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Deciphering the Complexity: Nephrotic Syndrome in Autosomal Dominant Polycystic Kidney Disease – A Case Report and Literature Review
No full textAutosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder marked by the formation of multiple kidney cysts and an increase in overall kidney volume, which frequently results in progressive kidney failure. Although glomerulonephritis can potentially occur as a complication, it is considered uncommon among patients with ADPKD, and the occurrence of nephrotic syndrome in this group is very rare. We report a case involving a young woman with ADPKD who developed nephrotic syndrome, likely attributed to minimal change disease. This review thoroughly examines the diagnostic challenges, management approaches, and current literature regarding this rare connection
Vanguard: generazione di un pancreas artificial per il trattamento del diabete di tipo 1
No full textIl trapianto intraepatico di isole pancreatiche rappresenta lo standard clinico per il trattamento del diabete di tipo1. Tuttavia, la procedura presenta significative limitazioni, tra cui: 1) la mancanza di supporto immediato dalla matrice extracellulare (ECM), una rapida vascolarizzazione, un adeguato apporto di ossigeno e nutrienti; 2) infiammazione nel sito del trapianto, correlati ad una perdita massiva di isole dopo l'infusione e 3) la carenza di donatori di organi. Per affrontare la carenza di isole umane per il trattamento su larga scala del diabete di tipo 1 (T1D), le cellule β derivate da iPSC rappresentano una promettente fonte alternativa, mostrando un ampio potenziale nel trattamento del T1D in modelli preclinici, con una limitazione sostanziale nell'innesto e nella funzione immediata dopo l'impianto. I recenti progressi nella bioingegneria del pancreas suggeriscono che un dispositivo terapeutico ideale dovrebbe rigenerare un microambiente endocrino funzionale in vitro, permettendo alle cellule β di sostenere la loro funzione endocrina. Il nostro laboratorio ha dimostrato che le cellule endocrine se organizzate in una struttura ECM tridimensionale vascolarizzata, che facilita la distribuzione dei nutrienti e la produzione di insulina in vitro ed in vivo. Inoltre, i recenti progressi nella generazione di sferoidi da isole umane e beta cellule derivanti da staminali hanno mostrato che la dissociazione delle isole e la riaggregazione cellulare in un'architettura definita, con il supporto di cellule come EC e MSC, può ulteriormente migliorare la funzione endocrina e ridurre il rischio di rigetto del trapianto. In questo contesto, il nostro obiettivo è bio-ingegnerizzare un dispositivo endocrino vascolarizzato composto da i) ECM derivante un organo, ii) cellule endoteliali umane e iii) sfere endocrine vascolarizzate, basate su isole umane o cellule β derivate da iPSC, per curare il T1D. Abbiamo sviluppato due tecnologie per valutare se gli stimoli biochimici o l'architettura dell'ECM dell'organo influenzano le performance del dispositivo. Abbiamo ipotizzato che l'ECM proveniente da due organi diversi (cioè la membrana amniotica e il polmone) possa influenzare il risultato in modo diverso, a causa delle caratteristiche distinte dell’ECM. La membrana amniotica, pur non essendo strutturalmente simile al tessuto endocrino del pancreas, è già ampiamente utilizzata in contesti clinici ed è conosciuta per le sue proprietà anti-fibrotiche, anti-infiammatorie e immuno-modulatorie. Da questa abbiamo creato un idrogel auto assemblante che incorpora gli stimoli dell’ECM dalla membrana amniotica, de-strutturandone l'architettura. Al contrario, il polmone offre una struttura ben definita a doppio compartimento che riflette la nicchia vascolare ed endocrini del pancreas, rendendolo potenzialmente adatto per la bioingegneria di un pancreas endocrino. In entrambi gli approcci, l’ECM è stata ripopolata con sferodi umani vascolarizzate, cellule endoteliali, per valutare sia in vitro che in vivo come questi componenti influenzino la funzione endocrina in presenza o assenza di architetture definite.As of now intrahepatic transplantation represents the clinical gold standard for islet infusion, but it faces significant limitations, including: 1) the lack of immediate extracellular matrix (ECM) support, rapid vascularization, and adequate oxygen and nutrient supply; 2) inflammation at the transplant site leading to the 50%-75% of islet loss after infusion and 3) the shortage of organ donor. To address the shortage of human islets for large-scale T1D treatment, iPSC-derived β cells represent a promising alternative source showing a wide range potential in treating T1D in preclinical models with a substantial limitation in engraftment and immediate function upon implantation. Recent advances in pancreas bioengineering suggest that an ideal therapeutic device should regenerate a functional endocrine microenvironment in vitro, allowing β cells to sustain their endocrine function. Our lab has shown that endocrine cells exhibit improved function in vitro when organized in a vascularized three- dimensional ECM structure, which facilitates nutrient distribution and insulin response to glucose stimuli. Moreover, recent progress in generation of human islet and stem cell like islet spheroids, have shown that islet dissociation and cell reaggregation into a defined spheroids architecture, with supportive of cells as ECs and MSCs, can further enhance endocrine function and reduce the risk of graft rejection.
