Clinical activity after fingolimod cessation: disease reactivation or rebound?

BACKGROUND AND PURPOSE: There is debate as to whether the apparent rebound after fingolimod discontinuation is related to the discontinuation itself or whether it is due to the natural course of highly active multiple sclerosis (MS). Our aim was to survey the prevalence of severe reactivation and rebound after discontinuation of fingolimod in a cohort of Italian patients with MS. METHODS: Patients with relapsing-remitting MS who were treated with fingolimod for at least 6 months and who stopped treatment for reasons that were unrelated to inefficacy were included in the analysis. RESULTS: A total of 100 patients who had discontinued fingolimod were included in the study. Fourteen patients (14%) had a relapse within 3 months after fingolimod discontinuation, and an additional 12 (12%) had a relapse within 6 months. According to this study's criteria, 10 patients (10%) had a severe reactivation. Amongst these patients, five (5%) had a reactivation that was considered to be a rebound. CONCLUSIONS: The present study showed that more than 26% of patients are at risk of having a relapse within 6 months after fingolimod discontinuation. Nevertheless, the risk of severe reactivations and rebound is lower than has been previously described.

Delayed luminescence induced by complex domains in water and in TEOS aqueous solutions.

Many recent studies on water have conjectured a complex structure composed of hydrogen bonded low- and high-density domains. In this work the structure of pure water and aqueous solutions of silica gel (TEOS) has been investigated by using delayed luminescence, which has previously shown a significant increase in aqueous salt solutions where low-density domain formation is expected. Photon emission shows an Arrhenius trend with an activation energy in water-TEOS solutions larger than in pure water and salt-water solutions. Moreover, delayed photon emission decay shows an intrinsic lifetime of about 5 µs both in solutions and in pure water that, along with secondary lifetimes induced by the presence of TEOS, could be related to the formation of different domains.

Association between maternal serum high mobility group box 1 levels and pregnancy complicated by gestational diabetes mellitus.

BACKGROUND AND AIMS: Gestational diabetes mellitus (GDM), is characterized by chronic, low-grade subclinical inflammation with altered production of cytokines and mediators. Recently, a new protein acting as a "danger signal", high mobility group box 1 (HMGB1), that migrates quickly during electrophoresis, has been identified. The aim of our study was to analyze serum levels of HMGB1 in pregnant women, with or without GDM, in the third trimester of pregnancy to evaluate correlation with insulin resistance and other risk factors for GDM. METHODS AND RESULTS: Seventy five pregnant women positive to the 75 g oral glucose tolerance test (OGTT) were included in the study group and 48 pregnant women who were negative to the screening test, were randomly selected using a computer-generated randomisation table. A significant positive univariate correlation was observed between serum HMGB1 levels, HOMA-IR index, glycaemia values at OGTT and pre-pregnancy BMI. Moreover, logistic regression analysis showed that serum HMGB1 was independent linked to GDM. CONCLUSION: Our study demonstrated that HMGB1, a marker of chronic inflammation, is associated to GDM and insulin resistance level, in the third trimester of pregnancy.

High mobility group protein B1: a new biomarker of obesity in pregnant women?

Obesity is associated with an increased risk of an adverse pregnancy outcome. The aim of this study was to analyze the serum levels of high mobility group protein B1 (HMGB1) in obese pregnant women, to assess the role of this protein in the pathogenesis of this disease and to evaluate its possible function as a diagnostic marker for obesity-related complications in obese women. Study participants were randomly selected, from a cohort of pregnant women afferent to our department. A total of 120 women were enrolled in this study: 60 pregnant women had normal body mass index (BMI) and 60 women resulted obese. Pre-pregnancy BMI, weight increase and HMGB1 levels were evaluated for each pregnant woman enrolled. Matching serum HMGB1 levels in two groups, our data evidenced higher levels in the obese women, with a statistically significant difference (p = 0.0023). A significant positive univariate correlation was observed between serum HMGB1 levels and BMI in obese women. HMGB1 serum levels may therefore represent a predictive marker of disease in pregnant women (r = 20.9 and p = 0.0001). Further studies are needed in order to validate the role of this cytokine, with the aim of making it possible to use in clinical practice not only for diagnostic purposes, but especially for the early recognition of complications related to it.

