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Objective: Vestibular schwannoma (VS) is a benign tumor of the lateral skull base. Different microscopic surgical techniques are described in literature: the retrosigmoid and translabyrinthine approaches are used to treat big tumors located in the cerebellopontine angle, and the middle cranial fossa approach is utilized for small tumors with good hearing preservation. The expanded transcanal transpromontorial (ExpTT) approach is a combined microscopic-endoscopic technique previously indicated for Koos stage I and II VS and now proposed for larger VS, up to 3 cm in diameter, with linear progression into the cerebellopontine angle and touching the brainstem. Study Design: The study was a retrospective case series of patients who underwent ExpTT surgery for VS in our ear, nose, and throat department. Setting: We reviewed the surgical videos and electrophysiologic data recorded during the surgical operations. Subjects and Methods: From January 2015 to January 2017, 20 patients affected by Koos stage II and III VS underwent surgery in our department with the ExpTT approach. This novel technique is described step by step, with a focus on the surgical procedure and anatomic landmarks; outcomes are detailed in terms of early and late complications. The mean follow-up was 15 months. Results: The ExpTT approach permitted, in all patients, gross total resection of the tumor without any complication and with preservation of facial nerve function. All patients had a good postoperative recovery. Conclusion: The ExpTT technique is a new approach that combines the advantages of a microscopic technique with the ones offered by the endoscope in removal of VS.

Objective: Complex middle and inner ear malformations are considered an important limitation for cochlear implant (CI) with traditional microscopic techniques. The aim of the present study is to describe the results of the endoscopic-assisted CI procedure in children with malformed ears. Study Design: Case series with chart review of consecutive patients. Setting: Two tertiary referral centers: University Hospital of Verona and University Hospital of Modena, Italy. Subjects and Methods: In total, 25 children underwent endoscopic-assisted cochlear implantation between January 2013 and January 2018. The audiologic and neuroradiologic assessment showed profound hearing loss and malformation of the middle and inner ear in all children. A complete review of anatomic features, surgical results, and audiologic outcomes was performed. The surgical technique is described step-by-step, and the outcomes are detailed. Results: All patients (mean age, 3.6 years; range, 2.8-9 years) underwent a transattical/endoscopic-assisted CI procedure. All children showed varying degrees of auditory benefit, as measured by routine audiometry, speech perception tests, and Categories of Auditory Performance scores (mean, 6). No immediate or late postoperative complications were noted. Conclusion: The endoscopic-assisted approach proved to be successful in cochlear implantation. The direct visualization and magnification allow (1) exploration of the tympanic cavity; (2) confirmation of all anatomic features, with strict control of the course of the facial nerve, round window area, and inner ear; and (3) performance of the cochleostomy with adequate insertion of the array.

Background For the detection of cardiac surgery-associated acute kidney injury (CS-AKI), the performance of urine tissue inhibitor of metalloproteinase 2 insulin-like growth factor-binding protein 7 (TIMP2 IGFBP7) has never been compared with that of very early changes in plasma creatinine (∆pCr). We hypothesized that, in the context of perioperative haemodilution, lack of postoperative decrease in pCr would be of honourable performance for the detection of CS-AKI. We therefore aimed at comparing these biomarkers and their kinetics (primary objective). As secondary objectives, we assessed plasma neutrophil gelatinase-associated lipocalin (pNGAL), cystatin C (pCysC) and urea (pUrea). We also determined the ability of these biomarkers to early discriminate persistent from transient CS-AKI. Methods Patients over 75 years-old undergoing aortic valve replacement with cardiopulmonary bypass (CPB) were included in this prospective observational study. Biomarkers were measured before/after CPB and at the sixth postoperative hour (H6). Results In 65 patients, CS-AKI occurred in 27 (42%). ∆pCr from post-CPB to H6 (∆pCrpostCPB-H6): outperformed TIMP2 IGFBP7 at H6 and its intra- or postoperative changes: area under the receiver operating characteristic curve (AUCROC) of 0.84 [95%CI:0.73–0.92] vs. ≤0.67 [95%CI:0.54–0.78], p ≤ 0.03. The AUCROC of pNGAL, pCysC and pUrea did not exceed 0.72 [95%CI:0.59–0.83]. Indexing biomarkers levels for blood or urine dilution did not improve their performance. Combining TIMP2 IGFBP7 and ∆pCrpostCPB-H6 was of no evident added value over considering ∆pCrpostCPB-H6 alone. For the early recognition of persistent CS-AKI, no biomarker outperformed ∆pCrpostCPB-H6 (AUCROC = 0.69 [95%CI:0.48–0.85]). Conclusions In this hypothesis-generating study mostly testing early detection of mild CS-AKI, there was no evident added value of the tested modern biomarkers over early minimal postoperative changes in pCr: despite the common perioperative hemodilution in the setting of cardiac surgery, if pCr failed to decline within the 6 h after CPB, the development of CS-AKI was likely. Confirmatory studies with more severe forms of CS-AKI are required.

BACKGROUND: Genome-wide association studies have reported that genetic variation at ANRIL (CDKN2B-AS1) is associated with risk of several chronic diseases including coronary artery disease, coronary artery calcification, myocardial infarction, and type 2 diabetes mellitus. ANRIL is located at the CDKN2A/B locus, which encodes multiple melanoma tumor suppressors. We investigated the association of these variants with melanoma prognostic characteristics. METHODS: The Genes, Environment, and Melanoma Study enrolled 3,285 European origin participants with incident invasive primary melanoma. For each of ten disease-associated single-nucleotide polymorphisms (SNPs) at or near ANRIL, we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and odds ratios (ORs) for presence of ulceration and tumor-infiltrating lymphocytes (TILs). We also assessed effect modification by tumor NRAS/BRAF mutational status. RESULTS: Rs518394, rs10965215, and rs564398 passed false discovery and were each associated (P ≤ 0.005) with TILs, although only rs564398 was independently associated (P = 0.0005) with TILs. Stratified by NRAS/BRAF mutational status, rs564398*A was significantly positively associated with TILs among NRAS/BRAF mutant, but not wildtype, cases. We did not find SNP associations with Breslow thickness or ulceration. CONCLUSIONS: ANRIL rs564398 was associated with TIL presence in primary melanomas, and this association may be limited to NRAS/BRAF mutant cases. IMPACT: Pathways related to ANRIL variants warrant exploration in relationship to TILs in melanoma, especially given the impact of TILs on immunotherapy and survival.

Introduction Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder persisting in adulthood in 40-60% of cases. Clinical and neuroimaging studies suggest that patients affected by both drug addiction and ADHD show higher rates of craving for drug than patients without ADHD. We designed a pilot open-label study to investigate the effects of ADHD on craving for heroin in methadone maintenance therapy patients. Method Patients were recruited from outpatient facilities in an addiction treatment unit in the municipality of Alba, Italy. They were assessed using the Structured Clinical Interview for DSM-5 (SCID-5), the SCID-5 for Personality Disorders (SCID-5-PD), the Diagnostic Interview for Adult ADHD, second edition (DIVA 2.0), and the Clinical Opiate Withdrawal Scale (COWS). Categorical variables were examined using the chi-square test, and continuous variables, the t-test and Mann-Whitney’s U test for normally and non-normally distributed data, respectively. Data distribution was evaluated using Shapiro-Wilk’s test. Significance was set at p=0.05. Bonferroni correction was applied (0.0063) to avoid type I error. Results A total of 104 patients were included in the study: 14 affected by ADHD (13.5%) and 90 were not affected (86.5%). Patients with ADHD showed higher intensity of craving for heroin than patients without ADHD in the absence of withdrawal symptoms. Conclusion Drug addiction and ADHD share various neurobiological mechanisms that mutually influence the evolution of both disorders. In particular, dopamine dysfunction within various brain circuits may influence impulsivity levels, motivation, inhibitory control, executive functions, and behavior and, consequently, the intensity of craving.