Herein, we aim to bioengineer a vascularized endocrine device composed by i) organ like ECM, ii) human endothelial cells and iii) vascularized endocrine spheroids, based on human islet or iPSC-derived β cells, to cure T1D.
To explore this, we developed two technologies to assess whether the biochemical cues or architecture of the organ ECM impacts the device's performance. We hypothesized that ECM from two different organs (i.e. amniotic membrane and lung) might influence the outcome differently due to their distinct features. The amniotic membrane, although not structurally similar to the pancreas's endocrine tissue, is already widely used in clinical settings and is known for its antifibrotic, anti-inflammatory, and immunomodulatory properties. We create a self-assembly hydrogel-based device incorporating ECM cues from the amniotic membrane, de-structuring its architecture. In contrast, the lung offers a dual-compartment well defined structure that mirrors the vascular and endocrine niches of the pancreas, making it potentially well-suited for bioengineering an endocrine pancreas. In both approaches the self- assembly or 3D structured ECM devices were repopulated with human vascularized spheroids, endothelial cells to evaluate both in vitro and in vivo how these components influence endocrine function in the presence or absence of defined architectural features
Artificial intelligence in medicine: a position paper by the Italian Society of Internal Medicine
No full textArtificial Intelligence (AI) represents an innovative technological support for clinical practice. The Italian Society of Internal Medicine (SIMI) emphasizes the need for clear guidance on the use of AI in medicine, recognizing that knowledge in this field is continuously evolving. This position paper presents a comprehensive vision for the responsible integration of AI into clinical practice. AI should serve as a support tool—not a replacement—for clinicians. It has the potential to improve diagnostic accuracy, reduce administrative workload, and strengthen the physician–patient relationship. In the light of these characteristics, SIMI advocates for transparency, data privacy, equity, and sustainability in the development and implemen- tation of AI systems. SIMI also highlights several ethical, legal, and methodological challenges that must be addressed, including algorithmic bias, environmental impact, and disparities in access. Ultimately, SIMI envisions a future in which AI augments human expertise, enabling more efficient, personalized, and compassionate care. SIMI calls for active clinician participation in the co-design and validation of AI tools to ensure alignment with real-world clinical needs. Key recom- mendations include the preferential use of certified AI systems, the integration of AI education into medical training, and continuous monitoring after deployment
AI-powered prostate cancer detection: a multi-centre, multi-scanner validation study
No full textObjectives: Multi-centre, multi-vendor validation of artificial intelligence (AI) software to detect clinically significant prostate cancer (PCa) using multiparametric magnetic resonance imaging (MRI) is lacking. We compared a new AI solution, validated on a separate dataset from different UK hospitals, to the original multidisciplinary team (MDT)-supported radiologist’s interpretations. Materials and methods: A Conformité Européenne (CE)-marked deep-learning (DL) computer-aided detection (CAD) medical device (Pi) was trained to detect Gleason Grade Group (GG) ≥ 2 cancer using retrospective data from the PROSTATEx dataset and five UK hospitals (793 patients). Our separate validation dataset was on six machines from two manufacturers across six sites (252 patients). Data included in the study were from MRI scans performed between August 2018 to October 2022. Patients with a negative MRI who did not undergo biopsy were assumed to be negative (90.4% had prostate-specific antigen density < 0.15 ng/mL2). ROC analysis was used to compare radiologists who used a 5-category suspicion score. Results: GG ≥ 2 prevalence in the validation set was 31%. Evaluated per patient, Pi was non-inferior to radiologists (considering a 10% performance difference as acceptable), with an area under the curve (AUC) of 0.91 vs. 0.95. At the predetermined risk threshold of 3.5, the AI software’s sensitivity was 95% and specificity 67%, while radiologists at Prostate Imaging-Reporting and Data Systems/Likert ≥ 3 identified GG ≥ 2 with a sensitivity of 99% and specificity of 73%. AI performed well per-site (AUC ≥ 0.83) at the patient-level independent of scanner age and field strength. Conclusion: Real-world data testing suggests that Pi matches the performance of MDT-supported radiologists in GG ≥ 2 PCa detection and generalises to multiple sites, scanner vendors, and models. Key Points: Question The performance of artificial intelligence-based medical tools for prostate MRI has yet to be evaluated on multi-centre, multi-vendor data to assess generalisability. Findings A dedicated AI medical tool matches the performance of multidisciplinary team-supported radiologists in prostate cancer detection and generalises to multiple sites and scanners. Clinical relevance This software has the potential to support the MRI process for biopsy decision-making and target identification, but future prospective studies, where lesions identified by artificial intelligence are biopsied separately, are needed