Role of psa levels and pathological stadiation before radiation therapy in predicting mp-MRI results in patients with prostate cancer recurrence after radical prostatectomy.

OBJECTIVE: To evaluate PSA value in mp-MRI results prediction, analyzing patients with high (GS≥8, pT≥3, pN1) and low grade (GS<8, pT<3, pN0) Prostate Cancer (PCa). MATERIALS AND METHODS: One hundred eighty-eight patients underwent 1.5-Tmp-MRI after Radical Prostatectomy (RP) and before Radiotherapy (RT). They were divided into 2 groups: A and B, for patients with biochemical recurrence (BCR) and without BCR but with high local recurrence risk. Considering Gleason Score (GS), pT and pN as independent grouping variables, ROC analyses of PSA levels at primary PCa diagnosis and PSA before RT were performed in order to identify the optimal cut-off to predict mp-MRI result. RESULTS: Group A and B showed higher AUC for PSA before RT than PSA at PCa diagnosis, in low and high grade tumors. For low grade tumors the best AUC was 0.646 and 0.685 in group A and B; for high grade the best AUC was 0.705 and 1 in group A and B, respectively. For low grade tumors the best PSA cut-off was 0.565-0.58ng/mL in group A (sensitivity, specificity: 70.5%, 66%), and 0.11-0.13ng/mL in B (sensitivity, specificity: 62.5%, 84.6%). For high grade tumors, the best PSA cut-off obtained was 0.265-0.305ng/mL in group A (sensitivity, specificity: 95%, 42.1%), and 0.13-0.15ng/mL in B (sensitivity, specificity: 100%). CONCLUSION: Mp-MRI should be performed as added diagnostic tool always when a BCR is detected, especially in high grade PCa. In patients without BCR, mp-MRI results, although poorly related to pathological stadiation, still have a good diagnostic performance, mostly when PSA>0.1-0.15ng/mL.

From eDNA to decisions using a multi-method approach to restoration planning in streams.

Reintroduction efforts are increasingly used to mitigate biodiversity losses, but are frequently challenged by inadequate planning and uncertainty. High quality information about population status and threats can be used to prioritize reintroduction and restoration efforts and can transform ad hoc approaches into opportunities for improving conservation outcomes at a landscape scale. We conducted comprehensive environmental DNA (eDNA) and visual encounter surveys to determine the distribution of native and non-native aquatic species in two high-priority watersheds to address key uncertainties-such as the distribution of threats and the status of existing populations-inherent in restoration planning. We then used these occurrence data to develop a menu of potential conservation actions and a decision framework to benefit an endangered vertebrate (foothill yellow-legged frog, Rana boylii) in dynamic stream systems. Our framework combines the strengths of multiple methods, allowing managers and conservation scientists to incorporate conservation science and site-specific knowledge into the planning process to increase the likelihood of achieving conservation goals.

Direct magnetic resonance (MR) shoulder arthrography: posterior approach under ultrasonographic guidance and abduction (PAUGA).