BRAF and NRAS mutations arise early in melanoma development, but their associations with low-penetrance melanoma susceptibility loci remain unknown. In the Genes, Environment and Melanoma Study, 1,223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms identified as low-penetrant melanoma-risk variants. We used multinomial logistic regression to simultaneously examine each single-nucleotide polymorphism's relationship to BRAF V600E, BRAF V600K, BRAF other, and NRAS+ relative to BRAF-/NRAS- melanoma adjusted for study features. IRF4 rs12203592*T was associated with BRAF V600E (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.43-0.79) and V600K (OR = 0.65, 95% CI = 0.41-1.03), but not BRAF other or NRAS+ melanoma. A global test of etiologic heterogeneity (Pglobal = 0.001) passed false discovery (Pglobal = 0.0026). PLA2G6 rs132985*T was associated with BRAF V600E (OR = 1.32, 95% CI = 1.05-1.67) and BRAF other (OR = 1.82, 95% CI = 1.11-2.98), but not BRAF V600K or NRAS+ melanoma. The test for etiologic heterogeneity (Pglobal) was 0.005. The IRF4 rs12203592 associations were slightly attenuated after adjustment for melanoma-risk phenotypes. The PLA2G6 rs132985 associations were independent of phenotypes. IRF4 and PLA2G6 inherited genotypes may influence melanoma BRAF/NRAS subtype development.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease characterized by progressive myocardial fibro-fatty replacement, arrhythmias and risk of sudden death. Its diagnosis is challenging and often it is achieved after disease onset or postmortem. In this study, we sought to identify circulating microRNAs (miRNAs) differentially expressed in ARVC patients compared to healthy controls. In the pilot study, we screened the expression of 754 miRNAs from 21 ARVC patients and 20 healthy controls. After filtering the miRNAs considering a log fold-change cut-off of ±1, p-value &lt, 0.05, we selected five candidate miRNAs for a subsequent validation study in which we used TaqMan-based real-time PCR to analyse samples from 37 ARVC patients and 30 healthy controls. We found miR-185-5p significantly upregulated in ARVC patients. Receiver operating characteristic analysis indicated an area under the curve of 0.854, corroborating the link of this miRNA and ARVC pathophysiology.

Background The transcanal transpromontorial approach has been introduced to remove vestibular schwannomas. As with other techniques, preservation of the facial nerve (FN) is challenging. This pilot study described FN outcomes of patients preoperatively and postoperatively assessed with electromyography (EMG) and blink reflex (BR). Methods Between September 2017 and December 2018, 10 patients (5 men; 5 women; mean age, 59.8 years; age range, 25–77 years) underwent removal of vestibular schwannoma via the transcanal transpromontorial approach. FN assessment using EMG/BR and clinical evaluation with the House-Brackmann (HB) grading scale was performed preoperatively and 2 months postoperatively. If facial impairment was present postoperatively, further analysis was performed 6 months after surgery. Results All 10 patients had normal FN function on preoperative EMG/BR. After 2 months, 4 patients had normal FN function on EMG/BR, 4 patients showed a slight delay of FN responses, 1 patient had moderate dysfunction, and 1 patient had consistent damage. After 6 months, among the 6 patients with a pathologic neurophysiologic study, consistent EMG/BR improvement was shown, with complete recovery in 3 cases. At the last follow-up, 8 patients had HB grade I, 1 patient had HB grade II, and 1 patient had HB grade III in 1, showing progression toward healing in 9 of 10 cases. Conclusions The transcanal transpromontorial approach is an effective procedure for vestibular schwannoma removal. EMG/BR represents an objective evaluation method to verify FN recovery after surgery and confirms the low impact of this surgical procedure on the FN.

Isolated REM sleep behaviour disorder (RBD) is an early-stage α-synucleinopathy in most, if not all, affected subjects. Detection of pathological α-synuclein in peripheral tissues of patients with isolated RBD may identify those progressing to Parkinson’s disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-time quaking-induced conversion (RT-QuIC) provided evidence of α-synuclein seeding activity in CSF and olfactory mucosa of patients with α-synucleinopathies. The aim of this study was to explore RT-QuIC detection of α-synuclein aggregates in olfactory mucosa of a large cohort of subjects with isolated RBD compared to patients with Parkinson’s disease and control subjects. This cross-sectional case-control study was performed at the Medical University of Innsbruck, Austria, the Hospital Clinic de Barcelona, Spain, and the University of Verona, Italy. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated RBD, 41 matched Parkinson’s disease patients and 59 matched control subjects were analysed by α-synuclein RT-QuIC in a blinded fashion at the University of Verona, Italy. Median age of patients with isolated RBD was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was α-synuclein RT-QuIC positive in 44.4% isolated RBD patients, 46.3% Parkinson’s disease patients and 10.2% control subjects. While the sensitivity for isolated RBD plus Parkinson’s disease versus controls was 45.2%, specificity was high (89.8%). Among isolated RBD patients with positive α-synuclein RT-QuIC, 78.6% had olfactory dysfunction compared to 21.4% with negative α-synuclein RT-QuIC (P

The steep increase in incidence of cutaneous malignant melanoma in white populations mainly applies to thin lesions with good survival suggesting overdiagnosis. Based on population-based cancer registries (CRs), we have investigated changes in aggressive melanoma, selecting only cases who died within 1 or 3 years after diagnosis in 11 European countries between 1995 and 2012. Trends in fatal cases were analysed by period of diagnosis, sex, tumour thickness, histologic subtype of the lesion, tumour site and CR with a multivariate generalised linear mixed effects model, where geographical area was considered as a random effect. We collected data on 123 360 invasive melanomas, with 5133 fatal cases at 1 year (4%) and 12 330 (10%) at 3 years. The number of fatal cases showed a 16% decrease at 1 year and 8% at 3 years between the first (1995-2000) and the last (2007-2012) period. The highest proportion of fatal cases was seen for men, older age (≥65 years), thick lesions (>1 mm), nodular melanoma, melanoma on the trunk and for poorly documented cases, lacking information about thickness and histologic subtype. The mixed-effects model showed a remarkable variability among European countries. The majority of registries showed a decreasing trend in fatal cases, but a few registries showed an opposite pattern. Trends in fatal melanoma cases, highlighting real changes in risk not related to overdiagnosis, showed a decrease in most European countries, with a few exceptions. Stronger efforts for early detection could lead to a more efficient treatment of melanoma in general.

