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Here we report an experimental, modelling and theoretical study of CNT growth and connection on a chip device with a flip chip configuration used to improve thermal management performances, in order to elaborate board design analysis. CNTs growth was obtained for the first time on AlN substrate typically used in high power electronic. The thermal conductivity of isolated CNT was 1698,5 W/mK. Moreover, the aim of this paper was to study the role of the design parameters to mitigate the effects of a non-correct thermal management obtained with the help of high thermal conductive CNT connections bumps. With the support of a simulator we evaluated thermal performances to help in a preliminary phase the board design. We worked on a configuration that would allow the direct integration into flip-chip devices in order to reduce the thermal contact resistance at interfaces from the die through the heat spreader and the junction temperature and thermal crosstalk.

Few layer graphene/SiO2/SiC (G/SiO2/SiC) core-layers-sheath nano-heterojunctions were obtained by a new easy and cheap designed procedure by thermal annealing at atmospheric pressure and low temperature on 3C-SiC powder derived from exhausted activated carbon. Recycled SiC was chosen as growth substrate to realize a convenient process and to increase the added value of the recycled, combining the favourable properties of different substances. SiC powder and the advanced materials obtained were carefully characterized by the combining use of different techniques: transmission electron microscopy (TEM) with EDAX probe, scanning electron microscopy (SEM), X-ray diffraction analysis, Raman spectroscopy, thermogravimetric analysis coupled with quadrupole mass detector (TG-DTG-MASS).

This trial was conducted to evaluate the effects of replacing soybean meal with microalgae meal (MM; Arthrospira spp.) during grower and finisher phases on productive performance, footpad dermatitis (FPD) occurrence, breast meat quality, amino acid digestibility and plasma metabolomics profile of broiler chickens. One thousand day-old Ross 308 male chicks were divided into 5 experimental groups (8 replicates, 25 birds/each): CON, fed a commercial soybean-based diet throughout the trial (0-41 d); F3 and F6, fed the CON diet up to 28 d of age and then a finisher diet (29-41 d) with either 30 or 60 g MM/kg, respectively; and GF3 and GF6, receiving CON diet until 14 d and then diets containing 30 or 60 g MM/kg from 15 to 41 d, respectively. All diets were iso-energetic and with a similar amino acid profile. Growth performances were recorded on a pen basis at the end of each feeding phase and apparent ileal amino acid digestibility was determined at 41 d. Footpad dermatitis occurrence was assessed on all processed birds, while breast and plasma samples were collected for meat quality and metabolomics analysis (proton nuclear magnetic resonance - 1 H-NMR). At 41 d, CON group showed higher body weight than F6 and GF6 ones (2,541 vs. 2,412 vs. 2,384 g, respectively; P < 0.05). Overall, GF6 group exhibited the highest feed conversion ratio, while F3 did not present significant differences compared to CON (1.785 vs. 1.810 vs. 1.934 g feed/g gain, respectively for CON, F3 and GF6; P < 0.01). The occurrence and the risk of developing FPD were similar among groups. MM administration increased breast meat yellowness and reduced amino acid digestibility (P < 0.001). The 1 H-NMR analysis revealed variations in the levels of some circulating metabolites, including histidine, arginine and creatine, which play important metabolic roles. Overall, these findings can contribute to expand the knowledge about the use of Arthrospira spp. as protein source in broiler diets., Competing Interests: DISCLOSURES The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Commercial laying hens have high frequency of damage to the keel bone (KB), which causes negative effects on health and welfare. KB damage may consist in fractures (KBF) and deviations (KBD). The aim of the present study was to compare the KB shape, by means of Geometric Morphometric, and the occurrence of fractures in different chicken genotypes reared either free-range (FR) or in enriched cages. Moreover, the relationship between KB shape, genotype and rearing system was analysed. Sixty birds/genotype (2 Italian local breeds, Bionda Piemontese and Robusta Maculata, their crossbreeds with Sasso and Lohmann Brown) were used. All the hens fed the same commercial feed throughout the trial. Body weight, egg production, feed intake and mortality were recorded from 25 to 66 weeks of age. Ca intake (IN) and output (OUT) were estimated and Ca OUT/IN was calculated. FR affected the occurrence of KB deviations but not the shape, whereas the fractures were mainly affected by genotype. Local breeds had a lower prevalence of KBF with similar level of KBD but with different shapes. Crossbreeds seemed to be a suitable compromise between egg deposition rate and occurrence of KB damages., (© 2023. The Author(s).)

