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Background Personalized mRNA vaccines are promising new therapeutic options for patients with cancer. Because mRNA vaccines are not yet approved for first-line therapy, the vaccines are presently applied to individuals that received prior therapies that can have immunocompromising effects. There is a need to address how prior treatments impact mRNA vaccine outcomes.
Method Therefore, we analyzed the response to BioNTech/Pfizer’s anti-SARS-CoV-2 mRNA vaccine in 237 oncology outpatients, which cover a broad spectrum of hematologic malignancies and solid tumors and a variety of treatments. Patients were stratified by the time interval between the last treatment and first vaccination and by the presence or absence of florid tumors and IgG titers and T cell responses were analyzed 14 days after the second vaccination.
Results Regardless of the last treatment time point, our data indicate that vaccination responses in patients with checkpoint inhibition were comparable to healthy controls. In contrast, patients after chemotherapy or cortisone therapy did not develop an immune response until 6 months after the last systemic therapy and patients after Cht-immune checkpoint inhibitor and tyrosine kinase inhibitor therapy only after 12 months.
Conclusion Accordingly, our data support that timing of mRNA-based therapy is critical and we suggest that at least a 6-months or 12-months waiting interval should be observed before mRNA vaccination in systemically treated patients.
Usability is considered a major success factor for current and future decision support systems. Such systems are increasingly used to assist human decision-makers in high-stakes tasks in complex domains such as health care, jurisdiction or finance. Yet, many if not most expert systems—especially in health care—fail to deliver the degree of quality in terms of usability that its expert users are used to from their personal digital consumer products. In this article, we focus on clinical decision support systems (CDSS) as an example for how important a human-centered design approach is when designing complex software in complex contexts. We provide an overview of CDSS classes, discuss the importance of systematically exploring mental models of users, and formulate challenges and opportunities of future design work on CDSS. We further provide a case study from a current research project to illustrate how we used codesign as a practical approach to produce usable software in a real-world context.
Practical Relevance: We make a point for usability to be considered a major success factor and non-negotiable characteristic of expert software. With software evolving into virtual coworkers in terms of supporting human decision-making in complex, high-risk domains, the necessity of and demand for systems that are unambiguously understandable and interpretable for their expert users have never been higher. We show that this is a real-world problem with high practical relevance by describing our work in the domain of clinical decision support systems (CDSS) as an example. We introduce the topic and a classification of CDSS. Thus, we highlight a conceptual framework of how to approach complex domains from a technology designer’s point of view. We continue by explaining why usability must be regarded as a major goal in software development. We derive challenges and opportunities that may well be transferred to other domains. Finally, be including a real-world example from our own professional work we propose a practical approach towards taking the challenges and exploiting the associated opportunities.
Background
To date, targeted tyrosine kinase inhibitors have been approved for FGFR2 and FGFR3 fusions (pemigatinib and erdafitinib, respectively), but the importance of FGFR2 mutations for transformation activity and as a druggable gene variant with response to different FGFR inhibitors is poorly understood. FGFR2 inhibitors present a mainstay of treatment for locally advanced or metastatic intrahepatic cholangiocellular carcinoma (iCCA).
Methods
A 74-year-old male was diagnosed with iCCA in liver segments seven and eight with infiltration of the hepatic veins and inferior vena cava revealed a C382R mutation of the intramembrane domain of FGRR2 receptor. We performed an in-silico study to understand the potential mode-of-action of the mutant FGFR2 targets. Based on experimentally determined structures we then used a structure generated by AlphaFold2 as the variation in question is located at a position not determined well in the experiments. This revealed that the C382R mutation is located in the trans-membranal domain at a position crucial for signal transduction, both for activation and inhibition of downstream-signaling. The Molecular Tumor Board decided to start the treatment with 13.5 mg pemigatinib once daily for 14 days, followed by 7 days of free therapy interval resulting in a sustained partial response. The patient continues to be treated of 13.5 mg as described above.
Results
In our case report, we were able to show that the patient in whom an C382R mutation was detected responded to the therapy with pemigatinib. This shows that real-world scenarios differ from the data of the approval studies, thereby illustrating how complex data on patients with FGFR mutations is. One of the main problems of large approval studies is that the functionality of the respective alterations is often disregarded.
Conclusions
Our results suggest that respective mutation may be successfully targeted by FGFR-selective tyrosine-kinase inhibitors, demonstrating the importance of the functional characterization of mutations.
no conflicts of interest.
Point mutations of the fibroblast growth factor receptor (FGFR)2 receptor in intrahepatic cholangiocarcinoma (iCC) are mainly of unknown functional significance compared to FGFR2 fusions. Pemigatinib, a tyrosine kinase inhibitor, is approved for the treatment of cholangiocarcinoma with FGFR2 fusion/rearrangement. Although it is hypothesized that FGFR2 mutations may cause uncontrolled activation of the signaling pathway, the data for targeted therapies for FGFR2 mutations remain unclear. In vitro analyses demonstrated the importance of the p.C382R mutation for ligand-independent constitutive activation of FGFR2 with transforming potential. The following report describes the clinical case of a patient diagnosed with an iCC carrying a FGFR2 p.C382R point mutation which was detected in liquid, as well as in tissue-based biopsies. The patient was treated with pemigatinib, resulting in a sustained complete functional remission in fluorodeoxyglucose-positron emission tomography/computed tomography over 10 months to date. The reported case is the first description of a complete functional remission under the treatment with pemigatinib in a patient with p.C383R mutation.
