IRIS UniSR (’Università Vita-Salute San Raffaele)
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Il bene, la ragion pratica e il giudizio morale. Interrogativi kantiani sull'etica di Descartes
No full textDescartes' ethics is based on the notion of valuing and is extremely interesting as an example of the search for a faculty of moral judgment distinct from theoretical and scientific reason. This might have generated the idea in modern moral philosophy that ethics is not the realm of reason but of passions. On the contrary, Kant highlighted an understanding of reason that recovered Aristotelian elements and defined a clear and autonomous role for practical rationality
Hematopoietic stem cell gene therapy of neurometabolic lysosomal storage diseases
Full text linkNeurometabolic disorders are rare, inherited monogenic diseases arising from mutations in genes whose products are essential for brain functions and cause local accumulation of toxic substrates. Central nervous system involvement can be severe, is progressive and frequently appears early in life. Current treatment options for neurometabolic disorders are represented mainly by enzyme replacement therapy (ERT) and allogeneic hematopoietic stem cell transplantation (HSCT) which do not sufficiently address clinical manifestations and leave patients with a substantial residual disease burden. Given this unmet medical need, alternative strategies based on genetic manipulation of patient's cells have been developed. Hematopoietic stem progenitor cells-gene therapy (HSPC-GT) entails the harvest autologous HSPCs which are ex-vivo manipulated by means of viral vectors to express the therapeutic gene and infused back into the patient after chemotherapy-based preparation. Modified HSPCs engraft and differentiate into the various hematopoietic cell lineages, producing the functional enzyme at either normal or supranormal levels. The number of clinical trials with HSPC-GT in neurometabolic disorders is rapidly increasing and some HSPC-GT products have recently received market approval. This review focuses on HSPC-GT strategies summarizing the most recent developments in the field of neurometabolic disorders
Cerebral asymmetries in schizophrenia
No full textHistorically, the first observations of a lower prevalence of right-handed patients among subjects with schizophrenia led to the hypothesis that brain asymmetry could play a significant role in the etiopathogenesis of the disease. Over the last decades, a growing number of findings obtained through many different techniques such as EEG, MEG, MRI, and fMRI, consistently reported reduction/loss of brain asymmetries as a core feature of schizophrenia, further suggesting such alterations to play a cardinal role in the pathogenesis of the disease. Moreover, several cognitive and psychopathologic dimensions have shown significant correlations with the reduced degree of asymmetry. In particular, the absence or even reversal of structural asymmetries has been documented in language-related brain such as the Sylvian fissure and planum temporale. These findings have been reprocessed within an evolutionary and psychopathologic framework pointing at the loss of asymmetry and the consequent language impairment as primum moves in the pathogenesis of schizophrenia. Overall, despite growing evidence demonstrating a heterogeneous and multifaced etiopathogenesis in schizophrenia, the “old concept” of brain asymmetry still offers intriguing hints and thought-provoking elements for clinicians and researchers who deal with schizophrenia
Validation of the PANAMA-Score for Survival and Benefit of Adjuvant Therapy in Patients with Resected Pancreatic Cancer After Neoadjuvant FOLFIRINOX
Full text linkAim: To validate the prognostic value of the PAncreatic NeoAdjuvant MAssachusetts (PANAMA)-score and to determine its predictive ability for survival benefit derived from adjuvant treatment in patients after resection of pancreatic ductal adenocarcinoma (PDAC) following neoadjuvant FOLFIRINOX Background: The PANAMA-score was developed to guide prognostication in patients after neoadjuvant therapy and resection for PDAC. As this score focuses on the risk for residual disease after resection, it might also be able to select patients who benefit from adjuvant after neoadjuvant therapy. Methods: This retrospective international multicenter study is endorsed by the European-African Hepato-Pancreato-Biliary Association (E-AHPBA). Patients with PDAC who underwent resection after neoadjuvant FOLFIRINOX were included. Mantel-Cox regression with interaction analysis was performed to assess the impact of adjuvant chemotherapy. Results: Overall, 383 patients after resection of PDAC following neoadjuvant FOLFIRINOX were included of whom 187 (49%), 137 (36%), and 59 (15%) had a low-risk, intermediate-risk, and high-risk PANAMA-score, respectively. A discrimination in median OS was observed stratified by risk groups (48.5, 27.6, and 22.3 months, Log-Rank-Plow-intermediate=0.004, Log-Rank-Pintermediate-high=0.027). Adjuvant therapy was not associated with an OS difference in the low-risk group (HR 1.50, 95%CI:0.92-2.50), whereas improved OS was observed in the intermediate (HR 0.58, 95%CI:0.34-0.97) and high-risk groups (HR 0.47, 95%CI:0.24-0.94) (p-interaction=0.008). Conclusions: The PANAMA 3-tier risk groups (low-risk, intermediate-risk, and high-risk, available via pancreascalculator.com) correspond with differential survival in patients with resected PDAC following neoadjuvant FOLFIRINOX. The risk groups also differentiate between survival benefit associated with adjuvant treatment, with only the intermediate- and high-risk groups associated with improved OS