Little attention has been paid to the biological role of arginine and its dietary supplementation in broilers under heat stress (HS) conditions. Therefore, the main aim of this study was to assess the response of broilers to arginine supplementation and cyclic HS, with a focus on liver, pectoral muscle, and blood metabolic profiles and the cecal microbiota. Day-old male Ross 308 broilers ( n = 240) were placed in 2 rooms with 12 pens each for a 44-day trial. Pens were assigned to one of two groups (6 pens/group/room): the control group (CON) was given a basal diet in mash form and the treated group (ARG) was fed CON diet supplemented with crystalline L -arginine. The total arginine:lysine ratio of CON diet ranged between 1.02 and 1.07, while that of ARG diet was 1.20. One room was constantly kept at thermoneutral (TN) conditions, while the birds in the other room were kept at TN conditions until D34 and subjected to cyclic HS from D35 onwards (∼34°C; 9:00 A.M.-6:00 P.M.). Blood, liver, Pectoralis major muscle, and cecal content were taken from 2 birds per pen (12 birds/group/room) for metabolomics and microbiota analysis. Growth performance data were also collected on a pen basis. Arginine supplementation failed to reduce the adverse effects of HS on growth performance. Supplemented birds showed increased levels of arginine and creatine in plasma, liver, and P. major and methionine in liver, and reduced levels of glutamine in plasma, liver, and P. major . HS altered bioenergetic processes (increased levels of AMP and reduced levels of fumarate, succinate, and UDP), protein metabolism (increased protein breakdown to supply the liver with amino acids for energy production), and promoted the accumulation of antioxidant and protective molecules (histidine-containing dipeptides, beta-alanine, and choline), especially in P. major . Arginine supplementation may have partially counterbalanced the effects of HS on energy homeostasis by increasing creatine levels and attenuating the increase in AMP levels, particularly in P. major . It also significantly reduced cecal observed diversity, while HS increased alpha diversity indices and affected beta diversity. Results of taxonomic analysis at the phylum and family level are also provided., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Brugaletta, Laghi, Zampiga, Oliveri, Indio, Piscitelli, Pignata, Petracci, De Cesare and Sirri.)

Aims: We aim to provide real-world evidence on the use of ocrelizumab for treating multiple sclerosis (MS), with specific regard to prescription pattern, adherence, persistence, healthcare resource utilization and related costs, also in relation to other disease-modifying treatments (DMTs)., Methods: We included 2495 people with MS from the Campania Region (South Italy) who received first or switch DMT prescription from Jan 2018 to Dec 2020, and with at least 6-month follow-up. We collected hospital discharge records, drug prescriptions, and related costs, and calculated persistence (time from first prescription to discontinuation or switch to other DMT), adherence (proportion of days covered (PDC)), annualized hospitalization rate (AHR) for MS-related hospital admissions, and DMT costs., Results: Ocrelizumab was the most commonly prescribed DMT (n = 399; age = 45.74 ± 10.98 years; females = 224), after dimethyl fumarate (n = 588) and fingolimod (n = 401); 26% patients treated with ocrelizumab were naïve. When compared with ocrelizumab, the risk of discontinuation was higher for other highly active DMTs (HR = 3.78; p = 0.01), and low/medium efficacy DMTs (HR = 7.59; p < 0.01). When compared with ocrelizumab, PDC was similar to other highly active DMTs (Coeff = 0.01; p = 0.31), but higher for low/medium efficacy DMTs (Coeff = 0.09; p < 0.01). When compared with ocrelizumab, AHR was similar to other highly active DMTs (Coeff = 0.01; p = 0.51), and low/medium efficacy DMTs (Coeff = 0.01; p = 0.55). When compared with ocrelizumab, DMT monthly costs were higher for other highly active DMTs (Coeff = 92.30; p < 0.01), but lower for low/medium efficacy DMTs (Coeff = - 1043.61; p < 0.01)., Discussion: Ocrelizumab was among the most frequently prescribed DMTs, with 26% prescriptions to treatment-naïve patients, suggesting its relevance in addressing unmet clinical needs (e.g., first approved treatment for primary progressive MS). Ocrelizumab was associated with the highest persistence, confirming its favorable benefit-risk profile. Costs for ocrelizumab were lower than those associated to similarly effective DMTs, in absence of changes in healthcare resource utilization., (© 2022. The Author(s).)

