Background & Aims
Colonization with multidrug‐resistant organisms (MDRO) has been shown to impair survival in patients with various malignancies. Despite the increasing spread of MDRO, its impact on ...patients with cholangiocarcinoma (CCA) is unclear. Aim of this study was to analyse the impact of MDRO‐colonization on overall prognosis in CCA patients.
Methods
All patients with surgically resected CCA diagnosed between August 2005 and November 2021 at the University Hospital Frankfurt were screened for MDRO. CCA patients with a positive MDRO screening before or within the first 90 days after diagnosis of CCA were defined as colonized. Patients with a negative MDRO screening were defined as non‐colonized.
Results
Hundred and sixty nine patients were included. 32% (n = 54) were screened MDRO positive, while 68% (115) were non‐colonized. Median overall survival (OS) for colonized patients was 17.1 months (95% CI = 9–25.2 months) compared to 50 months (95% CI = 37.1–62.8) for MDRO‐negative patients (p ≤ .001). Non‐cancer‐related mortality (p ≤ .001) and infectious‐related death (p ≤ .001) was significantly higher in the MDRO‐colonized group. In multivariate analysis, MDRO colonization (HR = 2.1, 95% CI = 1.4–3.3, p = .001), ECOG 1 (HR = 2.5, 95% CI = 1.6–4, p ≤ .001) and N1 status (HR = 1.7, 95% CI = 1.1–2.6, p = .017) were independent risk factors for OS.
Conclusion
MDRO‐colonization contributes to poor survival in patients with surgically resected CCA. MDRO surveillance is necessary to optimize clinical management of infections and to potentially reduce mortality in this critical population.
Intrahepatic cholangiocarcinoma (iCCA) is the most frequent subtype of cholangiocarcinoma (CCA), and the incidence has globally increased in recent years. In contrast to surgically treated iCCA, data ...on the impact of fibrosis on survival in patients undergoing palliative chemotherapy are missing. We retrospectively analyzed the cases of 70 patients diagnosed with iCCA between 2007 and 2020 in our tertiary hospital. Histopathological assessment of fibrosis was performed by an expert hepatobiliary pathologist. Additionally, the fibrosis-4 score (FIB-4) was calculated as a non-invasive surrogate marker for liver fibrosis. For overall survival (OS) and progression-free survival (PFS), Kaplan-Meier curves and Cox-regression analyses were performed. Subgroup analyses revealed a median OS of 21 months (95% CI = 16.7-25.2 months) and 16 months (95% CI = 7.6-24.4 months) for low and high fibrosis, respectively (
0.152). In non-cirrhotic patients, the median OS was 21.8 months (95% CI = 17.1-26.4 months), compared with 9.5 months (95% CI = 4.6-14.3 months) in cirrhotic patients (
0.007). In conclusion, patients with iCCA and cirrhosis receiving palliative chemotherapy have decreased OS rates, while fibrosis has no significant impact on OS or PFS. These patients should not be prevented from state-of-the-art first-line chemotherapy.
Induction of autophagy can have beneficial effects in several human diseases, e.g. cancer and neurodegenerative diseases (ND). Here, we therefore evaluated the potential of two novel ...autophagy-inducing compounds, i.e. STF-62247 and pimozide, to stimulate autophagy as well as autophagic cell death (ACD) using mouse embryonic fibroblasts (MEFs) as a cellular model. Importantly, both STF-62247 and pimozide triggered several hallmarks of autophagy in MEFs, i.e. enhanced levels of LC3B-II protein, its accumulation at distinct cytosolic sites and increase of the autophagic flux. Intriguingly, autophagy induction by STF-62247 and pimozide resulted in cell death that was significantly reduced in ATG5- or ATG7-deficient MEFs. Consistent with ACD induction, pharmacological inhibitors of apoptosis, necroptosis or ferroptosis failed to protect MEFs from STF-62247- or pimozide-triggered cell death. Interestingly, at subtoxic concentrations, pimozide stimulated fragmentation of the mitochondrial network, degradation of mitochondrial proteins (i.e. mitofusin-2 and cytochrome c oxidase IV (COXIV)) as well as a decrease of the mitochondrial mass, indicative of autophagic degradation of mitochondria by pimozide. In conclusion, this study provides novel insights into the induction of selective autophagy as well as ACD by STF-62247 and pimozide in MEFs.
Artificial intelligence (AI) holds the potential to make significant advancements in pathology. However, its actual implementation and certification for practical use are currently limited, often due ...to challenges related to model transferability. In this context, we investigate the factors influencing transferability and present methods aimed at enhancing the utilization of AI algorithms in pathology.
Various convolutional neural networks (CNNs) and vision transformers (ViTs) were trained using datasets from two institutions, along with the publicly available TCGA-MIBC dataset. These networks conducted predictions in urothelial tissue and intrahepatic cholangiocarcinoma (iCCA). The objective was to illustrate the impact of stain normalization, the influence of various artifacts during both training and testing, as well as the effects of the NoisyEnsemble method.
We were able to demonstrate that stain normalization of slides from different institutions has a significant positive effect on the inter-institutional transferability of CNNs and ViTs (respectively +13% and +10%). In addition, ViTs usually achieve a higher accuracy in the external test (here +1.5%). Similarly, we showcased how artifacts in test data can negatively affect CNN predictions and how incorporating these artifacts during training leads to improvements. Lastly, NoisyEnsembles of CNNs (better than ViTs) were shown to enhance transferability across different tissues and research questions (+7% Bladder, +15% iCCA).
It is crucial to be aware of the transferability challenge: achieving good performance during development does not necessarily translate to good performance in real-world applications. The inclusion of existing methods to enhance transferability, such as stain normalization and NoisyEnsemble, and their ongoing refinement, is of importance.