Atypical mediastinal mass in the fetus: a review of the literature
Full text linkObjectives: Congenital thoracic masses (CTMs) are suspected in presence of solid or cystic thoracic lesions at ultrasound. The common typical fetal CTMs encompass: hyperechogenic lung lesions such as congenital pulmonary airway malformation (CPAM), broncopulmonary sequestration (PS) and congenital high airway obstruction syndrome (CHAOS); less common solid thoracic masses are mediastinal/pericardial tumors as rhabdomyoma and teratoma. The aim of our study is to gather the available evidence on cases of atypical CTMs of difficult classification, for which the diagnosis remains often uncertain. Methods: A review of the literature on the prenatal diagnosis of CTMs was performed, focusing on ultrasound features, postnatal manifestation, treatment and neonatal outcome. Inclusion criterion was prenatal diagnosis of CTM cases with difficult classification in six typical categories. A summary of results was carried out. Results: The literature review included six studies in the analysis. Two cases experienced intrauterine fetal death, one with hydrops in rhabdomyoma and another one for a rapid growth of the mass, with autopsies precising the diagnoses. In two other instances, surgery after birth provided also different histologic diagnoses. All surviving children were asymptomatic at follow-up. One case with rhabdomyoma and another one with atypical pericardial teratoma showed spontaneous regression. Moreover we are presenting our unpublished case of an atypical mass diagnosed as rhabdomyoma or broncopulmonary sequestration. Conclusions: Some masses may present atypical presentation of a known disease or we may face rare diagnosis for which there is lack of information in the literature. The definitive diagnosis still relies on histologic analysis
Environmental agency, moral reasoning, and moral disengagement in adults
No full textTo assess the relationships between environmental agency, prosocial moral reasoning, and civic moral disengagement, 544 community-dwelling adults were administered the image-based Environmental Agency Scale (EAS), the Prosocial Moral Reasoning Objective Measure (PROM), and the Civic Moral Disengagement Scale (CMDS). The EAS Agentic Self and Agentic Other dimensions proved to be reliable measures and showed adequate factor validity. Mean/median score comparisons between EAS Agentic Self Scale and Agentic Other Scale scores indicated that participants viewed society-level actions as more relevant than individual-level actions when environment defense is at issue. Partial correlation analysis results showed that environmental agentic self was grounded in individual differences in prosocial moral reasoning. Civic moral disengagement yielded negative associations with EAS Agentic Other Scale scores, providing further support to the relevance of moral disengagement process in environmental sensitivity. These results may improve our understanding of environmental agency and its connections with prosocial moral reasoning and moral disengagement.To assess the relationships between environmental agency, prosocial moral reasoning, and civic moral disengagement, 544 community-dwelling adults were administered the image-based Environmental Agency Scale (EAS), the Prosocial Moral Reasoning Objective Measure (PROM), and the Civic Moral Disengagement Scale (CMDS). The EAS Agentic Self and Agentic Other dimensions proved to be reliable measures and showed adequate factor validity. Mean/median score comparisons between EAS Agentic Self Scale and Agentic Other Scale scores indicated that participants viewed society-level actions as more relevant than individual-level actions when environment defense is at issue. Partial correlation analysis results showed that environmental agentic self was grounded in individual differences in prosocial moral reasoning. Civic moral disengagement yielded negative associations with EAS Agentic Other Scale scores, providing further support to the relevance of moral disengagement process in environmental sensitivity. These results may improve our understanding of environmental agency and its connections with prosocial moral reasoning and moral disengagement
Comparison of fludarabine/melphalan (FM140) with fludarabine/melphalan/BCNU (FBM110) in patients with relapsed/refractory AML undergoing allogeneic hematopoietic cell transplantation – a registry study on behalf of the EBMT Acute Leukemia Working Party