Background: The introduction of trastuzumab biosimilars in clinical practice plays an important role in promoting the sustainability of healthcare systems. By contrast, the switching process can be challenging to the clinics. This survey describes the switching process at a National Cancer Institute over a period of 2 years., Methods: Data regarding all trastuzumab-based regimens for breast cancer (BC) from 1 January 2019 and 31 December 2020 were extracted from both adverse drug reactions (ADRs) reporting systems and electronic systems involved in inventory management, prescribing, dispensing, and administration. Both patients under monotherapy and combination treatment regimens were included. There were no exclusion criteria., Results and Conclusions: Overall 354 patients received at least one trastuzumab-based regimen for a total of 493 lines of treatment and 5769 administrations. Biosimilar were used in 34.3% of trastuzumab-based treatments. No differences between biosimilars and reference drug have been observed in terms of ADRs. The effective cost-saving of the first 2 years is greater than EUR 800,000 and it is estimated to increase over time.

Exposure to aversive events during sensitive developmental periods can affect the preferential coping strategy adopted by individuals later in life, leading to either stress-related psychiatric disorders, including depression, or to well-adaptation to future adversity and sources of stress, a behavior phenotype termed "resilience". We have previously shown that interfering with the development of mother-pups bond with the Repeated Cross Fostering (RCF) stress protocol can induce resilience to depression-like phenotype in adult C57BL/6J female mice. Here, we used patch-clamp recording in midbrain slice combined with both in vivo and ex vivo pharmacology to test our hypothesis of a link between electrophysiological modifications of dopaminergic neurons in the intermediate Ventral Tegmental Area (VTA) of RCF animals and behavioral resilience. We found reduced hyperpolarization-activated (I h ) cation current amplitude and evoked firing in VTA dopaminergic neurons from both young and adult RCF female mice. In vivo , VTA-specific pharmacological manipulation of the I h current reverted the pro-resilient phenotype in adult early-stressed mice or mimicked behavioral resilience in adult control animals. This is the first evidence showing how pro-resilience behavior induced by early events is linked to a long-lasting reduction of I h current and excitability in VTA dopaminergic neurons., Competing Interests: None., (© 2021 The Author(s).)

Background: The introduction of immune checkpoint inhibitors (ICIs) in clinical practice has brought significant benefits for patients. Seven ICIs are available in Europe: nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, and ipilimumab. Despite their proven clinical efficacy, these innovative drugs may cause serious immune-related adverse drugs reactions (irADRs). Given the significance of these ADRs for patients' health, we analyzed individual case safety reports (ICSRs) related to ICIs, focusing on those reporting irADRs, collected in the Italian spontaneous reporting database., Methods: We analyzed ICI-induced irADRs collected in the Italian Pharmacovigilance database (Rete Nazionale di Farmacovigilanza [RNF]) from January 1, 2002, to February 28, 2019, focusing on those reported in the Campania Region. We retrieved from an open-access Italian pharmacovigilance system, the RAM system (for national safety data), and from the RNF (for Campania safety data) all ICSRs reporting ADRs related to ICIs authorized until the analysis date. Focusing on irADRs, we performed descriptive and disproportionality analyses through the reporting odds ratio (ROR) with 95% confidence interval., Results: National results . Among 2,088 ICI-related ICSRs, 801 reported irADRs. The majority of such ADRs occurred in male patients reporting gastrointestinal and skin toxicities. Nivolumab and pembrolizumab were drugs most commonly reported as suspect drugs. Compared to other ICIs, ROR was statistically significant for pembrolizumab and ipilimumab. Campania Region results . Out of 253 ICI-related ICSRs sent to Regional Pharmacovigilance Center of Campania Region, 121 reported at least one ICI-induced irADR. These were serious in 37.2% of cases and had an unfavorable outcome in 32.2% of cases. Overall, out of 8 ICSRs reported ADR with a fatal outcome, four reported irADRs. From disproportionality analyses on Campania Region ICSRs, statistically significant ROR emerged only for ipilimumab., Conclusions: Our results showed that during the study period several serious irADRs were reported, some of which had fatal outcome. Given the clinical relevance of irADRs, further investigations in real-life context are necessary for a better characterization of ICIs safety profiles. Oncologists should be trained to early recognize and adequately manage irADRs. Patients should also be educated to immediately report any new symptom or worsening of pre-existed ones during the ICI treatment., (Copyright © 2020 Ruggiero, Fraenza, Scavone, di Mauro, Piscitelli, Mascolo, Ferrajolo, Rafaniello, Sportiello, Rossi and Capuano.)

