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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.
With the rapid improvements in machine learning and deep learning, decisions made by automated decision support systems (DSS) will increase. Besides the accuracy of predictions, their explainability becomes more important. The algorithms can construct complex mathematical prediction models. This causes insecurity to the predictions. The insecurity rises the need for equipping the algorithms with explanations. To examine how users trust automated DSS, an experiment was conducted. Our research aim is to examine how participants supported by an DSS revise their initial prediction by four varying approaches (treatments) in a between-subject design study. The four treatments differ in the degree of explainability to understand the predictions of the system. First we used an interpretable regression model, second a Random Forest (considered to be a black box [BB]), third the BB with a local explanation and last the BB with a global explanation. We noticed that all participants improved their predictions after receiving an advice whether it was a complete BB or an BB with an explanation. The major finding was that interpretable models were not incorporated more in the decision process than BB models or BB models with explanations.
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.
In the era of personalized medicine, the identification of driver mutations has paved the way towards targeted therapy. With the identification of anaplastic lymphoma kinase (ALK) as an oncogenic driver mutation, ALK rearrangements became druggable by tyrosine kinase inhibitors and, thus, have improved the prognosis for patients. Nevertheless, these approaches are limited by resistances occurring within the first or second year of administering ALK inhibitors. Among the different ALK resistant mutations, G1202R is the most common mutation, located in the kinase domain of the ALK protein resulting in resistance to treatment with the first- and second-generation kinase inhibitors (e.g., crizotinib, ceritinib, brigatenib and alectinib). Conflicting reports exist regarding the efficacy of lorlatinib, a next generation ALK inhibitor. The aim of this study is to access the potential impact of lorlatinib as a second-line treatment for a metastatic progressive NSCLC disease harboring genomic alteration of ALK G1202R, an AKLi-resistant mutation. The case of a patient with advanced lung cancer and the mentioned mutation is described.
SARS-CoV-2 antibody development and immunity will be crucial for the further course of the pandemic. Until now, it has been assumed that patients who are infected with SARS-CoV-2 will develop antibodies as has been the case with other coronaviruses, like MERS-CoV and SARS-CoV. In the present study, we analyzed the development of antibodies in 77 patients with an oncologic diagnosis 26 days after positive RT-qPCR testing for SARS-CoV2. RT-qPCR and anti-SARS-CoV2-antibody methods from BGI (MGIEasy Magnetic Beads Virus DNA/RNA Extraction Kit) and Roche (Elecsys Anti-SARS-CoV-2 immunoassay) were used, respectively, according to the manufacturers’ specifications. Surprisingly, antibody development was detected in only 6 of 77 individuals with a confirmed history of COVID-19. Despite multiple testing, the remaining patients did not show measurable antibody concentrations in subsequent tests. These results undermine the previous hypothesis that SARS-CoV2 infections are regularly associated with antibody development and cast doubt on the provided immunity to COVID-19. Understanding the adaptive and humoral response to SARS-CoV2 will play a key role in vaccine development and gaining further knowledge on the pathogenesis.
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.
Oncologic patients are regarded as the population most at risk of developing a severe course of COVID-19 due to the fact that malignant diseases and chemotherapy often weaken the immune system. In the face of the ongoing SARS-CoV-2 pandemic, how particular patients deal with this infection remains an important question. In the period between the 15 and 26 April 2020, a total of 1227 patients were tested in one of seven oncologic outpatient clinics for SARS-CoV-2, regardless of symptoms, employing RT-qPCR. Of 1227 patients, 78 (6.4%) were tested positive of SARS-CoV-2. Only one of the patients who tested positive developed a severe form of COVID-19 with pneumonia (CURB-65 score of 2), and two patients showed mild symptoms. Fourteen of 75 asymptomatic but positively tested patients received chemotherapy or chemo-immunotherapy according to their regular therapy algorithm (±4 weeks of SARS-CoV-2 test), and 48 of 78 (61.5%) positive-tested patients received glucocorticoids as co-medication. None of the asymptomatic infected patients showed unexpected complications due to the SARS-CoV-2 infection during the cancer treatment. These data clearly contrast the view that patients with an oncologic disease are particularly vulnerable to SARS-CoV-2 and suggest that compromising therapies could be continued or started despite the ongoing pandemic. Moreover the relatively low appearance of symptoms due to COVID-19 among patients on chemotherapy and other immunosuppressive co-medication like glucocorticoids indicate that suppressing the response capacity of the immune system reduces disease severity.
After several years of negative phase III trials in gastric and esophageal cancer, a significant breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is now becoming evident with the emerging of precision oncology and implementation of molecular targets in tumor treatment. In addition, new generation studies such as umbrella and basket trials are focused on these molecular targets, which makes an early molecular diagnosis based on IHC/ISH and NGS necessary. The required companion diagnostics of Her2neu overamplification or PD-L1 expression is based on immunohistochemistry (IHC) or additionally in situ hybridization (ISH) in case of an IHC Her2neu score of 2+. However, there are investigator-dependent differences in the assessment of Her2neu amplification and different PD-L1 scoring systems obtained by IHC/ISH. The use of high-throughput technologies such as next-generation sequencing (NGS) holds the potential to standardize the analysis and thus make them more comparable. In the presented study, real-world multigene sequencing data of 72 Caucasian patients diagnosed with metastatic adenocarcinomas of GEJ and stomach were analyzed. In the clinical companion diagnostics, we found ESCAT level I molecular targets in one-third of our patients, which directly determined the therapy. In addition, we found potential targets in 14/72 patients (19.4%) who potentially qualify for precision therapies in corresponding molecular studies. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment.