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Context The variability of the positive predictive value (PPV) represents a significant factor affecting the diagnostic performance of multiparametric magnetic resonance imaging (mpMRI). Objective To analyze published studies reporting mpMRI PPV and the reasons behind the variability of clinically significant prostate cancer (csPCa) detection rates on targeted biopsies (TBx) according to Prostate Imaging Reporting and Data System (PI-RADS) version 2 categories. Evidence acquisition A search of PubMed, Cochrane library’s Central, EMBASE, MEDLINE, and Scopus databases, from January 2015 to June 2020, was conducted. The primary and secondary outcomes were to evaluate the PPV of PI-RADS version 2 in detecting csPCa and any prostate cancer (PCa), respectively. Individual authors’ definitions for csPCa and PI-RADS thresholds for positive mpMRI were accepted. Detection rates, used as a surrogate of PPV, were pooled using random-effect models. Preplanned subgroup analyses tested PPV after stratification for PI-RADS scores, previous biopsy status, TBx technique, and number of sampled cores. PPV variation over cancer prevalence was evaluated. Evidence synthesis Fifty-six studies, with a total of 16 537 participants, were included in the quantitative synthesis. The PPV of suspicious mpMRI for csPCa was 40% (95% confidence interval 36–43%), with large heterogeneity between studies (I2 94%, p Conclusions Our meta-analysis underlines that the PPV of mpMRI is strongly dependent on the disease prevalence, and that the main factors affecting PPV are PI-RADS version 2 scores and prior biopsy status. A substantially low PPV for PI-RADS 3 lesions was reported, while it was still suboptimal in PI-RADS 4 and 5 lesions. Lastly, even if the added value of a systematic biopsy for csPCa is relatively low, this rate can improve patient risk assessment and staging. Patient summary Targeted biopsy of Prostate Imaging Reporting and Data System 3 lesions should be considered carefully in light of additional individual risk assessment corroborating the presence of clinically significant prostate cancer. On the contrary, the positive predictive value of highly suspicious lesions is not high enough to omit systematic prostate sampling.

Background: The optimal definition and prognostic significance of persistently elevated prostate-specific antigen (PSA) after salvage lymph node dissection (sLND) for node-only recurrent prostate cancer (PCa) remain unknown. Objective: To assess the definition and clinical implications of persistently elevated PSA after sLND for node-only recurrent PCa after radical prostatectomy. Design, setting, and participants: The study included 579 patients treated with sLND at 11 high-volume centers between 2000 and 2016. Outcome measurements and statistical analysis: We assessed the linear relationship between the first PSA after sLND and death from PCa. Different definitions of PSA persistence were included in a multivariable model predicting cancer-specific mortality (CSM) after surgery to identify the best cutoff value. We investigated the association between PSA persistence and oncologic outcomes using multivariable regression models. Moreover, the effect of early androgen deprivation therapy (ADT) after sLND was tested according to PSA persistence status and estimated risk of CSM. Results and limitations: We found an inverse relationship between the first PSA after sLND and the probability of cancer-specific survival. PSA persistence defined as first postoperative PSA ≥0.3 ng/ml provided the best discrimination accuracy (C index 0.757). According to this cutoff, 331 patients (57%) experienced PSA persistence. The median follow-up for survivors was 48 mo (interquartile range 27-74). After adjusting for confounders, men with persistently elevated PSA had higher risk of clinical recurrence (hazard ratio [HR] 1.61), overall mortality (HR 2.20), and CSM (HR 2.59; all p 10%. Conclusions: PSA persistence after sLND independently predicts adverse prognosis, with the best discrimination accuracy for CSM provided by a definition of PSA ≥ 0.3 ng/ml. We showed that when stratifying patients by final pathology results and PSA persistence status, early ADT use after sLND was beneficial only for patients with PSA persistence or with a calculated 5-yr risk of CSM of >10%, which could be useful as we await results from ongoing prospective trials. Patient summary: We found that for patients with prostate cancer who had lymph nodes removed after their cancer recurred, persistently elevated prostate-specific antigen (PSA) levels predict poorer prognosis. We showed that a PSA level of ≥0.3 ng/ml provides the best accuracy in identifying patients with worse prognosis. This may help to improve risk stratification after lymph node removal and allow physicians to optimize treatment strategies after surgery.

Patrizia Alvisi,1 Serena Arrigo,2 Salvatore Cucchiara,3 Paolo Lionetti,4 Erasmo Miele,5 Claudio Romano,6 Alberto Ravelli,7 Daniela Knafelz,8 Stefano Martelossi,9 Graziella Guariso,10 Salvatore Accomando,11 Giovanna Zuin,12 Costantino De Giacomo,13 Lucio Balzani,14 Monia Gennari,15 Marina Aloi3 On behalf of the SIGENP IBD Working Group 1Pediatric Gastroenterology Unit, Pediatric Department, Maggiore Hospital, Bologna, Italy; 2Pediatric Gastroenterology and Endoscopy Unit, G Gaslini Children’s Hospital, Genoa, Italy; 3Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy; 4Gastroenterology and Nutrition Unit, Meyer Children’s Hospital, Florence, Italy; 5Pediatric Department, Federico II University of Naples, Naples, Italy; 6Pediatric Gastroenterology, University of Messina, Messina, Italy; 7Gastroenterology and GI Endoscopy Unit, University Department of Pediatrics, Children’s Hospital, Brescia, Italy; 8Hepatology and Gastroenterology Unit, Bambino Gesù Hospital, Rome, Italy; 9Department of Pediatrics, Institute of Child Health, IRCSS Burlo Garofolo, Trieste, Italy; 10University of Padua, Padua, Italy; 11Pediatric Department, University of Palermo, G di Cristina Children’s Hospital, Palermo, Italy; 12Pediatric Unit, Buzzi Hospital, Milan, Italy; 13Pediatric Unit, Niguarda Hospital, Milan, Italy; 14Morgagni Hospital, Forlì, Italy; 15Emergency Pediatric Department, S Orsola Hospital, Bologna, Italy Background: Adalimumab (Ada) treatment is an available option for pediatric Crohn’s disease (CD) and the published experience as rescue therapy is limited.Objectives: We investigated Ada efficacy in a retrospective, pediatric CD cohort who had failed previous infliximab treatment, with a minimum follow-up of 6 months.Methods: In this multicenter study, data on demographics, clinical activity, growth, laboratory values (CRP) and adverse events were collected from CD patients during follow-up. Clinical remission (CR) and response were defined with Pediatric CD Activity Index (PCDAI) score ≤10 and a decrease in PCDAI score of ≥12.5 from baseline, respectively.Results: A total of 44 patients were consecutively recruited (mean age 14.8 years): 34 of 44 (77%) had active disease (mean PCDAI score 24.5) at the time of Ada administration, with a mean disease duration of 3.4 (range 0.3–11.2) years. At 6, 12, and 18 months, out of the total of the enrolled population, CR rates were 55%, 78%, and 52%, respectively, with a significant decrease in PCDAI scores (P2 years was negatively correlated with final PCDAI score (P

Background Despite the key importance of magnetic resonance imaging (MRI) parameters, risk classification systems for biochemical recurrence (BCR) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) are still based on clinical variables alone. Objective We aimed at developing and validating a novel classification integrating clinical and radiological parameters. Design, setting, and participants A retrospective multicenter cohort study was conducted between 2014 and 2020 across seven academic international referral centers. A total of 2565 patients treated with RP for PCa were identified. Outcome measurements and statistical analysis Early BCR was defined as two prostate-specific antigen (PSA) values of ≥0.2 ng/ml within 3 yr after RP. Kaplan-Meier and Cox regressions tested time and predictors of BCR. Development and validation cohorts were generated from the overall patient sample. A model predicting early BCR based on Cox-derived coefficients represented the basis for a nomogram that was validated externally. Predictors consisted of PSA, biopsy grade group, MRI stage, and the maximum diameter of lesion at MRI. Novel risk categories were then identified. The Harrel’s concordance index (c-index) compared the accuracy of our risk stratification with the European Association of Urology (EAU), Cancer of the Prostate Risk Assessment (CAPRA), and International Staging Collaboration for Cancer of the Prostate (STAR-CAP) risk groups in predicting early BCR. Results and limitations Overall, 200 (8%), 1834 (71%), and 531 (21%) had low-, intermediate-, and high-risk disease according to the EAU risk groups. The 3-yr overall BCR-free survival rate was 84%. No differences were observed in the 3-yr BCR-free survival between EAU low- and intermediate-risk groups (88% vs 87%; p = 0.1). The novel nomogram depicted optimal discrimination at external validation (c-index 78%). Four new risk categories were identified based on the predictors included in the Cox-based nomogram. This new risk classification had higher accuracy in predicting early BCR (c-index 70%) than the EAU, CAPRA, and STAR-CAP risk classifications (c-index 64%, 63%, and 67%, respectively). Conclusions We developed and externally validated four novel categories based on clinical and radiological parameters to predict early BCR. This novel classification exhibited higher accuracy than the available tools. Patient summary Our novel and straightforward risk classification outperformed currently available preoperative risk tools and should, therefore, assist physicians in preoperative counseling of men candidate to radical treatment for prostate cancer.

Objective: Significant efforts are currently being made to identify novel biomarkers for the diagnosis and risk stratification of prostate cancer (PCa). Metabolomics can be a very useful approach in biomarker discovery because metabolites are an important read-out of the disease when characterized in biological samples. We aimed to determine a metabolomic signature which can accurately distinguish men with clinically significant PCa from those affected by benign prostatic hyperplasia (BPH). Methods: We first performed untargeted metabolomics using ultrahigh-performance liquid chromatography tandem mass spectrometry on expressed prostatic secretion urine (EPS-urine) from 25 patients affected by BPH and 25 men with clinically significant PCa (defined as Gleason score ≥ 3 + 4). Diagnosis was histologically confirmed after surgical treatment. The EPS-urine metabolomic approach was then applied to a larger, prospective cohort of 92 consecutive patients undergoing multiparametric magnetic resonance imaging for clinical suspicion of PCa prior to biopsy. Results: We established a novel metabolomic signature capable of accurately distinguishing PCa from benign tissue. A metabolomic signature was associated with clinically significant PCa in all subgroups of the Prostate Imaging Reporting and Data System (PI-RADS) classification (100% and 89.13% of accuracy when the PI-RADS was in range of 1–2 and 4–5, respectively, and 87.50% in the more critical cases when the PI-RADS was 3). Conclusions: A combination of metabolites and clinical variables can effectively help in identifying PCa patients that might be overlooked by current imaging technologies. Metabolites from EPS-urine should help in defining the diagnostic pathway of PCa, thus improving PCa detection and decreasing the number of unnecessary prostate biopsies.

Modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine + nab-paclitaxel (GemNab) regimens represent a standard treatment in advanced pancreatic cancer (aPC). DPYD and UGT1A1 variants are relevant predictors of fluoropyrimidine and irinotecan-associated adverse events (AEs). Furthermore, data about the associations between polymorphisms in ABCB and CDA genes and GemNab-related toxicities are still controversial. The present study analyzes the association between DPYD, UGT, ABCB1, CDA variants, and AEs in aPC patients (pts) treated with mFOLFIRINOX or GemNab. Blood samples collected from 104 aPC pts treated with mFOLFIRINOX and 63 with GemNab were tested for DPYD c.1679T>G, IVS14+1G>A, c.2194G>A, c.2846A>T, UGT1A1*28, CDA c.79A>C, and ABCB1 c.1236C>T, c.2677G>T/A, c.3435C>T by real-time PCR and automatic sequencing. In mFOLFIRINOX cohort, DPYD IVS14+1GA genotype was associated with G4 hematological AEs, while the UGT1A1*28 significantly correlated with the risk of thrombocytopenia (p = 0.006). In the GemNab cohort, a significant association between CDA c.79CC and high-grade nausea was observed (p = 0.002). Moreover, the presence of at least a mutant allele in ABCB1 increased the risk of overall hematological AEs (p = 0.01), both further strengthened by the presence of CDA c.79CC (p = 0.0002). DPYD IVS14+1A allele is confirmed to be associated with fluoropyrimidine life-threatening toxicities, and UGT1A1*28 is related with a higher risk of hematologic AEs following irinotecan treatment. CDA c.79C and ABCB1 c.1236T, c.2677T/A, and c.3435T mutant alleles are predictive biomarkers of GemNab-related AEs. All these variants should be considered in aPC pts candidate to mFOLFIRINOX or GemNab treatments.

OBJECTIVES While the algorithm to diagnose celiac disease (CD) in children with elevated anti-transglutaminase IgA (TGA-IgA) titers (>10 times upper limit of normal, ULN) is well defined, the management of children with low TGA-IgA values represents a clinical challenge. We aimed to identify the diagnostic value of persistently low positive TGA-IgA titers in predicting CD in children. METHODS We retrospectively analyzed children with symptoms or signs of CD, not eligible for a no-biopsy approach. We included children with at least 2 TGA-IgA measurements, endomysial antibody (EMA) assessment and esophagogastroduodenoscopy with biopsies. TGA-IgA values were provided as multiples of ULN. Patients were classified in groups according to median TGA-IgA values: A (TGA-IgA>1 ≤ 5 × ULN; defined as "low-positive"), B (TGA-IgA > 5 < 10 × ULN; "moderate-positive"), and C (controls). RESULTS Data of 281 children were analyzed. Of 162 children in group A, CD was diagnosed in 142 (87.7%), whereas normal duodenal mucosa was found in 20. In group B, all 62 children (100%) received a CD diagnosis. Group C included 57 controls. EMA were undetectable in 31 (15%) of mucosal atrophy cases. On the receiver-operating characteristic curve (area under the curve = 0.910), a mean value of 1.7 ULN showed a sensitivity of 81.4% and specificity of 81.8% to predict mucosal damage. CONCLUSIONS Repeated low or moderate TGA-IgA values (

Abiraterone became a standard hormonal therapy for patients with metastatic castration-resistance prostate cancer (mCRPC). However, patients may experience primary resistance to treatment. To date, few predictive biomarkers of efficacy have been identified. Our aim was to investigate the association between the single nucleotide polymorphism (SNP) c.-362T>C in the CYP17A1 gene, and clinical outcome in mCRPC patients treated with abiraterone. mCRPC patients candidate to receive abiraterone were enrolled in the present retrospective pharmacogenetic study. Based on a literature selection, CYP17A1 rs2486758 (c.-362T > C) was selected and analysed by real-time PCR on genomic DNA extracted from whole blood. Univariate analysis was performed to test the association between the SNP and treatment-related clinical outcomes. Sixty mCRPC patients were enrolled in the present study. Patients carrying the mutant CYP17A1 c.-362CT/CC genotypes showed a shorter median progression-free survival (PFS) and prostate-specific antigen-PFS (PSA-PFS) compared to patients carrying the TT genotype (10.7 vs 14.2 months and 8 vs 16 months, respectively; p = 0.04). No association between the selected SNP and the overall survival was found. These findings suggest an association between CYP17A1 c.-362T>C polymorphism and poorer clinical outcome with abiraterone for mCRPC patients. However, further validations on larger cohort of patients are needed to confirm its role as a predictive biomarker for abiraterone resistance.

Prostate-specific membrane antigen (PSMA) imaging is characterized by superior accuracy compared to conventional imaging for identification of nodal and distant metastases in prostate cancer. The majority of international clinical guidelines recommend PSMA positron emission tomography/computed tomography for patients experiencing biochemical recurrence, even at low prostate-specific antigen values, to identify candidates for salvage therapies. However, its use in for primary staging is still not recommended.

Introduction Genetic and imaging studies demonstrate a link between vascular morphology and migraine with aura (MA). We examined the relationship between basilar artery (BA) curvature and MA in a population-based cohort of stroke-free participants. Methods This cross-sectional study included participants from the MRI substudy of the Northern Manhattan Study. Participants had structured migraine assessments at enrollment and underwent brain MR angiography. BA curvature was defined as the sum of the total BA horizontal deviation from midline at the distal tip, mid-pons, and vertebrobasilar junction, and was the primary independent variable in logistic regression analyses. BA measurements were obtained blinded to migraine status. We compared groups of all migraine vs no migraine, migraine without aura (MwoA) vs no migraine, and MA vs no migraine. Results Of 880 participants, 146 had MwoA and 32 had MA. Average BA curvatures were 15.2 ± 8.9 mm in non-migraineurs, 15.8 ± 9.3 mm in MwoA, and 18.5 ± 11.4 mm in MA. In an adjusted model, greater BA curvature was associated with MA (OR 1.042 per mm, 95% CI 1.006–1.080) but not with MwoA (OR 1.014 per mm, 95% CI 0.993–1.035), when compared to non-migraineurs. Conclusions Greater BA curvature was associated with MA. Given aura typically originates from the occipital cortex, understanding the physiopathology of this association may provide clues to migraine's underlying mechanisms and relationship with stroke.

Transcranial Doppler (TCD) ultrasound of the vertebrobasilar system offers a practical, non-invasive evaluation of the posterior circulation and may be helpful in the identification of cerebral vasospasm, intracranial vascular stenotic disease, and microembolus signal detection. Hemodynamics of the posterior circulation can be assessed using ultrasound in stroke and traumatic brain injury (TBI) and basilar artery flow characteristics are part of the complete TCD assessment for brain death. Cerebral autoregulation and vascular reactivity can offer insight into brain health in the posterior circulation, particularly in TBI. While anatomic limitations exist, size, patency, direction, and velocity of flow as well as microembolus detection are all feasible in the vertebrobasilar circulation using ultrasound.

Background The aim of this study was to define clusters of activity in a population-based cohort during the first 5 years after diagnosis in children with ulcerative colitis [UC] and to identify early prognostic risk factors. Methods All UC patients from the SIGENP IBD registry with a complete follow-up of at least 5 years were included. Active disease was defined every 6 months in the presence of at least one of the following: clinical activity [Paediatric Ulcerative Colitis Activity Index ≥ 35]; endoscopic activity [Mayo score ≥ 1]; faecal calprotectin > 250 µg/g; hospitalization; surgery; or treatment escalation. Formula-based clusters were generated based on four published questionnaire-based activity patterns in adults, plus one additional cluster. Results In total, 226 patients were identified. Forty-two [19%] had moderate–severe chronically active disease, 31 [14%] chronic–intermittent, 75 [33%] quiescent, 54 [24%] active disease in the first 2 years after the diagnosis, then sustained remission, and 24 [11%] a remission in the first 2 years then an active disease. Mild disease onset along with a lower clinical severity not requiring the use of corticosteroids at 6 months were related to a quiescent disease course at the next follow-up (logistic model area under the curve 0.86 [95% confidence interval 0.78–0.94]; positive predictive value 67%; negative predictive value 70%). Eight per cent of patients needed surgery, none in the quiescent group [p = 0.04]. Conclusions More than one-third of children with UC present with a chronically active or intermittent course during the first 5 years of follow-up. A significant group of patients has active disease in the first 2 years and then sustained remission. Interestingly, after initial treatment, one-third of patients have well-controlled disease throughout.

Objectives The gut-liver axis has been recently investigated in depth in relation to intestinal and hepatic diseases. Key actors are bile acid (BA) receptors, as farnesoid-X-receptor (FXR), pregnane-X-receptor (PXR), and G-protein-coupled-receptor (GPCR; TGR5), that control a broad range of metabolic processes as well as inflammation and fibrosis. The present study aims to investigate the impact of intestinal inflammation on liver health with a focus on FXR, PXR, and TGR5 expression. The strategy to improve liver health by reducing gut inflammation is also considered. Modulation of BA receptors in the inflamed colonic tissues of inflammatory bowel disease (IBD) pediatric patients is analyzed. Methods A dextran sodium sulphate (DSS) colitis animal model was built. Co-cultures with Caco2 and HepG2 cell lines were set up. Modulation of BA receptors in biopsies of IBD pediatric patients was assessed by real-time PCR and immunohistochemistry. Results Histology showed inflammatory cell infiltration in the liver of DSS mice, where FXR and PXR were significantly decreased and oxidative stress was increased. Exposure of Caco2 to inflammatory stimuli resulted in the reduction of BA receptor expression in HepG2. Caco2 treatment with dipotassium glycyrrhizate (DPG) reduced these effects on liver cells. Inflamed colon of patients showed altered FXR, PXR, and TGR5 expression. Conclusions This study strongly suggests that gut inflammation affects hepatic cells by altering BA receptor levels as well as increasing the production of pro-inflammatory cytokines and oxidative stress. Hence, reducing gut inflammation is needed not only to improve the intestinal disease but also to protect the liver.