Introduction: Low back pain is one of the most frequent causes of consultation of the General Practitioner (GP). The purpose of the present study is to analyze the therapeutic management of low back pain, in relation to pain intensity, in the primary care setting and to assess its impact on the patient's quality of life., Methods: From the computerized medical records of 65 GPs, all working in the Salerno province (South of Italy), data concerning non-cancer subjects affected by low back or sciatica pain, over 18 years, who consulted the GP in the period between February 1, 2015 and January 31, 2016, were extracted. Pain intensity and quality of life were reported using the 0-10 numeric rating scale (NRS) and the EQ-5D instruments, respectively., Results: A total of 2555 subjects were identified: 28.7% reported mild pain (NRS 0-3), 55.6% moderate pain (NRS 4-6) and 15.7% severe pain (NRS 7-10). Only 35% of patients received a prescription for pain therapy (24.5% in mild pain; 34.1% in moderate pain and 57.1% in severe pain); non-steroidal anti-inflammatory drugs in monotherapy were the most prescribed therapeutic category regardless of pain intensity (61.1% in mild pain, 65.1% in moderate pain and 57.6% in severe pain, p=0.099), followed by strong opioids (17.2%, 15.3% and 24.5%, p=0.011). Overall, mean value for EQ-5D utility was 0.44 (0.61 in mild pain, 0.47 in moderate pain, 0.22 in severe pain)., Conclusions: The results of this study highlight that low back pain is a highly debilitating condition, probably still under-treated or inadequately treated by the GP.

Background & Aims: Hepatitis C (HCV) is associated with several extrahepatic manifestations, and estimates of the hospitalization burden related to these comorbidities are still limited. The aim of this study is to quantify the hospitalization risk associated with comorbidities in an Italian cohort of HCV-infected patients and to assess which of these comorbidities are associated with high hospitalization resource utilization., Methods: Individuals aged 18 years and older with HCV-infection were identified in the Abruzzo's and Campania's hospital discharge abstracts during 2011-2014 with 1-year follow-up. Cardio-and cerebrovascular disease, diabetes and renal disease were grouped as HCV-related comorbidities. Negative binomial models were used to compare the hospitalization risk in patients with and without each comorbidity. Logistic regression model was used to identify the characteristics of being in the top 20% of patients with the highest hospitalization costs (high-cost patients)., Results: 15,985 patients were included; 19.9% had a liver complication and 48.6% had one or more HCV-related comorbidities. During follow-up, 36.0% of patients underwent at least one hospitalization. Liver complications and the presence of two or more HCV-related comorbidities were the major predictors of hospitalization and highest inpatient costs. Among those, patients with cardiovascular disease had the highest risk of hospitalization (Incidence Rate Ratios = 1.42;95%CI:1.33-1.51) and the highest likelihood of becoming high-cost patients (Odd Ratio = 1.37;95%CI:1.20-1.57)., Conclusion: Beyond advanced liver disease, HCV-related comorbidities (especially cardiovascular disease) are the strongest predictors of high hospitalization rates and costs. Our findings highlight the potential benefit that early identification and treatment of HCV might have on the reduction of hospitalization costs driven by extrahepatic conditions., Competing Interests: The authors have declared that no competing interests exist.

Testicular germ cell tumors (TGCTs) represent the most common solid tumors affecting young men. They constitute a distinct entity because of their embryonic origin and their unique biological behavior. Recent preclinical data regarding biological signaling machinery as well as genetic and epigenetic mechanisms associated with molecular patterns of tumors have contribute to explain the pathogenesis and the differentiation of TGCTs and to understand the mechanisms responsible for the development of resistance to treatment. In this review, we discuss the main genetic and epigenetic events associated with TGCTs development in order to better define their role in the pathogenesis of these tumors and in cisplatin-acquired resistance., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

[This corrects the article DOI: 10.18632/oncotarget.16725.].

Testicular cancer (TC) is one of the most common neoplasms that occurs in male and includes germ cell tumors (GCT), sex cord-gonadal stromal tumors and secondary testicular tumors. Diagnosis of TC involves the evaluation of serum tumor markers alpha-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase, but clinically several types of immunohistochemical markers are more useful and more sensitive in GCT, but not in teratoma. These new biomarkers are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency-related cells but not in normal adult germ cells and they include PLAP, OCT3/4 (POU5F1), NANOG, SOX2, REX1, AP-2γ (TFAP2C) and LIN28. Gene expression in GCT is regulated, at least in part, by DNA and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation. There are different epigenetic modifications in TG-subtypes that reflect the normal developmental switch in primordial germ cells from an under- to normally methylated genome. The main purpose of this review is to illustrate the findings of recent investigations in the classification of male genital organs, the discoveries in the use of prognostic and diagnostic markers and the epigenetic aberrations mainly affecting the patterns of DNA methylation/histone modifications of genes (especially tumor suppressors) and microRNAs (miRNAs)., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Prostate cancer is the second highest cause of cancer mortality after lung tumours. In USA it affects about 2.8 million men and the incidence increases with age in many countries. Therefore, early diagnosis is a very important step for patient clinical evaluation and for a selective and efficient therapy. The study of miRNAs' functions and molecular mechanisms has brought new knowledge in biological processes of cancer. In prostate cancer there is a deregulation of several miRNAs that may function as tumour suppressors or oncogenes. The aim of this review is to analyze the progress made to our understanding of the role of miRNA dysregulation in prostate cancer tumourigenesis.

