A multimodal investigation of cerebellar integrity associated with high-risk cannabis use.

With legalization efforts across the United States, cannabis use is becoming increasingly mainstream. Various studies have documented the effects of acute and chronic cannabis use on brain structure and cognitive performance, including within the frontal executive control network, but little attention has been given to the effects on the cerebellum. Recent evidence increasingly points to the role of the cerebellum in various nonmotor networks, and the cerebellum's expression of cannabinoid receptors may pose particular vulnerabilities to the consequences of cannabis use. Using a combined approach of resting-state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), the present study aims to assess how cannabis use relates to the cerebellum's intrinsic functional connectivity and underlying white matter structure and whether these properties are associated with craving or severity of cannabis use. Resting-state fMRI and DTI data, as well as self-reports of substance use history, were analyzed from a sample of 26 adults at risk for cannabis use disorder (CUD) and an age- and sex-matched comparison group of 25 cannabis-naïve adults (control). Results demonstrated that individuals at risk for a CUD showed key differences in cerebellar functional connectivity, with specific impacts on the dorsal attention and default mode networks. In addition, group differences in white matter were localized to the middle cerebellar peduncle (MCP), with a relationship between lower MCP diffusivity and higher levels of self-reported craving. These findings lend further support to the cerebellum's role in key cognitive networks and potential consequences for substance use disorders.

APOLLO 11 Project, Consortium in Advanced Lung Cancer Patients Treated With Innovative Therapies: Integration of Real-World Data and Translational Research.

INTRODUCTION: Despite several therapeutic efforts, lung cancer remains a highly lethal disease. Novel therapeutic approaches encompass immune-checkpoint inhibitors, targeted therapeutics and antibody-drug conjugates, with different results. Several studies have been aimed at identifying biomarkers able to predict benefit from these therapies and create a prediction model of response, despite this there is a lack of information to help clinicians in the choice of therapy for lung cancer patients with advanced disease. This is primarily due to the complexity of lung cancer biology, where a single or few biomarkers are not sufficient to provide enough predictive capability to explain biologic differences; other reasons include the paucity of data collected by single studies performed in heterogeneous unmatched cohorts and the methodology of analysis. In fact, classical statistical methods are unable to analyze and integrate the magnitude of information from multiple biological and clinical sources (eg, genomics, transcriptomics, and radiomics). METHODS AND OBJECTIVES: APOLLO11 is an Italian multicentre, observational study involving patients with a diagnosis of advanced lung cancer (NSCLC and SCLC) treated with innovative therapies. Retrospective and prospective collection of multiomic data, such as tissue- (eg, for genomic, transcriptomic analysis) and blood-based biologic material (eg, ctDNA, PBMC), in addition to clinical and radiological data (eg, for radiomic analysis) will be collected. The overall aim of the project is to build a consortium integrating different datasets and a virtual biobank from participating Italian lung cancer centers. To face with the large amount of data provided, AI and ML techniques will be applied will be applied to manage this large dataset in an effort to build an R-Model, integrating retrospective and prospective population-based data. The ultimate goal is to create a tool able to help physicians and patients to make treatment decisions. CONCLUSION: APOLLO11 aims to propose a breakthrough approach in lung cancer research, replacing the old, monocentric viewpoint towards a multicomprehensive, multiomic, multicenter model. Multicenter cancer datasets incorporating common virtual biobank and new methodologic approaches including artificial intelligence, machine learning up to deep learning is the road to the future in oncology launched by this project.

Here's the Story: Narrative Ability and Executive Function in Autism Spectrum Disorder.

