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BACKGROUND: Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 10 9 cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear. OBJECTIVE: To estimate the long-term risk difference for cancer with the immediate ART strategy.DESIGN: Multinational prospective cohort study.SETTING: The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States.PARTICIPANTS: 8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016).MEASUREMENTS: The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts RESULTS: During 64 021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 10 9 cells/L and less than 350 × 10 9 cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer. LIMITATION: Potential residual confounding due to observational study design.CONCLUSION: In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer.PRIMARY FUNDING SOURCE: Highly Active Antiretroviral Therapy Oversight Committee.

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Background Multiparametric magnetic resonance imaging (mpMRI) can guide the surgical plan during robot-assisted radical prostatectomy (RARP), and intraoperative frozen section (IFS) can facilitate real-time surgical margin assessment. Objective To assess a novel technique of IFS targeted to the index lesion by using augmented reality three-dimensional (AR-3D) models in patients scheduled for nerve-sparing RARP (NS-RARP). Design, setting, and participants Between March 2019 and July 2019, 20 consecutive prostate cancer patients underwent NS-RARP with IFS directed to the index lesion with the help of AR-3D models (study group). Control group consists of 20 patients matched with 1:1 propensity score for age, clinical stage, Prostate Imaging Reporting and Data System score v2, International Society of Urological Pathology grade, prostate volume, NS approach, and prostate-specific antigen in which RARP was performed by cognitive assessment of mpMRI. Surgical procedure In the study group, an AR-3D model was superimposed to the surgical field to guide the surgical dissection. Tissue sampling for IFS was taken in the area in which the index lesion was projected by AR-3D guidance. Measurements Chi-square test, Student t test, and Mann-Whitney U test were used to compare, respectively, proportions, means, and medians between the two groups. Results and limitations Patients in the AR-3D group had comparable preoperative characteristics and those undergoing the NS approach were referred to as the control group (all p ≥ 0.06). Overall, positive surgical margin (PSM) rates were comparable between the two groups; PSMs at the level of the index lesion were significantly lower in patients referred to AR-3D guided IFS to the index lesion (5%) than those in the control group (20%; p = 0.01). Conclusions The novel technique of AR-3D guidance for IFS analysis may allow for reducing PSMs at the level of the index lesion. Patient summary Augmented reality three-dimensional guidance for intraoperative frozen section analysis during robot-assisted radical prostatectomy facilitates the real-time assessment of surgical margins and may reduce positive surgical margins at the index lesion.

Major cerebral vessels have been proposed as a target of defective mitochondrial metabolism in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS). Cerebral angiographic techniques are not routinely performed in MELAS patients. A systematic literature review was performed to identify studies describing major vessel caliber alterations in MELAS. Twenty-three studies reporting on 46 MELAS patients were included. Alterations in major caliber vessels were present in 59% (27/46) of patients. Dilation occurred in 37% (17/46) of patients, and in 88% (15/17) of them during a stroke-like episode (SLE). Stenosis was reported in 24% (11/46) of patients: 36% (4/11) related to an SLE and 64% (7/11) to dissections or degenerative changes. During an SLE, identification of intracranial vessels dilation or stenosis could be a selection tool for new treatment protocols. Outside SLE, identification of major cerebral vessels dissections and degenerative changes may help to prevent subsequent complications. (c) 2021 Elsevier Masson SAS. All rights reserved.

To date, there are no standardized systemic treatment options for patients with metastatic pituitary carcinoma progressed to chemo and radiation therapy. Immune-checkpoint inhibitors (ICIs) have been successfully assessed in other solid malignancies and could be a concrete hope for these patients. We performed a critical review of the literature aimed to evaluate studies assessing ICIs in pituitary malignancies. We also conducted research about published translational data assessing immune-contexture in these malignancies. Some preliminary reports reported a successful administration of pembrolizumab or the combination between nivolumab and ipilimumab in patients with metastatic ACTH-secreting pituitary carcinomas. Translational data suggest that adenomas secreting growth hormone and ACTH have a suppressed immune-microenvironment, which could be more likely to benefit from ICIs. Immune-checkpoint inhibitors can be an effective treatment in patients with pituitary carcinoma and maybe also recurrent adenoma. Tumors secreting growth hormone and ACTH are more likely to benefit from ICIs due to a different immune-microenvironment.

Glioblastoma (GBM) is the most common primary tumor of the central nervous system. Arising from neuroepithelial glial cells, GBM is characterized by invasive behavior, extensive angiogenesis, and genetic heterogeneity that contributes to poor prognosis and treatment failure. Currently, there are several molecular biomarkers available to aid in diagnosis, prognosis, and predicting treatment outcomes; however, all require the biopsy of tumor tissue. Nevertheless, a tissue sample from a single location has its own limitations, including the risk related to the procedure and the difficulty of obtaining longitudinal samples to monitor treatment response and to fully capture the intratumoral heterogeneity of GBM. To date, there are no biomarkers in blood or cerebrospinal fluid for detection, follow-up, or prognostication of GBM. Liquid biopsy offers an attractive and minimally invasive solution to support different stages of GBM management, assess the molecular biology of the tumor, identify early recurrence and longitudinal genomic evolution, predict both prognosis and potential resistance to chemotherapy or radiotherapy, and allow patient selection for targeted therapies. The aim of this review is to describe the current knowledge regarding the application of liquid biopsy in glioblastoma, highlighting both benefits and obstacles to translation into clinical care.Implications for PracticeTo translate liquid biopsy into clinical practice, further prospective studies are required with larger cohorts to increase specificity and sensitivity. With the ever-growing interest in RNA nanotechnology, microRNAs may have a therapeutic role in brain tumors.

Objective The purpose of this study was to investigate correlations between brain proton magnetic resonance spectroscopy (1H‐MRS) findings with serum biomarkers and heteroplasmy of mitochondrial DNA (mtDNA) mutations. This study enrolled patients carrying mtDNA mutations associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke‐like episodes (MELAS), and MELAS‐Spectrum Syndrome (MSS). Methods Consecutive patients carrying mtDNA mutations associated with MELAS and MSS were recruited and their serum concentrations of lactate, alanine, and heteroplasmic mtDNA mutant load were evaluated. The brain protocol included single‐voxel 1H‐MRS (1.5T) in the medial parieto‐occipital cortex (MPOC), left cerebellar hemisphere, parieto‐occipital white matter (POWM), and lateral ventricles. Relative metabolite concentrations of N‐acetyl‐aspartate (NAA), choline (Cho), and myo‐inositol (mI) were estimated relative to creatine (Cr), using LCModel 6.3. Results Six patients with MELAS (age 28 ± 13 years, 3 [50%] female) and 17 with MSS (age 45 ± 11 years, 7 [41%] female) and 39 sex‐ and age‐matched healthy controls (HC) were enrolled. These patients demonstrated a lower NAA/Cr ratio in MPOC compared to HC (p = 0.006), which inversely correlated with serum lactate (p = 0.021, rho = −0.68) and muscle mtDNA heteroplasmy (p

Brain metastases (BMs) represent a negative prognostic factor for patients with solid malignancies. BMs are generally approached with loco-regional treatments and the blood–brain barrier limits the efficacy of some systemic drugs. The aim of this review is to summarize current knowledge about the role of immune checkpoint inhibitors for the management of brain metastases in patients with solid malignancies. We performed a review of available literature. Immune checkpoint inhibitors represent the standard treatment for several advanced solid malignancies. However, with the exception of melanoma their clinical role in other solid malignancies is not completely clear due to the exclusion of patients with BM from approval clinical trials. Immune-checkpoint inhibitors may be an effective treatment of brain metastases of melanoma while their clinical role on brain metastases from other solid malignancies is uncertain.