Background:
Data on SARS-CoV-2 infections in oncological patients in the outpatient settings are scarce.
Methods:
During the spread of the delta variant between April 2021 and September 2021, a total of 10.677 patients were tested for SARS-CoV-2 infection by RT-qPCR in seven outpatient clinics in Bavaria, Germany.
Results:
Within the tested patient cohort, 4.960 patients (46.5%) suffered from a malignant disease (74% solid tumors and 26% malignant hematological diseases). This group was compared with 5.717 patients (53.5%) without a malignant disease (33.1% with other hematological diseases and 66.9% patients without a hematological or oncological disease). During the observation period, 119 (2.4%) patients with malignancies were tested positive (88 patients with solid tumors; 31 patients with malignant hematological diseases) compared to 115 positive patients (2.0%) in the control group. 32 of 119 positively tested patients (26.9%) suffering from malignant disease required hospitalization and 9/32 patients (28.1%) died during the clinical course.
Conclusions:
These observations are in clear contrast to data from patients we evaluated during the pre-delta variants period between 15 and 26 April 2020 in the same seven outpatient clinics. In this period, a total of 1.227 patients were tested for SARS-CoV-2 by RT-qPCR. 78/1227 patients (6.3%) were tested positive in RT-qPCR and most showed mild symptoms of infection. None of the SARS-CoV-2 infected patients died. These data were analyzed when no vaccination was available. These data were evaluated during a period where no vaccine was available. Vaccination of patients with malignancies with BiontechPfizer's mRNA vaccines was started in April 2021. The response to the vaccine was tested by an antibody assay (Elecsys Anti-SARS-CoV-2 S-immunoassay, Roche) at the earliest four weeks after the second vaccination. To assess the response, we compared five patient cohorts: Patients who received (i) B cell depleting antibodies, (ii) checkpoint inhibitors (ICI), (iii) chemotherapy, or (iv) tyrosin kinase inhibitors (TKIs), and (v) healthy controls. The patients treated with ICI or TKI showed a comparable vaccination response to the healthy patients, while patients receiving Rituximab/Obinutuzumab showed no significant humoral vaccination response at all. The more severe disease course of patients infected by the SARS-CoV-2 delta variant compared to the initial waves of infections strongly underline the importance of vaccination in cancer patients.
German cancer registries offer a systematic approach for the collection, storage, and management of data on patients with cancer and related diseases. Much hope in research and healthcare in general is depending on such register-based analyses in order to comprehensively consider the features of a highly diverse population. Next to the data collection the cancer registries are responsible for data protection. To fulfill legal regulations, access to data has to be controlled in a strict way leading to sometimes bureaucratic and slow processes. The situation is especially complicated in Germany, since cancer data is distributed over numerous federal cancer registries. If a nationwide data evaluation is conducted a research team has to negotiate a separate contract with each cancer registry.In a joint work in progress effort of cancer registries, technical, medical, and economical experts we propose a different solution for cooperative data processing. Our approach aims for combining data in a virtual pool based on the selection criteria of individual requests from researchers. To achieve our goal, we adapt the Fraunhofer Medical Data Space as enabling technology. The architecture we propose will allow us to pool data of multiple partners regulated by data access policies. In doing so, each of the data sources can introduce its own rules and specifications on how data is used. Additionally, we add a digital consent management that will allow individual patients to decide how their data is used. Finally, we show the high potential of the cooperative analysis of distributed cancer data supported by the proposed solution in our approach.
Der Einsatz künstlicher Intelligenz (KI) wird unsere Lebenswirklichkeit nachhaltig beeinflussen. Mittels technischer Verfahren maschinellen Lernens oder tiefer neuronaler Netze können Modelle aus existierenden Datenbeständen gelernt und Vorhersagen abgeleitet werden. Wir stellen skizzenartig zwei aktuelle Projekte vor, die sich u.a. mit den Potentialen und der menschzentrierten Gestaltung von Systemen künstlicher Intelligenz beschäftigen. Wir betten dies schlaglichtartig in den Kontext der aktuellen Debatte über die Entwicklung und Gestaltung von KI Systemen ein. Im Zuge dessen umreißen wir Herausforderungen und Chancen für die partizipative und sozialverantwortliche Technologieentwicklung von komplexen und auf Verfahren der künstlichen Intelligenz basierenden Systemen. Schließlich fokussieren wir dabei auf die Arbeitsebene und beschreiben kurz, welche konkreten Aktivitäten wir planen und stellen diese zur Diskussion.
Artificial Intelligence (AI) and Machine Learning (ML) promise to significantly enhance the capabilities of decision support systems in medicine. Yet, if these systems fail to providean understandable rationale of the decision making process the adoption of this powerful technology will be difficult. Hence, there is growing interest in Explainable Artificial Intelligence (XAI). Explanations that speak the language of the user are a cornerstone for Fair AI. In this position paper, we reflect on research about XAI and designing decision support in medicine. From there, we lay out an approach to use co-design methodology to explore how users perceive and interact with explanations of decision support systems.