Background: Difficulties with narrative have been reported in individuals diagnosed with autism spectrum disorder (ASD), but the role of executive function on narrative ability has not been examined in ASD. In this study, we aimed to (1) examine whether narrative abilities of ASD children differed from neurotypical (NT) children who did not differ in age, sex, and IQ; and (2) investigate relations between executive function and narrative ability in ASD children. Method: Narratives were elicited from 64 ASD children and 26 NT children using a wordless picture book and coded to derive several aspects of narrative ability such as propositions, evaluative devices, and self-repairs. Executive functions (specifically, inhibition and working memory) were measured using both experimenter-administered assessment and parent-report measures. Results: Compared to NT children, ASD children produced fewer propositions but did not differ in their use of evaluative devices and self-repairs during narrative production. Greater inhibitory challenges related to more self-repairs involving repetition of story elements, whereas working memory did not relate to any of the measures of narrative ability among ASD children. Conclusions: This study revealed that narratives by verbally fluent ASD children were shorter and less complex than those by NT children but did not differ in the specific features of narratives. Furthermore, although ASD children did not make more self-repairs than NT children, difficulty with inhibition was related to more self-repairs, indicating more dysfluent narrative production in ASD children, which has implications for intervention.

Mytomicin-C, Metronomic Capecitabine, and Bevacizumab in Patients With Unresectable or Relapsed Pseudomyxoma Peritonei of Appendiceal Origin.

INTRODUCTION: Pseudomyxoma peritonei (PMP) is a rare, slow growing tumor, traditionally considered chemoresistant. The only curative approach is cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC). At disease relapse, or in patients with inoperable disease at diagnosis, no standard treatment has been defined, though nonrandomized series showed promising results with fluoropyrimidine-based regimens. PATIENTS AND METHODS: We conducted a prospective study in patients with relapsed or unresectable PMP and confirmed disease progression at baseline. Patients received MMC (7 mg/m2 every 6 weeks, up to a maximum of 4 cycles) plus metronomic capecitabine (625 mg/sqm/day b.i.d.) and bevacizumab (7.5 mg/kg every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), overall response rate according to RECIST v1.1 criteria, serum markers response and safety. RESULTS: Fifteen patients were included. At a median follow-up of 26.1 months (IQR, 17.7-49.6), median PFS was 17.9 months (95% CI, 11.0-NE), with 1-year PFS and OS rates of 73% and 87%. Safety profile was manageable, with only 13% G3/G4 treatment-related adverse events. CONCLUSION: Metronomic capecitabine, bevacizumab, and MMC are an active regimen in advanced and progressive PMP and favorably compares with historical series.

A preliminary randomized, controlled trial of executive function training for children with autism spectrum disorder.

LAY ABSTRACT: Executive function, which is a set of thinking skills that includes stopping unwanted responses, being flexible, and remembering information needed to solve problems, is a challenge for many children on the autism spectrum. This study tested whether executive function could be improved with a computerized executive function training program under the guidance of a coach who reinforced the use of executive function skills. Seventy children with autism spectrum disorder from age 7 to 11 years of age participated in the study. They were randomly assigned to receive training or to a waiting group. The tests most likely to determine whether the training may be effective were chosen from a larger battery before the study started and included one task measuring brain responses, two measures of executive function in the lab, and a parent questionnaire. Changes in social functioning and repetitive behaviors were also explored. All children assigned to training completed the program and families generally reported the experience was positive. Brain responses of the training group changed following training, but not within the waiting group during a similar time period. Children who received training did not exhibit behavioral changes during the two the lab-based tasks. Parent report on questionnaires indicated that neither group showed a significant change in their broad use of executive function in other settings. Yet, children who received training were reported to have fewer restricted and repetitive behaviors following training. These initial findings suggest that short executive function training activities are feasible and may improve some functioning of school-aged children on the autism spectrum.

Clinical Impact and Prognostic Role of Triglyceride to High-Density Lipoprotein Cholesterol Ratio in Patients With Chronic Coronary Syndromes at Very High Risk: Insights From the START Study.

