A Multidisciplinary Hyper-Modeling Scheme in Personalized In Silico Oncology: Coupling Cell Kinetics with Metabolism, Signaling Networks, and Biomechanics as Plug-In Component Models of a Cancer Digital Twin.

The massive amount of human biological, imaging, and clinical data produced by multiple and diverse sources necessitates integrative modeling approaches able to summarize all this information into answers to specific clinical questions. In this paper, we present a hypermodeling scheme able to combine models of diverse cancer aspects regardless of their underlying method or scale. Describing tissue-scale cancer cell proliferation, biomechanical tumor growth, nutrient transport, genomic-scale aberrant cancer cell metabolism, and cell-signaling pathways that regulate the cellular response to therapy, the hypermodel integrates mutation, miRNA expression, imaging, and clinical data. The constituting hypomodels, as well as their orchestration and links, are described. Two specific cancer types, Wilms tumor (nephroblastoma) and non-small cell lung cancer, are addressed as proof-of-concept study cases. Personalized simulations of the actual anatomy of a patient have been conducted. The hypermodel has also been applied to predict tumor control after radiotherapy and the relationship between tumor proliferative activity and response to neoadjuvant chemotherapy. Our innovative hypermodel holds promise as a digital twin-based clinical decision support system and as the core of future in silico trial platforms, although additional retrospective adaptation and validation are necessary.

On the Methodological Aspects of the Clinical Trials for COVID-19 Conducted in the First Year of the Pandemic: A Descriptive Analysis.

In 2020, the whole planet was plagued by the extremely deadly COVID-19 pandemic. More than 83 million people had been infected with COVID-19 while more than 1.9 million people around the planet had died from this virus in the first year of the pandemic. From the first moment, the medical community started working to deal with this pandemic. For this reason, many clinical trials have been and continue to be conducted to find a safe and efficient cure for the virus. In this paper, we review the 96 clinical trials, registered in the ClinicalTrials.gov database, that had been completed by the end of the first year of the pandemic. Although the clinical trials contained significant heterogeneity in the main methodological features (enrollment, duration, allocation, intervention model, and masking) they seemed to be conducted based on an appropriate methodological basis.

Bilateral hypoplasia of the internal carotid artery and ectasia of the internal jugular vein.

Hypoplasia of the internal carotid artery and internal jugular vein ectasia are rare congenital abnormalities, whose diagnosis and treatment are not uniformly described. A 32-year-old neurologically asymptomatic woman with renal failure had a carotid artery duplex ultrasound scan as part of an evaluation for renal transplantation and was found to have bilateral internal carotid artery hypoplasia. Computed tomography angiography confirmed congenital bilateral internal carotid artery stenosis and left internal jugular vein ectasia. She had no neurologic deficits. She underwent antiplatelet treatment.

Case report of a patient with VEXAS syndrome.

RATIONALE: Hematological malignancies have always been a challenge for scientists because there is a constant need to better define these entities. Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis. Cytogenetics and molecular findings are a prerequisite for these syndromes as they confirm the clonal nature of the disease. However, MDS is often linked to autoimmunity and inflammation as part of its pathogenesis. Recently, VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) linked these two in a single mutation, suggesting that the heterogeneity among hematological malignancies often demands a more personalized medicine by tailoring medical treatment to the individual characteristics of each patient. PATIENT CONCERNS: We present a case of VEXAS syndrome regarding a 63-year-old male patient who initially presented with episodes of low fever, polyarthritis of the knees and ankles, polymyalgia, and fatigue. His laboratory examinations revealed increased levels of serum inflammatory markers. DIAGNOSES: Diagnosis was based on high clinical suspicion, laboratory findings, and vacuolization of the erythroid and myeloid precursors in the bone marrow evaluation. Mutational status of ubiquitin-like modifier activating enzyme 1 gene was positive with a 68.8% allelomorph frequency (rs782416867). INTERVENTIONS: Therapy was based on controlling inflammation with the use of glucocorticoids and treating MDS-related anemia with the use of erythropoietin. OUTCOMES: Currently, the patient visits our department regularly. He is still receiving the aforementioned treatment. He did not mention any new incidents for the time being. LESSONS: VEXAS syndrome as a newly identified entity might be often underestimated since its clinical presentation is notably diverse.

Spontaneous tumor lysis syndrome in patients with solid tumors: a scoping review of the literature.