INTRODUCTION AND OBJECTIVE:Previous studies on genitourinary malignancies have demonstrated a survival advantage for patients affected by high BMI, attributed to an inverse correlation between onco...

INTRODUCTIONAND OBJECTIVE: Docetaxel is widely used in metastatic castration-resistant prostate cancer (mCRPC), however its optimal use remains unclear. Biomarkers and prediction models assessing e...

Background and study aims Two scores have been implemented to standardize capsule endoscopic (CE) findings in patients with Crohn’s disease (CD): Lewis score (LS) and Capsule Endoscopy Crohnʼs Disease Activity Index (CECDAI). Both have limitations and are not well validated in the pediatric population. The aim of our study was to assess a new score (capsule endoscopy – Crohn’s disease index, CE-CD) in pediatric patients with CD and to compare it to preexisting scores. Patients and methods This was a double-center, retrospective study involving pediatric subjects with CD who underwent CE. Correlation analyses between CE-CD, endoscopy scores and noninvasive markers of disease activities were performed. The ability of different CE scores to predict clinical and endoscopic outcomes was evaluated with regression and survival analyses. Results A total of 312 subjects were analyzed. The CE-CD score showed a moderate (Pearson’s r = 0.581, P Conclusions The CE-CD score is a simple, reliable, reproducible, and predictive score for evaluation of small bowel inflammation in pediatric patients with CD. Prospective validation is needed to confirm the applicability of this new index in clinical practice.

INTRODUCTION AND OBJECTIVE:Cytoreductive radical prostatectomy (cRP) might be an option in oligometastatic prostate cancer (PCa). However, no preoperative risk tool is available to select candidate...

Introduction Non-alcoholic fatty liver disease (NAFLD), considered the leading cause of chronic liver disease in children, can often progress from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). It is clear that obesity is one of the main risk factors involved in NAFLD pathogenesis, even if specific mechanisms have yet to be elucidated. We investigated the distribution of intestinal bifidobacteria and lactobacilli in the stools of four groups of children: obese, obese with NAFL, obese with NASH, and healthy, age-matched controls (CTRLs). Material and methods Sixty-one obese, NAFL and NASH children and 54 CTRLs were enrolled in the study. Anthropometric and metabolic parameters were measured for all subjects. All children with suspected NASH underwent liver biopsy. Bifidobacteria and lactobacilli were analysed in children's faecal samples, during a broader, 16S rRNA-based pyrosequencing analysis of the gut microbiome. Results Three Bifidobacterium spp. (Bifidobacterium longum, Bifidobacterium bifidum, and Bifidobacterium adolescentis) and five Lactobacillus spp. (L. zeae, L. vaginalis, L. brevis, L. ruminis, and L. mucosae) frequently recurred in metagenomic analyses. Lactobacillus spp. increased in NAFL, NASH, or obese children compared to CTRLs. Particularly, L. mucosae was significantly higher in obese (p = 0.02426), NAFLD (p = 0.01313) and NASH (p = 0.01079) than in CTRLs. In contrast, Bifidobacterium spp. were more abundant in CTRLs, suggesting a protective and beneficial role of these microorganisms against the aforementioned diseases. Conclusions Bifidobacteria seem to have a protective role against the development of NAFLD and obesity, highlighting their possible use in developing novel, targeted and effective probiotics.

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

Introduction Cervical internal carotid artery (ICA) atherosclerotic plaque and stenosis is often asymmetric. We hypothesized that hyoid bone proximity to the ICA also may be asymmetric and may increase the risk of traumatic endothelial injury and accelerate atherosclerotic stenosis. Methods A retrospective cross-sectional and longitudinal cohort design evaluated consecutive adult patients at 3 hospitals who underwent repeat computed tomography angiography (CTA) of the neck 2 calendar years apart (01/2000–07/2017). ICA plaque thickness, luminal stenosis, and their progression over time were compared between side with the nearer hyoid wing (proximal side) to the further side (distal side). Results Sixty-six patients were included with a median age of 64y (IQR 53–73), 37 (56.1%) female, had a median hyoid-ICA distance of 3.06 mm (IQR 1.27–6.20 mm) and median difference between sides of 2.11 mm (IQR 0.70–3.97 mm). The median plaque thickness was 3.5 mm (IQR 2–4) and median stenosis was 10% (IQR 0–33%). Comparing the proximal to distal side, there was no difference in ICA plaque thickness (median 2.5 mm [IQR 1–4] vs. 3.0 mm [IQR 2–4], p = 0.366) or stenosis (7% [IQR 0–31%] vs. 12% [IQR 0–39%], p = 0.21). After a median follow-up of 1002 days (range 392–3397 days), there was no difference in the change in plaque thickness (0.5 cm [IQR 0–1] vs. 0.0 cm [IQR −0.5–0.5], p = 0.21) or stenosis (0% [IQR −2.5–13%] vs. 0% [IQR −6–5%], p = 0.34) between proximal and distal ICAs. Conclusions The presence and progression of atherosclerotic plaque and stenosis were unrelated to hyoid-ICA distance in this cross-sectional and longitudinal cohort study.

Hormone therapy is currently the mainstay in the management of locally advanced and metastatic prostate cancer. Degarelix (Firmagon), a gonadotropin-releasing hormone (GnRH) receptor antagonist differs from luteinizing hormone-releasing hormone (LHRH) agonists by avoiding “testosterone flare” and lower follicle-stimulating hormone (FSH) levels. The direct effect of degarelix and leuprolide on human prostate cancer cells was evaluated. In LNCaP, C4-2BMDVR, and CWR22Rv1 cells, degarelix significantly reduced cell viability compared with the controls (P ≤ 0.01). Leuprolide was stimulatory in the same cell lines. In C4-2B MDVR cells, degarelix alone or combined with abiraterone or enzalutamide reduced the AR-V7 protein expression compared with the control group. SCID mice bearing VCaP xenograft tumors were divided into 4 groups and treated with surgical castration, degarelix, leuprolide, or buffer alone for 4 weeks. Leuprolide slightly suppressed tumor growth compared with the vehicle control group (P > 0.05). Tumors in degarelix-treated mice were 67% of those in the leuprolide-treatment group but 170% larger than in surgically castrated ones. Measurements of intratumoral steroids in serum, tumor samples, or treated cell pellets by LC/MS confirmed that degarelix better decreased the levels of testosterone and steroidogenesis pathway intermediates, comparable to surgical castration, whereas leuprolide had no inhibitory effect. Collectively, our results suggested a selective mechanism of action of degarelix against androgen steroidogenesis and AR-variants. This study provides additional molecular insights regarding the mechanism of degarelix compared with GnRH agonist therapy, which may have clinical implications.