Background: To date, no prospective study has been conducted to investigate the role of socioeconomic status (SES) on clinical outcome of glioblastoma (GBM) in Italy, where there is a National Health Service that provides universal coverage regardless of the patient's economic status. Methods: We performed a prospective observational study investigating the association between SES and survival in GBM patients at our institution, a hub centre for brain cancer research and treatment. We included GBM patients who underwent medical treatment or chemo-radiation between April 2017 and December 2017. The SES was measured using the income-brackets, attributed by the Italian Ministry of Finance on the basis of the income of the fiscal family unit, referring to the previous year. Results: One hundred and six patients were included in the study. In multivariate analysis, overall survival (OS) correlated significantly with higher-income (HR = 0.623.95% CI 0.467–0.832; p = 0.001) and MGMT methylation status (HR = 0.158.95% CI 0.082–0.304; P < 0.001). When adjusted for age, performance status and extension of surgery, survival benefit remained superior for higher-income HR = 0.641 (95% CI 0.478–0.858; p = 0.003) and MGMT methylated tumours HR = 0.167 (95% CI 0.084–0.331; p < 0.001). Conclusions: SES is an important determinant of prognosis in GBM even in the Italian National Health Service, which provides universal, largely free and relatively comprehensive healthcare. Despite aspirations to achieve equality in healthcare, socioeconomic differences exist and may impact the clinical outcome.

Background There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. Methods The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group – KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients’ outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. Results One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p Conclusion Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.

Background Root canal treatment (RoCT), or endodontic treatment, is a common procedure in dentistry. The main indications for RoCT are irreversible pulpitis and necrosis of the dental pulp caused by carious processes, tooth cracks or chips, or dental trauma. Successful RoCT is characterised by an absence of symptoms (i.e. pain) and clinical signs (i.e. swelling and sinus tract) in teeth without radiographic evidence of periodontal involvement (i.e. normal periodontal ligament). The success of RoCT depends on a number of variables related to the preoperative condition of the tooth, as well as the endodontic procedures. This review updates the previous version published in 2007. Objectives To determine whether completion of root canal treatment (RoCT) in a single visit or over two or more visits, with or without medication, makes any difference in term of effectiveness or complications. Search methods We searched the following electronic databases: Cochrane Oral Health's Trials Register (to 14 June 2016), Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 5), MEDLINE Ovid (1946 to 14 June 2016), and Embase Ovid (1980 to 14 June 2016). We searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials to 14 June 2016. We did not place any restrictions on the language or date of publication when searching the electronic databases. Selection criteria We included randomised controlled trials (RCTs) and quasi-RCTs of people needing RoCT. We excluded surgical endodontic treatment. The outcomes of interest were tooth extraction for endodontic problems; radiological failure after at least one year, i.e. periapical radiolucency; postoperative pain; swelling or flare-up; painkiller use; sinus track or fistula formation; and complications (composite outcome including any adverse event). Data collection and analysis We collected data using a specially designed extraction form. We contacted trial authors for further details where these were unclear. We assessed the risk of bias in the studies using the Cochrane tool and we assessed the quality of the body of evidence using GRADE criteria. When valid and relevant data were collected, we undertook a meta-analysis of the data using the random-effects model. For dichotomous outcomes, we calculated risk ratios (RRs) and 95% confidence intervals (CIs). For continuous data, we calculated mean differences (MDs) and 95% CIs. We examined potential sources of heterogeneity. We conducted subgroup analyses for necrotic and vital teeth. Main results We included 25 RCTs in the review, with a total of 3780 participants, of whom we analysed 3751. We judged three studies to be at low risk of bias, 14 at high risk, and eight as unclear. Only one study reported data on tooth extraction due to endodontic problems. This study found no difference between treatment in one visit or treatment over multiple visits (1/117 single-visit participants lost a tooth versus 2/103 multiple-visit participants; odds ratio (OR) 0.44, 95% confidence interval (CI) 0.04 to 4.78; very low-quality evidence). We found no evidence of a difference between single-visit and multiple-visit treatment in terms of radiological failure (risk ratio (RR) 0.91, 95% CI 0.68 to 1.21; 1493 participants, 11 studies, I2 = 18%; low-quality evidence); immediate postoperative pain (dichotomous outcome) (RR 0.99, 95% CI 0.84 to 1.17; 1560 participants, 9 studies, I2 = 33%; moderate-quality evidence); swelling or flare-up incidence (RR 1.36, 95% CI 0.66 to 2.81; 281 participants, 4 studies, I2 = 0%; low-quality evidence); sinus tract or fistula formation (RR 0.98, 95% CI 0.15 to 6.48; 345 participants, 2 studies, I2 = 0%; low-quality evidence); or complications (RR 0.92, 95% CI 0.77 to 1.11; 1686 participants, 10 studies, I2 = 18%; moderate-quality evidence). The studies suggested people undergoing RoCT in a single visit may be more likely to experience pain in the first week than those whose RoCT was over multiple visits (RR 1.50, 95% CI 0.99 to 2.28; 1383 participants, 8 studies, I2 = 54%), though the quality of the evidence for this finding is low. Moderate-quality evidence showed people undergoing RoCT in a single visit were more likely to use painkillers than those receiving treatment over multiple visits (RR 2.35, 95% CI 1.60 to 3.45; 648 participants, 4 studies, I2 = 0%). Authors' conclusions There is no evidence to suggest that one treatment regimen (single-visit or multiple-visit root canal treatment) is better than the other. Neither can prevent all short- and long-term complications. On the basis of the available evidence, it seems likely that the benefit of a single-visit treatment, in terms of time and convenience, for both patient and dentist, has the cost of a higher frequency of late postoperative pain (and as a consequence, painkiller use).

We report the longest follow-up of clinical and biochemical features of two previously reported adult mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients treated with liver transplantation (LT), adding information on a third, recently transplanted, patient. All three patients overcame the early post-operative period and tolerated immunosuppressive therapy. Plasma nucleoside levels dramatically decreased, with evidence of clinical improvement of ambulation and neuropathy. Conversely, other features of MNGIE, as gastrointestinal dysmotility, low weight, ophthalmoparesis, and leukoencephalopathy were essentially unchanged. A similar picture characterized two patients treated with allogenic hematopoietic stem cell transplantation (AHSCT). In conclusion, LT promptly and stably normalizes nucleoside imbalance in MNGIE, stabilizing or improving some clinical parameters with marginal periprocedural mortality rate as compared to AHSCT. Nevertheless, restoring thymidine phosphorylase (TP) activity, achieved by both LT and AHSCT, does not allow a full clinical recovery, probably due to consolidated cellular damage and/or incomplete enzymatic tissue replacement.

