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Cumulative review of cardiac failure with acalabrutinib in the treatment of chronic lymphocytic leukemia using data from clinical trials and postmarketing experience
Get PDFHow to Do Echo for Noninvasive Hemodynamic Evaluation of the Patient in the Intensive Care Unit: A Consensus Statement of the Italian Society of Echocardiography and Cardiovascular Imaging
Get PDFCritically ill patients in the intensive care unit (ICU) require continuous hemodynamic monitoring to guide therapeutic decisions and prevent clinical deterioration. Echocardiography has emerged as a cornerstone for noninvasive hemodynamic assessment, offering real‐time, bedside evaluation of key parameters such as venous congestion, pulmonary pressures, left atrial pressure (LAP), systemic vascular resistances, cardiac output, and ventricular–arterial coupling. Systemic venous congestion and right atrial pressure (RAP) can be assessed through inferior vena cava diameter measurement and respiratory variation, with additional accuracy provided by the VeXUS score, which incorporates hepatic, portal, and renal vein Doppler profiles. Internal jugular vein assessment and left ventricular (LV) stroke volume variability further refine RAP estimation. Pulmonary hypertension (PH) and right ventricular dysfunction can be evaluated through echocardiographic markers that differentiate precapillary from postcapillary PH, enabling tailored treatment strategies. In addition, echocardiography is fundamental for detecting right ventricular failure, particularly in PH and cardiogenic shock. LAP and systemic hemodynamics are integral to assessing LV diastolic and systolic dysfunction, which are pivotal in heart failure and cardiogenic shock management. Echocardiography also provides insights into vascular system properties and their interaction with cardiac performance, while lung ultrasound aids in detecting interstitial edema of cardiac origin. As a fast, reliable, and reproducible tool, echocardiography is the gold standard for noninvasive hemodynamic assessment in ICU patients, facilitating prompt and precise therapeutic decisions
Reliability of paramagnetic rim lesion detection at 1.5T MRI in multiple sclerosis patients
No full textBackground: Paramagnetic rim lesions (PRL) are valuable for diagnosing and prognosing multiple sclerosis (MS) and detectable at 7T and 3T MRI. For translation into clinical practice, it is essential assessing their visibility on 1.5T clinical scanners. Objective: To evaluate the reliability of detecting PRL using commercially available susceptibility-weighted imaging (SWI) at 1.5 versus 3T MRI. Methods: SWI images were obtained in 20 people with MS at 1.5T and 3T MRI, with an average scan interval of 1.1 years. Only stable, non-enhancing lesions visible on both scans were analyzed. PRL at 3T were identified by two expert raters using NAIMS PRL criteria and used as a reference. Four raters, blinded to 3T results, assessed PRL at 1.5T. Discrepancies were resolved by consensus. Results: PRL were identified in 16 of 20 patients. At 3T, 95 PRL were identified by consensus (mean 5 PRL per patient, range 0–30). Blinded to 3T scans, 82% of PRL were visible at 1.5T (78 of 95 PRL). Interrater reliability was “almost perfect” for both 1.5 and 3T scans. Raters accurately classified all patients as having ⩾1PRL or not at 1.5T. Conclusion: The majority of PRL are detectable at 1.5T without significantly reducing the specificity of PRL identification or increasing the detection of pseudo-PRL. This may facilitate their clinical use in MS diagnosis and prognosis
Digital Cognitive Assessment and its Relationship with Disability in Multiple Sclerosis
No full textIntroduction. Cognitive impairment is common in people with MS (pwMS) and significantly impacts functional independence. The Symbol-Digit Modalities Test (SDMT) is widely used to assess cognitive deficits in pwMS. Electronic adaptations of the SDMT (eSDMT) can enable remote monitoring and capture more detailed performance metrics, compared to pen-and-paper tests. This study details the development and validation of a custom-made eSDMT intended to enable long-term remote cognitive monitoring of pwMS.
Methods. I designed an eSDMT which enables remote and autonomous cognitive testing using people’s own PCs or laptops. Ninety-four pwMS were recruited consecutively between March 2023 and December 2024. Participants completed one eSDMT session in the clinic and then performed weekly remote testing for up to 12 months of follow-up, upon which they returned to the clinic for a final follow-up assessment. I investigated the following psychometric properties: concurrent validity with the oral SDMT, test-retest reliability between different settings and across repeated assessments, ability to differentiate between pwMS with or without cognitive impairment (discriminant validity). I also assessed the feasibility of the eSDMT and adherence to long-term remote monitoring. Finally, I explored the use of granular eSDMT data to provide novel information on MS-specific cognitive profiles, novel methods that can advance the state of the art of digital cognitive testing, and the predictive validity of eSDMT scores.
Results. The eSDMT demonstrated good-to-excellent concurrent validity, test-retest reliability, and discriminant validity. Usability was also rated as excellent, whereas adherence fell quickly to almost 50% after 6 months, and continued decreasing up to 12 months of follow-up. I demonstrated that granular eSDMT data can improve the informative value of digital cognitive testing, and that novel processing techniques can improve the reliability of the eSDMT. Lastly, I provided preliminary results on the use of remote monitoring data to improve the prediction of cognitive performance after one year.
Conclusions. This eSDMT was demonstrated to be a valid and reliable tool to enable remote monitoring of pwMS. Adherence remains a significant obstacle, and further studies will be needed to validate the long-term predictive validity of remote monitoring data. Given the many upsides of remote monitoring, further efforts are warranted, to continue improving the state of the art and finally enable its implementation in routine clinical care or clinical trialsIntroduzione. Il deterioramento cognitivo è comune nelle persone con SM (pwMS) e ha un impatto significativo sull’indipendenza funzionale. Il Symbol-Digit Modalities Test (SDMT) è ampiamente utilizzato per valutare i deficit cognitivi nelle pwMS. Gli adattamenti elettronici dell'SDMT (eSDMT) possono consentire il monitoraggio remoto e acquisire metriche di prestazione più dettagliate, rispetto ai test cartacei. Questo studio descrive in dettaglio lo sviluppo e la convalida di un eSDMT personalizzato destinato a consentire il monitoraggio cognitivo remoto a lungo termine delle pwMS.
Metodi. Ho progettato un eSDMT che consente test cognitivi remoti e autonomi utilizzando i PC o i laptop delle persone. Novantaquattro pwMS sono stati reclutati consecutivamente tra marzo 2023 e dicembre 2024. I partecipanti hanno completato una sessione eSDMT in clinica e quindi hanno eseguito test remoti settimanali per un massimo di 12 mesi di follow-up, dopodiché sono tornati in clinica per una valutazione di follow-up finale. Ho studiato le seguenti proprietà psicometriche: validità concorrente con la SDMT orale, affidabilità test-retest tra diversi contesti e attraverso valutazioni ripetute, capacità di distinguere tra pwMS con o senza deterioramento cognitivo (validità discriminante). Ho anche valutato la fattibilità dell'eSDMT e l'aderenza al monitoraggio remoto a lungo termine. Infine, ho esplorato l'uso di dati eSDMT granulari per fornire nuove informazioni sui profili cognitivi specifici della SM, nuovi metodi che possono far progredire lo stato dell'arte dei test cognitivi digitali e la validità predittiva dei punteggi eSDMT.
Risultati. L'eSDMT ha dimostrato validità concorrente da buona a eccellente, affidabilità test-retest e validità discriminante. Anche l'usabilità è stata valutata come eccellente, mentre l'aderenza è scesa rapidamente a quasi il 50% dopo 6 mesi e ha continuato a diminuire fino a 12 mesi di follow-up. Ho dimostrato che i dati eSDMT granulari possono migliorare il valore informativo dei test cognitivi digitali e che nuove tecniche di elaborazione possono migliorare l'affidabilità dell'eSDMT. Infine, ho fornito risultati preliminari sull'uso dei dati di monitoraggio remoto per migliorare la previsione delle prestazioni cognitive dopo un anno.