ObjectiveTo examine factors associated with disability following TIA and minor stroke, including poststroke complications such as stroke recurrence, major bleeding, and other adverse medical events.MethodsThe SOCRATES trial randomized patients with TIA/minor stroke (NIH Stroke Scale [NIHSS] score ≤5) within 24 hours of onset. We performed a post hoc analysis of factors associated with disability (modified Rankin Scale [mRS] score >1). TIA and minor stroke were analyzed separately. Patients with premorbid mRS >0 were excluded.ResultsAt 90 days, 687/3,663 (19%) patients with stroke were disabled; for TIA, 122/2,384 (5%) were disabled. In multivariate analyses, age, diabetes, and NIHSS were associated with disability in the stroke cohort, and age with disability in the TIA cohort. Postrandomization events (recurrent stroke, myocardial infarction, major bleeding, serious adverse events) were strongly associated with disability in both cohorts (stroke cohort: odds ratio [OR] 5.6, 95% confidence interval [CI] 4.5–6.9; TIA cohort: OR 14.8, 95% CI 9.9–22.0). Of the TIA patients who ended up disabled, 65% experienced a postrandomization event; for stroke patients who ended up disabled, 39% had a postrandomization event. Disability increased linearly with NIHSS score (p < 0.0001) and was greater in those with limb weakness (p < 0.0001).ConclusionsAfter TIA and minor stroke, subsequent stroke and medical complications are strongly associated with disability. In addition, even within a low range of baseline scores, the NIHSS is a powerful predictor of disability in minor stroke patients, with items scoring limb weakness particularly associated with subsequent disability.

Purpose: The aim of the present study is to investigate the synergic role of 68Ga-PSMA PET/MRI and 68Ga-DOTA-RM2 PET/MRI in PCa staging. Methods: Fifteen patients with biopsy-proven PCa underwent both 68Ga-PSMA PET/MRI and 68Ga-DOTA-RM2 PET/MRI within one month. TNM classification based on image findings was performed and semi-quantitative PET and quantitative MRI parameters were collected for each scan. Finally, DICE score between regions of interest manually segmented on the primary tumor on 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and on T2 MRI was computed. Results: All imaging modalities detected the primary PCa in 15 patients, with slight differences regarding the multifocality of intra-prostatic findings. Two patients presented seminal vesicles involvement on MRI, one of these was also detected by 68Ga-PSMA, with no uptake on 68Ga-DOTA-RM2 images. Regarding extra prostatic disease, 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and MRI resulted positive in 6, 2 and 4 patients at lymph-nodal level, respectively, and at bone level in 2, 0 and 1 patients, respectively, with 68Ga-PSMA PET detecting more lesions compared to 68Ga-DOTA-RM2 PET. The different findings detected by 68Ga-PSMA PET and 68Ga-DOTA-RM2 PET might reflect the complementary role of these radiotracers, as they detected different foci of intraprostatic disease, seminal vesicle invasion, lymph nodal and bone involvement. Conclusion: These preliminary results suggest a synergic role of 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and mpMRI in PCa characterization during the staging phase. (EudraCT: 2018-001034-18)

Background We examined sex differences in nonstenotic carotid plaque composition in patients with embolic stroke of undetermined source (ESUS). Methods and Results Patients with anterior circulation ischemic stroke imaged with neck computed tomographic angiography who met criteria for ESUS or had atrial fibrillation were identified. Patients with atrial fibrillation were included as a negative control. Semiautomated plaque quantification software analyzed carotid artery bifurcations. Plaque subcomponent (calcium, intraplaque hemorrhage [IPH], and lipid rich necrotic core) volumes were compared by sex and in paired analyses of plaque ipsilateral versus contralateral to stroke. Multivariate linear regressions tested for associations. Ninety‐four patients with ESUS (55% women) and 95 patients with atrial fibrillation (47% women) were identified. Men with ESUS showed significantly higher volumes of calcified plaque (63.9 versus 19.6 mm 3 , P 3 , P =0.008) and a IPH/lipid rich necrotic core ratio (0.17 versus 0.07, P =0.03) in carotid plaque ipsilateral to stroke side than women. The atrial fibrillation cohort showed no significant sex differences in plaque volumes ipsilateral to stroke. Multivariate analyses of the ESUS cohort showed male sex was associated with IPH ipsi (β=0.49; 95% CI, 0.11–0.87) and calcium ipsi (β=0.78; 95% CI, 0.33–1.23). Paired plaque analyses in men with ESUS showed significantly higher calcified plaque (63.9 versus 34.1 mm 3 , P =0.03) and a trend of higher IPH ipsi (9.4 versus 7.5 mm 3 , P =0.73) and lipid rich necrotic core ipsi (59.0 versus 48.4 mm 3 , P =0.94) volumes. Conclusions Sex differences in carotid plaque composition in ESUS suggest the possibility of a differential contribution of nonstenosing carotid plaque as a stroke mechanism in men versus women.

Transplant eligibility for hepatocellular carcinoma (HCC) is determined by the imaging identification of tumor burden within the Milan criteria. Transjugular intrahepatic portosystemic shunt(s) (TIPS) reduce portal hypertension but may impact HCC visualization. It was hypothesized that the presence of pretransplant TIPS would correlate with occult HCC and reduced survival. A single-center, retrospective, case control study was performed among liver transplant recipients with HCC (2000-2017). The primary endpoint was occult disease on explant pathology. Backward stepwise logistic regression was performed. The secondary endpoints disease-free survival (DFS) and overall survival (OS) were evaluated with Kaplan-Meier curves and Cox regression analysis. Of 640 patients, 40 had TIPS and more frequently exhibited occult disease (80.0% versus 43.1%; P

Introduction: Non-stenotic carotid plaque may be the cause of ischemic stroke in some patients with embolic stroke of undetermined source (ESUS). We examined sex-differences in carotid plaque composition in patients with ESUS. Methods: A retrospective cohort of anterior circulation acute ischemic stroke patients with CTA head/neck and meeting criteria for ESUS was identified. Carotid artery bifurcations (4cm segment) ipsilateral to the stroke were evaluated using a semi-automated segmentation software to measure total plaque volume and plaque subcomponents (calcium, intraplaque hemorrhage [IPH], and lipid rich necrotic core [LRNC]). Sex-differences in baseline vascular risk factors and plaque subcomponent volumes were tested by Mann-Whitney U tests or students t-tests for continuous variables and Fisher’s exact test for categorical variables. Associations of each plaque subcomponent were tested by multivariate linear regressions. Results: Of 94 patients, 55% were women. Mean age of the cohort was 65 years. Women had higher body mass indices than men (29.2 vs 26.3; p=0.02). There were no other significant differences in age or vascular risk factors between men and women. Overall plaque volume (p=0.001) was significantly greater in men as was the volume of calcification (p Conclusions: Sex-differences in carotid plaque composition in ESUS suggest the possibility of a differential contribution of non-stenotic carotid plaque to stroke mechanism in men versus women.