Fluorescence-based confocal microscopy (FCM) can be used to create virtual H&E sections in real time. So far, FCM has been used in dermato-, uro-, and gynecopathology. FCM allows the creation of ...a completely digitized frozen section, which could potentially replace conventional frozen sections in the future.
The aim of the current work is to implement FCM technology as a component of fully digitized processes in the pathological workflow. For this purpose, the current use of FCM in liver transplant pathology will be extended to other disciplines such as urology and otorhinolaryngology.
The FCM technique continues to be used prospectively on native tissue samples from potential donor livers. Conventional frozen sections are used comparatively to virtual FCM scans.
The data show a nearly perfect agreement for the detection of cholangitis, fibrosis, and malignancy, and a high level of agreement for, e.g., macrovesicular steatosis, inflammation, steatohepatitis, and necrosis between virtual FCM scans and conventional routine diagnostic frozen sections.
Since the availability of time- and cost-intensive frozen section diagnostics in the context of transplant pathology in continuous operation (24/7) is now only established at very few university centers in Germany due to an increasing shortage of specialists, the use of FCM could be an important building block in the current process leading towards a fully digitized pathology workflow and should thus be extended to various disciplines.
Zusammenfassung
Ziel der Arbeit
Künstliche Intelligenz hat das Potenzial, in der Pathologie weitreichende Fortschritte zu erzielen. Doch die tatsächliche Anwendung und Zertifizierung für die Praxis ...bleibt begrenzt, oft aufgrund von Herausforderungen bei der Transferierbarkeit von Modellen. In diesem Kontext untersuchen wir die Faktoren, die die Transferierbarkeit beeinflussen, und präsentieren Methoden, die dazu beitragen, die Nutzung von KI-Algorithmen in der Pathologie zu verbessern.
Material und Methoden
Mithilfe von Datensätzen aus 2 Instituten und dem öffentlich zugänglichen TCGA-MBIC-Datensatz (TCGA, The Cancer Genome Atlas) wurden Convolutional Neural Networks (CNN) und Vision Transformer (ViT) für Vorhersagen an Urothelgewebe (Karzinom- vs. Normalgewebe) und an intrahepatischen Cholangiokarzinomen (iCCA, „small vs. large duct“) trainiert. Veranschaulicht wird der Einfluss von Farbnormalisierung, Bildartefakten in Training und Anwendung sowie der NoisyEnsemble-Methode.
Ergebnisse
Wir konnten demonstrieren, dass Farbnormalisierung von Gewebeschnitten einen positiven Effekt auf die Interinstitutstransferierbarkeit von CNNs und ViTs hat (respektive +13 % und +10 %) und ViTs meist eine höhere Genauigkeit im externen Test erzielen (hier +1,5 %). Ebenso konnten wir zeigen, dass Artefakte in Testdaten die Vorhersagen von CNNs negativ beeinflusst und dass das Einbeziehen dieser Artefakte während des Trainings zu einer Verbesserung führt. Schließlich erhöhen NoisyEnsembles aus CNNs (besser als aus ViTs) auf verschiedenen Geweben und Fragestellungen die Transferierbarkeit (+7 % Blase, +15 % iCCA).
Diskussion
Wichtig ist vor allem, sich dem Problem der Transferierbarkeit bewusst zu sein: Gute Performance in der Entwicklung bedeutet nicht gute Performance in der Anwendung. Der Einbezug vieler bereits existierender Methoden zur Verbesserung der Transferierbarkeit, wie z. B. Farbnormalisierung und NoisyEnsemble, und deren Weiterentwicklung sind von großer Wichtigkeit.
Zusammenfassung
Hintergrund
Mit Hilfe der fluoreszenzbasierten Konfokalmikroskopie (FCM) lassen sich virtuelle HE-Schnitte in Echtzeit erstellen. Bislang findet die FCM Anwendung in der Derma‑/Uro- ...und Gynäkopathologie. Die FCM eröffnet die Perspektive eines digitalen Gefrierschnitts, der den herkömmlichen Gefrierschnitt in Zukunft ersetzen könnte.
Ziel der Arbeit (Fragestellung)
Ziel unserer aktuellen Arbeit ist die Implementierung der FCM als Bestandteil vollständig digitalisierter Abläufe im pathologischen Workflow. Hierfür wird der aktuelle Einsatz der FCM in der Transplantationspathologie auf weitere Fachdisziplinen wie Urologie und HNO ausgeweitet.
Material und Methoden
Der Einsatz der FCM-Technik erfolgt aktuell weiterhin prospektiv bei nativen Gewebeproben potenzieller Spenderlebern. Die herkömmliche Schnellschnittdiagnostik in Gefriertechnik wird vergleichend zu virtuellen FCM-Scans angewandt.
Ergebnisse
Die Daten zeigen eine nahezu perfekte Übereinstimmung für den Nachweis von Cholangitis, Fibrose und Malignität sowie ein hohes Maß an Übereinstimmung für z. B. makrovesikuläre Steatose, Entzündung, Steatohepatitis und Nekrose zwischen virtuellem FCM-Scan und herkömmlichen Schnellschnitt.
Schlussfolgerung
Da die Verfügbarkeit der zeit-, und kostenintensiven Schnellschnittdiagnostik im Rahmen der Transplantationspathologie im Dauerbetrieb (24/7) aufgrund eines zunehmenden Fachkräftemangels mittlerweile nur noch an sehr wenigen universitären Zentren in Deutschland etabliert ist, könnte der Einsatz der FCM-Technik ein wichtiger Baustein im aktuellen Prozess hin zu einer vollständig digitalisierten Pathologie sein und sollte somit auf verschiedene Fachdisziplinen ausgeweitet werden.
In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, ...multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺
-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺
-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺
-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.
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