Overcoming Resistance to CDK4/6 inhibitors in Hormone Receptor positive, HER2 negative breast cancer: Innovative Combinations and Emerging Strategies
No full textCyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) improve outcomes patients affected by metastatic and early-stage hormone receptor-positive, HER2-negative breast cancer. However, approximately 20% of these tumors exhibit intrinsic resistance to such therapies, and most develop acquired resistance mechanisms that drive progression. Biomarker analyses of biological samples from patients treated with CDK4/6i plus ET have identified potential targets for therapeutic combinations. In this review, we discuss the mechanisms of action and resistance to CDK4/6i, providing a comprehensive overview of emerging efficacy and safety data, biomarker-driven strategies, and ongoing clinical trials. Finally, we delineate key research priorities aimed at guiding the development of innovative therapeutic combinations
Novel Benchmark for Robotic Liver Resection - Bridging Tradition with Innovation
No full textObjective: To establish benchmark cutoffs for robotic liver resection (R-LR), encompassing both major and minor resections, and to determine the impact of patient selection on outcomes. Background: R-LR is a key advancement in minimally invasive liver surgery but lacks standardized benchmarks, especially for minor resections. While guidelines endorse R-LR, its role in optimizing outcomes remains unclear. This study establishes the first benchmarks for R-LR, enabling comparisons across surgical modalities and refining patient selection. Methods: This retrospective, multicenter study analyzed consecutive adult patients undergoing R-LR at 30 international centers (2020-2023). Benchmark centers had an annual case volume of ≥15 R-LR. Benchmark criteria included ASA ≤2, no major comorbidities, no prior liver resections, and Child-Pugh A status. Benchmark cutoffs for 14 key outcomes were set at the 50th and 75th percentiles of median values across benchmark centers. Multivariable logistic regression identified predictors of textbook outcomes. Results: Eighteen high-volume centers contributed 4028 cases with 2632 (65.3%) meeting benchmark criteria. Malignancy was the indication in 29.6%, most commonly hepatocellular carcinoma followed by colorectal liver metastases. Major liver resection was performed in 42.6%. The distribution of Iwate difficulty scores was low (25.4%), intermediate (53.9%), advanced (15.9%), and expert (4.9%). Benchmark cutoffs were established for minor and major resection, and stratified by Iwate low (0-3), intermediate (4-6) and high (7-12): Open conversion (≤6.5% minor, ≤10.5% major), major complications within 90 days (≤5.2% minor, ≤16.7% major), R1 resection (≤9.2% minor, ≤6.7% major). Benchmark cases performed at low-volume centers were able to achieve outcomes within the corresponding benchmark cutoffs. In fact, patient selection reflected by the proportion of benchmark patients, rather than case volume, was associated with textbook outcomes. Conclusions: This study defines R-LR benchmarks, emphasizing patient selection over center volume for optimal outcomes. Benchmark cutoffs guide training and support the expansion of R-LR
Tricuspid Regurgitation Disease Stages and Treatment Outcomes After Transcatheter Tricuspid Valve Repair
Get PDFBackground: Tricuspid transcatheter edge-to-edge repair (T-TEER) has emerged as a treatment option for patients with severe tricuspid regurgitation (TR). However, randomized trials have not shown a survival benefit, possibly because of the inclusion of patients in an early or too advanced disease stage. Objectives: The authors sought to investigate the association between disease stage and outcomes following T-TEER. Methods: In total, 1,885 patients with significant TR were analyzed, including 585 conservatively treated individuals and 1,300 patients who received T-TEER. Patients were evaluated as part of the prospective EuroTR (European Registry of Transcatheter Repair for Tricuspid Regurgitation) registry and grouped into early, intermediate, and advanced disease stage. Disease stage was based on left and right ventricular function, renal function, and natriuretic peptide levels. The stratification was validated in an external cohort. The primary endpoint was 1-year mortality. Results: Overall, 395 patients (21% [395/1,885]) were categorized as early, 1,173 patients (62% [1,173/1,885]) as intermediate, and 317 patients (17% [317/1,885]) as advanced disease stage. In patients with early and advanced disease, mortality did not differ between interventional and conservative treatment (early-stage HR: 0.78; 95% CI: 0.34-1.80; P = 0.54; advanced stage HR: 1.06; 95% CI: 0.71-1.60; P = 0.78). However, mortality was significantly lower in patients undergoing percutaneous treatment with intermediate disease stage (HR: 0.73; 95% CI: 0.52-0.99; P = 0.03). Conclusions: Compared to medically treated controls, T-TEER was associated with 1-year survival at intermediate stage disease but not at early or advanced disease stages. The timing of T-TEER with regard to disease stages might be crucial to optimize treatment benefits
Cardiac remodelling in the era of the recommended four pillars heart failure medical therapy
No full text: Cardiac remodelling is a key determinant of worse cardiovascular outcome in patients with heart failure (HF) and reduced ejection fraction (HFrEF). It affects both the left ventricle (LV) structure and function as well as the left atrium (LA) and the right ventricle (RV). Guideline recommended medical therapy for HF, including angiotensin-converting enzyme inhibitors/angiotensin receptors II blockers/angiotensin receptor blocker-neprilysin inhibitors (ACE-I/ARB/ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose transport protein 2 inhibitors (SGLT2i), have shown to improve morbidity and mortality in patients with HFrEF. By targeting multiple pathophysiological pathways, foundational HF therapies are supposed to drive their beneficial clinical effects by a direct myocardial effect. Simultaneous initiation of guideline directed medical therapy (GDMT) through a synergistic effect promotes a 'reverse remodelling', leading to a full or partial recovered structure and function by enhancing systemic neurohumoral regulation and energy metabolism, reducing cardiomyocyte apoptosis, lowering oxidative stress and inflammation and adverse extracellular matrix deposition. The aim of this review is to describe how these classes of drugs can drive reverse remodelling in the LV, LA and RV and improve prognosis in patients with HFrEF.Cardiac remodelling is a key determinant of worse cardiovascular outcome in patients with heart failure (HF) and reduced ejection fraction (HFrEF). It affects both the left ventricle (LV) structure and function as well as the left atrium (LA) and the right ventricle (RV). Guideline recommended medical therapy for HF, including angiotensin-converting enzyme inhibitors/angiotensin receptors II blockers/angiotensin receptor blocker-neprilysin inhibitors (ACE-I/ARB/ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose transport protein 2 inhibitors (SGLT2i), have shown to improve morbidity and mortality in patients with HFrEF. By targeting multiple pathophysiological pathways, foundational HF therapies are supposed to drive their beneficial clinical effects by a direct myocardial effect. Simultaneous initiation of guideline directed medical therapy (GDMT) through a synergistic effect promotes a ‘reverse remodelling’, leading to a full or partial recovered structure and function by enhancing systemic neurohumoral regulation and energy metabolism, reducing cardiomyocyte apoptosis, lowering oxidative stress and inflammation and adverse extracellular matrix deposition. The aim of this review is to describe how these classes of drugs can drive reverse remodelling in the LV, LA and RV and improve prognosis in patients with HFrEF
Machine learning based prediction model for bile leak following hepatectomy for liver cancer
No full textObjective: We sought to develop a machine learning (ML) preoperative model to predict bile leak following hepatectomy for primary and secondary liver cancer. Methods: An eXtreme Gradient Boosting (XGBoost) model was developed to predict post-hepatectomy bile leak using data from the ACS-NSQIP database. The model was externally validated using data from hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) multi-institutional databases. Results: Overall, 20,570 and 2253 patients were identified from the ACS-NSQIP and multi-institutional databases, respectively. The incidence rates of bile leak were 7.0 %, 6.3 % and 10.2 % in the ACS-NSQIP, HCC and ICC databases, respectively. The XGBoost model achieved areas under receiver operating characteristic curves (AUROC) of 0.748, 0.719 and 0.711 in the training, testing and external validation cohorts, respectively. The SHAP algorithm demonstrated that the factors most strongly predictive of postoperative bile leak were serum alkaline phosphatase, surgical approach and cancer diagnosis. An online tool was developed for ease-of-use and clinical applicability (https://altaf-pawlik-bileleak-calculator.streamlit.app/). Conclusion: A novel ML model demonstrated strong discrimination power to preoperatively identify patients at high risk of developing bile leak post-hepatectomy. The online calculator may be used as a clinical tool to inform preoperative surgical planning, intraoperative decision-making, and postoperative recovery protocols for patients undergoing hepatectomy