death, where a 38-year-old man fired a single gunshot to his own right temple, killing himself and his 50-year-old wife, lying on the bed beside him. The integration of radiological, autoptic and histological data allowed us to reconstruct the trajectory of the gunshot, the most probable dynamics of the event, and to classify the incident as a "suicide-homicide", because the female victim died a few minutes later than her husband and murderer., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Breast cancer-related lymphedema (LE) represents an important morbidity that jeopardizes breast cancer patients' quality of life. Different attempts to prevent LE brought about improvements in the incidence of the pathology but LE still represents a frequent occurrence in breast cancer survivors. Over 4 years ago, Lymphatic Microsurgical Preventing Healing Approach (LYMPHA) was proposed and long-term results are reported in this study. From July 2008 to December 2012, 74 patients underwent axillary nodal dissection for breast cancer treatment together with LYMPHA procedure. Volumetry was performed preoperatively in all patients and after 1, 3, 6, 12 months, and once a year. Lymphoscintigraphy was performed in 45 patients preoperatively and in 30 also postoperatively after at least over 1 year. Seventy one patients had no sign of LE, and volumetry was coincident to preoperative condition. In three patients, LE occurred after 8-12 months postoperatively. Lymphoscintigraphy showed the patency of lymphatic-venous anastomoses at 1-4 years after operation. LYMPHA technique represents a successful surgical procedure for primary prevention of arm LE in breast cancer patients., (© 2014 Wiley Periodicals, Inc.)

Objectives: EGFR inhibitors are ineffective against most EGFR wild-type non-small cell lung cancer, for which novel treatment strategies are needed. AKT signalling is essential for mediating EGFR survival signals in NSCLC. We evaluated the combination of gefitinib and two different AKT inhibitors, the allosteric inhibitor AKTi-1/2 and the ATP-competitive pan-AKT inhibitor AZD5363, in EGFR-mutant (HCC-827 and PC-9) and -wild-type (NCI-H522, NCI-H1651), non-small cell lung cancer cell lines., Materials and Methods: Drug interaction was studied in two EGFR mutant and two EGFR wild-type non-small cell lung cancer cell lines by calculating combination index (CI) using median effect analysis. The effects on p-EGFR, p-ERK, p-AKT, p-S6 and apoptosis were studied by Western blot analysis., Results: The combination of gefitinib and AKTi-1/2 or AZD5363 showed synergistic growth inhibition in all cell lines. CI values for the combination of gefitinib and AKTi-1/2 were 0.35 (p=0.0048), 0.56 (p=0.036), 0.75 (p=0.13) and 0.64 (p=0.0003) in NCI-H522, NCI-H1651, HCC-827 and PC-9 cell lines, respectively; CI values of 0.45 (p=0.0087) and 0.22 (p<0.0001) were observed in NCI-H522 and PC-9 cells, respectively, when gefitinib was combined with AZD5363. Additive inhibition of signalling output through AKT and key downstream proteins (S6) and increased apoptosis were demonstrated., Conclusion: Dual inhibition of EGFR and AKT may be a useful up-front strategy for patients with EGFR-mutant and -wild-type non-small cell lung cancer., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: We investigated the association between skin rash and plasma creatine kinase (CK) levels in oncology phase I trials., Methods: We analysed data from 295 patients treated at our institution within 25 phase I trials which included CK measurements in the protocol. Trials involved drugs targeting EGFR/HER2, m-TOR, VEGFR, SRC/ABL, aurora kinase, BRAF/MEK, PARP, CDK, A5B1 integrin, as well as oncolytic viruses and vascular disrupting agents., Results: Creatine kinase measurements were available for 278 patients. The highest levels of plasma CK during the trial were seen among patients with Grade (G) 2/3 rash (median 249 U l(-1)) compared with G1 (median 81 U l(-1)) and no rash (median 55 U l(-1)) (P<0.001). There was a significant reduction in CK after the rash resolved (mean 264.2 vs 100.1; P=0.012) in 25 patients, where serial CK values were available. In vitro exposure of human keratinocytes to EGFR, MEK and a PI3Kinase/m-TOR inhibitor led to the increased expression of CK-brain and not CK-muscle or mitochondrial-CK., Conclusion: Plasma CK elevation is associated with development of skin rash caused by novel anticancer agents. This should be studied further to characterise different isoforms as this will change the way we report adverse events in oncology phase I clinical trials.