Background and Purpose: It is unknown when to start anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF). Early anticoagulation may prevent recurrent infarctions but may provoke hemorrhagic transformation as AF strokes are typically larger and hemorrhagic transformation-prone. Later anticoagulation may prevent hemorrhagic transformation but increases risk of secondary stroke in this time frame. Our aim was to compare early anticoagulation with apixaban in AF patients with stroke or transient ischemic attack (TIA) versus warfarin administration at later intervals. Methods: AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) was an open-label, randomized controlled trial comparing the safety of early use of apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized AIS ( Results: Although AREST ended prematurely after a national guideline focused update recommended direct oral anticoagulants over warfarin for AF, it revealed that apixaban had statistically similar yet generally numerically lower rates of recurrent strokes/TIA (14.6% versus 19.2%, P =0.78), death (4.9% versus 8.5%, P =0.68), fatal strokes (2.4% versus 8.5%, P =0.37), symptomatic hemorrhages (0% versus 2.1%), and the primary composite outcome of fatal stroke, recurrent ischemic stroke, or TIA (17.1% versus 25.5%, P =0.44). One symptomatic intracerebral hemorrhage occurred on warfarin, none on apixaban. Five asymptomatic hemorrhagic transformation occurred in each arm. Conclusions: Early initiation of anticoagulation after TIA, small-, or medium-sized AIS from AF does not appear to compromise patient safety. Potential efficacy of early initiation of anticoagulation remains to be determined from larger pivotal trials. Registration: URL: https://www.clinicaltrials.gov/ ; Unique identifier: NCT02283294.

Background Transition from pediatric to adult care of patients affected by Inflammatory Bowel Disease (IBD) is a critical step that needs specific care and multidisciplinary involvement. The aim of our study was to evaluate the outcome of the transition process of a cohort of IBD patients, exploring their readiness and the possible impact on quality of life. Methods This observational study followed transitioned IBD patients from pediatric to adult care. Transition was carried-out through combined visits, jointly performed by the pediatrician and the adult gastroenterologist. Clinical data were collected before and after transition. A subgroup of patients was submitted to an anonymous online questionnaire of 38 items based on the validated questionnaires TRAQ and SIBDQ within the first 6 months from the beginning of the transition process. Results Eighty-two patients with IBD were enrolled, with a mean age at transition of 20.2±2.7 years. Before transition, 40.2% of patients already had major surgery and 64.6% started biologics. At transition, 24% of patients were in moderate to severe active phase of their disease and 40% of them had already been treated with ≥ 2 biologics. The mean score of the TRAQ questionnaires collected is 3.4±1.5 and the mean score of SIBDQ is 53.9±9.8. A significant association was found between a TRAQ mean score > 3 and a SIBDQ > 50 (p=0.0129). Overall, 75% of patients had a positive opinion of the transition model adopted. Conclusions A strong association has been found between TRAQ and SIBDQ questionnaires, showing how transition readiness has a direct impact on the quality of life of the young adult with IBD.

Lenvatinib is a non-selective tyrosine kinase inhibitor (TKI) with high in vitro potency against vascular endothelial growth factor receptors. Although this drug is used to treat several cancer types, it is the most effective TKI used in patients with thyroid cancer. Lenvatinib is well tolerated and the most common adverse drug reactions can be adequately managed by dose adjustment. Particularly, blood pressure and cardiac function monitoring, as well as antihypertensive treatment optimization, may be required in patients treated with lenvatinib. Dose reduction should be taken into account in patients with body weight

Introduction: Tumor necrosis factor-α (TNF-α)-blocking agents are drugs approved for the treatment of inflammatory bowel diseases (IBDs). Infliximab and adalimumab are approved for the treatment of IBD in the pediatric setting with the improvement of therapeutic management. Biological agents, also in the pediatric population, can be administered either alone or in combination with immunomodulators. Their use has raised safety concerns regarding the risk of infections and malignancies.Areas covered: A broad review of the safety concerns for the use of anti-TNF-α drugs in children with IBD was performed, and information regarding the risk of infections and malignancies were updated, also in comparison with the safety of traditional drugs such as steroids and/or immunosuppressants.Expert commentary: Anti-TNF-α drugs have shown favorable safety profiles, and adalimumab treatment is associated with lower immunogenicity compared with infliximab. Heightened awareness and vigilant surveillance leading to prompt diagnosis and treatment are important for optimal management.

Introduction: A considerable proportion of patients are still found with nodal involvement when considering prostate (PCa), bladder (BCa) and renal cancer (RCC). This scenario is often related to poorer oncological outcomes, but evidence supporting this correlation remain scarce or controversial. Areas covered: A review was conducted to provide updated evidence in the field of pathological nodal involvement in PCa, BCa, and RCC. Nodal-staging process, role of lymphadenectomy and available therapeutic strategies were covered. Expert opinion: Nodal staging mostly relies on CT scan. FDG-PET for BCa and RCC and PSMA-PET for PCa have shown promising results, although some issues like availability and cost-effectiveness still need to be addressed. For PCa, pre-operative nomograms have almost completely replaced the need for imaging with nodal staging purposes. Still, the gold standard remains lymphadenectomy. The oncological benefit of LND is still not clear for PCa and RCC but is related to a better oncological outcome for BCa. For PCa the use of androgen deprivation therapy combined with radiotherapy, particularly in men with high risk of local recurrence, is supported. For BCa, the use of adjuvant chemotherapy is suggested. In regards to RCC, the oncological benefit of adjuvant therapies is still unclear.