Conclusioni. Questo eSDMT ha dimostrato di essere uno strumento valido e affidabile per consentire il monitoraggio remoto di pwMS. L'aderenza rimane un ostacolo significativo e saranno necessari ulteriori studi per convalidare la validità predittiva a lungo termine dei dati di monitoraggio remoto. Dati i numerosi vantaggi del monitoraggio remoto, sono giustificati ulteriori sforzi per continuare a migliorare lo stato dell'arte e infine consentirne l'implementazione nell'assistenza clinica di routine o negli studi clinic
Hyaluronic Acid Filler Injection in the Nose in Correlation With Rhinoplasty
No full text: The use of hyaluronic acid (HA) fillers in both primary and revision rhinoplasties has gained increasing popularity among physicians in recent years. Although surgical rhinoplasty remains the gold standard for nasal reconstruction and correction, HA fillers provide a minimally invasive alternative with immediate results and a low morbidity rate. This study aimed to evaluate the proposed non-surgical rhinoplasty algorithm, which focuses on the correction of 4 specific anatomic points, by assessing aesthetic outcomes, patient satisfaction, and associated complications. Horizontal and vertical sagittal stability were monitored using profilometric Arnett analysis, focusing on measurements of the Nasion (Na), Rhinion (Rh), Pronasion (Prn), and Subnasal (Sn). The application of the 4 anatomic point treatment algorithm demonstrated significant improvements in nasal profile and overall facial harmony. This technique offers a safe and effective solution, avoiding the challenges associated with surgical interventions, such as scarring and general anesthesia, while ensuring high patient satisfaction
ZUMA-8: a phase 1 study of brexucabtagene autoleucel in patients with relapsed/refractory chronic lymphocytic leukemia
No full textZUMA-8 evaluated the safety of brexucabtagene autoleucel (brexu-cel), a CD19-directed autologous chimeric antigen receptor (CAR) T-cell immunotherapy, for patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Patients with ≥2 prior lines of therapy (including a Bruton tyrosine kinase inhibitor) underwent leukapheresis, optional bridging therapy, and conditioning chemotherapy (fludarabine/cyclophosphamide) before infusion of 1 × 106 (cohort 1) or 2 × 106 (cohort 2) anti-CD19 CAR T cells per kg. Patients in cohort 3 (low tumor burden), and cohort 4A (postibrutinib) received 1 × 106 cells per kg. Fifteen patients, median age of 63 years (range, 52-79), were treated in cohorts 1 (n = 6), 2 (n = 3), 3 (n = 3), and 4A (n = 3). Median follow-up was 24.3 months. One dose-limiting toxicity was observed in cohort 3 (grade 4 cytokine release syndrome). Grade ≥3 neurologic events occurred in 3 patients (20%). Seven of 15 patients responded (overall response rate, 47%; complete response [CR], 7%), including all 3 patients in cohort 3 (1 with CR). CAR T-cell expansion occurred in 4 patients (27%), with an apparent weak inverse correlation with absolute lymphocyte count before apheresis. Brexu-cel had no new safety signals in R/R CLL. CAR T-cell expansion and responses occurred in patients with low tumor burden. This trial was registered at www.clinicaltrials.gov as #NCT03624036
Prevention of diabetic ketoacidosis in relatives screened for islet autoantibodies and followed up in the TrialNet Pathway to Prevention study at a single institution in Italy
No full textAims/hypothesis: Screening for islet autoantibodies is an effective method for identifying individuals with pre-symptomatic (stage 1 and 2) type 1 diabetes. This approach offers a valuable opportunity for education and monitoring, which can help to reduce the severity of clinical manifestations at clinical onset (stage 3), including diabetic ketoacidosis. The aim of the study was to evaluate the progression to stage 3 and the incidence of diabetic ketoacidosis in relatives of individuals with type 1 diabetes screened and followed up at a single institution in Italy. Methods: This was a single-centre observational study conducted at San Raffaele Hospital, Milan, Italy, within the international multisite TrialNet Natural History Study-Pathway to Prevention. First-degree (aged 1-45 years) and second-degree (aged 1-20 years) relatives were screened primarily for GADA, IAA and IA-2A. In the event of a positive result, subsequent testing was conducted for ICA and ZnT8A. Periodic autoantibody testing, metabolic monitoring and educational support were offered to all autoantibody-positive participants. Participants were screened between July 2005 and February 2020, with the latest update obtained between January 2023 and June 2024. Results: In total, 4046 relatives were screened at a median (IQR) age of 17.6 (7.9-38.0) years. At first screening, 4.9% were found to be positive, with 3.1% having a single autoantibody and 1.8% multiple autoantibodies. Follow-up data were available for 78.5% of the participants, with a median (IQR) follow-up time of 9.9 (6.5-13.5) years. Progression to stage 3 was observed in 51 (1.6%) participants. Disease onset occurred in 0.4% of autoantibody-negative, 6.5% of single-positive and 43.1% of multiple-positive participants after a median (IQR) time of 7.8 (5.4-10.4), 7.9 (2.1-11.8) and 2.9 (0.9-6.5) years, respectively (p=0.012). The Kaplan-Meier survival free of clinical diabetes