During recent years, research on meat quality in poultry has aimed to evaluate the presence and consequences of breast myopathies as well as the factors which can affect their occurrence by modifying the growth rate. A total of 900 broiler chickens were reared until slaughter (48 D) to evaluate the effect of 2 genetic lines (A vs. B) and feeding plans (ad libitum [AL], early restricted [ER], from 13 to 23 D of age, and late restricted [LR], from 27 to 37 D of age; restriction rate: 80%) on performance, meat quality, and breast muscle myopathies. Calsequestrin and vascular endothelial growth factor (VEGF) expressions, and muscle fiber degeneration (MFD) were recorded at 22, 36, and 48 D. Chickens in the AL treatment had greater final live (P < 0.01) and carcass weights and proportion of pectoralis major muscle (P = 0.04) compared to chickens in the LR treatment, whereas chickens in the ER treatment had intermediate final live (3,454g) and carcass weights, and proportion of pectoralis major muscle (25.6%). Chickens of line A were heavier than chickens of line B (P < 0.001), and had a greater feed conversion rate. Chickens of line A also had a greater dressing out percentage (P < 0.001), but a lower proportion of pectoralis major muscle (P = 0.04), as well as a greater meat pH (P < 0.001), meat cooking losses (P < 0.01), and shear force of the pectoralis major muscle (P = 0.03). Calsequestrin and VEGF mRNA were significantly lower in ER and LR chickens compared to AL chickens after feed restriction and during refeeding (P < 0.05). MFD scores increased with chicken age (P < 0.001) and differed between genetic lines (P < 0.001). Neither feeding plan nor genetic line affected the occurrence of white striping or wooden breast condition.

Background To enforce the evidence for causality between high-risk human papillomavirus (hrHPV) infections and neck squamous cell carcinoma from unknown primary (NSCCUP) and provide biological basis for treatment de-intensification, we searched for TP53 mutations in association with HPV status. Methods TP53 mutations were searched for by amplification of exons 4 to 10. Results Of the 70 NSCCUP, 27 (39%) harbored HPV infection. TP53 sequencing resulted in the identification of 19 patients harboring single mutations including 16 disruptive alterations (84%). The association of TP53 mutations and HPV could be evaluated in 48 NSCCUP including those with disruptive mutation in any exon (n = 16) and those without mutations but with complete sequence of exons 4 to 9 (n = 32): no disruptive mutations were found in the 17 HPV-driven NSCCUP but in 16 of the 31 non-HPV-driven NSCCUP (P = .0002). Conclusion In a fraction of cases, NSCCUP is an HPV-driven entity harboring wild-type TP53 gene or nondisruptive TP53 mutations. HPV-driven NSCCUP might benefit from treatment de-intensification.

The early and accurate in vivo diagnosis of sporadic Creutzfeldt&ndash, Jakob disease (sCJD) is essential in order to differentiate CJD from treatable rapidly progressive dementias. Diagnostic investigations supportive of clinical CJD diagnosis include magnetic resonance imaging (MRI), electroencephalogram (EEG), 14-3-3 protein detection, and/or real-time quaking-induced conversion (RT-QuIC) assay positivity in the cerebrospinal fluid (CSF) or in other tissues. The total CSF tau protein concentration has also been used in a clinical setting for improving the CJD diagnostic sensitivity and specificity. We analyzed 182 CSF samples and 42 olfactory mucosa (OM) brushings from patients suspected of having sCJD with rapidly progressive dementia (RPD), in order to determine the diagnostic accuracy of 14-3-3, the total tau protein, and the RT-QuIC assay. A probable and definite sCJD diagnosis was assessed in 102 patients. The RT-QuIC assay on the CSF samples showed a 100% specificity and a 96% sensitivity, significantly higher compared with 14-3-3 (84% sensitivity and 46% specificity) and tau (85% sensitivity and 70% specificity), however, the combination of RT-QuIC testing of the CSF and OM samples resulted in 100% sensitivity and specificity, proving a significantly higher accuracy of RT-QuIC compared with the surrogate biomarkers in the diagnostic setting of patients with RPD. Moreover, we showed that CSF blood contamination or high protein levels might interfere with RT-QuIC seeding. In conclusion, we provided further evidence that the inclusion of an RT-QuIC assay of the CSF and OM in the diagnostic criteria for sCJD has radically changed the clinical approach towards the diagnosis.

To determine whether (1) computer-based self-training for CT colonography (CTC) improves interpretation performance of novice readers; (2) computer-aided detection (CAD) use during training affects learning. Institutional review board approval and patients’ informed consent were obtained for all cases included in this study. Twenty readers (17 radiology residents, 3 radiologists) with no experience in CTC interpretation were recruited in three centres. After an introductory course, readers performed a baseline assessment test (37 cases) using CAD as second reader. Then they were randomized (1:1) to perform either a computer-based self-training (150 cases verified at colonoscopy) with CAD as second reader or the same training without CAD. The same assessment test was repeated after completion of the training programs. Main outcome was per lesion sensitivity (≥ 6 mm). A generalized estimating equation model was applied to evaluate readers’ performance and the impact of CAD use during training. After training, there was a significant improvement in average per lesion sensitivity in the unassisted phase, from 74% (356/480) to 83% (396/480) (p < 0.001), and in the CAD-assisted phase, from 83% (399/480) to 87% (417/480) (p = 0.021), but not in average per patient sensitivity, from 93% (390/420) to 94% (395/420) (p = 0.41), and specificity, from 81% (260/320) to 86% (276/320) (p = 0.15). No significant effect of CAD use during training was observed on per patient sensitivity and specificity, nor on per lesion sensitivity. A computer-based self-training program for CTC improves readers’ per lesion sensitivity. CAD as second reader does not have a significant impact on learning if used during training. • Computer-based self-training for CT colonography improves per lesion sensitivity of novice readers. • Self-training program does not increase per patient specificity of novice readers. • CAD used during training does not have significant impact on learning.

Background We analysed trends in incidence for in situ and invasive melanoma in some European countries during the period 1995–2012, stratifying for lesion thickness. Material and methods Individual anonymised data from population-based European cancer registries (CRs) were collected and combined in a common database, including information on age, sex, year of diagnosis, histological type, tumour location, behaviour (invasive, in situ) and lesion thickness. Mortality data were retrieved from the publicly available World Health Organization database. Results Our database covered a population of over 117 million inhabitants and included about 415,000 skin lesions, recorded by 18 European CRs (7 of them with national coverage). During the 1995–2012 period, we observed a statistically significant increase in incidence for both invasive (average annual percent change (AAPC) 4.0% men; 3.0% women) and in situ (AAPC 7.7% men; 6.2% women) cases. Discussion The increase in invasive lesions seemed mainly driven by thin melanomas (AAPC 10% men; 8.3% women). The incidence of thick melanomas also increased, although more slowly in recent years. Correction for lesions of unknown thickness enhanced the differences between thin and thick cases and flattened the trends. Incidence trends varied considerably across registries, but only Netherlands presented a marked increase above the boundaries of a funnel plot that weighted estimates by their precision. Mortality from invasive melanoma has continued to increase in Norway, Iceland (but only for elder people), the Netherlands and Slovenia.

Evidence on the relationship between the vitamin D pathway and outcomes in melanoma is growing, although it is not always clear. We investigated the impact of measured levels of sun exposure at diagnosis on associations of vitamin D receptor gene (VDR) polymorphisms and melanoma-death in 3336 incident primary melanoma cases. Interactions between six SNPs and a common 3′ end haplotype were significant (p

A 6-months-old male mixed-breed dog was admitted to the veterinary hospital with lameness in the right pelvic limb, proprioceptive ataxia, and suspected spinal cord injury in the lumbosacral segment. Upon palpation, firm nodules were noted on the bony surface of the thoracic and pelvic limbs, ribs, vertebrae, and tail. The radiographic study showed nodules of low radiopacity with well-defined limits and smooth contours, one of which was overlapping the fifth lumbar vertebra. Given the clinical presentation indicative of spinal cord injury, the animal was subjected to hemilaminectomy for nodular resection. Histopathological examination of the biopsy enabled the diagnosis of osteochondroma. The clinical follow up after surgery showed improvement in walking, despite persistent monoparesis in the right pelvic limb. The radiographic study in association with clinical and histopathological exams allowed the diagnosis and monitoring of the lesions.