Background: This study defined the risk of serious toxicity in phase I trials of molecularly targeted agents (MTA)., Patients and Methods: A retrospective analysis of toxicity data from patients treated in phase I trials of MTAs was carried out to define the rate of treatment-related grade 3/4 toxic effects, deaths and risk factors associated with grade 3 or more toxicity., Results: Data from 687 patients [median age, 59.1 years (range 12.5-85.5)] treated in 36 trials were analysed. Two hundred and eleven patients were of Eastern Cooperative Oncology Group performance status (PS) zero, 432 of PS one, 38 of PS two and 6 unknown. The rate of grade 3 and 4 events was 14.1% (n=97) and 1.9% (n=13), respectively. Twenty-four percent of events were gastrointestinal, 22% constitutional and 20% metabolic. PS two was associated with a higher risk of toxicity [odds ratio (OR), 2.6; 95% confidence interval (CI) 1.1-6.1; P=0.032] as was receiving >100% of maximum tolerated dose or maximum administered dose (OR 2.5; CI 1.6-3.9; P<0.001). Mortality rate was 0.43% (n=3)., Conclusions: Therapy with novel MTAs in phase I trials is associated with a moderate risk of significant toxicity. This appears less than in phase I studies involving cytotoxic agents, particularly in relation to grade 4 toxicity. The risk of death is low.

Background: The aim of this study was to assess if (18)F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)-CT scanning could minimise the time non-responding patients were exposed to erlotinib (Tarceva)., Methods: Patients were selected for clinical factors that would predict response to erlotinib. A FDG PET-CT and diagnostic contrast-enhanced (traditional) CT scan were carried out at baseline, and then a FDG PET-CT at 6 weeks and a traditional CT at 12 weeks were repeated. The primary end-point was rate of early progression in patients after 6 weeks, of which a minimum 12 out of 35 were required to make the study worthwhile. The responses at 6 (PET-CT) and 12 weeks (traditional CT) were compared and correlated with symptomatic response at both these time points., Results: Forty seven patients were recruited with 38 and 33 patients assessable by FDG PET-CT at 6 weeks and traditional CT at 12weeks, respectively. There was good correlation between Partial response (PR) at both time points and all 10 patients who had a PR at 12 weeks had a PR at 6 weeks. Of the 13 patients with progressive disease (PD) at 12 weeks, seven had PD at 6 weeks and could have had their treatment stopped early. No evaluable patient with stable disease (SD) (8/38) or PD (9/38) on FDG PET-CT at 6 weeks went on to have a later response. Symptomatic response at 6 or 12 weeks did not correlate well with objective response on scanning at either time point., Conclusions: The primary end-point of this study was met as >12 (15/38) patients could have stopped treatment early on the basis of the FDG PET-CT scan result. A FDG PET-CT evaluable response of SD or PD at 6 weeks does predict future lack of response. No correlation was found between response and symptomatic response at either 6 or 12 weeks., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to evaluate any correlations between baseline creatinine clearance and the development of grade 3/4 toxicities during treatment within oncology phase I trials of molecularly targeted agents where entry criteria mandate a serum creatinine of ≤ 1.5 × the upper limit of normal., Methods: Documented toxicity and creatinine clearance (calculated by the Cockcroft-Gault formula) from all patients treated with molecularly targeted agents in the context of phase I trials within our centre over a 5-year period were analyzed., Results: Data from 722 patients were analyzed; 116 (16%) developed at least one episode of grade 3/4 toxicity. Patients who developed a late-onset (>1 cycle) grade 3/4 toxicity had a lower creatinine clearance than those who did not (82.69 ml/min vs. 98.97 ml/min; p = < 0.001)., Conclusion: Creatinine clearance (even when within normal limits) should be studied as a potential factor influencing late toxicities in the clinical trials of molecularly targeted anti-cancer drugs., (Copyright © 2012 S. Karger AG, Basel.)