Given the prolonged natural history of clinically localized, high-risk prostate cancer, there is a need for the identification of intermediate clinical endpoints (ICEs) to predict long-term overall survival (OS). To explore the role of novel potential ICEs based on clinical follow-up to predict long-term survival in patients with high-risk prostate cancer. Overall, 3507 patients treated at 12 tertiary referral centers between 1988 and 2016 were evaluated. Radical prostatectomy (RP) with extended pelvic lymph node dissection. The impact of biochemical recurrence (BCR) and clinical recurrence (CR) within 1, 3, 5, and 7yr after surgery on the risk of OS was evaluated in multivariable Cox regression analyses. In patients with BCR, the impact of progression to CR within 6mo and 1, 3, and 5yr on long-term OS was investigated. Discrimination was assessed using Harrell's c index. Median follow-up for survivors was 76mo. The 5- and 10-yr OS and cancer-specific survival rates were 94% and 81% versus 98% and 95%, respectively. On a time-varying multivariable analysis, BCR (hazard ratio [HR]: 1.02; 95% confidence interval [CI]: 1.00, 1.04) and CR (HR: 1.05; 95% CI: 1.03-1.07) emerged as predictors of OS (p

Context Pheochromocytomas and paragangliomas (PCC/PGL) are neuroendocrine tumors with discrete catecholamine profiles that cause incompletely understood metabolic and physiologic changes. Objective The objective was to evaluate relationships between plasma catecholamines, body weight, and hemoglobin A1c (HbA1c). We hypothesized that individual catecholamines would correlate negatively with weight and glucose control. Design A retrospective cohort study was performed (1999-2020). Wilcoxon rank-sum tests compared nonparametric, continuous variables; mixed-effect linear modeling (MEM) evaluated relationships between catecholamines and weight or HbA1c. The median study duration was 54.2 months [interquartile range (IQR) 19.0-95.1]. Setting Tertiary academic hospital. Patients 360 patients were identified prospectively by referral to our center for management or surveillance of PCC/PGL. The median age was 59 years (IQR 45-67) and 56.4% (n = 203) were female. Main outcome measures The primary and secondary outcomes were weight and HbA1c, respectively. Results On multivariable MEM, norepinephrine (P Conclusion Plasma norepinephrine and its metabolite directly correlate with HbA1c and inversely correlate with weight in PCC/PGL. After resection, declining normetanephrine levels correlate with improving HbA1c despite an increase in patient body weight. Persistently elevated catecholamines and decreasing weight are observed in MRD.

Introduction: Long-term monitoring for atrial fibrillation (AF) is recommended in patients, who have experienced a cryptogenic stroke (CS). Clinical trials have identified AF in ~30% of patients after 3 years of continuous monitoring with insertable cardiac monitors (ICMs). Hypothesis: In a real-world analysis from a large academic healthcare system, we sought to evaluate a CS population with ICMs and a) determine the yield of AF and subsequent initiation of anticoagulation; and b) identify the presence of other arrhythmias. Methods: We evaluated all CS patients who had received an ICM between October 2014 and April 2020. We manually reviewed all stored electrocardiograms that were automatically labeled as AF by the ICM and adjudicated them as either a) AF or b) other cardiac arrhythmia including premature atrial contractions (PAC), premature ventricular contractions (PVC), supraventricular tachycardia (SVT), or nonsustained ventricular tachycardia (NSVT). Results: A total of 84 CS patients with ICMs were included: 51% men, mean age 63 years, and mean CHA 2 DS 2 -VASc 4.1. Over a median follow-up duration of 15.7 months, there were 34 patients (40% of the cohort) who did not have any AF alerts. In the remaining 50 patients, there were 960 stored electrograms that were adjudicated. Only 154 recordings from 16 patients (19% of the entire cohort) were adjudicated as AF. Oral anticoagulation was initiated in all these patients with adjudicated AF. The remaining tracings, which had been automatically categorized by the ICM as AF alerts, represented 34 patients (40% of the cohort). These patients had other arrhythmias including frequent PACs or PVCs, SVT, or NSVT. Conclusions: Compared to clinical trials, our real-world assessment suggests that the yield of AF following CS is lower - approximately 20%. Our findings highlight the importance for reviewing device tracings given the high rates of false positive for AF. Further research to refine AF detection algorithms in ICMs is needed.

Given the substantial heterogeneity of stroke brain injury, there is a clear need for a biomarker that determines the degree of neuroaxonal injury across diverse stroke types. We evaluated whether blood neurofilament light (NFL), a major component of neuronal axons, would fulfill this purpose for patients with acute cerebral infarction (ACI, N=227), aneurysmal subarachnoid hemorrhage (aSAH, N=58) or non-traumatic intracerebral hemorrhage (ICH, N=29). We additionally validated our findings in two independent cohorts of patients with ICH (N=96 and N=54) given the scarcity of blood biomarker studies for this deadliest stroke type. Compared to healthy individuals (N=79 and 48 for the discovery and validation cohorts, respectively), NFL was higher for all stroke types. NFL associated with radiographic markers of brain tissue damage. It correlated with the extent of early ischemic injury in patients with ACI, hemorrhage severity in patients with aSAH, and intracranial hemorrhage volume in patients with ICH. In all patients, NFL independently correlated with scores from the NIH Stroke Scale, the modified Rankin Scale, and the Mini-Mental State Examination at blood draw, which respectively assess neurological, functional, and cognitive status. Furthermore, higher NFL concentrations independently associated with 3- or 6-month functional disability and higher all-cause mortality. These data support NFL as a uniform method to estimate neuroaxonal injury and forecast mortality regardless of stroke mechanism. As a prognostic biomarker, blood NFL has the potential to assist with planning supportive and rehabilitation services, and improving the efficiency of acute therapeutic drug and device trials, and of recovery trials.

Probiotics are living microorganisms, which, upon oral ingestion, may prevent antibiotic-associated diarrhea (AAD) through the normalization of an unbalanced gastrointestinal flora. The objective of this study was to evaluate the benefits of a probiotic combination (Limosilactibacillus reuteri LRE02-DSM 23878 and Lacticaseibacillus rhamnosus LR04-DSM 16605) on the prevention of AAD in an outpatient pediatric setting. Questionnaires were delivered to pediatricians by each patient/parent during the visits after antibiotics and probiotics treatment to monitor physiological parameters. The primary outcome of both groups (probiotics and no probiotics treated) was the evaluation of the prevalence of AAD between the two groups. Evaluation of stool consistency using the Bristol Stool Scale (BSS) score was performed, as well as the evaluation of AAD duration, frequencies of daily evacuation, and the beginning of diarrhea and weight loss during AAD in both groups and related to antibiotic categories. Results indicated that probiotics, at the recommended dosage of 1.2 × 109 CFU (Colony Forming Unit) per day for 30 days, are associated with lower rates of AAD and a decreased number of days with diarrhea, independent of the type of antibiotic used. Moreover, the use of probiotics resulted in a normal stool consistency in a shorter time period, as evaluated by the BSS.