No systematic synthesis of all cases of spontaneous tumor lysis syndrome (STLS) in adult patients with solid tumors is available to date. Herein, we aim to recognize specific STLS characteristics and parameters related to a worse prognosis. We conducted a systematic search for randomized controlled trials, cohorts, case-control studies, and case reports. The primary endpoints were death and the need for renal replacement therapy (RRT) due to STLS. We estimated crude odds ratios (ORs) with 95% confidence intervals (95%CI) via univariate binary logistic regression. We included one cohort of 9 patients and 66 case reports of 71 patients [lung cancer 15(21.1%)]. Regarding the case reports, most patients [61(87.1%)] had metastatic disease [liver 46(75.4%)], developed acute kidney injury [59(83.1%)], needed RRT [25(37.3%)], and died due to STLS [36(55.4%)]. Metastatic disease, especially in the liver [p = 0.035; OR (95%CI): 9.88 (1.09, 89.29)] or lungs [p = 0.024; 14.00 (1.37, 142.89)], was significantly associated with STLS-related death compared to no metastasis. Cases resulting in death had a significantly higher probability of receiving rasburicase monotherapy than receiving no urate-lowering agents [p = 0.034; 5.33 (1.09, 26.61)], or the allopurinol-rasburicase combination [p = 0.023; 7.47 (1.40, 39.84)]. Patients receiving allopurinol were less likely to need RRT compared to those not receiving it or those receiving rasburicase. In conclusion, current anecdotal evidence demonstrated that metastatic disease, especially in the liver and lungs, may be associated with STLS-related death compared to no metastatic status. Careful surveillance of high-risk cases within larger studies is essential to identify markers predicting morbidity or mortality.

Percutaneous Ablation of Metastatic Lymph Nodes: An Insight from the Comparison of Efficacy and Safety Between Cryoablation and Radiofrequency Ablation.

PURPOSE: To retrospectively compare efficacy and safety of computed tomography (CT)-guided percutaneous ablation of metastatic lymph nodes (LN) between cryoablation (CA) and radiofrequency ablation (RFA). MATERIALS AND METHODS: A bi-central institutional database research identified 28 patients (42 metastatic LNs) who underwent percutaneous CT-guided ablation. RFA group included 18 patients/26 tumors; CA group included 10 patients/16 tumors. Contrast-enhanced CT or MRI was used for post-ablation follow-up. Patient and tumor characteristics, technical and clinical success on a per tumor and a per patient basis and complication rates were recorded, evaluated and compared between the 2 groups. RESULTS: Both RFA and CA groups had the same median tumor size (2.00 vs. 2.20 cm, p = 0.257), the same median follow-up time (20.50 vs. 20.00 months, p = 0.923) and the same median length of hospital stay (1.00 vs. 1.00 days, p = 0.283). CA group had a higher median procedure time (110.50 vs. 52.00 min, p = 0.001). On a per lesion basis, the overall complete response post-ablation was 88.46% (23/26 lesions) in the RFA and 93.75% (15/16 lesions) in the CA group; no association was revealed between local tumor control and ablation technique (p = 0.709). No complications were recorded in both Groups. On a per patient basis, CA had a longer disease-free interval (24.00 vs. 14.50, p = 0.012) which, however, did not affect the overall survival between the two techniques (26.0 vs. 22.0, p = 0.099 for CA and RFA respectively). CONCLUSION: Our limited data suggest that CT-guided RFA and CA are equally effective on terms of efficacy and safety for the treatment of metastatic lymph nodes.

A Modular Repository-based Infrastructure for Simulation Model Storage and Execution Support in the Context of In Silico Oncology and In Silico Medicine.

The plethora of available disease prediction models and the ongoing process of their application into clinical practice - following their clinical validation - have created new needs regarding their efficient handling and exploitation. Consolidation of software implementations, descriptive information, and supportive tools in a single place, offering persistent storage as well as proper management of execution results, is a priority, especially with respect to the needs of large healthcare providers. At the same time, modelers should be able to access these storage facilities under special rights, in order to upgrade and maintain their work. In addition, the end users should be provided with all the necessary interfaces for model execution and effortless result retrieval. We therefore propose a software infrastructure, based on a tool, model and data repository that handles the storage of models and pertinent execution-related data, along with functionalities for execution management, communication with third-party applications, user-friendly interfaces to access and use the infrastructure with minimal effort and basic security features.

Functional p53 can modulate the relationship between E2F-1 expression and tumor kinetics in Hodgkin lymphoma.

E2F-1 is the best-described member of the E2F family of transcriptional factors and is particularly interesting in view of its often opposing roles. Our purpose was to examine the immunohistochemical expression of E2F-1 in Hodgkin lymphoma (HL) and to correlate it with proliferation and apoptosis of the tumor, clinicopathological parameters and patient outcome, as well as with expression of the downstream molecules p53 and p21. The median percentage of E2F-1-expressing Hodgkin Reed-Sternberg (HRS) cells was 80.2%. A significant positive correlation was found between expression of E2F-1 and p53 (p = 0.034). Following stratification of our cases, within the group harboring functional p53, a statistically significant inverse correlation was identified between E2F-1 and Topo IIa (p = 0.019). E2F-1 is up-regulated in the context of HL and its expression is inversely associated with proliferation. It seems that functional p53 can modulate the relationship between E2F-1 expression and tumor kinetics in HL.

Prognostic significance of immunohistochemical expression of the angiogenic molecules vascular endothelial growth factor-A, vascular endothelial growth factor receptor-1 and vascular endothelial growth factor receptor-2 in patients with classical Hodgkin lymphoma.