Prostate cancer is a main urological disease associated with significant morbidity and mortality. Radical prostatectomy and radiotherapy are potentially curative for localized prostate cancer, while androgen deprivation therapy is the initial systemic therapy for metastatic prostate disease. However, despite temporary response, most patients relapse and evolve into castration resistant cancer.Epithelial-mesenchymal transition (EMT) is a complex gradual process that occurs during embryonic development and/or tumor progression. During this process, cells lose their epithelial characteristics and acquire mesenchymal features. Increasing evidences indicate that EMT promotes prostate cancer metastatic progression and it is closely correlated with increased stemness and drug resistance.In this review, we discuss the main molecular events that directly or indirectly govern the EMT program in prostate cancer, in order to better define the role and the mechanisms underlying this process in prostate cancer progression and therapeutic resistance.

This review summarizes the main pathophysiological basis of the relationship between metabolic syndrome, endocrine disruptor exposure and prostate cancer that is the most common cancer among men in industrialized countries. Metabolic syndrome is a cluster of metabolic and hormonal factors having a central role in the initiation and recurrence of many western chronic diseases including hormonal-related cancers and it is considered as the world's leading health problem in the coming years. Many biological factors correlate metabolic syndrome to prostate cancer and this review is aimed to focus, principally, on growth factors, cytokines, adipokines, central obesity, endocrine abnormalities and exposure to specific endocrine disruptors, a cluster of chemicals, to which we are daily exposed, with a hormone-like structure influencing oncogenes, tumor suppressors and proteins with a key role in metabolism, cell survival and chemo-resistance of prostate cancer cells. Finally, this review will analyze, from a molecular point of view, how specific foods could reduce the relative risk of incidence and recurrence of prostate cancer or inhibit the biological effects of endocrine disruptors on prostate cancer cells. On the basis of these considerations, prostate cancer remains a great health problem in terms of incidence and prevalence and interventional studies based on the treatment of metabolic syndrome in cancer patients, minimizing exposure to endocrine disruptors, could be a key point in the overall management of this disease.

The gold standard for the detection of urothelial carcinoma is represented by urethro-cystoscopy and biopsy. Both procedures are invasive and expensive and therefore cytology is often used as first approach to investigate on a possible neoplasia, being a safe and cost-effective diagnostic modality of evaluation. Because cytology alone is not highly sensitive for detection of low grade urothelial carcinoma and recurrence of the disease, several adjunct markers and urine based tests for urothelial carcinoma have been developed, which can help in the final diagnosis. In particular, ProEx C is an immunohistochemical cocktail containing antibodies direct against topoisomerase IIα (TOP2A) and minichromosome maintenance 2 (MCM2) proteins. It proved to be a valid biomarker especially in detecting squamous intraepithelial lesions in cervical liquid-based samples and in discerning these lesions from their mimickers, as well as in ovarian, endometrial, vulvar, primary and metastatic melanomas, breast, pancreatic and renal cell carcinomas. This brief review covers the effective utility of ProEx C as adjunct tool in assessing the urothelial lesions in urine cytology, also providing prognostic and therapeutic information to help in clinical decisions., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Purpose: The aim of this review was to compare radiation toxicity in Localized Prostate Cancer (LPC) patients who underwent conventional fractionation (CV), hypofractionated (HYPO) or extreme hypofractionated (eHYPO) radiotherapy. We analyzed the impact of technological innovation on the management of prostate cancer, attempting to make a meta-analysis of randomized trials., Methods: PubMed database has been explored for studies concerning acute and late urinary/gastrointestinal toxicity in low/intermediate risk LPC patients after receiving radiotherapy. Studies were then gathered into 5 groups: detected acute and chronic toxicity data from phase II non randomized trials were analyzed and Odds Ratio (OR) was calculated by comparing the number of patients with G0-1 toxicity and those with toxicity > G2 in the studied groups. A meta-analysis of prospective randomized trials was also carried out., Results: The initial search yielded 575 results, but only 32 manuscripts met all eligibility requirements: in terms of radiation-induced side effects, such as gastrointestinal and genitourinary acute and late toxicity, hypofractionated 3DCRT seemed to be more advantageous than 3DCRT with conventional fractionation as well as IMRT with conventional fractionation compared to 3DCRT with conventional fractionation; furthermore, IMRT hypofractionated technique appeared more advantageous than IMRT with conventional fractionation in late toxicities. Randomized trials meta-analysis disclosed an advantage in terms of acute gastrointestinal and late genitourinary toxicity for Hypofractionated schemes., Conclusions: Although our analysis pointed out a more favorable toxicity profile in terms of gastrointestinal acute side effects of conventional radiotherapy schemes compared to hypofractionated ones, prospective randomized trials are needed to better understand the real incidence of rectal and urinary toxicity in patients receiving radiotherapy for localized prostate cancer.