Purpose: To prospectively assess the efficacy of the lymphatic microsurgical preventive healing approach (LYMPHA) to prevent lymphedema after axillary dissection (AD) for breast cancer treatment., Methods: Among 49 consecutive women referred from March 2008 to September 2009 to undergo complete AD, 46 were randomly divided in 2 groups. Twenty-three underwent the LYMPHA technique for the prevention of arm lymphedema. The other 23 patients had no preventive surgical approach (control group). The LYMPHA procedure consisted of performing lymphatic-venous anastomoses (LVA) at the time of AD. All patients underwent preoperative lymphoscintigraphy (LS). Patients were followed up clinically at 1, 3, 6, 12, and 18 months by volumetry. Postoperatively, LS was performed after 18 months in 41 patients (21 treatment group and 20 control group). Arm volume and LS alterations were assessed., Results: Lymphedema appeared in 1 patient in the treatment group 6 months after surgery (4.34%). In the control group, lymphedema occurred in 7 patients (30.43%). No statistically significant differences in the arm volume were observed in the treatment group during follow-up, while the arm volume in the control group showed a significant increase after 1, 3, and 6 months from operation. There was significant difference between the 2 groups in the volume changes with respect to baseline after 1, 3, 6, 12, and 18 months after surgery (every timing P value < 0.01)., Conclusions: LYMPHA represents a valid technique for primary prevention of secondary arm lymphedema with no risk of leaving undetected malignant disease in the axilla.

Background: In a randomized trial with a median follow-up of 18.4 months, 6 months of induction chemotherapy with a three-drug regimen comprising 5-fluorouracil (by continuous infusion)-leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) demonstrated statistically significant improvements in response rate, radical surgical resection of metastases, progression-free survival, and overall survival compared with 6 months of induction chemotherapy with fluorouracil-leucovorin and irinotecan (FOLFIRI)., Methods: From November 14, 2001, to April 22, 2005, we enrolled 244 patients with metastatic colorectal cancer. To evaluate if the superiority of FOLFOXIRI is maintained in the long term, we updated the overall and progression-free survival data to include events that occurred up to February 12, 2009, with a median follow-up of 60.6 months. We performed a subgroup and a risk-stratified analysis to examine whether outcomes differed in specific patient subgroups, and we analyzed the results of treatment after progression. Survival curves were estimated by the Kaplan-Meier method. Multivariable Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided., Results: FOLFOXIRI demonstrated statistically significant improvements in median progression-free survival (9.8 vs 6.8 months, HR for progression = 0.59, 95% CI = 0.45 to 0.76, P < .001) and median overall survival (23.4 vs 16.7 months, HR for death = 0.74, 95% CI = 0.56 to 0.96, P = .026) with a 5-year survival rate of 15% (95% CI = 9% to 23%) vs 8% (95% CI = 4% to 14%). The improvements in progression-free survival and, to a lesser extent, in overall survival were evident even when the analysis excluded patients who received radical resection of metastases. With regard to the risk-stratified analysis, FOLFOXIRI results in longer progression-free survival and overall survival than FOLFIRI in all risk subgroups., Conclusions: Six months of induction chemotherapy with FOLFOXIRI is associated with a clinically significant improvement in the long-term outcome compared with FOLFIRI with an absolute benefit in survival at 5 years of 7%.

Introduction: First-line treatment options utilizing chemotherapy and cytokine-based treatments for patients with metastatic melanoma (MM) are unsatisfactory. We analyzed the clinical outcomes of patients with MM treated in phase I trials of novel agents. We hypothesized that patients included in phase I clinical trials did not have worse outcomes than with the chemotherapy and cytokine-based first-line treatment., Methods: Data of patients with MM treated at The Drug Development Unit between 2004 and 2010 were collected. The response rate (RR) and time to progression (TTP) for first-line therapy were compared to those of phase I trial therapy. Patients acted as their own controls for statistical analyses., Results: Sixty-five patients were treated in 31 phase I trials. First-line treatment included dacarbazine or temozolomide in 58 (89%) cases and interferon-α in 5 patients (8%) and cisplatin-based treatment in 2 patients (3%). There was no significant difference in either the RR (11 vs. 14%, p = 0.87) or TTP (90 vs. 53 days, p = 0.15) in patients treated with first-line treatment versus phase I treatment, respectively., Conclusion: Phase I clinical trials of molecularly targeted agents show clinical activity that is not dissimilar to that of treatment with existing chemotherapy and cytokine-based treatment., (Copyright © 2011 S. Karger AG, Basel.)