Objective Hearing restoration has always been a dream in vestibular schwannoma (VS) surgery. The aim of this study is to describe an endoscopic assisted transcanal retrocochlear approach to the internal auditory canal (IAC) with total removal of the VS; simultaneously we assessed the anatomical and functional aspects of hearing restoration with cochlear implant (CI). Study design A retrospective case series. Setting Tertiary referral center. Patients Six patients affected by VS involving the fundus of the IAC (Koos stage I-II) were included in this study. The patients already demonstrated symptoms of IAC involvement by the neuroma, with severe to profound hearing loss. Interventions Transcanal microscopic, endoscopic assisted, approach was chosen for total tumor removal. Preoperative and intraoperative electrophysiological monitoring was performed using electrically evoked auditory brainstem responses (EABR) to evaluate preservation of cochlear function. Main outcome and measures A retrospective evaluation of electrophysiological data collected during surgeries has been conducted; clinical outcomes, surgical complications, and postoperative radiological evaluations were also considered. Results Total tumor removal was achieved in all patients with no major complications. One patient showed temporary facial palsy (HB stage II). We were able to preserve cochlear function in five out of six patients. In those patients intraoperative monitoring with EABR was performed after tumor removal with good responses. Conclusions Transcanal retrocochlear approach for VS removal allows preservation of cochlea and cochlear nerve function. This is the first step towards developing an effective surgical technique for VS removal and hearing rehabilitation with CI.

Objective: To define a new surgical option, with lower morbidity, for the treatment of intralabyrinthine schwannomas. Study design: Retrospective case review. Setting: Tertiary referral centers. Patients: Eight patients affected by an intralabyrinthine schwannoma, with or without extension to the internal auditory canal, that underwent surgery with a transcanal transpromontorial approach, were included in the study. The average age at presentation was 47years. Patients’ characteristics, symptoms, tumor features, and surgical results were analyzed. Interventions: All patients were diagnosed and evaluated pre-operatively with high-resolution, gadolinium-enhanced MRI and CT scan of the temporal bone, and underwent surgery via either transcanal transpromontorial endoscopic approach (TTEA) or enlarged transcanal transpromontorial endoscopic approach (ETTA). Main outcome measures: Hearing function was evaluated with the Hearing Classification System according to the Committee on Hearing and Equilibrium Guidelines. Facial nerve function was evaluated using the House–Brackmann grading system (HB). Results: In six patients out of eight, a TTEA was performed, whereas, due to the extension of the pathology to the cerebellopontine angle, two patients underwent an ETTA. The mean follow-up period was 15.5months (range 1–69). No intra-operative and post-operative major complications were observed. Post-operative facial nerve function was normal in seven out of eight patients (grade I HB). One patient presented a grade II HB. Conclusion: The endoscopic approach to cochlear schwannoma represents a good treatment option for patients and should be preferred to other more invasive surgical techniques when indicated, to reduce complications, hospitalization, and offer to patients the chance to eradicate the disease, thus avoiding the stress of a long-life radiological follow-up. Level of evidence: 4.

The dosage of prostate-specific antigen (PSA), an easily evaluable and non-invasive biomarker, has made early detection of prostate cancer (PCa) possible. However, it leads to high percentages of unnecessary biopsies and may miss aggressive tumors in men with PSA levels below 4 ng/ml. Therefore, we propose to combine circulating microRNAs (miRs) with PSA, to improve the diagnostic route for PCa. Plasma miR profiling identified candidate diagnostic miRs in a discovery cohort of 60 tumors and 60 controls (men with benign prostatic hyperplasia or healthy donors). Linear models with an empirical Bayesian approach and multivariate penalized logistic regression were applied to select tumor-associated miRs and/or clinical variables. A classifier was developed and tested on a validation cohort of 68 tumors and 174 controls consecutively collected, where miRs were evaluated by quantitative real-time polymerase chain reaction. A classifier based on miR-103a-3p, let-7a-5p and PSA could detect both overall and clinically significant tumors better than PSA alone, even in 50-69 years aged men with PSA ≤ 4 ng/ml. Even in the validation cohort, the classifier performed better than PSA alone in terms of specificity and positive predictive value, allowing to correctly identify eight out of nine tumors undetected by PSA, including three high-risk and three tumors in 50-69 years old men. Of carriers of non-malignant lesions with PSA in the 4-16 ng/ml interval, who may avoid unnecessary biopsies, 34% were correctly identified. Coupling two circulating miRs with PSA could be a useful strategy to diagnose clinically significant PCa and avoid an important fraction of unnecessary biopsies.

The aim of this study is to describe the experience of a multidisciplinary skull base team with transnasal endoscopic surgery for anterior cranial base tumors.A retrospective chart review was conducted on patients who underwent an exclusive expanded transnasal approach to the anterior skull base in the period from December 2014 to November 2015. Data on patient demographics, tumor characteristics, surgical information, imaging, and postoperative complications were collected and analyzed.From a total of 120 patients with skull base diseases managed by the skull base team, 36 were admitted to this study. The overall complication rate in this series was 16.7%, gross total resection was achieved in 32 cases (88.9%) and postoperative CSF leakage occurred in 5 cases (13.9%).Our preliminary results confirm that an exclusive endoscopic transnasal approach to the anterior cranial base is a reliable technique with acceptable perioperative morbidity.

This study investigates the functional role of calsequestrin 2 (CASQ2) in both fast-twitch and slow-twitch skeletal muscles by using CASQ2-/- mice; CASQ2 is expressed throughout life in slow-twitch muscles, but only in the developmental and neonatal stages in fast-twitch muscles. CASQ2-/- causes increase in calsequestrin 1 (CASQ1) expression, but without functional changes in both muscle types. CASQ2-/- mice have ultrastructural changes in fast-twitch muscles only, i.e., formation of pentads and stacks in the sarcoplasmic reticulum.

Background Zika virus (ZIKV) became a global human health concern owing to its rapid spread worldwide and its association with congenital and neurological disorders. The current epidemiological profile of arboviruses in Brazil is characterized by widespread co-circulation of Dengue virus, Chikungunya virus, and ZIKV throughout the country. These viruses cause acute diseases frequently with overlapping symptoms, which could result in an inaccurate diagnosis based solely on clinical and epidemiological grounds. Here we conducted a screening for ZIKV RNA in serum samples from patients across Brazil with suspected ZIKV infection. Methods Using RT-qPCR, we investigated ZIKV RNA in 3001 serum samples. Samples were passively acquired through a private laboratory network, between December 2015 and August 2016, from 27 Brazilian Federative Units. We performed descriptive statistics on demographic variables including sex, age, and geographic location. Results ZIKV was detected in 11.4% (95%CI = 10.3–12.6%) of the sera. ZIKV RNA was detected in sera collected throughout the country, but during the analyzed period, RNA was more frequently detected in samples from the Southeast, Midwest, and North regions (3.9 to 5.8 times higher) when compared to the Northeast and South regions. Conclusions These data reinforce the importance of laboratory diagnosis, surveillance systems, and further epidemiological studies to understand the dynamics of outbreaks and diseases associated with ZIKV and other arboviruses. Electronic supplementary material The online version of this article (10.1186/s12985-018-1070-z) contains supplementary material, which is available to authorized users.

