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Artificial Intelligence ( ai ) systems are precious support for decision-making, with many applications also in the medical domain. The interaction between md s and ai enjoys a renewed interest following the increased possibilities of deep learning devices. However, we still have limited evidence-based knowledge of the context, design, and psychological mechanisms that craft an optimal human– ai collaboration. In this multicentric study, 21 endoscopists reviewed 504 videos of lesions prospectively acquired from real colonoscopies. They were asked to provide an optical diagnosis with and without the assistance of an ai support system. Endoscopists were influenced by ai ( O R = 3.05 ), but not erratically: they followed the ai advice more when it was correct ( O R = 3.48 ) than incorrect ( O R = 1.85 ). Endoscopists achieved this outcome through a weighted integration of their and the ai opinions, considering the case-by-case estimations of the two reliabilities. This Bayesian-like rational behavior allowed the human– ai hybrid team to outperform both agents taken alone. We discuss the features of the human– ai interaction that determined this favorable outcome.

Accurate in-vivo optical characterization of colorectal polyps is key to select the optimal treatment regimen during colonoscopy. However, reported accuracies vary widely among endoscopists. We developed a novel intelligent medical device able to seamlessly operate in real-time using conventional white light (WL) endoscopy video stream without virtual chromoendoscopy (blue light, BL). In this work, we evaluated the standalone performance of this computer-aided diagnosis device (CADx) on a prospectively acquired dataset of unaltered colonoscopy videos. An international group of endoscopists performed optical characterization of each polyp acquired in a prospective study, blinded to both histology and CADx result, by means of an online platform enabling careful video assessment. Colorectal polyps were categorized by reviewers, subdivided into 10 experts and 11 non-experts endoscopists, and by the CADx as either “adenoma” or “non-adenoma”. A total of 513 polyps from 165 patients were assessed. CADx accuracy in WL was found comparable to the accuracy of expert endoscopists (CADx WL /Exp; OR 1.211 [0.766–1.915]) using histopathology as the reference standard. Moreover, CADx accuracy in WL was found superior to the accuracy of non-expert endoscopists (CADx WL /NonExp; OR 1.875 [1.191–2.953]), and CADx accuracy in BL was found comparable to it (CADx BL /CADx WL ; OR 0.886 [0.612–1.282]). The proposed intelligent device shows the potential to support non-expert endoscopists in systematically reaching the performances of expert endoscopists in optical characterization.

Previous experimental and clinical studies suggested a beneficial effect of statins, metformin, angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers (RASi) on portal hypertension. Still, their effects on hard cirrhosis-related clinical endpoints, such as variceal bleeding and bleeding-related mortality, remain to be investigated. Thus, we recorded the use of statins, metformin and RASi in a large cohort of cirrhotic patients undergoing endoscopic band ligation (EBL) for primary (PP, n = 440) and secondary bleeding prophylaxis (SP, n = 480) between 01/2000 and 05/2020. Variceal (re-) bleeding and survival rates were compared between patients with vs. without these co-medications. A total of 920 cirrhotic patients with varices were included. At first EBL, median MELD was 13 and 515 (56%) patients showed ascites. Statins, metformin and RASi were used by 49 (5.3%), 74 (8%), and 91 (9.9%) patients, respectively. MELD and platelet counts were similar in patients with and without the co-medications of interest. Rates of first variceal bleeding and variceal rebleeding at 2 years were 5.2% and 11.7%, respectively. Neither of the co-medications were associated with decreased first bleeding rates (log-rank tests in PP: statins p = 0.813, metformin p = 0.862, RASi p = 0.919) nor rebleeding rates (log-rank tests in SP: statin p = 0.113, metformin p = 0.348, RASi p = 0.273). Similar mortality rates were documented in patients with and without co-medications for PP (log-rank tests: statins p = 0.630, metformin p = 0.591, RASi p = 0.064) and for SP (statins p = 0.720, metformin p = 0.584, RASi p = 0.118). In clinical practice, variceal bleeding and mortality rates of cirrhotic patients were not reduced by co-medication with statins, metformin or RASi. Nevertheless, we recommend the use of these co-medications by indication, as they may still exert beneficial effects on non-bleeding complications in patients with liver cirrhosis.

In cirrhotic patients, portal hypertension (PHT) deteriorates survival, yet treatment options are limited. A major contributor to increased intrahepatic vasoconstriction in PHT is dysfunctional nitric-oxide signaling. Soluble guanylate cyclase (sGC) is the receptor of nitric-oxide and can be stimulated by riociguat. Riociguat is approved for pulmonary hypertension but has not been studied in liver cirrhosis. In this study we assessed the effects of riociguat on PHT and liver fibrosis in cholestatic (bile duct ligation, BDL) and toxic (carbon-tetrachloride, CCl4) rat models. In cirrhotic livers sGC expression was upregulated. In BDL rats, riociguat reduced liver fibrosis and decreased portal pressure without affecting systemic hemodynamics. In an early BDL disease stage, riociguat decreased bile duct proliferation, improved sinusoidal vascular dysfunction and inhibited angiogenesis. In advanced BDL riociguat exhibited anti-inflammatory effects. In CCl4 rats the beneficial effects of riociguat treatment were less pronounced and confined to an early disease stage. Similarly, in patients with cholestatic cirrhosis and PHT nitrates (that induce sGC activity) decreased portal pressure more effectively than in patients with non-cholestatic etiology. We also found an improvement of transaminases in patients with pulmonary hypertension receiving riociguat. Our findings support the clinical development of sGC stimulators in patients with cirrhotic PHT.