Full text linkThe treatment of relapsed/refractory acute myeloid leukemia (AML) is associated with a dismal prognosis. The allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed as salvage therapy. Reduced intensity conditioning protocols have been developed with the aim of reducing the leukemia burden without increasing their toxicity. We compared the reduced intensity conditioning FM140 (fludarabine, 150 mg/m2; melphalan 140 mg/m2) with FBM110 (fludarabine 150 mg/m2; BCNU, also known as carmustine, 300–400 mg/m2; and melphalan 110 mg/m2). From the European Bone Marrow Transplantation (EBMT) Acute Leukemia Working Party registry, we identified 293 adult patients (FM140, n = 118 and FBM110, n = 175) with AML with relapsed/refractory disease prior to allo-HCT. There were some differences such as age (FM140 = 59.5 years vs. FBM110 = 65.1 years, p < 0.001) and graft-versus-host disease (GvHD) prophylaxis based on in vivo T-cell depletion (TCD, FM140 = 39% vs. FBM110 = 75%, p < 0.001). No differences were observed between FM140- and FBM110-treated patients regarding overall survival (OS) (2-year OS: 39.3% vs. 45.7%, p = 0.58), progression-free survival (PFS) (2-year PFS: 36.1% vs. 37.3%, p = 0.69), non-relapse mortality (NRM) (2-year NRM: 15.3% vs. 25.7%, p = 0.10) and relapse incidence (RI) (2-year RI: 48.6% vs. 37.0%, p = 0.7). In conclusion, despite differences in age and GvHD prophylaxis, AML patients with active disease undergoing allo-HCT after FBM110 conditioning showed similar outcomes compared to FM140.The treatment of relapsed/refractory acute myeloid leukemia (AML) is associated with a dismal prognosis. The allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed as salvage therapy. Reduced intensity conditioning protocols have been developed with the aim of reducing the leukemia burden without increasing their toxicity. We compared the reduced intensity conditioning FM140 (fludarabine, 150 mg/m2; melphalan 140 mg/m2) with FBM110 (fludarabine 150 mg/m2; BCNU, also known as carmustine, 300–400 mg/m2; and melphalan 110 mg/m2). From the European Bone Marrow Transplantation (EBMT) Acute Leukemia Working Party registry, we identified 293 adult patients (FM140, n = 118 and FBM110, n = 175) with AML with relapsed/refractory disease prior to allo-HCT. There were some differences such as age (FM140 = 59.5 years vs. FBM110 = 65.1 years, p < 0.001) and graft-versus-host disease (GvHD) prophylaxis based on in vivo T-cell depletion (TCD, FM140 = 39% vs. FBM110 = 75%, p < 0.001). No differences were observed between FM140- and FBM110-treated patients regarding overall survival (OS) (2-year OS: 39.3% vs. 45.7%, p = 0.58), progression-free survival (PFS) (2-year PFS: 36.1% vs. 37.3%, p = 0.69), non-relapse mortality (NRM) (2-year NRM: 15.3% vs. 25.7%, p = 0.10) and relapse incidence (RI) (2-year RI: 48.6% vs. 37.0%, p = 0.7). In conclusion, despite differences in age and GvHD prophylaxis, AML patients with active disease undergoing allo-HCT after FBM110 conditioning showed similar outcomes compared to FM140
Abnormal choroid plexus, hippocampus, and lateral ventricles volumes as markers of treatment‐resistant major depressive disorder
No full textAim: One-third of patients with major depressive disorder (MDD) do not achieve full remission and have high relapse rates even after treatment, leading to increased medical costs and reduced quality of life and health status. The possible specificity of treatment-resistant depression (TRD) neurobiology is still under investigation, with risk factors such as higher inflammatory markers being identified. Given recent findings on the role of choroid plexus (ChP) in neuroinflammation and hippocampus in treatment response, the aim of the present study was to evaluate inflammatory- and trophic-related differences in these regions along with ventricular volumes among patients with treatment-sensitive depression (TSD), TRD, and healthy controls (HCs). Methods: ChP, hippocampal, and ventricular volumes were assessed in 197 patients with MDD and 58 age- and sex-matched HCs. Volumes were estimated using FreeSurfer 7.2. Treatment resistance status was defined as failure to respond to at least two separate antidepressant treatments. Region of interest volumes were then compared among groups. Results: We found higher ChP volumes in patients with TRD compared with patients with TSD and HCs. Our results also showed lower hippocampal volumes and higher lateral ventricular volumes in TRD compared with both patients without TRD and HCs. Conclusions: These findings corroborate the link between TRD and neuroinflammation, as ChP volume could be considered a putative marker of central immune activity. The lack of significant differences in all of the region of interest volumes between patients with TSD and HCs may highlight the specificity of these features to TRD, possibly providing new insights into the specific neurobiological underpinnings of this condition
Evaluating Biparametric Versus Multiparametric Magnetic Resonance Imaging for Diagnosing Clinically Significant Prostate Cancer: An International, Paired, Noninferiority, Confirmatory Observer Study