The capabilities approach provides a rich evaluative framework to guide transformative change in the community mental health system. This study reports the content and construct validity and psychometric properties of a contextualized measure of the extent to which mental health programs foster achieved capabilities. The Achieved Capabilities Questionnaire for Community Mental Health (ACQ-CMH), adapted from Nussbaum's capabilities framework, was developed previously with consumer collaboration. Content validity was assessed through a collaborative process, involving a panel of eight consumers, staff members, and senior researchers. The resulting shorter version (ACQ-CMH-98) was completed by 332 community mental health consumers sampled throughout Portugal. Factor (PCA) analysis, internal consistency reliability, and test-retest reliability over 2 weeks (N = 33) showed good psychometric properties. The resulting six-factor structure with 48 items explains 48.88% of the total variance (KMO = 0.89; Bartlett p = .00). Internal consistency of the obtained dimensions ranges from .91 to .76. Associations of the measure with recovery, quality of life, and psychological distress scales add further evidence of construct validity. The adaptation of Nussbaum's framework stressed specific components that may enhance understanding and change within the community mental health system. Fundação para a Ciência e a Tecnologia - FCT info:eu-repo/semantics/publishedVersion

Objective: Craniofacial disharmony in skeletal diseases is strongly associated with sleep-disordered breathing. This study was aimed at studying the sleep respiratory patterns in young children with rare skeletal disorders. Design: This retrospective study included children with achondroplasia (ACH), osteogenesis imperfecta (OI) and Ellis van Creveld Syndrome. Our subjects underwent an in-laboratory overnight respiratory polygraph between January 2012 and April 2016. All medical records were reviewed and brain Magnetic Resonance Imaging was conducted on patients with ACH, nasopharynx, oropharynx and laryngopharynx spaces. Patients: Twenty-four children were enrolled, 13 with ACH, 2 with spondyloepiphyseal dysplasia, 1 with odontochondrodysplasia, 6 with OI and 2 with Ellis van Creveld Syndrome. Results: Children with ACH, who had adenotonsillectomy, showed fewer sleep respiratory involvement than untreated children. Among 13 patients with ACH, brain magnetic resonance imaging was available in 10 subjects and significant negative correlation was found between sleep respiratory patterns, nasopharynx and oropharynx space (p < 0.05). In 2 patients with spondyloepiphyseal dysplasia, mild-to-moderate sleep respiratory involvement was found. Both subjects had a history of adenotonsillectomy. Mild sleep respiratory involvement was also observed in 4 out of 6 patients with OI. One patient with Ellis van Creveld syndrome had mild sleep respiratory disturbance. Conclusions: Sleep respiratory disturbances were detected in children with ACH, and with less severity also in OI and Ellis van Creveld syndrome. Adenotonsillectomy was successful in ACH in reducing symptoms. In light of our findings, multicenter studies are needed to obtain further information on these rare skeletal diseases.

SERCA2a is the Ca2+ ATPase playing the major contribution in cardiomyocyte (CM) calcium removal. Its activity can be regulated by both modulatory proteins and several post-translational modifications. The aim of the present work was to investigate whether the function of SERCA2 can be modulated by treating CMs with the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA). The incubation with SAHA (2.5 µM, 90 min) of CMs isolated from rat adult hearts resulted in an increase of SERCA2 acetylation level and improved ATPase activity. This was associated with a significant improvement of calcium transient recovery time and cell contractility. Previous reports have identified K464 as an acetylation site in human SERCA2. Mutants were generated where K464 was substituted with glutamine (Q) or arginine (R), mimicking constitutive acetylation or deacetylation, respectively. The K464Q mutation ameliorated ATPase activity and calcium transient recovery time, thus indicating that constitutive K464 acetylation has a positive impact on human SERCA2a (hSERCA2a) function. In conclusion, SAHA induced deacetylation inhibition had a positive impact on CM calcium handling, that, at least in part, was due to improved SERCA2 activity. This observation can provide the basis for the development of novel pharmacological approaches to ameliorate SERCA2 efficiency.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treatment options. Sarcomatoid/biphasic mesotheliomas are characterized by more aggressive behaviour and a poorer prognosis compared with the epithelioid subtype. To date prognostic and tailored therapeutic biomarkers are lacking. The present study analyzed the expression levels of MDM2 and HIF1alpha in different histologic subtypes from chemonaive MPM patients. Diagnostic biopsies of MPM patients from four Italian cancer centers were centrally collected and analyzed. MDM2 and HIF1alpha expression levels were investigated through immunohistochemistry and RT-qPCR. Pathological assessment of necrosis, inflammation and proliferation index was also performed. Molecular markers, pathological features and clinical characteristics were correlated to overall survival (OS) and progression free survival (PFS). Sixty MPM patients were included in the study (32 epithelioid and 28 non-epithelioid). Higher levels of MDM2 (p < 0.001), HIF1alpha (p = 0.013), necrosis (p = 0.013) and proliferation index (p < 0.001) were seen mainly in sarcomatoid/biphasic subtypes. Higher levels of inflammation were significantly associated with epithelioid subtype (p = 0.044). MDM2 expression levels were correlated with HIF1alpha levels (p = 0.0001), necrosis (p = 0.008) and proliferation index (p = 0.009). Univariate analysis showed a significant correlation of non-epithelioid histology (p = 0.04), high levels of necrosis (p = 0.037) and proliferation index (p = 0.0002) with shorter PFS. Sarcomatoid/biphasic and epithelioid mesotheliomas showed different MDM2 and HIF1alpha expression levels and were characterized by different levels of necrosis, proliferation and inflammation. Further studies are warranted to confirm a prognostic and predictive role of such markers and features.

OBJECTIVES/HYPOTHESIS: The possibility that long-term mobile phone use increases the incidence of astrocytoma, glioma and acoustic neuroma has been investigated in several studies. Recently, our group showed that direct exposure (in a surgical setting) to cell phone electromagnetic fields (EMFs) induces deterioration of auditory evoked cochlear nerve compound action potential (CNAP) in humans. To verify whether the use of Bluetooth devices reduces these effects, we conducted the present study with the same experimental protocol. STUDY DESIGN: Randomized trial. METHODS: Twelve patients underwent retrosigmoid vestibular neurectomy to treat definite unilateral Ménière's disease while being monitored with acoustically evoked CNAPs to assess direct mobile phone exposure or alternatively the EMF effects of Bluetooth headsets. RESULTS: We found no short-term effects of Bluetooth EMFs on the auditory nervous structures, whereas direct mobile phone EMF exposure confirmed a significant decrease in CNAPs amplitude and an increase in latency in all subjects. CONCLUSIONS: The outcomes of the present study show that, contrary to the finding that the latency and amplitude of CNAPs are very sensitive to EMFs produced by the tested mobile phone, the EMFs produced by a common Bluetooth device do not induce any significant change in cochlear nerve activity. The conditions of exposure, therefore, differ from those of everyday life, in which various biological tissues may reduce the EMF affecting the cochlear nerve. Nevertheless, these novel findings may have important safety implications. LEVEL OF EVIDENCE: 4

Breslow thickness is considered to be the most important prognostic tumor feature in melanoma patients and is associated with age, sex, and phenotypic risk factors for melanoma such as number of nevi. However, its association with inherited genetic variants in recently identified melanoma risk loci is largely unknown. In a Western Australian Melanoma Health Study (WAMHS) study, published in the British Journal of Dermatology, IRF4 rs12203592, OCA2 rs1800401 and TP53 rs1042522 were significantly associated (P < 0.05) with Breslow thickness; however, these associations did not pass false discovery. This article is protected by copyright. All rights reserved.