The chemokine receptor CXCR4 and CD133, putative stem cell markers, were previously described in renal cancer (RCC). To evaluate the biological and prognostic role of CD133 and CXCR4 in RCC the expression was evaluated through qPCR and immunoblotting in human renal cancer cell lines (786-O, A498, ACHN, CAKI-1, SN12C, TK10, UO31) and patients biopsies. Renal cancer cells and surgical biopsies expressed functional CXCR4 while CD133 was not detectable. CXCR4 and CD133 expression was then evaluated in 240 renal cancer patients through immunohistochemistry. CXCR4 and CD133 were low in 19.1% and 59.6%; intermediate in 20% and 17.9%; high in 60.8% and 22.5% of the cases, respectively. CXCR4 was overexpressed in tumours (p= 0.02), while CD133 was over expressed in healthy tissues (p= 0.04). Disease free survival Kaplan Meier plots suggest that prognosis is unfavourable for patients whose primary tumours express CXCR4 (p= 0.0199) but nor CD133 (p= 0.151) neither the concomitant CXCR4-CD133 (p=0.848) high expression affected prognosis. Analysis of prognostic factors suggests that age, clinical presentation, AJCC stage and CXCR4 had a significant prognostic value at the univariate analysis. The CXCR4 predictive ability was confirmed at the multivariate analysis while no prognostic role was identified for CD133.Thus concomitant CD133 and CXCR4 evaluation is not worth in RCC patient while the CXCR4 prognostic role encourage CXCR4 antagonists as promising therapeutic option.

Background: Until recently, histology has not been clearly or consistently described in the literature as a prognostic or predictive variable in advanced NSCLC studies. We have categorised patients treated with vinorelbine and gemcitabine based first line chemotherapy regimes for advanced NSCLC as either squamous or non-squamous, and also as either adenocarcinoma and non-adenocarcinoma, and compared outcome., Material and Methods: 420 patients treated with platinum/gemcitabine, platinum/vinorelbine or single agent gemcitabine or vinorelbine as first line chemotherapy for advanced NSCLC were identified. The influence of pathology on progression free survival (PFS) and overall survival (OS) has been investigated by means of a Cox regression analysis. Hazard ratios with 95% CIs have been given for each pathological type after adjusting for the effects of age, gender, stage (III vs. IV), PS (0/1 vs. 2/3) and treatment type (platinum doublet vs. single agent)., Results: Neither univariate nor multivariate analysis suggested that there was a significant difference in the response rates for adenocarcinoma vs. non-adenocarcinoma or between squamous and non-squamous pathology. There was no difference in PFS between adenocarcinoma and non-adenocarcinoma pathologies until 8 months (p = 0.98), and there was a statistically significant advantage in PFS for squamous vs. non-squamous pathologies (p = 0.04). Using multivariate Cox regression analysis to adjust for the effects of age, gender, stage, PS, and treatment type, the pathology subtype was not significant. There was no difference in OS in any group., Conclusions: These results suggest that histology may not be considered as a predictor of clinical outcome using these drugs., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Differentiated thyroid carcinoma accounts for 90% of all thyroid cancers and occurs as papillary carcinoma in 90% of cases. It was shown as this is characterized by an excellent long-term prognosis, although in follow-up long series, were described recurrence rates up to 35%. Although in the past has not been attributed prognostic significance to the lymph nodes, in the last decade has shown how these can affect the rate of locoregional recurrence of differentiated thyroid carcinoma. This renewed interest in lymph node metastatic disease has prompted a shift in surgical treatments more aggressive, with a view to achieving a low incidence of locoregional recurrence. Analyzing the more recent guidelines formulated at the international level, we can highlight how we gradually consolidated the role of prophylactic central compartment lymphadenectomy in the surgical treatment of patients with differentiated thyroid carcinoma. The aim of this treatment, in fact, is not only to reduce the mortality of patients, but to obtain an adequate staging, facilitate radiotherapy treatment, obtain undetectable thyroglobulin levels, avoiding the need for repeated reiterventi, made more simple follow-up. All these objectives can be achieved by careful surgery. Total thyroidectomy associated with prophylactic lymphadenectomy of the central compartment was found to achieve these objectives, although in the absence of data from randomized trials, its role remains controversial.