PURPOSE: This study was undertaken to assess the reliability of the posterior approach under ultrasonographic guidance (PAUGA), with the arm abducted, before performing direct magnetic resonance (MR) arthrography of the shoulder. MATERIALS AND METHODS: A total of 111 (82 men, 29 women; mean age, 24 years) underwent direct MR arthrography of the shoulder. Patients were enrolled because of glenohumeral instability (n=71), chronic shoulder pain (n=25), suspicion of rotator cuff tear (n=13) and adhesive capsulitis (n=2). Patients were placed in the lateral position, on the contralateral side to that being examined; the arm of the shoulder undergoing the examination was placed in slight internal rotation with the hand under the contralateral armpit. A gadolinium-based solution was injected into the articular capsule under cryoanaesthesia and sonographic guidance. A posterior approach was systematically applied. For each patient, the number of injection attempts, room time, complications and pain, as recorded on a 10-point visual analogue scale (VAS), were noted. For quantitative parameters (room time and pain intensity), the mean and standard deviation (SD) were calculated. RESULTS: Direct MR arthrographies were performed successfully in all patients; no immediate or late major complications were observed. Fourteen patients (12.6%) reported temporary and self-limiting compromise of arm movements, and 13 patients (11.7%) reported a vagal reaction not requiring medication. In 102 cases (92%), the injection was successful at the first attempt, whereas in the remaining nine cases (8%), needle repositioning without any additional puncture was required to obtain clear sonographic depiction of the position of the needle tip. Mean room time was 7.2±1.4 min. Mean pain intensity was 3.2±0.4 on the 10-point VAS scale. CONCLUSIONS: PAUGA is a reliable and rapid technique that is well tolerated by patients and easy for the radiologist to perform.

Dynamic contrast-enhanced MR evaluation of prostate cancer before and after endorectal high-intensity focused ultrasound.

PURPOSE: The authors sought to determine the diagnostic performance of dynamic contrast-enhanced magnetic resonance (DCE-MR) imaging in the evaluation of prostate cancer before and after transrectal high-intensity focused ultrasound (HIFU) treatment. MATERIALS AND METHODS: We analysed 25 patients with prostate cancer. The prostate-specific antigen (PSA) value was evaluated 1, 4 and 6 months after treatment. DCE-MR imaging was performed the day prior to and 1, 4 and 6 months after HIFU treatment. Transrectal prostate biopsies were obtained at the time of diagnosis and 6 months after treatment. RESULTS: Before treatment, intraglandular lesions were considered to be potential sites of neoplasm and subsequently confirmed as sites of prostate adenocarcinoma in all 25 patients based on prostatespecific antigen (PSA) values and histological examinations (rho=1; p<0.001). Using histology as the gold standard, DCE-MR imaging displayed 100% sensitivity, 100% specificity, 100% positive predictive value and 100% negative predictive value before treatment. After HIFU treatment, DCE-MR imaging showed 100% sensitivity and 96% specificity. CONCLUSIONS: DCE-MR imaging can be used to visualise prostate adenocarcinoma. Several morphological and postgadolinium modifications in the follow-up DCE-MR images after HIFU treatment were also observed.

Impact of adipose tissue distribution on prostate cancer recurrence after radical prostatectomy.

OBJECTIVE: The aim of our study is to correlate the CT adipose tissue distribution and recurrence risk of Prostatic Cancer (PCa) after Radical Prostatectomy (RP). Furthermore, we evaluated the association of adipose tissue and PCa aggressiveness. MATERIALS AND METHODS: We identified two groups of patients based on presence (group A) and absence (group B or control group) of Bio-chemical Recurrence (BCR) after RP. A semi-automatic function able to recognize the typical attenuation values of adipose tissue was used for sub-cutaneous (SCAT), visceral (VAT), total (TAT) and periprostatic (PPAT) adipose tissues. For both groups of patients, a descriptive analysis of continuous variables and categorical variables was performed. RESULTS: After comparing between groups, a statistically significant difference was found for VAT (p<0.001) and for VAT/TAT ratio (p=0.013). No statistically significant correlation was found for PPAT and SCAT, even if higher values were found in patients with high grade tumors. CONCLUSION: This study confirms visceral adipose tissue as a quantitative imaging parameter related to oncological risk of PCa recurrence development, and the role of abdominal fat distribution measured with CT before RP as an important tool to predict the PCa recurrence risk, particularly in patients with high grade tumors.

Radiofrequency ablation of renal cell carcinoma in patients with a solitary kidney: a retrospective analysis of our experience.

PURPOSE: This study was done to evaluate the feasibility and safety of radiofrequency ablation (RFA) of renal cell carcinomas (RCCs) in patients with solitary kidney. MATERIALS AND METHODS: Seven patients (two men, five women; age range 52-70 years; mean age 59.7 years) were treated under computed tomography (CT) and ultrasound (US) guidance. Three patients had single lesions, and the remaining four had multiple lesions. Seventeen lesions (4 cortical, 13 exophytic, maximum diameter range 12-40 mm, mean 21.0 mm) not located close to the renal pelvis were treated. CT or magnetic resonance (MR) imaging follow-up studies were obtained for all patients at the end of the procedure and at 1, 3, 6 and 12 months; serum creatinine was also monitored. RESULTS: Ten ablation sessions were performed. In two patients, a perinephric haematoma was detected, and one of these patients had two episodes of self-limiting haematuria. Contrast-enhanced CT and MR imaging at the end of the procedure and at 1 month demonstrated 100% technical success; these results were confirmed at 3, 6 and 12 month. Fisher's test comparing serum creatinine obtained 1 day before and 1 day after the procedure showed no case of acute renal failure (mean serum creatinine 24 h before the procedure 1.02 mg/dl; mean serum creatinine 24 h after the procedure 0.95 mg/dl; p=0.114; not significant). Serum creatinine at follow-up was always within the normal range. CONCLUSIONS: Radiofrequency ablation in the solitary kidney is a safe and effective procedure for treating RCC.

MR imaging of rectal cancer before and after chemoradiation therapy.

PURPOSE: This study was done to determine the diagnostic accuracy of magnetic resonance (MR) imaging in patients with rectal carcinoma by comparing post-chemoradiation MR imaging with pathological specimens. MATERIALS AND METHODS: We enrolled 39 patients with locally advanced rectal cancer. All patients received chemoradiation therapy before surgery and neoadjuvant chemoradiation therapy followed by MR imaging. MR images were analysed by a team of two expert radiologists unaware of the clinical and histopathological findings. RESULTS: Following neoadjuvant chemoradiation therapy, the analysis of MR images showed 23 (59%) patients with a rectal disease staged ≤T2 and 16 (41%) with a disease staged >T2. Post-treatment histological staging (TNM) revealed 13 patients with a disease >T2 and 26 patients with a disease ≤T2. Cohen's kappa to measure concordance between post-chemoradiation MR staging and histological response showed 83.6% concordance for disease confined to the serosa (≤T3): concordance was 97.22% for disease ≤N1 and 33.33% for disease >N1. CONCLUSIONS: MR imaging is critical for discovering T3 disease; moreover, morphological MR imaging does not always provide the opportunity to discern small residual cancer cells hidden in fibrotic tissue that could cause involvement of circumferential resection margin (CRM) on histology.

The role of multiparametric mri in the diagnosis of local recurrence after radical prostatectomy and before salvage radiotherapy.

PURPOSE: Assess multiparametric-MRI (mp-MRI) diagnostic accuracy in the detection of local recurrence of Prostate Cancer (PCa) after Radical Prostatectomy (PR) and before Radiation Therapy (RT). MATERIALS AND METHODS: A total of 188 patients underwent 1.5-T mp-MRI after RP before RT. Patients were divided into two groups: with biochemical recurrence (group A) and without but with high risk of local recurrence (group B). Continuous variables were compared between two groups using T-Student; categoric variables were analyzed using Pearson chi-square. ROC analysis was performed considering PSA before RT, ISUP, pT and pN as grouping variables. RESULTS: PCa recurrence (reduction of PSA levels after RT) was 89.8% in the group A and 80.3% in the group B. Comparing patients with and without PCa recurrence, there was a significant difference in PSA values before RT for group A and for PSA values before RT and after RT for group B. In group A, there was a significant correlation between PSA before RT and diameter of recurrence and between PSA before RT and time spent before recurrence. The mp-MRI diagnostic accuracy in detecting PCa local recurrence after RP is of 62.2% in group A and 38% in group B. DWI is the most specific MRI-sequence and DCE the most sensitive. For PSA = 0.5 ng/ml, the AUC decreases while sensitivity and accuracy increase for each MRI-sequence. For PSA = 0.9 ng/ml, DCE-AUC increases significantly. CONCLUSION: mp-MRI should always be performed before RT when a recurrence is suspected. New scenarios can be opened considering the role of DWI for PSA ≤ 0.5 ng/ml.

Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy.

Infantile neuroaxonal dystrophy, INAD, is a severe progressive psychomotor disorder with infantile onset and characterized by the presence of axonal spheroids throughout the central and peripheral nervous systems. A subset of INAD patients shows also brain iron accumulation which represents instead the distinctive feature of the idiopathic neurodegeneration with brain iron accumulation, NBIA. These diseases share the same causative gene, PLA2G6, encoding iPLA2-VIA, a calcium-independent phospholipase. Mutations that lead to a complete absence of protein are associated with a severe INAD profile, while compound heterozygous mutations with possibly a residual protein activity are instead associated with the less severe NBIA phenotype. Here we describe two INAD patients both with an unusually rapid disease progression and a peculiar neuroradiological presentation in one of them. Compound heterozygosity for a large intragenic deletion and a nonsense mutation was found in one of them while the other is carrying two novel splice-site mutations. Breakpoint-sequence analysis suggests a non-allelic-homologous-recombination (NAHR) event, probably underlying the rearrangement. These findings, while supporting the genotype-phenotype correlation already observed in INAD patients, provide the first sequence characterization of a genomic rearrangement in PLA2G6 gene, thus orienting the search for missing mutant alleles in PLA2G6 related diseases.

Differentiation of normal and neoplastic bone tissue in dynamic gadolinium-enhanced magnetic resonance imaging: validation of a semiautomated technique.

PURPOSE: This study was undertaken to clinically validate the accuracy of a semiautomated software tool for analysing the enhancement curve in focal malignant bone lesions. MATERIALS AND METHODS: Twenty-three patients affected by cancer with malignant focal bone lesions underwent dynamic gadolinium-enhanced magnetic resonance (MR) imaging using the following protocol: T1-weighted turbo spin-echo sequences (time to repeat [TR] 600 ms, time to echo [TE] 8.6 ms, field of view [FOV] 40x40 cm) before and after intravenous injection of gadolinium-containing contrast agent. Image postprocessing was performed using the software DyCoH. Each region of interest (5x5 pixels), drawn to include the area of the lesion with the highest values of the area under the curve map, was analysed to obtain time-intensity curves and relative perfusion parameters: time to peak (TTP), peak intensity (PI), slope (60-s slope), intensity at 60 s after contrast agent injection (60-s I) and final intensity (FI). RESULTS: Data were obtained by analysing 86 malignant lesions and 86 apparently normal bone regions. PI, 60-s slope, 60-s I and FI were significantly different between neoplastic and apparently normal (p<0.001) samples. Sensitivity, specificity and accuracy were, respectively, 94%, 93% and 94% at a PI threshold of 100 (signal-to-noise ratio), with positive and negative predictive values of 93% and 94%. At a threshold value of 0.85 for 60-s slope, sensitivity and specificity values were both 91%. CONCLUSIONS: The semiautomated technique we report appears to be accurate for identifying neoplastic tissue and for mapping perfusion parameters, with the added value of a consistent measurement of perfusion parameters on colour-coded maps.

Reversible Electrochemotherapy (ECT) as a Treatment Option for Local RCC Recurrence in Solitary Kidney.

A 61-year-old female underwent a right radical nephrectomy and a left nephron sparing surgery in 2014 due to renal cell carcinoma. A renal cell carcinoma local recurrence, 28 mm in size, centrally located in the left kidney was treated using cryoablation in 2016. In November 2018, computed tomography (CT) scan showed three nodules (maximum size 15 × 11 mm) in the left kidney, and CT-guided needle biopsy was performed. For multifocal recurrence and the anatomical site of these three nodules, a simultaneous reversible electrochemotherapy treatment was performed in April 2019. At 6-month CT control, no evidence of residual disease was found. Electrochemotherapy could be used to treat locoregional renal cell carcinoma recurrence when other ablative techniques are not suitable. LEVEL OF EVIDENCE: Level 4, Case Report.

Spatial memory of body linear displacement: what is being stored?

The ability to evaluate traveled distance is common to most animal species. Head trajectory in space is measured on the basis of the converging signals of the visual, vestibular, and somatosensory systems, together with efferent copies of motor commands. Recent evidence from human studies has shown that head trajectory in space can be stored in spatial memory. A fundamental question, however, remains unanswered: How is movement stored? In this study, humans who were asked to reproduce passive linear whole-body displacement distances while blindfolded were also able to reproduce velocity profiles. This finding suggests that a spatiotemporal dynamic pattern of motion is stored and can be retrieved with the use of vestibular and somesthetic cues.

Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis.

BACKGROUND: Patients with a microscopically visible deletion of the distal part of the long arm of chromosome 1 have a recognisable phenotype, including mental retardation, microcephaly, growth retardation, a distinct facial appearance and various midline defects including corpus callosum abnormalities, cardiac, gastro-oesophageal and urogenital defects, as well as various central nervous system anomalies. Patients with a submicroscopic, subtelomeric 1qter deletion have a similar phenotype, suggesting that the main phenotype of these patients is caused by haploinsufficiency of genes in this region. OBJECTIVE: To describe the clinical presentation of 13 new patients with a submicroscopic deletion of 1q43q44, of which nine were interstitial, and to report on the molecular characterisation of the deletion size. RESULTS AND CONCLUSIONS: The clinical presentation of these patients has clear similarities with previously reported cases with a terminal 1q deletion. Corpus callosum abnormalities were present in 10 of our patients. The AKT3 gene has been reported as an important candidate gene causing this abnormality. However, through detailed molecular analysis of the deletion sizes in our patient cohort, we were able to delineate the critical region for corpus callosum abnormalities to a 360 kb genomic segment which contains four possible candidate genes, but excluding the AKT3 gene.

Radiofrequency versus microwave ablation for treatment of the lung tumours: LUMIRA (lung microwave radiofrequency) randomized trial.

The LUMIRA trial evaluated the effectiveness of radiofrequency (RFA) and microwave ablation (MWA) in lung tumours ablation and defining more precisely their fields of application. It is a controlled prospective multi-centre random trial with 1:1 randomization. Fifty-two patients in stage IV disease (15 females and 37 males, mean age 69 y.o., range 40-87) were included. We randomized the patients in two different subgroups: MWA group and RFA group. For each group, we evaluated the technical and clinical success, the overall survival and complication rate. Inter-group difference was compared using Chi-square test or Fisher's exact test for categorical variables and one-way ANOVA test for continuous variables. For RFA group, there was a significant reduction in tumour size only between 6 and 12 months (p value = 0.0014). For MWA group, there was a significant reduction in tumour size between 6 and 12 months (p value = 0.0003) and between pre-therapy and 12 months (p value = 0.0215). There were not significant differences between the two groups in terms of survival time (p value = 0.883), while the pain level in MWA group was significantly less than in RFA group (1.79 < 3.25, p value = 0.0043). In conclusion, our trial confirms RFA and MWA are both excellent choices in terms of efficacy and safety in lung tumour treatments. However, when compared to RFA therapy, MWA produced a less intraprocedural pain and a significant reduction in tumour mass.