The current work examined a consecutive series of patients presenting vascular malformations (VMs) and venous lakes (VLs) of the lip and oral mucosa who were treated with transmucosal diode laser applications and assessed over a 1 year period.Fifty-nine patients (31 males and 28 females) presenting low-flow VMs or VLs of the oral cavity were treated transmucosally using a diode laser (with an 830 nm operating wavelength and 1.6 W output power) with a 320 µm diameter flexible fiber. All the lesions were assessed 7 days, 30 days, and 1 year after the laser treatment, and the lesion reduction percentage was scored on a one to five scale. The patients were also asked to assess their pain perception daily during the 7 days following the treatment using a visual analog scale (VAS).There were no procedure-related intra- or post-operative complications; only modest pain intensity was reported. Thirty days after the treatment, lesion reduction was described as excellent or good in 52 cases; it was fair or poor in 7. Six patients (F:M ratio 2:4) required a second diode laser application. At the 1 year follow-up, volume reduction was complete in 48 out of 59 patients; there were five recurrences (F:M ratio 3:2). No relevant gender-related differences were noted.The use of diode laser application to treat small oral VMs and VLs was associated to shorter operating times and fewer postoperative complications with respect to the scapel surgery approach. More than one session may nevertheless be required if the anomaly is larger than 10 mm. Lasers Surg. Med. 50:111-116, 2018. © 2017 Wiley Periodicals, Inc.

Associations of MC1R with BRAF mutations in melanoma have been inconsistent between studies. We sought to determine for 1,227 participants in the international population-based Genes, Environment, and Melanoma (GEM) study whether MC1R and phenotypes were associated with melanoma BRAF/NRAS subtypes. We used logistic regression adjusted by age, sex, and study design features and examined effect modifications. BRAF+ were associated with younger age, blond/light brown hair, increased nevi, and less freckling, and NRAS+ with older age relative to the wild type (BRAF-/NRAS-) melanomas (all P < 0.05). Comparing specific BRAF subtypes to the wild type, BRAF V600E was associated with younger age, blond/light brown hair, and increased nevi and V600K with increased nevi and less freckling (all P < 0.05). MC1R was positively associated with BRAF V600E cases but only among individuals with darker phototypes or darker hair (Pinteraction < 0.05) but inversely associated with BRAF V600K (Ptrend = 0.006) with no significant effect modification by phenotypes. These results support distinct etiologies for BRAF V600E, BRAF V600K, NRAS+, and wild-type melanomas. MC1R's associations with BRAF V600E cases limited to individuals with darker phenotypes indicate that MC1R genotypes specifically provide information about BRAF V600E melanoma risk in those not considered high risk based on phenotype. Our results also suggest that melanin pathways deserve further study in BRAF V600E melanomagenesis.

Type I is the most common Chiari malformation in children. In this condition, the lower part of the cerebellum, but not the brain stem, extends into the foramen magnum at the base of the skull leading to intermittent brain hypertension. In symptomatic children, central sleep apneas are shown in polysomnography evaluation. A central apnea index of 1/h or more is considered abnormal, but5/h is clearly considered pathological. Therefore, central sleep apnea evaluation in pediatric age may show great age-related variability.We present three patients who were assessed by polysomnography with two different scores for central sleep apneas published in the literature: the method by Scholle (2011) and the American Academy of Sleep Medicine scoring system (2012).We speculated that the Scholle scoring system can be more helpful in assessing children with asymptomatic Chiari 1 malformation for a closer follow-up. More studies are needed.

Importance Early and accurate in vivo diagnosis of Creutzfeldt-Jakob disease (CJD) is necessary for quickly distinguishing treatable from untreatable rapidly progressive dementias and for future therapeutic trials. This early diagnosis is becoming possible using the real-time quaking-induced conversion (RT-QuIC) seeding assay, which detects minute amounts of the disease-specific pathologic prion protein in cerebrospinal fluid (CSF) or olfactory mucosa (OM) samples. Objective To develop an algorithm for accurate and early diagnosis of CJD by using the RT-QuIC assay on CSF samples, OM samples, or both. Design, Setting, and Participants In this case-control study, samples of CSF and OM were collected from 86 patients with a clinical diagnosis of probable (n = 51), possible (n = 24), or suspected (n = 11) CJD and 104 negative control samples (54 CSF and 50 OM). The CSF and OM samples were analyzed using conventional RT-QuIC. The CSF samples underwent further testing using improved RT-QuIC conditions. In addition, the diagnostic performance of a novel, easy-to-use, gentle flocked swab for sampling of OM was evaluated. Data were collected from January 1 to June 30, 2015. Main Outcome and Measures Correlations between RT-QuIC results and the final diagnosis of recruited patients. Results Among the 86 patients (37 men [43%] and 49 women [57%]; mean [SD] age, 65.7 [11.5] years) included for analysis, all 61 patients with sporadic CJD had positive RT-QuIC findings using OM or CSF samples or both for an overall RT-QuIC diagnostic sensitivity of 100% (95% CI, 93%-100%). All patients with a final diagnosis of non–prion disease (71 CSF and 67 OM samples) had negative RT-QuIC findings for 100% specificity (95% CI, 94%-100%). Of 8 symptomatic patients with various mutations causing CJD or Gerstmann-Straussler-Scheinker syndrome, 6 had positive and 2 had negative RT-QuIC findings for a sensitivity of 75% (95% CI, 36%-96%). Conclusions and Relevance A proposed diagnostic algorithm for sporadic CJD combines CSF and OM RT-QuIC testing to provide virtually 100% diagnostic sensitivity and specificity in the clinical phase of the disease.

Congenital pseudomyotonia in Chianina cattle is a muscle function disorder very similar to that of Brody disease in humans. Mutations in the human ATP2A1 gene, encoding SERCA1, cause Brody myopathy. The analysis of the collected Chianina pedigree data suggested monogenic autosomal recessive inheritance and revealed that all 17 affected individuals traced back to a single founder. A deficiency of SERCA1 function in skeletal muscle of pseudomyotonia affected Chianina cattle was observed as SERCA1 activity in affected animals was decreased by about 70%. Linkage analysis showed that the mutation was located in the ATP2A1 gene region on BTA25 and subsequent mutation analysis of the ATP2A1 exons revealed a perfectly associated missense mutation in exon 6 (c.491G>A) leading to a p.Arg164His substitution. Arg164 represents a functionally important and strongly conserved residue of SERCA1. This study provides a suitable large animal model for human Brody disease.

Aims and background Cancer registration in Piedmont currently covers the city of Turin and the province of Biella, together representing 24% of the regional population. The objective of this paper is to provide estimates of the incidence and mortality rates and prevalence proportions for cancer of the lung, breast, cervix, prostate, colon-rectum and stomach and melanoma of the skin for 2012 and the time trends up to 2015 for the Piedmont and Aosta Valley regions. Methods The estimates were obtained by applying the MIAMOD method, a statistical back-calculation approach to derive incidence and prevalence figures starting from mortality and relative survival data. Published data from the Italian cancer registries were modeled in order to estimate the regional cancer survival. The MIAMOD estimates were also compared with those obtained by applying a method based on the mortality-incidence and prevalence-incidence ratios. Results The most frequently diagnosed cancers in absolute terms were prostate, colorectal, breast and lung cancer with about 5,000, 4,700, 3,300, and 2,900 new cases, respectively, in 2012. Incidence rates were rising for melanoma in both sexes and lung cancer in women, while they diminished for cervical and stomach cancer. For prostate cancer and male lung cancer the rates initially increased but were estimated to decrease in the most recent period. Colorectal cancer also increased up to the 1990s but was estimated to reach a plateau in the final years of estimation. Prevalence increased for all the considered cancers with the exception of cervical cancer. Mortality was declining for all considered cancers with the exception of lung cancer in women. Conclusions Monitoring indicators of the cancer burden is crucial for setting priorities among possible health system activities in a limited-resource setting. Piedmont has long invested in organized, population-based screening programs: these will have to be extended and accompanied by greater efforts in primary prevention.