Angiogenesis leads to new blood vessel formation and is implicated in both physiological and pathological situations. The vascular endothelial growth factor (VEGF) family is the major mediator of this process. The aim of our study was to evaluate the expression of VEGF-A, vascular endothelial growth factor receptor-1 (VEGFR-1) and VEGFR-2 and their correlation with clinicopathological parameters and prognosis in patients with classical Hodgkin lymphoma (cHL), since the role of angiogenesis in this tumor still remains unclear. The immunohistochemical expression of VEGF-A, VEGFR-1 and VEGFR-2 was examined in 194 patients with cHL. The neoplastic Hodgkin Reed-Sternberg (HRS) cells expressed VEGF-A, VEGFR-1 and VEGFR-2 in 90.3%, 97.2% and 94.1% of cases, respectively. Only the expression of VEGFR-2 was positively correlated with serum albumin levels ≥ 4 g/dL. No correlation with patient outcome was observed. All three molecules were statistically correlated with ramifications of blood vessels. Summarizing, our results are not sufficient to consider VEGF-A and/or VEGF receptors as prognosticators in cHL.

The technologically integrated oncosimulator: combining multiscale cancer modeling with information technology in the in silico oncology context.

This paper outlines the major components and function of the technologically integrated oncosimulator developed primarily within the Advancing Clinico Genomic Trials on Cancer (ACGT) project. The Oncosimulator is defined as an information technology system simulating in vivo tumor response to therapeutic modalities within the clinical trial context. Chemotherapy in the neoadjuvant setting, according to two real clinical trials concerning nephroblastoma and breast cancer, has been considered. The spatiotemporal simulation module embedded in the Oncosimulator is based on the multiscale, predominantly top-down, discrete entity-discrete event cancer simulation technique developed by the In Silico Oncology Group, National Technical University of Athens. The technology modules include multiscale data handling, image processing, invocation of code execution via a spreadsheet-inspired environment portal, execution of the code on the grid, and the visualization of the predictions. A refining scenario for the eventual coupling of the oncosimulator with immunological models is also presented. Parameter values have been adapted to multiscale clinical trial data in a consistent way, thus supporting the predictive potential of the oncosimulator. Indicative results demonstrating various aspects of the clinical adaptation and validation process are presented. Completion of these processes is expected to pave the way for the clinical translation of the system.

Towards in silico oncology: adapting a four dimensional nephroblastoma treatment model to a clinical trial case based on multi-method sensitivity analysis.

In the past decades a great progress in cancer research has been made although medical treatment is still widely based on empirically established protocols which have many limitations. Computational models address such limitations by providing insight into the complex biological mechanisms of tumor progression. A set of clinically-oriented, multiscale models of solid tumor dynamics has been developed by the In Silico Oncology Group (ISOG), Institute of Communication and Computer Systems (ICCS)-National Technical University of Athens (NTUA) to study cancer growth and response to treatment. Within this context using certain representative parameter values, tumor growth and response have been modeled under a cancer preoperative chemotherapy protocol in the framework of the SIOP 2001/GPOH clinical trial. A thorough cross-method sensitivity analysis of the model has been performed. Based on the sensitivity analysis results, a reasonable adaptation of the values of the model parameters to a real clinical case of bilateral nephroblastomatosis has been achieved. The analysis presented supports the potential of the model for the study and eventually the future design of personalized treatment schemes and/or schedules using the data obtained from in vitro experiments and clinical studies.

Exploiting clinical trial data drastically narrows the window of possible solutions to the problem of clinical adaptation of a multiscale cancer model.

The development of computational models for simulating tumor growth and response to treatment has gained significant momentum during the last few decades. At the dawn of the era of personalized medicine, providing insight into complex mechanisms involved in cancer and contributing to patient-specific therapy optimization constitute particularly inspiring pursuits. The in silico oncology community is facing the great challenge of effectively translating simulation models into clinical practice, which presupposes a thorough sensitivity analysis, adaptation and validation process based on real clinical data. In this paper, the behavior of a clinically-oriented, multiscale model of solid tumor response to chemotherapy is investigated, using the paradigm of nephroblastoma response to preoperative chemotherapy in the context of the SIOP/GPOH clinical trial. A sorting of the model's parameters according to the magnitude of their effect on the output has unveiled the relative importance of the corresponding biological mechanisms; major impact on the result of therapy is credited to the oxygenation and nutrient availability status of the tumor and the balance between the symmetric and asymmetric modes of stem cell division. The effect of a number of parameter combinations on the extent of chemotherapy-induced tumor shrinkage and on the tumor's growth rate are discussed. A real clinical case of nephroblastoma has served as a proof of principle study case, demonstrating the basics of an ongoing clinical adaptation and validation process. By using clinical data in conjunction with plausible values of model parameters, an excellent fit of the model to the available medical data of the selected nephroblastoma case has been achieved, in terms of both volume reduction and histological constitution of the tumor. In this context, the exploitation of multiscale clinical data drastically narrows the window of possible solutions to the clinical adaptation problem.