Background: Several studies have reported that the combination of high TG and low HDL-C, as simplified by the TG/HDL-C ratio, was a predictor of cardiovascular disease independent of LDL-C level. Nevertheless, poor data are available on the predictive role of TG/HDL-C ratio in very high risk (VHR) patients with chronic coronary syndromes (CCS). Methods: Using the data from the STable Coronary Artery Diseases RegisTry (START) study, an Italian nationwide registry, we assessed the association between the TG/HDL-C ratio and baseline clinical characteristics, pharmacological treatment, and major adverse cardio-cerebrovascular events (MACCE) at 1 year in a large cohort of CCS patients at VHR. Results: VHR patients with both TG and HDL-C levels available were grouped in tertiles of TG/HDL-C ratio: low (TG/HDL-C ratio <2, n = 967), middle (TG/HDL-C ratio 2-3.3, n = 1,071) and high (TG/HDL-C ratio >3.3, n = 1,028). At 1 year from enrolment, 232 (7.6%) patients presented a MACCE, with a higher incidence in the higher tertile, even though not statistically significant (6.0, 8.2, and 8.4% in the low, middle and high tertile, respectively; p = 0.08). At multivariable analysis, the TG/HDL-C ratio in tertiles did not result an independent predictor of the MACCE (p = 0.29) at 1-year follow-up (HR: 1.30; 95% CI: 0.93-1.82; p = 0.12 middle vs. lower tertile, and HR: 1.22; 95% CI: 0.87-1.72; p = 0.25 higher vs. lower). Conclusions: In the present large, nationwide cohort of CCS patients at VHR a high TG/HD ratio did not emerge as independent predictor of MACCE at 1 year. Further studies with a longer follow-up are needed to better define the prognostic role of TG/HDL ratio in CCS.

Case Report: Exceptional Response to Poziotinib in Patient with Metastatic Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutation.

Among the several next-generation tyrosine kinase inhibitors (TKIs) tested against uncommon EFGR alterations, poziotinib has been demonstrated to be a powerful agent for metastatic non-small-cell lung cancer (mNSCLC) with aberrations in HER2 exon 20, and FDA approval is being sought in the previously-treated population. Poziotinib has also shown activity in mNSCLC with aberrations in EGFR exon 20. Herein, we report the first published case of a patient affected by mNSCLC harbouring an EGFR exon 20 insertion (EGFRex20ins) mutation who achieved a complete response (CR) under treatment with poziotinib as part of the ZENITH20 trial. In January 2021, a former smoker 62-year-old female patient was diagnosed with relapse, after two surgeries and post-operative chemotherapy of mNSCLC, at liver and retroperitoneal nodes. Given the identification by Next Generation Sequencing (NGS) of EGFRex20ins mutation, she was enrolled in ZENITH20-cohort 5 trial, a phase 2 multicentre study aimed to assess the efficacy and safety of poziotinib in patients with EGFR or HER2 exon 20 insertion mutations. Poziotinib as first-line systemic therapy for metastatic disease was initiated at the end of January 2021 and administrated at the initial dosage of 8 mg orally twice daily (BID). The most common side effects from the beginning of the treatment included alopecia, macular skin rash, diarrhoea, xerostomia, and conjunctivitis. Due to these adverse events, poziotinib was discontinued during the first 3 months and then reduced to 6 mg orally BID in April 2021. After the dose de-escalation, the adverse events ameliorated, and the patient better tolerated the treatment without further interruption. Since the first reevaluation (after 4 weeks of therapy), the treatment with poziotinib resulted to be remarkably effective, with a partial response (PR) subsequently confirmed in May and July 2021. Then, in October 2021, a CT scan confirmed a CR, maintained with good tolerance at the last reevaluation in February 2022. Treatment is still ongoing at the same dosage. In this case, poziotinib has represented a successful and well-tolerated first-line treatment alternative to chemotherapy in this patient with EGFR exon 20 insertion mutated mNSCLC.

Management of serious complications in intra-abdominal desmoid-type fibromatosis.