Hearing threshold identification in very young children is always problematic and challenging. Electrophysiological testing such as auditory brainstem responses (ABR) is still considered the most reliable technique for defining the hearing threshold. However, over recent years there has been increasing evidence to support the role of auditory steady-state response (ASSR). Retrospective study. Forty-two children, age range 3-189 months, were evaluated for a total of 83 ears. All patients were affected by sensorineural hearing loss (thresholds ≥ 40 dB HL according to a click-ABR assessment). All patients underwent ABRs, ASSR and pure tone audiometry (PTA), with the latter performed according to the child's mental and physical development. Subjects were divided into two groups: A and B. The latter performed all hearing investigations at the same time as they were older than subjects in group A, and it was then possible to achieve electrophysiological and PTA tests in close temporal sequence. There was no significant difference between the threshold levels identified at the frequencies tested (0.25, 0.5, 1, 2 and 4 kHz), by PTA, ABR and ASSR between the two groups (Mann Whitney U test, p0.05). Moreover, for group A, there was no significant difference between the ASSR and ABR thresholds when the children were very young and the PTA thresholds subsequently identified at a later stage. Our results show that ASSR can be considered an effective procedure and a reliable test, particularly when predicting hearing threshold in very young children at lower frequencies (including 0.5 kHz).Stima di soglia mediante potenziali evocati uditivi di stato stazionario in età pediatrica.Effettuare una stima di soglia in età pediatrica è compito spesso difficile e complesso. A tal proposito, i potenziali evocati uditivi del tronco (ABR) rappresentano ancora la tecnica più affidabile per la definizione di soglia, sebbene il ruolo dei potenziali evocati uditivi di stato stazionario (ASSR) sia stato rivalutato negli ultimi anni. In questo studio retrospettivo sono stati valutati 42 bambini, di età compresa tra 3 e 189 mesi, per un totale di 83 orecchie. Tutti i pazienti inclusi sono risultati affetti da ipoacusia neurosensoriale (≥ 40 dB HL in base alla valutazione click-ABR). Tutti i pazienti sono stati sottoposti ad ABR, ASSR ed audiometria tonale, quest’ultima eseguita appena lo sviluppo psico-fisico del bambino lo ha consentito. I soggetti sono stati suddivisi in due gruppi: gruppo A e B, quest’ultimo ha effettuato tutte le indagini audiologiche quasi nello stesso momento, in quanto i bambini erano più grandi rispetto ai soggetti del gruppo A (in particolare sia le valutazioni elettrofisiologiche che l’audiometria tonale sono state eseguite quasi contemporaneamente). Non sono risultate differenze significative tra i livelli di soglia individuati, alle frequenze testate (0,25, 0,5, 1, 2 e 4 kHz), mediante audiometria tonale, ABR e ASSR, tra i due gruppi (test di U Mann Whitney, p0,05 ). Inoltre, considerando i bambini del gruppo A, non si è rilevata alcuna differenza significativa tra le soglie identificate mediante ASSR e ABR rilevate quando i bambini erano molto piccoli, e le soglie di audiometria tonale identificate successivamente. Nella nostra esperienza quindi, i potenziali evocati uditivi di stato stazionario possono essere considerati una metodica efficace ed affidabile soprattutto nella stima di soglia dei bambini molto piccoli e per le basse frequenze (compreso 0.5 kHz).

This Report intends to estimate the total number of people still alive in 2010 after cancer diagnosis in Italy, regardless of the time since diagnosis, and to project these estimates to 2015. This study is also aimed to estimate the number of already cured cancer patients, whose mortality rates have become undistinguishable from that of the general population of the same age and sex.The study took advantage of the information from the AIRTUM database, which included 29 Cancer Registries (covering 21 million people, 35% of the Italian population). A total of 1,624,533 cancer cases diagnosed between 1976 and 2009 contributed to the study. For each registry, the observed prevalence was calculated. Prevalence for lengths of time exceeding the maximum duration of the registration and of the complete prevalence were derived by applying an estimated correction factor, the completeness index. This index was estimated by means of statistical regression models using cancer incidence and survival data available in registries with 18 years of observation or more. For 50 types or combinations of neoplasms, complete prevalence was estimated at 1.1.2010 as an absolute number and as a proportion per 100,000 inhabitants by sex, age group, area of residence, and years since diagnosis. Projections of complete prevalence for 1.1.2015 were computed under the assumption of a linear trend of the complete prevalence observed until 2010. Validated mixture cure models were used to estimate: the cure fraction, that is the proportion of patients who, starting from the time of diagnosis, are expected to reach the same mortality rate of the general population; the conditional relative survival (CRS), that is the cumulative probability of surviving some additional years, given that patients already survived a certain number of years; the time to cure, that is the number of years necessary so that conditional survival in the following five years (5-year CRS) exceeds the conventional threshold of 95% (i.e., mortality rates in cancer patients become undistinguishable compared to those of the general population); the proportion of patients already cured, i.e., people alive since a number of years exceeding time to cure.As of 1.1.2010, it was estimated that 2,587,347 people were alive after a cancer diagnosis, corresponding to 4.4% of the Italian population. A relevant geographical heterogeneity emerged, with a prevalence above 5% in northern registries and below 4% in southern areas. Men were 45% of the total (1,154,289) and women 55% (1,433,058). In the population aged 75 years or more, the proportions of prevalent cases were 20% in males and 13% in females, 11% between 60 and 74 years of age in both sexes. Nearly 600,000 Italian women were alive after a breast cancer diagnosis (41% of all women with this neoplasm), followed by women with cancers of the colon rectum (12%), corpus uteri (7%), and thyroid (6%). In men, 26% of prevalent cases (295,624) were patients with prostate cancer, 16% with either bladder or colon rectum cancer. The projections for 1.1.2015 are of three million (3,036,741) people alive after a cancer diagnosis, 4.9% of the Italian population; with a 20% increase for males and 15% for females, compared to 2010. The cure fractions were heterogeneous according to cancer type and age. Estimates obtained as the sum of cure fractions for all cancer types showed that more than 60% of patients diagnosed below the age of 45 years will reach the same mortality rate of the general population. This proportion decreased with increasing age and it was30% for cancer diagnosed after the age of 74 years. It was observed that 60% of all prevalent cases (1,543,531 people or 2.6% of overall Italian population) had been diagnosed5 years earlier (long-term survivors). Time to cure (5-year CRS95%) was reached in10 years by patients with cancers of the stomach, colon rectum, pancreas, corpus and cervix uteri, brain, and Hodgkin lymphoma. Mortality rates similar to the ones reported by the general population were reached after approximately 20 years for breast and prostate cancer patients. Five-year CRS remained95% for25 years after cancer diagnosis in patients with liver and larynx cancers, non-Hodgkin lymphoma, myeloma, and leukaemia. Time to cure was reached by 27% (20% in men and 33% in women) of all people living after a cancer diagnosis, defined as already cured.The study showed a steady increase over time (nearly +3% per year) of prevalent cases in Italy. A quarter of Italian cancer patients alive in 2010 can be considered as already cured. The AIRTUM Report 2014 describes characteristics of cancer patients and former-patients for 50 cancer types or combinations by sex and age. This detailed information promotes the conduction of studies aimed at expanding the current knowledge on the quality of life of these patients during and after the active phase of treatments (prevalence according to health status), on the long-term effects of treatments (in particular for paediatric patients), on the cost profile of cancer patients, and on rare tumours. All these observations have a high potential impact on health planning, clinical practice, and, most of all, patients' perspective.