Background Acidosis-induced kidney injury is mediated by the intrarenal renin-angiotensin system, for which urinary renin is a potential marker. Therefore, we hypothesized that sodium bicarbonate supplementation reduces urinary renin excretion in patients with chronic kidney disease (CKD) and metabolic acidosis. Methods Patients with CKD stage G4 and plasma bicarbonate 15–24 mmol/l were randomized to receive sodium bicarbonate (3 × 1000 mg/day, ~ 0.5 mEq/kg), sodium chloride (2 × 1,00 mg/day), or no treatment for 4 weeks (n = 15/arm). The effects on urinary renin excretion (primary outcome), other plasma and urine parameters of the renin-angiotensin system, endothelin-1, and proteinuria were analyzed. Results Forty-five patients were included (62 ± 15 years, eGFR 21 ± 5 ml/min/1.73m2, plasma bicarbonate 21.7 ± 3.3 mmol/l). Sodium bicarbonate supplementation increased plasma bicarbonate (20.8 to 23.8 mmol/l) and reduced urinary ammonium excretion (15 to 8 mmol/day, both P P = 0.07) and potassium (5.1 to 4.8 mmol/l, P = 0.06) was observed in patients receiving sodium bicarbonate. Sodium bicarbonate did not significantly change the urinary excretion of renin, angiotensinogen, aldosterone, endothelin-1, albumin, or α1-microglobulin. Sodium chloride supplementation reduced plasma renin (166 to 122 ng/L), and increased the urinary excretions of angiotensinogen, albumin, and α1-microglobulin (all P Conclusions Despite correction of acidosis and reduction in urinary ammonium excretion, sodium bicarbonate supplementation did not improve urinary markers of the renin-angiotensin system, endothelin-1, or proteinuria. Possible explanations include bicarbonate dose, short treatment time, or the inability of urinary renin to reflect intrarenal renin-angiotensin system activity. Graphic abstract

Background The coronavirus disease 2019 (COVID-19) pandemic disrupted access to and uptake of hepatitis C virus (HCV) care services in the United States. It is unknown how substantially the pandemic will impact long-term HCV-related outcomes. Methods We used a microsimulation to estimate the 10-year impact of COVID-19 disruptions in healthcare delivery on HCV outcomes including identified infections, linkage to care, treatment initiation and completion, cirrhosis, and liver-related death. We modeled hypothetical scenarios consisting of an 18-month pandemic-related disruption in HCV care starting in March 2020 followed by varying returns to pre-pandemic rates of screening, linkage, and treatment through March 2030 and compared them to a counterfactual scenario in which there was no COVID-19 pandemic or disruptions in care. We also performed alternate scenario analyses in which the pandemic disruption lasted for 12 and 24 months. Results Compared to the “no pandemic” scenario, in the scenario in which there is no return to pre-pandemic levels of HCV care delivery, we estimate 1060 fewer identified cases, 21 additional cases of cirrhosis, and 16 additional liver-related deaths per 100 000 people. Only 3% of identified cases initiate treatment and Conclusions A recommitment to the HCV epidemic in the United States that involves additional resources coupled with aggressive efforts to screen, link, and treat people with HCV is needed to overcome the COVID-19-related disruptions.

Hepatocellular carcinoma (HCC) with portal vein tumoral thrombosis (PVTT) represents a major concern especially in the field of deceased donor liver transplantation (DDLT). However, when receiving transarterial radioembolization (TARE), a considerable percentage of such patients are able to achieve a radiologic complete response with adequate survival rates. In this pilot prospective study, we evaluated the effect of TARE in downstaging HCC patients with PVTT to meet criteria for DDLT. Between May 2013 and November 2016, patients were evaluated to be enrolled into our “Superdownstaging” protocol. Patients received yttrium-90 TARE and were enlisted for DDLT in case of complete and sustained (6months) radiological response. Patients with tumor thrombus in the main trunk and/or in the contralateral portal vein branch were excluded. TARE was effective in downstaging and receiving DDLT in 5/17 patients (29.4%). The 5-year overall survival was significantly higher in patients who underwent DDLT compared with those who were not transplanted (60.0% versus 0.0%, P=0.03). Three out of 5 patients developed recurrence within 1year after LT. The current series showed a clear survival gain in those patients who were able to receive DDLT after TARE but careful selection for DDLT is however advised.

The primary aim of the study was to evaluate the role of [18F]Fluciclovine PET/CT in the characterization of intra-prostatic lesions in high-risk primary PCa patients eligible for radical prostatectomy, in comparison with conventional [11C]Choline PET/CT and validated by prostatectomy pathologic examination. Secondary aims were to determine the performance of PET semi-quantitative parameters (SUVmax, target-to-background ratios [TBRs], using abdominal aorta, bone marrow and liver as backgrounds) for malignant lesion detection (and best cut-off values) and to search predictive factors of malignancy. A six sextants prostate template was created and used by PET readers and pathologists for data comparison and validation. PET visual and semi-quantitative analyses were performed: for instance, patient-based, blinded to histopathology, subsequently lesion-based, un-blinded, according to the pathology reference template. Among 19 patients included (mean age 63 years, 89% high and 11% very-high-risk, mean PSA 9.15 ng/mL), 45 malignant and 31 benign lesions were found and 19 healthy areas were selected (n = 95). For both tracers, the location of the “blinded” prostate SUVmax matched with the lobe of the lesion with the highest pGS in 17/19 cases (89%). There was direct correlation between [18F]Fluciclovine uptake values and pISUP. Overall, lesion-based (n = 95), the performance of PET semiquantitative parameters, with either [18F]Fluciclovine or [11C]Choline, in detecting either malignant/ISUP2-5/ISUP4-5 PCa lesions, was moderate and similar (AUCs ≥ 0.70) but still inadequate (AUCs ≤ 0.81) as a standalone staging procedure. A [18F]Fluciclovine TBR-L3 ≥ 1.5 would depict a clinical significant lesion with a sensitivity and specificity of 85% and 68% respectively, whereas a SUVmax cut-off value of 4 would be able to identify a ISUP 4-5 lesion in all cases (sensitivity 100%), although with low specificity (52%). TBRs (especially with threshold significantly higher than aorta and slightly higher than bone marrow), may be complementary to implement malignancy targeting.

This study assessed the potential short-term effects of COVID-19 stay-at-home restrictions on ratings of ASD and comorbid symptoms severity and adaptive functioning of 69 youth, ages 8-16 years with ASD without intellectual disability. Parent/caregiver ratings were being collected in fall and spring over approximately two years when the restrictions were imposed four months prior to the final data collection point. Results indicated no significant changes in parent/caregiver ratings of ASD symptom severity, comorbid symptoms severity, social skills, or adaptive behaviors following the stay-at-home restrictions and little variability across the four data collection points. Although findings suggested minimal short-term effects on these symptoms and adaptive skills, ongoing monitoring is needed to assess longer-term impacts.

Objectives The present research used a continuous measurement approach to extend the evidence that autism is associated with significant struggles in physical health as well as mental health and psychological well-being. Methods The relationship of autism characteristics to physical health and psychological well-being was examined in 294 individuals (M age = 70.51, SD age = 8.17, age range = 53–96). The sample is 57.4% female (n = 166) and primarily White (n = 270, 96.8%). The majority of the participants did not identify as having an autism diagnosis (n = 284, 96.6%). Participants completed the Autism-Spectrum Quotient Scale alongside self-report measures of physical health, mental health, and psychological well-being. Results Autism characteristics correlated strongly with challenges in social engagement due to poor health (r = 0.46), depression (r = 0.39) and anxiety (r = 0.47), limitations due to poor mental health (r = 0.41), satisfaction with life (r = −0.47), and psychological well-being (r = −0.62). Discussion These findings help shed light on the challenges experienced by individuals aging with elevated autism characteristics. The limitations of this study and prior work on this topic help identify important avenues for future research in this area.

