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Tumor mutation profiling from a blood sample, known as liquid biopsy, is a reality that has already been approved for some cancers. This molecular diagnostic method complements tissue biopsy but is less invasive and therefore more easily applied, especially during tumor evolution. Its use should allow detection of residual disease, evaluation of treatment response or resistance, and selection of targeted treatments. However, implementation of liquid biopsy in routine clinical practice is hindered by unsolved issues, one of which is the scarcity of circulating tumor DNA in blood samples drawn from peripheral veins. To address this problem, we propose minimally invasive selective venous sampling from the region of interest, as used for some hormonal studies and for mapping of endocrine tumors. Intuitively, selective sampling should improve the sensitivity of liquid biopsy by avoiding the dilution of tumor biomarkers that occurs in the peripheral circulation. We report three cases that illustrate the potential utility of selective liquid biopsy in complex clinical settings, providing implications for diagnosis and treatment as well as for monitoring over time, disease localization, identification of drug resistance, and differential diagnosis.

Background and Objectives The goal of this work was to investigate the natural history and outcomes after treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral amyloid angiopathy–related inflammation (CAA-ri). Methods This was a multicenter, hospital-based, longitudinal, prospective observational study of inpatients meeting CAA-ri diagnostic criteria recruited through the Inflammatory Cerebral Amyloid Angiopathy and Alzheimer's Disease βiomarkers International Network from January 2013 to March 2017. A protocol for systematic data collection at first-ever presentation and at subsequent in-person visits, including T1-weighted, gradient recalled echo–T2*, fluid-suppressed T2-weighted (fluid-attenuated inversion recovery), and T1 postgadolinium contrast-enhanced images acquired on 1.5T MRI, was used at the 3-, 6-, 12-, and 24-month follow-up. Centralized reads of MRIs were performed by investigators blinded to clinical, therapeutic, and time-point information. Main outcomes were survival, clinical and radiologic recovery, intracerebral hemorrhage (ICH), and recurrence of CAA-ri. Results The study enrolled 113 participants (10.6% definite, 71.7% probable, and 17.7% possible CAA-ri). Their mean age was 72.9 years; 43.4% were female; 37.1% were APOEε4 carriers; 36.3% had a history of Alzheimer disease; and 33.6% had a history of ICH. A history of ICH and the occurrence of new ICH at follow-up were more common in patients with cortical superficial siderosis at baseline (52.6% vs 14.3%, p < 0.0001 and 19.3% vs 3.6%, p < 0.009, respectively). After the first-ever presentation of CAA-ri, 70.3% (95% confidence interval [CI] 61.6%–78.5%) and 84.1% (95% CI 76.2%–90.6%) clinically recovered within 3 and 12 months, followed by radiologic recovery in 45.1% (95% CI 36.4%–54.8%) and 77.4% (95% CI 67.7%–85.9%), respectively. After clinicoradiologic resolution of the first-ever episode, 38.3% (95% CI 22.9%–59.2%) had at least 1 recurrence within the following 24 months. Recurrence was more likely if IV high-dose corticosteroid pulse therapy was suddenly stopped compared to slow oral tapering off (hazard ratio 4.68, 95% CI 1.57–13.93; p = 0.006). Discussion These results from the largest longitudinal cohort registry of patients with CAA-ri support the transient and potentially relapsing inflammatory nature of the clinical-radiologic acute manifestations of the disease and the effectiveness of slow oral tapering off after IV corticosteroid pulse therapy in preventing recurrences. Our results highlight the importance of differential diagnosis for spontaneous ARIA-like events in β-amyloid–driven diseases, including treatment-related ARIA in patients with Alzheimer disease exposed to immunotherapy drugs.