The advent of modern treatments together with the improvement of the surgical techniques has significantly increased 5-year survival rates of young patients with cancer. Although the deleterious effects of chemotherapy and radiation are well documented, controversies exist about the effect of cancer itself on semen parameters before treatment. We collected data on 236 patients representative of different types of cancers reoffered at our institution for sperm cryopreservation with the aim to correlate the pre-freeze semen parameters with type of cancer, disease stage and with semen quality of 102 fertile and healthy men. The median baseline semen parameters of all our patients with cancer are placed above the 5th percentile of the World Health Organization reference value, but the type of cancer may impact the sperm parameters. In testicular tumours and in Hodgkin lymphoma, we show a semen concentration statistically lower than in the fertile population, while in patients with other cancers, there is no difference with the healthy men. We found no correlation between semen quality and disease stage. Eighty-six per cent of our patients do not have children at the time of semen cryopreservation, and the only established clinical option for preserving fertility of these men is cryopreservation of spermatozoa.

Part of this work has been presented at the Fifth Congress on Trends in Medical Mycology, Valencia, Spain, 2011 (Abstract no. 308); International audience; OBJECTIVES:Triazole resistance in Aspergillus fumigatus due to a single azole resistance mechanism (TR/L98H) is increasingly reported in European countries. Data from patients with cystic fibrosis (CF) are limited. Our study aimed to investigate the prevalence and molecular mechanisms of azole resistance in A. fumigatus in a cohort of patients with CF.METHODS:Eighty-five A. fumigatus isolates from 50 CF patients, collected between January 2010 and April 2011, were retrospectively analysed for azole resistance using agar plates containing 4 mg/L itraconazole. MICs of itraconazole, voriconazole and posaconazole were determined according to EUCAST methodology for each isolate able to grow on this medium. Species identification was performed by sequencing of the β-tubulin gene. Sequencing analysis of the cyp51A gene and its promoter region was conducted.RESULTS:Nine isolates (four patients, 8% prevalence) were able to grow on itraconazole-containing agar plates. Itraconazole resistance was confirmed by EUCAST methodology (MICs >2 mg/L). All isolates had mutations in the cyp51A gene at residues previously involved in azole resistance: L98H (n = 5), M220T (n = 4) and G54R (n = 1). One patient had three genetically distinct azole-resistant isolates identified during the study. The isolates with L98H that were recovered from three patients (6% prevalence) also had the 34 bp tandem repeat in the promoter region of cyp51A (TR/L98H) and displayed multiazole resistance.CONCLUSIONS:We report an 8% prevalence of itraconazole resistance in CF patients in our centre, mostly driven by TR/L98H (6%). Our data confirm that TR/L98H occurs in France and can be highly prevalent in CF patients.

SERCA2a is the Ca2+ ATPase playing the major contribution in cardiomyocyte (CM) calcium removal. Its activity can be regulated by both modulatory proteins and several post-translational modifications. The aim of the present work was to investigate whether the function of SERCA2 can be modulated by treating CMs with the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA). The incubation with SAHA (2.5 µM, 90 min) of CMs isolated from rat adult hearts resulted in an increase of SERCA2 acetylation level and improved ATPase activity. This was associated with a significant improvement of calcium transient recovery time and cell contractility. Previous reports have identified K464 as an acetylation site in human SERCA2. Mutants were generated where K464 was substituted with glutamine (Q) or arginine (R), mimicking constitutive acetylation or deacetylation, respectively. The K464Q mutation ameliorated ATPase activity and calcium transient recovery time, thus indicating that constitutive K464 acetylation has a positive impact on human SERCA2a (hSERCA2a) function. In conclusion, SAHA induced deacetylation inhibition had a positive impact on CM calcium handling, that, at least in part, was due to improved SERCA2 activity. This observation can provide the basis for the development of novel pharmacological approaches to ameliorate SERCA2 efficiency.

The purpose of this study was to compare our experience with ultrasound (US)-guided percutaneous radiofrequency thermal ablation (RFA) of renal tumors with results of CT-guided and MRI-guided series in the current literature. Of 90 consecutive renal tumors treated with RFA in 71 patients, 87 lesions were ablated under US guidance. We performed a retrospective analysis of clinical outcome and safety. Results were then compared to published case series where CT and MRI guidances were used exclusively. In our series we had a major complication rate of 4.6%, whereas in CT- and MRI-based series it was 0-12% (mean, 2.2%) and 0-8.3% (mean, 4.1%), respectively. During follow-up (1-68 months; mean, 24 months) technical effectiveness was 89.7%, while it was between 89.5% and 96% in CT-guided series and between 91.7% and 100% in MRI-guided series. The size of successfully treated lesions (28 mm) was lower than that of partially-ablated lesions (36 mm; p = 0.004) and only central lesion location proved to be a negative prognostic factor (p = 0.009); in CT-guided series, positive prognostic factors were exophytic growth and size/=3 cm. "Tumor-specific" 2-year survival was 92% in our series, 90-96% in CT-guided series, and not reported in MRI-guided series. In conclusion, despite common beliefs, US guidance in RFA of renal tumors is not less favorable than other guidance techniques. Thus the interventional radiologist can choose his or her preferred technique taking into account personal experience and available equipment.

The aim of our study was to evaluate the radiologist's role in managing paediatric orthotopic liver transplantation (OLT) through a retrospective review of our experience in diagnosing and treating post-OLT complications. Forty children (mean age 4.6 years) underwent 44 OLTs over 71 months. The follow-up period (mean 724 days) was divided into three phases: hospital stay, up to three months after discharge and subsequent period. The number and type of radiological examinations, radiologically detectable complications and interventional procedures were analysed. Most examinations were carried out with ultrasound (US) (859/931 of all radiological studies performed during the first two phases, 92.3%). Colour-Doppler US enabled early detection and treatment of all vascular complications (9/40, 22.5% of patients; 13 complications in nine patients, eight arterial and five portal complications; 1.4 for each patient with complications). Computed tomography (CT) or angiography was very rarely employed. US also detected biliary complications (11 patients, 27.5%: three cases of segmental ducts excluded from the anastomosis, four cases of stenosis of the biliodigestive anastomosis, one lithiasis, three stenoses associated with lithiasis), which were successfully managed in 75% of the cases treated with interventional radiology procedures (percutaneous bilioplasty and/or lithotripsy). At the time of writing this paper, the patient survival rate was 100%, and the organ survival rate was 91% (40/44). There were four retransplantations: three due to hepatic artery thrombosis and one to biliary stenosis with lithiasis. The radiologist's role is fundamental for early sonographic diagnosis of post-OLT complications in children. Vascular complications are often associated in a single patient, and early treatment may improve the prognosis. Interventional radiology represents a safe and effective treatment for many biliary complications.