at 15 years was 99.5% (95% CI 99.1, 99.7), 87.3% (95% CI 74.4, 94.0) and 45.9% (95% CI 31.1, 59.6), respectively (p<0.001). At the time of disease onset, no occurrences of diabetic ketoacidosis were documented. Median (IQR) HbA1c was 64 (52-86) mmol/mol (8.0 [6.9-10.0]%) and median (IQR) venous pH at onset was 7.37 (7.35-7.39). Hospitalisation occurred in 22 paediatric participants, as part of standard practice for newly diagnosed patients at our institution aiming to provide disease education and insulin therapy optimisation. Conclusions/interpretation: The early identification of individuals at risk for type 1 diabetes through a single-centre approach, combining autoantibody screening and regular monitoring, completely prevented diabetes-associated ketoacidosis at disease onset in relatives of individuals with type 1 diabetes. Trial registration: ClinicalTrials.gov NCT00097292
Laparoscopic versus open resection for hepatocellular carcinoma according to the procedure's complexity: real-world weighted data from a national register
No full textBackground: Minimal access liver surgery (MALS) is considered superior to open liver resection (OLR) in reducing the perioperative risk in patients affected by hepatocellular carcinoma (HCC). No national-level comparisons exist based on procedure complexity. This study aims to compare postoperative complications, postoperative ascites (POA), and major complications (MC) between MALS and OLR. Methods: Data were retrieved from the Italian HE. RC.O.LE.S. registry. Patients were categorized into OLR or MALS groups and stratified by complexity grade (CP1, CP2, CP3). An inverse probability weighting (IPW) was performed to ensure balanced comparisons. Results: From 2008 to 2021, 4738 patients were included: 1596 (33.7 %) underwent MALS, and 3142 (66.3 %) underwent OLR. CP1 procedures were conducted in 2522 cases (53.2 %), CP2 in 974 cases (20.5 %), and CP3 in 1242 cases (26.2 %). For CP1, MALS was associated with reduced POA (OR 0.356, 95%CI:0.29–0.43, p < 0.001), and MC (OR 0.738, 95%CI:0.59–0.91, p: 0.006). In CP2, MALS showed association with MC (OR 0.557, 95%CI:0.37–0.82, p:0.004), but not with POA. For CP3, MALS was associated with increased MC risk (OR 1.441, 95%CI:1.10–1.88, p:0.008). Low-volume centers had significantly higher MC risks after CP2 and CP3 procedures than medium or high-volume centers. Conclusion: In CP1 and CP2 procedures, MALS was proven advantageous in reducing POA and MC. Among CP3, MALS increased the risk of MC, but not among high-volume centres
“Biological R2” resection for intrahepatic cholangiocarcinoma: identification of patients at risk for poor oncologic outcomes after curative-intent resection
No full textIntroduction: We sought to define a cohort of patients with “biological R2” (bR2) resection, defined as recurrence within 12 weeks, following curative-intent resection for intrahepatic cholangiocarcinoma (ICC). In addition, we sought to identify factors associated with bR2 risk. Methods: Patients who underwent upfront curative-intent surgery for ICC were identified from an international, multi-institutional database. The weighted beta-coefficients of preoperative risk factors were used to construct an online tool to predict bR2. Results: Among 1138 patients, 106 (9.3 %) patients had a bR2 resection. Patients with bR2 were more likely to be younger (OR 0.97) and non-White (OR 2.19), as well as more often had cirrhosis (OR 2.11), a higher neutrophil-to-lymphocyte ratio (OR 1.07), a higher tumor burden score (OR 1.16), and metastatic nodal disease on preoperative imaging (OR 1.92). Patients categorized as low-risk had a 3.2 % risk of bR2, intermediate-risk patients had an 11.1 % risk of bR2, whereas patients in the high-risk category had a 27.6 % risk of bR2 (p < 0.001). An online tool was made available at https://junkawashima.shinyapps.io/bR2_ICC/, https://junkawashima.shinyapps.io/CRLMfollwingchemotherapy/. Conclusions: Approximately one in ten patients with resectable ICC had a bR2 resection. An online calculator can may help clinicians identify patients with ICC at highest risk of a bR2 resection
Discovery of 22(S)-23-phenyl-24-norchol-5-en-3β,22-diol (PFM046) as the first-in-class, steroidal, non-sulfated Liver X Receptor antagonist with anticancer activity
Get PDFA plethora of studies have demonstrated the crucial role played by Liver X Receptors (LXRs) in cancer. However, whether LXRs activation results in pro-versus anti-tumor effects is still matter of debate. Recently, we have reported the ability of 22(S)-hydroxycholesterol-3-sulfate (PFM037) to antagonize LXRα activity, and, at the same time, its capability to improve in-vivo anti-tumor immune responses. Herein we report the first study aimed at the definition of structure-activity relationships of PFM037. Successfully, we identified 22(S)-23-phenyl-24-norchol-5-en-3β,22-diol (PFM046) as a more potent LXRs antagonist than PFM037. PFM046 showed a peculiar LXR target gene expression profile, being able, as expected for an antagonist, to suppress SCD1 and FASN expression, while surprisingly maintaining the ability to upregulate ABCA1 gene, as typical for an agonist. PFM046 showed a remarkable antitumor activity in two both in vitro-and in-vivo mouse models, highlighting the high potential of LXRs antagonists in oncological applications