Purpose of ReviewThe natural history and classification systems of small varices (≤ 5 mm in diameter) in cirrhotic patients with portal hypertension are summarized. Studies that assessed the course of and therapeutic intervention for small varices are discussed.Recent FindingsCurrent non-invasive methods show suboptimal sensitivity to detect small varices in patients with cirrhosis. Next to etiological therapy, hepatic venous pressure gradient (HVPG)-guided non-selective betablocker or carvedilol treatment has shown to impact on natural history of small varices.SummaryThe main therapeutic focus in cirrhotic patients with small varices is the cure of the underlying etiology. The optimal management of small varices should include measurement of HVPG. A pharmacological decrease in HVPG by non-selective betablocker therapy of ≥ 10% reduces the risk of progression to large varices, first variceal bleeding, and hepatic decompensation. If HVPG is not available, we would recommend carvedilol 12.5 mg q.d. for treatment of small varices in compensated patients without severe ascites. Only if small esophageal varices (EV) are not treated or in hemodynamic non-responders, follow-up endoscopies should be performed in 1–2 years of intervals considering the activity of liver disease or if hepatic decompensation occurs.

To the Editor: In their article on the PAPILLON trial, Zhou et al. (Nov. 30 issue) 1 describe the promising efficacy of amivantamab plus chemotherapy in patients with untreated advanced non–small-cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) exon 20 insertions. However, highly relevant questions remain open concerning the cardiovascular safety of amivantamab-based therapies, an issue that has been raised in previous studies. 2-4 In particular, a high risk of venous thromboembolism (VTE) was reported in several trials investigating amivantamab in NSCLC as compared with control therapies, with the incidence of VTE ranging from 10% with amivantamab to 21 to . . .

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Inflammation is gradually compartmentalized and restricted to specific tissue niches such as the lesion rim. However, the precise cell type composition of such niches, their interactions and changes between chronic active and inactive stages are incompletely understood. We used single-nucleus and spatial transcriptomics from subcortical MS and corresponding control tissues to map cell types and associated pathways to lesion and nonlesion areas. We identified niches such as perivascular spaces, the inflamed lesion rim or the lesion core that are associated with the glial scar and a cilia-forming astrocyte subtype. Focusing on the inflamed rim of chronic active lesions, we uncovered cell–cell communication events between myeloid, endothelial and glial cell types. Our results provide insight into the cellular composition, multicellular programs and intercellular communication in tissue niches along the conversion from a homeostatic to a dysfunctional state underlying lesion progression in MS. Lerma-Martin et al. generated a paired single-nucleus RNA sequencing and spatial transcriptomics dataset from subcortical multiple sclerosis lesions, identifying spatial niches and key cell interactions driving inflammation and disease progression at the lesion rim.

Medical oncology is rapidly evolving with the implementation of personalized, targeted therapies. Advances in molecular diagnostics and the biologic understanding of cancer pathophysiology led to the identification of specific genetic alterations as drivers of cancer progression. Further, improvements in drug development enable the direct interference with these pathways, which allow tailoring personalized treatments based on a distinct molecular characterization of tumors. Thereby, we are currently experiencing a paradigm-shift in the treatment of cancers towards cancer-type agnostic, molecularly targeted, personalized therapies. However, this concept has several important hurdles and limitations to overcome to ultimately increase the proportion of patients benefitting from the precision oncology approach. These include the assessment of clinical relevancy of identified alterations, capturing and interpreting levels of heterogeneity based on intra-tumoral or time-dependent molecular evolution, and challenges in the practical implementation of precision oncology in routine clinical care. In the present review, we summarize the current state of cancer-agnostic precision oncology, discuss the concept of molecular tumor boards, and consider current limitations of personalized cancer therapy. Further, we provide an outlook towards potential future developments including the implementation of functionality assessments of identified genetic alterations and the broader use of liquid biopsies in order to obtain more comprehensive and longitudinal genetic information that might guide personalized cancer therapy in the future.

Despite advances in metastatic colorectal cancer (mCRC) treatment, long-term survival remains poor, particularly in right-sided colorectal cancer (RCRC), which has a worse prognosis compared to left-sided CRC (LCRC). This disparity is driven by the complex biological diversity of these malignancies. RCRC and LCRC differ not only in clinical presentation and outcomes but also in their underlying molecular and genetic profiles. This article offers a detailed literature review focusing on the distinctions between RCRC and LCRC. We explore key differences across embryology, anatomy, pathology, omics, and the tumor microenvironment (TME), providing insights into how these factors contribute to prognosis and therapeutic responses. Furthermore, we examine the therapeutic implications of these differences, considering whether the conventional classification of CRC into right- and left-sided forms should be refined. Recent molecular findings suggest that this binary classification may overlook critical biological complexities. Therefore, we propose that future approaches should integrate molecular insights to better guide personalized treatments, especially anti-EGFR therapies, and improve patient outcomes.