We report a clinical update of the hemoglobin (Hb) variant [β27(B9)Ala→Gly; HBB: c.83C>G], named Hb Siirt, that was previously described as a silent variant in a 23-year-old Kurdish female. The patient was also a carrier of the codon 5 (-CT) (HBB: c.17&#95;18delCT) frameshift mutation and of the ααα anti 3.7 triplication. Her initial moderate β-thalassemia intermedia (β-TI) phenotype worsened with time, causing the patient to become a transfusion-dependent subject at the age of ∼40 years. Subsequent molecular characterization of both parents revealed that the Hb Siirt variant was inherited by the mother, while the other two globin alterations (HBB: c.17&#95;18delCT and ααα anti 3.7 triplication) were genetically transmitted by the father. The latter remained a carrier of a mild β-TI phenotype throughout his life, at least until the age of 65 years. We hypothesize that the worsened clinical conditions in the daughter were due to the additional, maternally inherited Hb Siirt variant. However, protein 3D conformational analysis did not seem to reveal substantial overall structural changes. Among the other three described variants [Hb Volga (HBB: c.83C>A), Hb Knossos (HBB: c.82 G>T), Hb Grange-Blanche (HBB: c.83C>T] that are due to nucleotide substitutions at codon 27 of the β-globin gene; only Hb Knossos causes a β + -thalassemia (β + -thal) phenotype.

Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) "unique" in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell "fate". Homologous Recombination deficiency has been assumed to be a Germ Cell Tumor characteristic underlying platinum-sensitivity, whereby Poly(ADP-ribose) polymerase (PARP), an enzyme involved in HR DNA repair, is an intriguing target: PARP inhibitors have already entered in clinical practice of other malignancies and trials are recruiting TGCT patients in order to validate their role in this disease. This paper aims to summarize evidence, trying to outline an overview of DDR implications not only in TGCT curability, but also in resistance to chemotherapy.

Axitinib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) after failure of prior treatment with Sunitinib or cytokine. The present study is an Italian Multi-Institutional Retrospective Analysis that evaluated the outcomes of Axitinib, in second-line treatment of mRCC. The medical records of 62 patients treated with Axitinib, were retrospectively reviewed. The Progression Free Survival (PFS), the Overall Survival (OS), the Objective Response Rate (ORR), the Disease Control Rate (DCR), and the safety profile of axitinib and sunitinib-axitinib sequence, were the primary endpoint. The mPFS was 5.83 months (95% CI 3.93-7.73 months). When patients was stratified by Heng score, mPFS was 5.73, 5.83, 10.03 months according to poor, intermediate, and favorable risk group, respectively. The mOS from the start of axitinib was 13.3 months (95% CI 8.6-17.9 months); the observed ORR and DCR were 25 and 71%, respectively. When stratified patients by subgroups defined by duration of prior therapy with Sunitinib (≤ vs. >median duration), there was a statistically significant difference in mPFS with 8.9 (95% CI 4.39-13.40 months) vs. 5.46 months (95% CI 4.04-6.88 months) for patients with a median duration of Sunitinib >13.2 months. DCR and ORR to previous Sunitinib treatment was associated with longer statistically mPFS, 7.23 (95% CI 3.95-10.51 months, p = 0.01) and 8.67 (95% CI 4.0-13.33 months, p = 0.008) vs. 2.97 (95% CI 0.65-5.27 months, p = 0.01) and 2.97 months (95% CI 0.66-5.28 months, p = 0.01), respectively. Overall Axitinib at standard schedule of 5 mg bid, was well-tolerated. The most common adverse events of all grades were fatig (25.6%), hypertension (22.6%), gastro-intestinal disorders (25.9%), and hypothyroidism (16.1%). The sequence Sunitinib-Axitinib was well-tolerated without worsening in side effects, with a median OS of 34.7 months (95% CI 18.4-51.0 months). Our results are consistent with the available literature; this retrospective analysis confirms that Axitinib is effective and safe in routine clinical practice.