Introduction: Recent development of anti-βamyloid drugs for dementigenic neurodegenerative diseases treatment necessitates identification of target patients in MCI stage. Clinical framing also relies on the identification of brain hypometabolism patterns suggestive of neurodegeneration detected by PET-FDG. New MRI perfusion methods such pseudo Continuous Arterial Spin Labeling (pCASL) that do not require contrast medium make it possible adding perfusion data to biomarkers useful for diagnosis. A study to define an optimized protocol analysis was conducted, to investigate the correlation between FDG-PET and pCASL information. Material and Methods: FDG-PET, pCASL and structural MR images were acquired from 15 patients (mean age 76 yr.). To validate the present analysis with a standard group analysis, a sample of 111 healthy subjects FDG-PET scans underwent the same processing. Starting from a standard SPM12 pipeline and using customized Matlab routines, an optimized protocol of preprocessing and ROI-based analysis were defined. Results: PET, pCASL and MR were normalized in MNI space and smoothed. A better spatial normalization for pCASL scans was obtained using the source image. Considering PET/pCASL low spatial resolution, different methods of Gray Matter (GM) segmentation were compared. A mean tissue probability map of GM, obtained from 662 healthy elderly subjects in the same patients range of age, was considered and used also for PVE correction in PET scans. For patients, GM obtained using the template was compared with the segmented one from the T1-weighted image to evaluate the eventual atrophy degree or possible cortex reduction due to incomplete atlas-patient cortex superimposition. Standardized Uptake Values (SUVr) from FDG-PET and Cerebral Blood Flow values (CBFr) values form pCASL, both normalized on cerebellar mean values, were calculated for all the 88 cortical regions of the Automated Anatomic Labeling template version 3 (AAL3) and for the 22 macro-regions obtained by combining sub-areas of AAL3. Discussion: According to this optimized protocol, further analysis on images are now being conducted. They will lead to the investigation of correlation between SUVr and CBFr values in the 88 regions and in the 22 macro-regions through Pearson coefficients, histograms and pattern similarities. A validation of the present analysis with the standard spm12 one was also conducted.

Introduction: Multimodal neuroimaging techniques allow to adequately address diagnosis questions issued by clinicians and researchers about human brain behavior. Multimodality means combining different type of information coming from functional and morpho-structural images. This is particularly important in case of neurodegenerative diseases, starting at Mild Cognitive Impairment (MCI) stage, ending to the effective progression to dementia. Brain hypometabolism patterns detected by 18FDG-PET can be combined with hypoperfusion information that nowadays can be non-invasively acquired with new MRI functional sequences, such as pseudo Continuous Arterial Spin Labeling (pCASL). This may allow pCASL to easily become an additional biomarker for diagnosis of dementia. A joint PET-pCASL analysis tool, optimized in preprocessing, was developed and then validated versus the conventional SPM12 toolbox. Material and Methods: An optimized protocol of preprocessing and ROI-based analysis was defined, starting from an SPM12 standard pipeline and using customized Matlab routines. Volumes were all normalized in MNI space. Normalization parameters for pCASL images were defined on the high resolution source image, co-registered to the T1-weigthed image. A mean Gray Matter (GM) tissue probability map, obtained from 662 healthy subjects in the patients range of age, was used for GM segmentation and for PVE correction in 18FDG-PET scans. The developed tool was validated on 20 MCI patients (mean age 76 yr.), assessing outcomes agreement vs a standard SPM12 analysis, using a single subject versus group analysis. This validation was performed on 18FDG-PET data only, where a sample of 111 healthy subjects 18FDG-PET scans was available as control group. In the SPM analysis a general linear model was applied, age was considered as covariate, and significance level was set at 0.05 (FWE-corrected) at a cluster level. Indirect validation for pCASL data, where normative data and a control group were not available, was derived by cross-correlation with 18FDG-PET results. Results: 18FDG-PET Standardized Uptake Values (SUVr) and pCASL Cerebral Blood Flow values (CBFr), both normalized on cerebellar mean values, were calculated in 22 macro-regions obtained by combining sub-areas of the Automated Anatomic Labeling template version 3 (AAL3). For 18FDG-PET, regions that fall outside normality range were the same found to belong to signifi cant clusters in the SPM referenceoutcome. Thereby, a comparison between 18FDG-PET and pCASL relying on SUVr and CBFr values incorresponding regions can be assessed (Fig. 1b). Both regional values and relative ratios between region scan be evaluated. Discussion: The validation of our tool on 18FDG-PET will allow it to be used for further investigation of correlation between SUVr and CBFr values in the 22 macro-regions. References: [1] Y. H. K. Cha, M. A. Jog, Y. C. Kim, S. Chakrapani, S. M. Kraman, and D. J. J. Wang, “Regional correlation between resting state FDG PET and pCASL perfusion MRI,” J. Cereb. Blood Flow Metab., vol. 33, no. 12, pp.1909–1914, Dec. 2013. [2] L. Yan et al., “Regional association of pCASL-MRI with FDG-PET and PiB-PET in people at risk for autosomal dominant Alzheimer’s disease,” NeuroImage. Clin., vol. 17, pp. 751–760, 2017.

The presence of CBFA2T3‐GLIS2 fusion gene has been identified in childhood Acute Myeloid Leukemia (AML). In view of the genomic studies indicating a distinct gene expression profile, we evaluated the role of immunophenotyping in characterizing a rare subtype of AML‐CBFA2T3‐GLIS2 rearranged. Immunophenotypic data were obtained by studying a cohort of 20 pediatric CBFA2T3‐GLIS2‐AML and 77 AML patients not carrying the fusion transcript. Enrolled cases were included in the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) AML trials and immunophenotypes were compared using different statistical approaches. By multiple computational procedures, we identified two main core antigens responsible for the identification of the CBFA2T3‐GLIS2‐AML. CD56 showed the highest performance in single marker evaluation (AUC = 0.89) and granted the most accurate prediction when used in combination with HLA‐DR (AUC = 0.97) displaying a 93% sensitivity and 99% specificity. We also observed a weak‐to‐negative CD45 expression, being exceptional in AML. We here provide evidence that the combination of HLA‐DR negativity and intense bright CD56 expression detects a rare and aggressive pediatric AML genetic lesion improving the diagnosis performance.

Background and purpose: Glioblastoma (GBM) is the most aggressive and frequent subtype of all malignant gliomas. At the time of recurrence, therapeutic options are lacking. Ortataxel, a second-generation taxane was reported to be effective in pre-clinical and phase I clinical studies. The aim of this study was to evaluate a potential therapeutic activity of ortataxel in patients with GBM recurring after surgery and first line treatment. Methods: In this phase II study, according to a two stage design, adult patients with histologically confirmed GBM in recurrence after surgery or biopsy, standard radiotherapy and chemotherapy with temozolomide were considered eligible. Patients included were treated with ortataxel 75mg/m2 i.v. every 3weeks until disease progression. The primary objective of the study was to evaluate the activity of ortataxel in terms of progression free survival (PFS) at 6months after the enrollment. PFS, overall survival at 9months after the enrollment, objective response rate, compliance and safety were evaluated as secondary endpoints. Results: Between Nov 26, 2013 and Dec 12, 2015, 40 patients were recruited across six centres. The number of patients alive and free from progression at 6months after the enrollment, observed in the first stage was four (11.4%), out of 35 patients included in the analysis, below the minimum number of events (7 out of 33) required to continue the study with the second stage The most important toxicities were neutropenia and hepatotoxicity that occurred in 13.2% of patients and leukopenia that occurred in 15.8% of patients. Conclusion: Overall ortataxel treatment fail to demonstrate a significant activity in recurrent GBM patients. However in a limited number of patients the drug produced a benefit that lasted for a long time. Trial registration: This study is registered with ClinicalTrials.gov, number NCT01989884.

We prove that if a quasiconvex subset $X$ of a metric space $Y$ has finite Nagata dimension and is Lipschitz $k$-connected or admits Euclidean isoperimetric inequalities up to dimension $k$ for some $k$ then $X$ is isoperimetrically undistorted in $Y$ up to dimension $k+1$. This generalizes and strengthens a recent result of the third named author and has several consequences and applications. It yields for example that in spaces of finite Nagata dimension, Lipschitz connectedness implies Euclidean isoperimetric inequalities, and Euclidean isoperimetric inequalities imply coning inequalities. It furthermore allows us to prove an analog of the Federer-Fleming deformation theorem in spaces of finite Nagata dimension admitting Euclidean isoperimetric inequalities.