Background PI3K pathway hyperactivation due to PIK3CA mutations contributes to endocrine resistance, and PIK3CA is one of the most frequently mutated genes in breast cancer (BC), occurring approximately 40 % of HR+, HER2- advanced BC (ABC). Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have changed the treatment landscape of HR+, HER2- ABC. Putative mechanisms of resistance to CDK4/6i have been identified, but limited data are available on PI3K deregulation. The present study evaluates the impact of PIK3CA mutations on CDK4/6i plus hormone therapy and evaluates potential characteristics that may suggest for a PI3K screening in patients with ABC. Methods ABC patients were enrolled, and 12 mL of blood were collected in EDTA tubes at baseline prior to CDK4/6i plus hormone therapy. Plasma was separated and circulating free DNA (cfDNA) was extracted. PIK3CA mutation analysis was performed on a ddPCR. Selected and analyzed mutations included: p.C420R, p.E542 K, p.E545A, p.E545D, p.E545G, p.E545K, p.Q546E, p.Q546R, p.H1047L, p.H1047R, p.H1047Y. Statistical analysis were performed to investigate the predictive power of such mutations and any association with clinical factors. Results Thirty patients were enrolled. PIK3CA mutation status at baseline was independently associated with shorter median PFS (7.44 vs 12.9 months, p = 0.01) in subject receiving CDK4/6i plus hormone therapy. PIK3CA mutations were found to be associated to Ki67 expression in primary lesions (p = 0.006). Moreover, the probability to find a PI3K mutation improved considering also the therapeutic management in previous lines of treatment (McFadden's R2 = 0.415, p = 0.004; AUC of the ROC curve = 0.914). Conclusion The findings of this pilot study suggest that the presence of a PI3K mutation in liquid biopsy correlates with a worse PFS in patients with ABC receiving CDK4/6i, and that liquid biopsy is a useful tool to suggests a better tailored pharmacological intervention.

Background and Purpose: Initial reports suggest a significant risk of thrombotic events, including stroke, in patients hospitalized with coronavirus disease 2019 (COVID-19). However, there is little systematic data on stroke incidence and mechanisms, particularly in racially diverse populations in the United States. Methods: We performed a retrospective, observational study of stroke incidence and mechanisms in all patients with COVID-19 hospitalized from March 15 to May 3, 2020, at 3 Philadelphia hospitals. Results: We identified 844 hospitalized patients with COVID-19 (mean age 59 years, 52% female, 68% Black); 20 (2.4%) had confirmed ischemic stroke; and 8 (0.9%) had intracranial hemorrhage. Of the ischemic stroke patients, mean age was 64 years, with only one patient (5%) under age 50, and 80% were Black. Conventional vascular risk factors were common, with 95% of patients having a history of hypertension and 60% a history of diabetes mellitus. Median time from onset of COVID symptoms to stroke diagnosis was 21 days. Stroke mechanism was cardioembolism in 40%, small vessel disease in 5%, other determined mechanism in 20%, and cryptogenic in 35%. Of the 11 patients with complete vascular imaging, 3 (27%) had large vessel occlusion. Newly positive antiphospholipid antibodies were present in >75% of tested patients. Of the patients with intracranial hemorrhage, 5/8 (63%) were lobar intraparenchymal hemorrhages, and 3/8 (38%) were subarachnoid hemorrhage; 4/8 (50%) were on extracorporeal membrane oxygenation. Conclusions: We found a low risk of acute cerebrovascular events in patients hospitalized with COVID-19. Most patients with ischemic stroke had conventional vascular risk factors, and traditional stroke mechanisms were common.

Atherosclerotic cardiovascular disease (ASCVD) events are the most common cause of death in the United States and for most individuals who experience these events, may be predicted by risk identification tools. ASCVD risk calculators enable a clinician-patient discussion and the presence of risk-enhancing factors may further inform decision-making with respect to preventive pharmacotherapy, especially statin prescription. In cases where the decision of whether to treat with medicine is unclear, coronary artery calcium scoring by computed tomography offers enhanced risk stratification and may allow both clinicians and patients to feel more at ease with the decision to withhold statin therapy. Despite this thoughtful approach, individual risk may still be underestimated. We present a case of a woman whose family history suggested increased short- and long-term ASCVD risk due to intracranial atherosclerosis, but whose tests suggested a more equivocal indication for treatment. Neither she nor her clinician appreciated the presence of significant enough risk to persevere through minor statin side effects for primary prevention, but she was lucky to have survived without appreciable harm from an acute cerebrovascular event and is now able to pursue an appropriate secondary preventive strategy. We discuss how exceptional characteristics may mislead clinicians, including misperception about lower risk due to gender, East Asian predisposition to intracranial more than coronary atherosclerosis, high levels of high density lipoprotein cholesterol (HDL-C), and CACS = 0.

Background and Purpose: Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT. Methods: Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death. Results: Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09–1.21]; P =0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32–1.34]; P =0.25) among noncarriers. There was no significant interaction by genotype for major ischemia ( P =0.36) or stroke ( P =0.33). Conclusions: This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00991029.

Objective Risk of early recurrent ischemic stroke in patients with atrial fibrillation may be high. ASA/AHA guidelines provide imprecise recommendations on the timing and anticoagulant choice for this indication. We assessed current opinions of stroke neurologists. Methods Case scenarios describing patients with acute ischemic stroke (AIS) due to paroxysmal atrial fibrillation (AF) were presented to US board-certified stroke neurologists in an internet-based questionnaire. Questions assessed timing and choice of anticoagulation for secondary stroke prevention, factors prompting earlier anticoagulation, reasons for specific anticoagulant choice, and alternatives to anticoagulation in ineligible patients. Open-ended comments were also solicited. Results Responses were available from 238/1239 stroke neurologists surveyed. In patients with small AIS without hemorrhagic transformation (HT), 51% elected to start anticoagulation within 96 hours. With increased stroke severity and asymptomatic HT, only 29% and 26% respectively chose to anticoagulate within 7 days. Few requested stability imaging before starting anticoagulation. With symptomatic HT the majority (79%) waited >14 days. 93% would anticoagulate earlier if left atrium/left atrial appendage or acute left ventricular thrombi, or mechanical heart valve were present. Direct oral anticoagulants (DOACs) were the preferred anticoagulation strategy (64%), and the remaining 38% preferred Warfarin. Aspirin was preferred by 57% in anticoagulation ineligible. Conclusion Apart from AIS with symptomatic HT, there is a remarkable lack of consensus among stroke neurologists regarding the timing of anticoagulation for secondary stroke prevention in patients with AIS due to PAF. DOACs are the preferred anticoagulation strategy. More studies are required to clarify anticoagulant management in this patient population.

INTRODUCTION AND OBJECTIVE:Single-nucleotide polymorphisms (SNPs) are the most common genetic alterations and SNPs in DNA repair genes, such as BRCA1/2, have a relationship with a variety of cancer...