Background Morphological evaluation of coronary lesion length is a paramount step during invasive assessment of coronary artery disease. Likewise, the extent of epicardial pressure losses can be measured using longitudinal vessel interrogation with fractional flow reserve (FFR) pullbacks. We aimed to quantify the mismatch in lesion length between morphological (based on quantitative coronary angiography, QCA, and optical coherence tomography, OCT) and functional evaluations. Methods This is a prospective and multicenter study of patients evaluated by QCA, OCT and motorized fractional flow reserve pullbacks (mFFR). The difference in lesion length between the functional and anatomical evaluations was referred to as FAM. Results 117 patients (131 vessels) were included. Median lesion length derived from angiography was 16.05 mm [11.40–22.05], from OCT was 28.00 mm [16.63–38.00] and from mFFR 67.12 mm [25.38–91.37]. There was no correlation between QCA and mFFR lesion length (r = 0.124, 95% CI -0.168-0.396, p = 0.390). OCT lesion length did correlate with mFFR (r = 0.469, 95% CI 0.156–0.696, p = 0.004). FAM was strongly associated with the improvement in vessel conductance with percutaneous coronary intervention (PCI), higher mismatch was associated with lower post-PCI FFR. Conclusions Lesion length assessment differs between morphological and functional evaluations. The morphological-functional mismatch in lesion length is frequent, and influences the results of PCI in terms of post-PCI FFR. Integration of the extent of pressure losses provides clinically relevant information that may be useful for clinical decision-making concerning revascularization strategy.

Amid the current US opioid crisis, hepatitis C virus (HCV) infection rates continue to rise in young adults, including among pregnant women, yet few studies describe linkage to care and treatment in pregnant or postpartum women with HCV infection. We used electronic health record data to estimate HCV treatment rates for postpartum women before (January 2014‐September 2016) and during (October 2016‐March 2018) implementation of a maternal–infant HCV linkage program in combination with a multidisciplinary clinic to colocate mother and infant care. Using Poisson regression models, we compared HCV treatment initiation rates, adjusting for demographics, substance use, and treatment. From January 2014 through March 2018, 343 women who were HCV seropositive delivered at our institution. Of these, 95% completed HCV nucleic acid testing and 255 women had chronic HCV infection. Mean age was 30 years, 96% were publicly insured, and 94% had documented substance use. HCV treatment initiation increased from 28/164 (17.1%) women with chronic HCV infection in the preintervention period to 16/66 (24.2%) with the linkage‐only intervention and 13/25 (52.0%) with the linkage intervention and colocated care. Adjusted analyses demonstrated that women delivering during the intervention period initiated HCV treatment at 2.40 times (95% confidence interval [CI], 1.10‐5.25; linkage only) and 3.36 times (95% CI, 1.57‐7.17; linkage and colocated care) the rate of women delivering preintervention. Women on buprenorphine had higher HCV treatment initiation rates compared with those on methadone (rate ratio, 2.10; 95% CI, 1.05‐4.21). Conclusion: HCV linkage to care and treatment rates improved in the setting of mother–infant linkage and colocated care interventions. Perinatal care may represent a critical venue to identify, link, and treat women for HCV infection to improve their own health and prevent transmission to subsequent pregnancies., Although US national guidelines now recommend screening all pregnant women for Hepatitis C virus (HCV) amidst rising incidence rates, few studies describe practices to link diagnosed women to HCV cure after pregnancy. This study measures HCV treatment initiation rates before and during implementation of a perinatal linkage to care program and maternal‐infant co‐located care clinic, adjusting for follow‐up time, age, and substance use. We found 2.4 to 3.9‐fold increased HCV treatment rates among women who delivered a baby since the programs began, compared with those who delivered prior, highlighting a simple intervention to improve HCV cure rates to help reach HCV elimination goals.

Different studies highlight photo-receptors’ presence on the hair follicle that seems to be capable of eliciting hair growth. This study aims to demonstrate blue light’s effectiveness on hair growth in patients affected by androgenetic alopecia. Twenty patients enrolled at Magna Graecia University Unit of Dermatology, affected by androgenetic alopecia, were treated with a blue LED light device at 417 ± 10 nm, fluence of 120 J/cm2, and power intensity of 60 mW/cm2 ± 20%. The treatments were performed twice a week for ten consecutive weeks. Patients were evaluated before and 1 month after the end of therapy clinically using standardized global photographs and dermoscopically estimating hair density and hair shaft width. An increase in hair density and hair shaft width was recorded in 90% of patients after 10 weeks. Photographic improvement was noted in 80% of the patients. No serious adverse events have been reported. The only side effect consisted in a darkening of the hair, perhaps due to melanic stimulation due to blue light in 2 patients. Blue light therapy is a promising therapy for patients affected by androgenetic alopecia and other diseases characterized by hair loss. Further studies will be necessary to confirm the findings of this preliminary study.

Oral Medicine is a young dental specialty born almost a century ago and deals with orofacial conditions not directly attributable to the most prevalent tooth pathologies such as dental caries or periodontal diseases. Presentations may reflect local disease or orofacial manifestations of more widespread pathology affecting other parts of the body. Due to its recency as a distinct discipline and to heterogeneous global settings, Oral Medicine has not yet achieved a shared scope and definition, as well as a recognized status across the globe. The current report presents survey data gathered from Oral Medicine practitioners in Europe and Australia and aimed to identify practitioner characteristics including demographics, training, clinical and research activity. As expected, Oral Medicine clinical practice commonly deals with conditions such as immune-mediated disorders, potentially malignant disorders, oral mucosal infections and chronic pain disorders, but geographical heterogeneities are observed. The present data, representative of current clinical practice, are valuable in order to understand the evolution of Oral Medicine as a distinct discipline and should be taken into consideration in order to create or update postgraduate training curricula able to meet the needs of future practitioners and the communities they serve.

OBJECTIVE: In early 2020, the spread of coronavirus disease-2019 (COVID-19) led the World Health Organization to declare this disease a pandemic. Initial epidemiological data showed that patients with cancer were at high risk of developing severe forms of COVID-19. National scientific societies published recommendations modifying the patients’ breast cancer (BC) management to preserve, in theory, quality oncologic care, avoiding the increased risk of contamination. The Senology International Society (SIS) decided to take an inventory of the actions taken worldwide. This study investigates COVID-19-related changes concerning BC management and analyzes the will to maintain them after the pandemic, evaluating their oncological safety consequences. MATERIALS AND METHODS: SIS network members participated in an online survey using a questionnaire (Microsoft(®) Forms) from June 15(th) to July 31(st), 2020. RESULTS: Forty-five responses from 24 countries showed that screening programs had been suspended (68%); magnetic resonance imagines were postponed (73%); telemedicine was preferred when possible (71%). Surgeries were postponed: reconstructive (77%), for benign diseases (84%), and in patients with significant comorbidities (66%). Chemotherapy and radiotherapy protocols had been adapted in 28% of patients in both. Exception for telemedicine (34%), these changes in practice should not be continued. CONCLUSION: The SIS survey showed significant changes in BC’s diagnosis and treatment during the first wave of the COVID-19 pandemic, but most of these changes should not be maintained. Indeed, women have fewer severe forms of COVID-19 and are less likely to die than men. The risk of dying from COVID-19 is more related to the presence of comorbidities and age than to BC. Stopping screening and delaying treatment leads to more advanced stages of BC. Only women aged over 65 with BC under treatment and comorbidities require adaptation of their cancer management.