Pazopanib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma. The present study analyzed the outcomes of pazopanib in first-line treatment of mRCC, in a single Italian cancer center. In the light of the retrospective, observational nature and the unselected population, our experience can be defined a "real-world" study. The medical records of 38 mRCC patients treated with front-line pazopanib were retrospectively reviewed and analyzed. The progression free survival (PFS) and the overall survival (OS) were the primary endpoints, while secondary objectives included objective response rate (ORR), disease control rate (DCR), and treatment tolerability. Pazopanib achieved a median PFS (mPFS) of 12.7 months (95% CI, 6.9-18.5 months). The median OS (mOS) was 26.2 months (95% CI, 12.6-39.9 months); the observed ORR and DCR were 30.3 and 72.7%, respectively, with a median duration of response of 11 weeks. mPFS appeared not to be influenced by number of co-morbidities (< 3 vs. ≥3), gender, Fuhrman grade and age. Conversely, the ORR and the DCR positively affect the mPFS (HR = 0.05 [95% CI, 0.05-0.55], p = 0.01; HR = 0.10 [95% CI, 0.02-0.43], p = 0.002, respectively). A worse outcome was associated with a lower mPFS in patients with liver metastases (p = 0.2) and with a high tumor burden (number of metastatic sites < 6 vs. ≥6) (p = 0.08). Worst OS was observed in patients aged ≥70 years old (HR = 6.91 [95% CI, 1.49-31.91], p = 0.01). The treatment was well-tolerated: no grade 4 adverse events, nor discontinuation due to toxicities was reported. Grade 3 hypertension affected positively the OS reaching the statistical significance (HR = 0.22 [95% CI, 0.05-0.8], p = 0.03). Thyroid dysfunction (hypo and hyperthyroidism) seems to correlate with better outcome in terms of a longer mPFS (HR = 0.12 [95% CI, 0.02-0.78], p = 0.02). Our results are consistent with those reported in prospective phase III trials and the published retrospective "real world" experiences. This analysis confirms the safety and efficacy of pazopanib in first-line setting, both in frail patients with multiple co-morbidities and Karnofsky PS < 80% and in younger, healthier patients with a number of metastatic sites < 6.

Background: The efficacy of Vinflunine, after failure of platinum-based chemotherapy in patients with metastatic or recurrent Transitional Cell Cancer of the Urothelial Tract, TCCU, has been demonstrated in an international, randomized, phase III trial comparing Vinflunine plus Best Supportive Care, BSC, with BSC alone. On the basis of that study vinflunine has been approved by the European Medicine Association, EMA, for treatment of TCCU patients after failure of a platinum treatment. However, since data in clinical trials often differ from routine clinical practice due to unselected population and less strict monitoring, "real life" experiences are very helpful to verify the efficacy of a new therapy., Methods: This was a spontaneous, observational, retrospective study involving 43 patients with metastatic TCCU treated with vinflunine at our cancer center, data about demographics, disease characteristics, and previous treatments were collected and outcome and toxicities of vinflunine were analyzed., Results: 41 of 43 patients were eligible for RR analysis, the Overall RR was 12%, the Disease Control Rate was 29%; when including only patients treated in II line the DCR rose to 33%; the median PFS and the median OS were 2.2 and 6.9 months, respectively., Conclusion: Our findings were consistent with the outcome data emerged in the phase III randomized trial and in the other observational studies conducted all around Europe in the last 2-3 years. This experience supports the use of vinflunine in patients with advanced TTCU as effective and manageable antineoplastic drug.