BACKGROUND: Desmoid fibromatosis (DF) is a rare and locally infiltrative monoclonal fibroblastic proliferation arising from connective tissues, with lack of metastatic potential. About 10% of all DF cases are intra-abdominally sited. Complications in this site, due to the locally infiltrative nature of the disease, may be severe and potentially life threatening. However, data on incidence, management, and outcome of these complications are limited. AIM: Data of patients with sporadic or FAP-related intra-abdominal DF treated at Istituto Nazionale dei Tumori (INT) in Milano from 2005 to 2020 who developed a serious complication during the course of their disease were retrospectively collected and analyzed with a descriptive statistics. METHODS AND RESULTS: Out of 72 intra-abdominal DF, 8 cases were identified (M/F: 5/3, median age: 35 years, FAP-related/sporadic: 2/6): 3 with bowel obstruction, 5 with bowel perforation. In 4 cases the serious complication was the first evidence of disease; in the other 4 cases it occurred at a time interval from diagnosis in the range of 4-44 months (during an active surveillance program in one case and during chemotherapy in the other 3 cases). A surgical treatment was feasible and successful in 5 cases. In 3 surgically unmanageable patients, all progressing and experiencing acute complications while on chemotherapy, a non-surgical approach with intensive supportive treatment and with a prompt change of chemotherapy regimen was implemented, being successful in two, the other patient dying due to a concomitant progressive lymphoma thereafter. CONCLUSION: In this series of intra-abdominal DF, the incidence of serious complications was 11%. Most patients were successfully treated with surgery. When surgery was deemed to be unfeasible, a conservative management with intensive supportive care and a careful choice of chemotherapy was adopted, ensuring a favorable outcome in most.

Poziotinib for EGFR and HER2 exon 20 insertion mutation in advanced NSCLC: Results from the expanded access program.

BACKGROUND: The treatment of metastatic non-small-cell lung cancer (mNSCLC) patients with EGFR/HER2 exon 20 insertion mutation (i-mut) remains an unmet clinical need. Poziotinib, a new generation tyrosine kinase inhibitor, is currently under investigation as a potential targeted therapy. This compassionate study of its use aims to describe the activity/toxicity of poziotinib in mNSCLC with EGFR/HER2-exon-20-i-mut. PATIENTS AND METHODS: NSCLC patients who were treated either with EGFR or HER2 exon 20-i-mut within an expanded access program were included in this study. Poziotinib (16 mg or less) was administrated orally quaque die (QD). The primary end-point was the overall response rate (ORR) assessed by central review using RECIST v1.1, and secondary end-points were median progression free survival (PFS), disease control rate (DCR), median overall survival (OS) and toxicity. RESULTS: The median age of all the 30 patients was 58 years (25-80 years), most of them were females (73%); ECOG 0-1 (83%), EGFR i-mut (73%) and pre-treated (83%). 73% started with poziotinib at a dose of 16 mg. At data cut-off, 22 of 33 patients (73%) experienced a progress in the disease and 12 of 30 (40%) died. Median PFS was 5.6 months (95% CI: 3.6-6.7 months) and the mOS 9.5 months (95% CI: 5.3 - not-reached months). The ORR was 30% (EGFR/HER2: 23/50%) and DCR 80%. G3 AEs were reported in 66% of the patients and were found with skin rash (50%), diarrhoea (17.6%), mucositis (7%) and paronychia (3%). G5, possibly associated with pneumonitis might also have occurred. CONCLUSIONS: Poziotinib exhibited effects in mNSCLC patients with EGFR/HER2-exon 20-i-mut. The toxicity rate was high leading to frequent dose interruption and reduction, thereby reducing mPFS in patients with good ORR/DCR. ZENITH20 trial is now being used to evaluate the low dose and new scheduled dose (e.g. bis in die (BID)).

FMRI correlates of olfactory processing in typically-developing school-aged children.