Objectives: To analyze psychological profiles, pain and oral symptoms in patients with oral lichen planus (OLP). Materials and methods: 300 patients with keratotic OLP (K-OLP; reticular, papular, plaque-like subtypes), 300 patients with predominant non-keratotic OLP (nK-OLP; erythematosus atrophic, erosive, ulcerative, bullous subtypes) and 300 controls were recruited in 15 universities. The number of oral sites involved and oral symptoms were recorded. The Numeric Rating Scale (NRS), Total Pain Rating Index (T-PRI), Hamilton Rating Scales for Depression and for Anxiety (HAM-D and HAM-A), Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were administered. Results: The OLP patients, especially the nK-OLP, showed higher scores in the NRS, T-PRI, HAM-D, HAM-A and PSQI compared with the controls (p-value

Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox–Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period.Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline.Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite.Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.

Background: The wellbeing of oral lichen planus patients (OLPs) may be strongly influenced by a poor quality of sleep (QoS) and psychological impairment. The aims were to analyze the prevalence of sleep disturbance, anxiety, and depression in OLPs and to validate the Pittsburgh Sleep Quality Index (PSQI) in OLPs. Methods: Three hundred keratotic OLPs (K-OLPs), 300 with predominant non-keratotic OLP (nK-OLPs), and 300 controls were recruited in 15 Italian universities. The PSQI, Epworth Sleepiness Scale (ESS), Hamilton Rating Scales for Depression and Anxiety (HAM-D and HAM-A), Numeric Rating Scale (NRS), and Total Pain Rating Index (T-PRI) were administered. Results: Oral lichen planus patients had statistically higher scores than the controls in the majority of the PSQI sub-items (p-values5) in K-OLPs and nK-OLPs, respectively. The PSQI’s validation demonstrated good internal consistency and reliability of both the total and subscale of the PSQI. Conclusions: The OLPs reported an overall impaired QoS, which seemed to be an independent parameter according to the regression analysis. Hence, clinicians should assess QoS in OLPs and treat sleep disturbances in order to improve OLPs management.

68Ga-labeled urea-based inhibitors of the prostate-specific membrane antigen (PSMA), such as 68Ga-PSMA-11, are promising small molecules for targeting prostate cancer (PCa). Although this radiopharmaceutical was produced mostly by means of manual synthesis and automated synthesis modules, a sterile cold kit was recently introduced. The aim of our study was to evaluate the image quality of 68Ga-PSMA-11 PET/CT (PSMA-PET) in a population of PCa patients after the injection of comparable activities of 68Ga-PSMA-11 obtained with the 2 different synthetic procedures. A secondary aim was to identify secondary factors that may have an impact on image quality and, thus, final interpretation. Methods: Two different groups of 100 consecutive PCa patients who underwent PSMA-PET were included in the study. The first group of patients was imaged with 68Ga-PSMA-11 obtained using synthesis modules, whereas the second group's tracer activity was synthesized using a sterile cold kit. All PET images were independently reviewed by 2 nuclear medicine diagnosticians with at least 2 y of experience in PSMA-based imaging and unaware of the patients' clinical history. The 2 reviewers independently rated the quality of each PSMA-PET scan using a 3-point Likert-type scale. In cases of discordance, the operators together reviewed the images and reached a consensus. Performance was evaluated on the basis of the expected biodistribution, lesion detection rate, and physiologic background uptake. Results: Overall, 104 of 200 (52%) PSMA-PET scans were positive for PCa-related findings. No significant differences in image quality between cold kits and synthesis modules were found (P = 0.13), although a higher proportion of images was rated as excellent by the observers for kits than for modules (45% vs. 34%). Furthermore, after image quality had been dichotomized as excellent or not excellent, multivariate regression analysis found several factors to be significantly associated with a not-excellent quality: an increase in patient age (+5 y: odds ratio [OR], 1.40; 95% confidence interval [CI], 1.12-1.75), an increase in patient weight (+5 kg: OR, 1.89; 95% CI, 1.53-2.32), an increase in 68Ga-PSMA-11 uptake time (+10 min: OR, 1.45; 95% CI, 1.08-1.96), and a decrease in injected activity (-10 MBq: OR, 1.28; 95% CI, 1.07-1.52). Conclusion: No significant differences were identified between the 2 groups of patients undergoing PSMA-PET; therefore, we were not able to ascertain any significant influences of tracer production methodology on final scan quality. However, increased patient age, increased patient weight, decreased injected activity, and increased 68Ga-PSMA-11 uptake time were significantly associated with an overall poorer image quality.

Purpose: To evaluate the role of F-18-Fluorothymidine (FLT) PET/CT in lymphoma patients with suspected recurrent or residual disease. Methods: Adult lymphoma patients presenting with positive or equivocal F-18-FDG PET/CT at end-treatment or follow-up were prospectively addressed to an additional F-18-FLT-PET/CT. SUV max and tumour-to-background ratios (TBRs) were recorded for the most avid lesion. Biopsy or, when not available, clinical or imaging assessment were employed as standard of reference. Results: Overall 52 patients were recruited. Histology was available in 20/52 patients (38%), proliferation-index (Ki-67) in 14/20. Disease was excluded in 13/52 patients (25%) (one reactive follicular hyperplasia, five reactive-inflammatory tissues, four reactive nodes, two nodal sarcoid-like and one non-specific peri-caecal finding). FDG and FLT scans were concordant in disease restaging in 34/52 patients (65%), whereas in 18/52 cases (35%) relevant discrepancies were recorded. SUV max and TBR were significantly higher in the disease versus the disease-free group, with both tracers (p = 0.0231 and 0.0219 for FDG; p = 0.0008 and 0.0016 for FLT). FLT-SUVmax demonstrated slightly better performance in discriminating benign from malignant lesions (ROC-AUC: 0.8116 and 0.7949 for FLT-SUV max and TBR; 0.7120 and 0.7140 for FDG). Optimal FLT-SUV max cut-offs were searched: three would lead to 95% sensitivity, 81% accuracy, and 39% specificity, whereas seven led to 100%, 41%, and 56% respectively. No statistically significant correlation was observed between the two FLT indices and Ki-67. Conclusions: According to our results in a clinical setting of recurrent or residual lymphoma, FLT is not significantly superior to FDG and it is unlikely that it will be employed independently. FLT may be restricted to a few specific cases, as complementary to standard FDG imaging, to confirm a diagnosis or to define a better target to biopsy. However, due to FLT suboptimal performance, many findings would remain inconclusive, requiring further diagnostic procedures and reducing the effectiveness of performing an additional FLT scan.

Introduction: The neuroanatomical substrate of stridor associated with Multiple System Atrophy (MSA) remains unclear. We evaluated stridor-related gray matter (GM) changes in MSA. Methods: 36 MSA patients underwent standardized nocturnal video-polysomnography and brain MRI. Differences in GM density between MSA patients with and without stridor and a sample of 22 matched healthy controls were evaluated with Voxel Based Morphometry protocol supplemented by a specific tool (SUIT) for analysing infratentorial structures. Results: Stridor was confirmed in 14 patients (10 MSA-cerebellar variant; 10 M; mean ± SD age = 61.6 ± 8.9years; disease duration = 5.2 ± 2.9years) and absent in 22 (11 MSA-cerebellar variant; 18 M; age = 61.4 ± 9.9years; disease duration = 4.8 ± 3.4years). Compared to MSA without stridor, patients with stridor showed higher GM density in the cerebellum (p < 0.05, corrected for the MSA-cerebellar variant and uncorrected when considering both MSA-variants) and lower in the striatum (p < 0.05, uncorrected). Conclusions: This preliminary study has demonstrated for the first time in MSA stridor-related GM changes in striatal and cerebellar regions. Abnormalities in these regions were previously reported in dystonic disorders affecting laryngeal muscles, suggesting the hypothesis that stridor pathophysiology is dystonia-related. These results need however to be confirmed in a larger sample of patients.