Introduction: Non-valvular atrial fibrillation (NVAF) is the most common cardiac arrhythmia and it is associated with a 5-fold increase in risk of ischemic stroke. Although clinical guidelines recommend antithrombotic therapy for stroke prevention in patients at moderate or high risk for stroke, little is known on the extent to which the increase of the risks influence the choice of the therapy., Aim: The aim of the study was to assess the level of adherence to the guidelines for the prevention of thromboembolic risk in patients with NVAF., Methods: A population-based cohort study was conducted using administrative data from a local health authority in the Campania Region (~1,000,000 inhabitants). NVAF was defined as one or more claims for atrial fibrillation between July, 2013 and June, 2014 where none of the claims were associated with cardioversion or cardiac ablation during the identification period and there was no evidence of valve-related diagnoses or procedures. The cohort was classified according to the first drug dispensing during 6 months from the discharge date for atrial fibrillation. Patients were categorized in low ischemic stroke risk (LR, score = 0), moderate-risk (MR, score = 1), high-risk (HR, score≥2) according to the CHA2DS2-VASc score. Multivariable logistic regression was used to evaluate the associations between ischemic stroke risk with the choice of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) therapy., Results: A total of 1963 patients were identified: 4.9% LR, 7.6% MR and 87.5% HR patients. Overall, 36.4% of patients were not treated (LR: 56.7%, MR: 55.0%, HR: 33.7%patients). The Vitamin K antagonists were prescribed to 17% of the patients (LR: 10.3%, MR: 12,1%, HR: 17,8%), NOAC to 12,7% (LR: 10,3%, MR: 8,1%, HR: 13,2%), low-dose aspirin to 17.5% (LR: 13,4%, MR: 15,4%, HR: 17,9%), other antiplatelet to 12,3% (LR: 7,2%, MR: 6,0%, HR: 13,2%). The ischemic stroke was not significantly associated with the choice of anticoagulant drug., Conclusions: High proportion of NVAF patients with CHA2DS2-VASc score of 2 or greater not received oral anticoagulant as recommended. In contrast with recent guidelines, aspirin was commonly prescribed even in HR patients. The stroke risk stratification did not influence the choice of anticoagulant drug.

Prostate cancer (PCa) is one of the most common cancer in men. It affects older men and the incidence increases with age; the median age at diagnosis is 67 years. The diagnosis of PCa is essentially based on three tools: digital rectal exam, serum concentration of prostate specific antigen, and transrectal ultrasound-guided biopsy. Currently, the therapeutic treatments of this cancer are different and range from the prostatectomy to hormonal therapy, to radiation therapy, to immunotherapy, and to chemotherapy. However, additional efforts are required in order to find new weapons for the treatment of metastatic setting of disease. The purpose of this review is to highlight new therapeutic strategies based on gene interference; in fact, numerous siRNA and miRNA in the therapeutic treatment of PCa are reported below.

To reduce the incidence of β-thalassaemia major and other severe haemoglobin-related disorders by the early identification of healthy carriers, the Centro Studi Microcitemie Roma has been organising since 1975 a prevention programme in Latium, an Italian central region. This programme entails two different types of carrier screening on a voluntary basis: a universal screening offered to secondary school students and a screening offered to young adults. In 36 years of scholastic screening (from 1975 until 2011), 1,466,100 students have been examined and 26,786 (1.8 %) carriers of non-α thalassaemia have been identified. In the extra-scholastic screening, 388,690 adult subjects (including the carriers' relatives) have been examined and a total of 38,457 (9.9 %) carriers of non-α thalassaemia have been detected. These results demonstrate that the precocious identification of healthy carriers allowed the identification of at-risk couples and reduced to zero the birth of affected babies in the Latium native population. This programme does not involve huge resources and is relatively inexpensive and, as such, it is essential to be offered to the total Latium scholastic and extra-scholastic population, which is epidemiologically changing due to migratory fluxes from countries in which haemoglobin disorders are common.

This article reviews the epidemiology and screening of sickle cell anemia in the Mediterranean area and in developing countries. Its aim is to create awareness of the global health burden of this condition, which is one of the most common genetic diseases worldwide. The constantly growing incidence of this condition, also caused by recent migrations, has induced the World Health Organization to pressure national health systems to strengthen prevention programs and to recognize it as a public health problem. However, scarce financial resources hinder implementation of activities.

We report a novel frameshift mutation in exon 3 of the β-globin gene, that, in the heterozygous state, leads to a β-thalassemia intermedia (β-TI) phenotype (marked anemia, splenomegaly, hyperbilirubinemia, jaundice, unbalanced synthesis of α/non-α chains in a 34-year-old Italian woman. This frameshift mutation, due to the deletion of the first nucleotide (-A) at codon 120, results in a β-globin chain that is elongated to 156 amino acid residues. These highly unstable abnormal chains precipitate in the erythroblasts as inclusion bodies, thus causing inefficient erythropoiesis and ultimately resulting in the observed dominant clinical phenotype.