No full textBackground and objective: Biparametric magnetic resonance imaging (bpMRI), excluding dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), is a potential replacement for multiparametric MRI (mpMRI) in diagnosing clinically significant prostate cancer (csPCa). An extensive international multireader multicase observer study was conducted to assess the noninferiority of bpMRI to mpMRI in csPCa diagnosis. Methods: An observer study was conducted with 400 mpMRI examinations from four European centers, excluding examinations with prior prostate treatment or csPCa (Gleason grade [GG] ≥2) findings. Readers assessed bpMRI and mpMRI sequentially, assigning lesion-specific Prostate Imaging Reporting and Data System (PI-RADS) scores (3–5) and a patient-level suspicion score (0–100). The noninferiority of patient-level bpMRI versus mpMRI csPCa diagnosis was evaluated using the area under the receiver operating curve (AUROC) alongside the sensitivity and specificity at PI-RADS ≥3 with a 5% margin. The secondary outcomes included insignificant prostate cancer (GG1) diagnosis, diagnostic evaluations at alternative risk thresholds, decision curve analyses (DCAs), and subgroup analyses considering reader expertise. Histopathology and ≥3 yr of follow-up were used for the reference standard. Key findings and limitations: Sixty-two readers (45 centers and 20 countries) participated. The prevalence of csPCa was 33% (133/400); bpMRI and mpMRI showed similar AUROC values of 0.853 (95% confidence interval [CI], 0.819–0.887) and 0.859 (95% CI, 0.826–0.893), respectively, with a noninferior difference of –0.6% (95% CI, –1.2% to 0.1%, p < 0.001). At PI-RADS ≥3, bpMRI and mpMRI had sensitivities of 88.6% (95% CI, 84.8–92.3%) and 89.4% (95% CI, 85.8–93.1%), respectively, with a noninferior difference of –0.9% (95% CI, –1.7% to 0.0%, p < 0.001), and specificities of 58.6% (95% CI, 52.3–63.1%) and 57.7% (95% CI, 52.3–63.1%), respectively, with a noninferior difference of 0.9% (95% CI, 0.0–1.8%, p < 0.001). At alternative risk thresholds, mpMRI increased sensitivity at the expense of reduced specificity. DCA demonstrated the highest net benefit for an mpMRI pathway in cancer-averse scenarios, whereas a bpMRI pathway showed greater benefit for biopsy-averse scenarios. A subgroup analysis indicated limited additional benefit of DCE MRI for nonexperts. Limitations included that biopsies were conducted based on mpMRI imaging, and reading was performed in a sequential order. Conclusions and clinical implications: It has been found that bpMRI is noninferior to mpMRI in csPCa diagnosis at AUROC, along with the sensitivity and specificity at PI-RADS ≥3, showing its value in individuals without prior csPCa findings and prostate treatment. Additional randomized prospective studies are required to investigate the generalizability of outcomes
Quantifying the impact of treatment delays on breast cancer survival outcomes: a comprehensive meta-analysis
No full textTreatment delay in breast cancer care represents a significant concern in oncology, potentially impacting patient survival outcomes. While various factors can contribute to delayed treatment initiation, the quantitative relationship between specific delay intervals and survival remains incompletely understood in breast cancer management. Our study aims to explore the impact of treatment delays on survival outcomes in breast cancer. A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science databases, covering publications from 2000 to 2025. From an initial 6222 records, 18 eligible studies comprising 25 cohorts were included. Hazard ratios (HRs) for all-cause and breast cancer–specific mortality were extracted or calculated for treatment delays of 4, 8, and 12 weeks. Random-effects meta-analyses were performed, and heterogeneity and publication bias were assessed using I2 statistics, funnel plots, and Egger’s test. This meta-analysis revealed progressively increasing mortality risks with longer treatment delays. For all-cause mortality, HRs increased from 1.12 (95% CI 1.08–1.15) at 4 weeks to 1.25 (95% CI 1.17–1.33) at 8 weeks, and 1.39 (95% CI 1.26–1.53) at 12 weeks. Breast cancer–specific mortality showed more pronounced effects, with HRs of 1.20 (95% CI 1.06–1.36), 1.43 (95% CI 1.11–1.84), and 1.71 (95% CI 1.18–2.49) for 4-, 8-, and 12-week delays, respectively. Analyses combining both survival outcomes demonstrated consistent risk elevation across all time intervals (4 weeks: HR = 1.12, 95% CI 1.09–1.16; 8 weeks: HR = 1.26, 95% CI 1.18–1.34; 12 weeks: HR = 1.41, 95% CI 1.29–1.55). While heterogeneity was significant (I2 = 54–92%), no substantial publication bias was detected. Delays in initiating breast cancer treatment are associated with significantly worse survival, particularly for cancer-specific mortality. Each additional 4-week delay increases the hazard of death by over 10%, underscoring the urgency of minimizing delays in diagnosis-to-treatment pathways. These findings have critical implications for healthcare systems, clinical decision-making, and public health policy