Persons with HIV (PWH) experience chronic pain and Post-Traumatic Stress Disorder (PTSD) at higher rates than the general population, and more often receive opioid medications to treat chronic pain. A known association exists between PTSD and substance use disorders, but less is known about the relationship between PTSD and risky opioid use among PWH taking prescribed opioid medications. In this observational study of PWH on long-term opioid medications for pain we examined associations between PTSD symptom severity based on the Post Traumatic Stress Disorder Checklist for DSM-5 (PCL-5, response range 0–80) and the following outcomes : 1) risk for opioid misuse (COMM score ≥13); 2) risky alcohol use (AUDIT score ≥8); 3) concurrent benzodiazepine prescription; and 4) morphine equivalent dose. Among 166 patients, 38 (23%) had a PCL-5 score over 38, indicating high PTSD symptom burden. Higher PCL-5 score (per 10 point difference) was associated with increased odds of opioid misuse (aOR 1.55; 95%CI: 1.31–1.83) and risky drinking (aOR: 1.28;1.07–1.52). No significant association was observed between PCL-5 score and benzodiazepine prescriptions or morphine equivalent dose. These findings suggest that when addressing alcohol and opioid use in PWH on long term opioid therapy, attention to PTSD symptoms is especially important given the higher risk for risky alcohol and opioid use among patients with this common comorbid condition.

Oral potentially malignant disorders (OPMDs) are associated with an increased risk of occurrence of cancers of the lip or oral cavity. This paper presents an updated report on the nomenclature and the classification of OPMDs, based predominantly on their clinical features, following discussions by an expert group at a workshop held by the World Health Organization (WHO) Collaborating Centre for Oral Cancer in the UK. The first workshop held in London in 2005 considered a wide spectrum of disorders under the term "potentially malignant disorders of the oral mucosa" (PMD) (now referred to as oral potentially malignant disorders: OPMD) including leukoplakia, erythroplakia, proliferative verrucous leukoplakia, oral lichen planus, oral submucous fibrosis, palatal lesions in reverse smokers, lupus erythematosus, epidermolysis bullosa, and dyskeratosis congenita. Any new evidence published in the intervening period was considered to make essential changes to the 2007 classification. In the current update, most entities were retained with minor changes to their definition. There is sufficient evidence for an increased risk of oral cancer among patients diagnosed with "oral lichenoid lesions" and among those diagnosed with oral manifestations of 'chronic graft-versus-host disease'. These have now been added to the list of OPMDs. There is, to date, insufficient evidence concerning the malignant potential of chronic hyperplastic candidosis and of oral exophytic verrucous hyperplasia to consider these conditions as OPMDs. Furthermore, due to lack of clear evidence of an OPMD in epidermolysis bullosa this was moved to the category with limited evidence. We recommend the establishment of a global research consortium to further study the natural history of OPMDs based on the classification and nomenclature proposed here. This will require multi-center longitudinal studies with uniform diagnostic criteria to improve the identification and cancer risk stratification of patients with OPMDs, link them to evidence-based interventions, with a goal to facilitate the prevention and management of lip and oral cavity cancer.

Radium-223 has demonstrated efficacy in improving overall survival (OS) and in delaying symptomatic skeletal-related events (SREs). Bone Health Agents (BHA), i.e. RANK ligand inhibitor (Denosumab) and bisphosphonate such as zoledronic acid, are indicated to prevent SREs without a clear survival benefit. SREs on patient health have a high impact and it is, therefore, important to consider the role of new therapies with BHA to better understand the involvement of combination therapy. The primary aim of this multicentric study is to assess OS in mCRPC patients treated with Radium-223 in combination with BHA.430 consecutive patients treated with Radium-223 alone or in combination with BHA, affected by mCRPC, from January 2015 to July 2019 in six Italian Nuclear Medicine Units, were included. Furthermore, data were collected at baseline, after every Radium-223 administration, and during follow-up, at 3 and 6 months and 1 year after the 6th cycle. Clinical data have been evaluated before starting treatment with Radium-223 and at the end of treatment and/or at progression. Patients who received target bone therapy with BHA before Radium-223 treatment together with patients who did not receive this therapy at all (NO BHA GROUP), were compared to patients treated with concomitant Radium-223 and BHA (BHA GROUP).In univariate models (At univariate analysis, our data showed that NO BHA GROUP and BHA GROUP differ in OS by 7 months (95%CI: (1-16.4)

Pharmaceutically purified oral cannabidiol (CBD) has been recently approved by the US Food and Drug Administration and European Medicines Agency as treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), which are severe and difficult-to-treat developmental and epileptic encephalopathies with onset in early childhood. This review will critically review the pharmacokinetic properties of CBD, the interactions with antiseizure and non-antiseizure medications, and the main tolerability and safety issues to provide guidance for its use in everyday practice. CBD is metabolized in the liver and can influence the activity of enzymes involved in drug metabolism. The best characterized drug-drug interaction is between CBD and clobazam. The most common adverse events include somnolence, gastrointestinal discomfort, and increase in serum transaminases. High-grade purified CBD oral solution represents an effective therapeutic option in patients with DS and LGS. The findings cannot be extrapolated to other cannabis-based products, synthetic cannabinoids for medicinal use and non-medicinal cannabis and CBD derivatives.

Objective Radium-223 (223Ra) has been approved for treatment in patients with metastatic castration-resistant prostatic cancer (mCRPC) and bone metastasis. This α-emitting radionuclide has a beneficial effect on pain and is also capable to increase overall survival (OS). Several studies evaluated the prognostic value of different biomarkers at baseline, such as serum values, imaging parameters or pain. To date, however, clinicians lack a validated and simple system to assess which patients will most likely benefit from 223Ra treatment. The 3-variable prognostic score (3-PS), proposed in a single-center study in 2017 classifies patients in five prognostic groups with a specific OS. This study aims to validate the 3-PS in a larger multicenter population. Methods Four hundred and thirty mCRPC patients treated with 223Ra from six different centers were analyzed. The 3-PS score consists of the collection of baseline hemoglobin, prostatic specific antigen and Eastern cooperative oncology group performance status and was initially applied to the whole population (total group). The score was then validated on the 338 patient’s subgroup (clean group) obtained by subtracting the 92 patients enrolled for the original study of the 3-PS score. This purified group served as further validation evidence. Results Statistical analysis showed that the 3-PS score was valid on the total group as well as in the clean group as the AUC estimated (0.74) falls within the CI of the AUC calculated on the validation sample (95% CI 0.66–0.82). Conclusion This study confirms the validity of the 3-PS score for mCRPC patients. This score is simple, noninvasive and affordable and can be easily used to select patients that will most probably complete 223Ra treatment. In addition, this tool provides an exact estimate of life expectancy in terms of OS.

We assessed associations between hazardous alcohol use and latent tuberculosis infection (LTBI) among adults living with human immunodeficiency virus (HIV) in Uganda. We compared tuberculin skin test positivity across medium, high, and very-high alcohol use levels, classified by AUDIT-C scores. In multivariable analysis, very high use was associated with LTBI (adjusted odds ratio 1.61, 95% confidence interval: 1.03–2.50).