Human olfactory processing is understudied relative to other sensory modalities, despite its links to neurodevelopmental and neurodegenerative disorders. To address this limitation, we developed a fast, robust fMRI odor paradigm that is appropriate for all ages and levels of cognitive functioning. To test this approach, thirty-four typically developing children aged 7-12 underwent fMRI during brief, repeated exposure to phenylethyl alcohol, a flower-scented odor. Prior to fMRI scanning, olfactory testing (odor detection and identification) was conducted. During fMRI stimulus presentation, odorant release was synchronized to each participant's inspiratory phase to ensure participants were inhaling during the odorant exposure. Between group differences and correlations between activation and odor detection threshold scores were tested using the FMRIB Software Library. Results demonstrated that our 2-min paradigm significantly activated primary and secondary olfactory regions. In addition, a significant relationship between odor detection threshold and higher activation in the right amygdala and lower activation in the left frontal, insular, occipital, and cerebellar regions was observed, suggesting that this approach is sensitive to individual differences in olfactory processing. These findings demonstrate the feasibility of studying olfactory function in children using brain imaging techniques.

Guanfacine extended release for the treatment of attention-deficit/hyperactivity disorder in children and adolescents.

INTRODUCTION: Guanfacine extended release (GXR) is a selective α(2A)-adrenoreceptor agonist originally developed as an antihypertensive agent and now FDA approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) as monotherapy and as adjunctive to psychostimulants in children and adolescents 6-17 years old. AREAS COVERED: Search of the PubMed and PsycInfo databases from 1990 to 2014 using the search term 'guanfacine'. Studies selected for review were either controlled or open trials of guanfacine or GXR. Shire Pharmaceuticals, Inc. was contacted and supplied a synopsis of all available ADHD studies on GXR for review. EXPERT OPINION: GXR is an evidence-based treatment for ADHD in children and adolescents. Because this compound has a smaller effect size than psychostimulants for the symptoms of ADHD, it is generally considered a second-line treatment after the psychostimulants or in combination with psychostimulants. Evidence for efficacy is more robust in children than for adolescents. Because of its pharmacodynamic actions in prefrontal cortex, GXR shows considerable promise for other behavioral conditions frequently comorbid with ADHD and potential promise for emotional and behavioral dysregulation secondary to traumatic stress.

In vivo isolation and characterization of stem cells with diverse phenotypes using growth factor impregnated biomatrices.

BACKGROUND: The stimulation to differentiate into specific cell types for somatic stem cells is largely due to a series of internal and external signals coming from the microenvironment that surrounds the stem cell. Even though intensive research has been made, the basic mechanisms of plasticity and/or the molecules regulating stem cells proliferation and differentiation are not completely determined. Potential answers concerning the problems could be derived from the studies of stem cells in culture. METHODOLOGY/PRINCIPLE FINDINGS: We combine a new procedure (using the matrigel biopolymer supplemented with a selected cytokine/growth factor) with classic techniques such as light, confocal and electron microscopy, immunohistochemistry and cell culture, to perform an analysis on stem cells involved in the leech (Hirudo medicinalis) repair tissues. The leech has a relative anatomical simplicity and is a reliable model for studying a variety of basic events, such as tissue repair, which has a striking similarity with vertebrate responses. Our data demonstrate that the injection of an appropriate combination of the matrigel biopolymer supplemented with a selected cytokine/growth factor in the leech Hirudo medicinalis is a remarkably effective tool for isolating a specific cell population in vivo. A comparative analysis of biopolymer in vivo sorted stem cells indicates that VEGF recruited cells of a hematopoietic/endothelial phenotype whereas MCP-1/CCL2 isolated cells that were of an early myeloid lineage. CONCLUSION: Our paper describes, for the first time, a method allowing not only the isolation of a specific cell population in relation to the cytokine utilized but also the possibility to culture a precise cell type whose isolation is otherwise quite difficult. This approach could be broadly applied to isolate stem cells of diverse origins based on the recruitment stimuli employed.