A prior cluster randomized controlled trial (RCT) compared outcomes for a comprehensive school intervention (schoolMAX) to typical educational programming (services-as-usual [SAU]) for 103 children with autism spectrum disorder (ASD) without intellectual disability. The schoolMAX intervention was superior to SAU in improving social-cognitive understanding (emotion-recognition), social/social-communication skills, and ASD-related impairment (symptoms). In the current study, a range of demographic, clinical, and school variables were tested as potential moderators of treatment outcomes from the prior RCT. Moderation effects were not evident in demographics, child IQ, language, or ASD diagnostic symptoms, or school SES. Baseline externalizing symptoms moderated the outcome of social-cognitive understanding and adaptive skills moderated the outcome of ASD-related symptoms (no other comorbid symptoms or adaptive skills ratings moderated outcomes on the three measures). Overall, findings suggest that the main effects of treatment were, with two exceptions, unaffected by third variables.

Radium-223 prolongs overall survival (OS) and delays time to the first symptomatic skeletal events in patients with symptomatic metastatic castration-resistant prostate cancer (mCRPC). There is a lack of evidence on the safety and efficacy of Radium-223 treatment in the very elderly population. Aim of this multicentre study is to analyze mCRPC patients treated with Radium-223 in terms of OS and to assess whether there are differences between young and elderly, as well as to verify efficacy and safety in patients ≥ 75 years of age. 430 mCRPC patients of six Italian Centres were analyzed in this multicenter retrospective study. At baseline and after each cycle were collected clinical and diagnostic patients’ parameters. The whole cohort was divided into two groups based on the age of the patients (

People living with HIV (PLWH) have high levels of functional impairment due to pain, also called pain interference. Long-term opioid therapy (LTOT) is commonly prescribed for chronic pain among PLWH. We sought to better understand the predictors of pain interference, measured with the Brief Pain Inventory Interference subscale (BPI-I), among PLWH with chronic pain on LTOT. Using a prospective cohort of PLWH on LTOT we developed a model to identify predictors of increased pain interference over 1 year of follow up. Participants (n=166) were 34% female, 72% African American with a median age of 55 years, and 40% had severe pain interference (BPI-I ≥7). In multivariable models, substance use disorder, depressive symptoms, PTSD symptoms, financial instability, and higher opioid doses were associated with increased pain interference. Measures of behavioral health and socioeconomic status had the most consistent association with pain interference. In contrast, the biomedical aspects of chronic pain and LTOT—comorbidities, duration of pain—were not predictive of pain interference. PLWH with chronic pain on LTOT with lower socioeconomic status and behavioral health symptoms have higher risk of pain interference. Addressing the social determinants of health and providing access to behavioral health services could improve patients’ pain-related functional status.

Bone is the most common site of metastasis in metastatic castration-resistant prostate cancer (mCRPC), which is associated with pain and skeletal events. Radium-223 dichloride (Xofigo) is an alpha-emitting radioactive isotope that can specifically target bone lesions. Herein, we report the results of a retrospective analysis that documents our experience in the use of radium-223. Data from 63 patients (pts) with mCRPC who underwent radium-223 treatment from December 2015 to September 2017 were collected. Radium-223 (55 kBq/kg) was administered every 4 weeks for up to 6 cycles. The primary endpoint was OS. Radium-223 was administered as first line therapy in 11 pts, as second line in 19 pts, as third line in 16 pts and in successive lines in 17 pts; 42 pts out of 63 (67%) completed all six cycles. Within one month after the end of 6 cycles of radium-223, 15 pts out of 42 (35.7%) had achieved PR, 11 pts out of 42 (26.2%) had SD and 14 pts out of 42 (33.3%) had PD. Levels of pain decreased with progressive cycles of radium-223. After a minimum follow-up of 2 months and a maximum of 43 months, median OS was 15 months and median PFS was 8 months. The most frequent radium-223 related toxicity was low grade haematologic toxicity, predominantly G1-G2, that occurred halfway through treatment in about 75% of pts. The favourable results reported herein confirm that radium-223 can be considered well tolerated and effective in mCRPC, and is associated with significant decreases in pain. Bone is the most common site of metastasis in metastatic castration-resistant prostate cancer (mCRPC), which is associated with pain and skeletal events. Radium-223 dichloride (Xofigo) is an alpha-emitting radioactive isotope that can specifically target bone lesions. Herein, we report the results of a retrospective analysis that documents our experience in the use of radium-223. Data from 63 patients (pts) with mCRPC who underwent radium-223 treatment from December 2015 to September 2017 were collected. Radium-223 (55 kBq/kg) was administered every 4 weeks for up to 6 cycles. The primary endpoint was OS. Radium-223 was administered as first line therapy in 11 pts, as second line in 19 pts, as third line in 16 pts and in successive lines in 17 pts; 42 pts out of 63 (67%) completed all six cycles. Within one month after the end of 6 cycles of radium-223, 15 pts out of 42 (35.7%) had achieved PR, 11 pts out of 42 (26.2%) had SD and 14 pts out of 42 (33.3%) had PD. Levels of pain decreased with progressive cycles of radium-223. After a minimum follow-up of 2 months and a maximum of 43 months, median OS was 15 months and median PFS was 8 months. The most frequent radium-223 related toxicity was low grade haematologic toxicity, predominantly G1-G2, that occurred halfway through treatment in about 75% of pts. The favourable results reported herein confirm that radium-223 can be considered well tolerated and effective in mCRPC, and is associated with significant decreases in pain.

Rough-toothed dolphins (Steno bredanensis) are regularly present in continental shelf areas of the South-western Atlantic. However, there is little information on the natural history and ecology of these delphinids. This study evaluated the occurrence, habitat use and individual movements of the species in coastal waters off Rio de Janeiro, south-eastern Brazil. Data were obtained from boat surveys between August 2011 and May 2018, during which rough-toothed dolphins were sighted in 21 distinct events, predominantly in autumn and winter. The mean group size was 29 individuals. Rough-toothed dolphins were usually recorded 130 to 2300 m from the coast, between 7.6 and 28 m depths. In total, 115 individuals were catalogued through dorsal fin marks and 61 (53%) were resighted between one (47.5%) and four (9.8%) occasions. The interval between resightings ranged from seven to 2087 days (mean = 268). Agglomerative hierarchical clustering indicated 30 individuals (49.2%) in low degree, 12 (19.7%) in medium degree and 19 (31.1%) in high degree of site fidelity. Dolphins showed a higher frequency of low degree of habitat use, despite the presence of multiyear recaptures, which may be related to the prevalence of dolphin occurrence in autumn and winter, a large home range and/or the abundance and distribution of food resources. Dedicated surveys and regional collaboration are needed to evaluate the home range and population status of this species for their effective conservation. Our findings enhanced knowledge of this little studied species facing increasing anthropogenic threats in coastal waters off Rio de Janeiro.

Purpose The canonical isocitrate dehydrogenase 1 R132 mutation (IDH1 R132) is the most frequent mutation among IDH mutated gliomas. Non-canonical IDH1 mutations or IDH2 mutations are unusual and their clinical and biological role is still unclear.Methods We performed a systematic review and meta-analysis aimed to assess the clinical role of IDH non-canonical mutations. ResultsOverall, we selected 13 of 3513 studies reporting data of 4007 patients with a diagnosis of grade 2 and grade 3 including 3091 patients with a molecularly proven IDH1 or IDH2 mutation. Patients with non-canonical IDH1 mutations were younger and presented a higher DNA methylation level as compared to those with canonical IDH1 R132H alteration. The overall incidence of non-canonical IDH1 mutations was 7.9% (95% CI 5.4 – 10.7%) in patients with IDH mutated gliomas. There was no statistical difference in terms of incidence between patients with grade 2 or grade 3 glioma. Patients with non-canonical IDH mutations had a lower rate of 1p19q codeletion (risk difference: 31%, 95% CI 23 -38%) and presented a significantly prolonged survival (pooled-HR 0.47, 95% CI, 0.28-0.81) as compared to those with IDH1 R132H mutation. Conclusion Non-canonical IDH1 mutations occur in 7.9% of IDH mutated gliomas and recognize a specific subgroup of patients with an improved survival despite a lower rate of 1p19q codeletion. Data about the type of IDH mutation should be collected in clinical practice and within interventional trials as this could be a critical variable for an improved patient’s stratification and selection.

Antiangiogenic agents can induce a distinct MRI pattern in glioblastoma, characterized by a decrease in the contrast enhancement on T1‐weighted images and a simultaneous hyperintensity on T2‐weighted or fluid‐attenuated inversion recovery images.

Breast cancer (BC) is the second most common tumour spreading to the central nervous system (CNS). The prognosis of patients with CNS metastases depends on several parameters including the molecular assessment of the disease. Although loco-regional treatment remains the best approach, systemic therapies are acquiring a role leading to remarkable long-lasting responses. The efficacy of these compounds diverges between tumours with different molecular assessments. Promising agents under investigation are drugs targeting the HER2 pathways such as tucatinib, neratinib, pyrotinib, trastuzumab deruxtecan. In addition, there are several promising agents under investigation for patients with triple-negative brain metastases (third-generation taxane, etirinotecan, sacituzumab, immune-checkpoint inhibitors) and hormone receptor-positive brain metastases (CDK 4/5, phosphoinositide-3-kinase-mammalian target of rapamycin [PI3K/mTOR] inhibitors). Also, the systemic treatment of leptomeningeal metastases, which represents a very negative prognostic site of metastases, is likely to change as several compounds are under investigation, some with interesting preliminary results. Here we performed a comprehensive review focusing on the current management of CNS metastases according to molecular subtypes, site of metastases (leptomeningeal vs brain), and systemic treatments under investigation.

Simple Summary Nowadays, very few systemic agents have shown clinical activity in patients with glioblastoma, making the research of novel therapeutic approaches a critical issue. Fortunately, the availability of novel compounds is increasing thanks to better biological knowledge of the disease. In this review we want to investigate more promising ongoing clinical trials in both primary and recurrent GBM. Furthermore, a great interest of the present work is focused on novel trial design strategies. Abstract Management of glioblastoma is a clinical challenge since very few systemic treatments have shown clinical efficacy in recurrent disease. Thanks to an increased knowledge of the biological and molecular mechanisms related to disease progression and growth, promising novel treatment strategies are emerging. The expanding availability of innovative compounds requires the design of a new generation of clinical trials, testing experimental compounds in a short time and tailoring the sample cohort based on molecular and clinical behaviors. In this review, we focused our attention on the assessment of promising novel treatment approaches, discussing novel trial design and possible future fields of development in this setting.

Differential diagnosis between primary progressive aphasia (PPA) and Alzheimer’s disease (AD) could be difficult if based on clinical grounds alone. We evaluated the combination of proton MR spectroscopy of posterior cingulate cortex (PCC) and quantitative structural imaging asymmetries to differentiate PPA from AD patients. A greater left-lateralized temporo-parietal atrophy (higher accuracy for the PCC, 81.4%) and metabolic neurodegenerative changes in PCC (accuracy 76.8%) was demonstrated in PPA versus AD. The combined multiparametric approach increased the accuracy to 94%in the differential diagnosis between these two neurodegenerative diseases.

Meningiomas are the most common primary intracranial tumors. The majority of meningiomas are benign, but they can present different grades of dedifferentiation from grade I to grade III (anaplastic/malignant) that are associated with different outcomes. Radiological surveillance is a valid option for low-grade asymptomatic meningiomas. In other cases, the treatment is usually surgical, aimed at achieving a complete resection. The use of adjuvant radiotherapy is the gold standard for grade III, is debated for grade II and is not generally indicated for radically resected grade I meningiomas. The use of systemic treatments is not standardized. Here we report a review of the literature on the clinical, radiological and molecular characteristics of meningiomas, available treatment strategies and ongoing clinical trials.

Diffuse low-grade gliomas account for approximately 20% of all primary brain tumors, they arise from glial cells and show infiltrative growth without histological features of malignancy. Mutations of the IDH1 and IDH2 genes constitute a reliable molecular signature of low-grade gliomas and are the earliest driver mutations occurring during gliomagenesis, representing a relevant biomarker with diagnostic, prognostic, and predictive value. IDH mutations induce a neomorphic enzyme that converts alpha-ketoglutarate to the oncometabolite D-2-hydroxyglutarate, which leads to widespread effects on cellular epigenetics and metabolism. Currently, there are no approved molecularly targeted therapies and the standard treatment for low-grade gliomas consists of radiation therapy and chemotherapy, with rising concern about treatment-related toxicities. Targeting D-2-hydroxyglutarate is considered a novel attractive therapeutic approach for low-grade gliomas and the insights from clinical trials suggest that mutant-selective IDH inhibitors are the ideal candidates, with a favorable benefit/risk ratio. A pivotal question is whether blocking IDH neomorphic activity may activate alternative oncogenetic pathways, inducing acquired resistance to IDH inhibitors. Based on this rationale, combination therapies to enhance the antitumor activity of IDH inhibitors and approaches aimed at exploiting, rather than inhibiting, the metabolism of IDH-mutant cancer cells, such as poly (adenosine 5 '-diphosphate-ribose) polymerase inhibitors, are emerging from preclinical research and clinical trials. In this review, we discuss the pivotal role of IDH mutations in gliomagenesis and the complex interactions between the genomic and epigenetic landscapes, providing an overview of how, in the last decade, therapeutic approaches for low-grade gliomas have evolved.

BACKGROUND Chronic trauma of oral mucosa, resulting from repeated and persistent mechanical irritative action of an intraoral injury agent, has repeatedly been reported to be possibly implicated in the development of oral squamous cell carcinoma (OSCC). OBJECTIVES The present systematic review aimed to assess whether chronic mechanical trauma can be considered a risk factor for OSCC. DATA SOURCES PubMed, CENTRAL (Cochrane Central Register of Controlled Trials), Scopus; EMBASE, Web of Science. STUDY ELIGIBILITY CRITERIA Cohort studies comparing OSCC incidence among subjects with/without chronic mechanical trauma or case-control or cross-sectional studies comparing chronic mechanical trauma among subjects with/without OSCC. RESULTS Only one prospective case-control study fulfilled the inclusion criteria, but the quality of the evidence provided is not enough to define trauma as a risk factor for OSCC. The main limitation is the presence of only one case-control study at high risk of bias. In the absence of strong evidence supporting the role of trauma in OSCC, a thorough discussion on trauma and carcinogenesis has been performed. CONCLUSIONS Available evidence does not support an active role for chronic trauma in oral carcinogenesis, neither as promoter nor as progressor factor. Prospective cohort studies able to better assess trauma in OSCC are needed.