Supporting the decision to perform molecular profiling for cancer patients based on routinely collected data through the use of machine learning.

BACKGROUND: Personalized medicine offers targeted therapy options for cancer treatment. However, the decision whether to include a patient into next-generation sequencing (NGS) testing is not standardized. This may result in some patients receiving unnecessary testing while others who could benefit from it are not tested. Typically, patients who have exhausted conventional treatment options are of interest for consideration in molecularly targeted therapy. To assist clinicians in decision-making, we developed a decision support tool using routine data from a precision oncology program. METHODS: We trained a machine learning model on clinical data to determine whether molecular profiling should be performed for a patient. To validate the model, the model's predictions were compared with decisions made by a molecular tumor board (MTB) using multiple patient case vignettes with their characteristics. RESULTS: The prediction model included 440 patients with molecular profiling and 13,587 patients without testing. High area under the curve (AUC) scores indicated the importance of engineered features in deciding on molecular profiling. Patient age, physical condition, tumor type, metastases, and previous therapies were the most important features. During the validation MTB experts made the same decision of recommending a patient for molecular profiling only in 10 out of 15 of their previous cases but there was agreement between the experts and the model in 9 out of 15 cases. CONCLUSION: Based on a historical cohort, our predictive model has the potential to assist clinicians in deciding whether to perform molecular profiling.

How can current oncological datasets be adjusted to support the automated patient recruitment in clinical trials?

OBJECTIVES: This study aims to identify necessary adjustments required in existing oncological datasets to effectively support automated patient recruitment. METHODS: We extracted and categorized the inclusion and exclusion criteria from 115 oncological trials registered on ClinicalTrials.gov in 2022. These criteria were then compared with the content of the oBDS (Oncological Base Dataset version 3.0), Germany's legally mandated oncological data standard. RESULTS: The analysis revealed that 42.9% of generalized inclusion and exclusion criteria are typically present as data fields in the oBDS. On average, 54.6% of all criteria per trial were covered. Notably, certain criteria such as comorbidities, pregnancy status, and laboratory values frequently appeared in trial protocols but were absent in the oBDS. CONCLUSION: The omission of criteria, notably comorbidities, within the oBDS restricts its functionality to support trial recruitment. Addressing this limitation would enhance its overall effectiveness. Furthermore, the implications of these findings extend beyond Germany, suggesting potential relevance and applicability to oncological datasets globally.

Closing the cancer care gap with a patient-reported nutrition screening: A retrospective analysis of a quality improvement project on an oncology ward (CCC study).

BACKGROUND & AIMS: Early identification of patients at risk for malnutrition followed by individualized nutrition interventions is a central step to the provision of appropriate nutrition care. However, a health care professional (HCP)-based nutrition screening is not always consistently integrated into routine care. Patient-reported (PR) nutrition screening could thus potentially alleviate the burden on the HCPs and contribute to a greater number of patients who are identified and treated for malnutrition. METHODS: In 2021 a Quality Improvement Project (QIP) at our out-patient oncology clinic was undertaken to implement the change from a HCP-based nutrition screening to a PR-screening. This was followed by a retrospective analysis in which the primary outcome measure was the rate of nutrition consultations initiated for patients undergoing cancer therapy. RESULTS: In total n = 1657 patient data sets derived from comparable time periods before and after the QIP were analyzed and compared. Both groups had a comparable mean age and gender distribution. The most common diagnosis in both groups was gastrointestinal tumors. The change in routine care from a HCP-based nutrition screening to a PR-screening led to a significant increase in nutrition consultation rates (RD = 19%; p < 0.001; 95% CI 14.4%-23.5%) and screening rates (RD = 30.5%; p < 0.001; 95% CI 26.2%-34.7%). CONCLUSIONS: The change to PR-screening potentially facilitates an increase in nutrition screening rates. This in turn leads to an increased rate of patients identified at risk for malnutrition and thus referrals for nutrition consultations. Our findings indicate that a PR nutrition screening tool could play a role in closing the care gap and contribute to reducing rates of malnutrition among this population where screening is not consistently integrated into routine care.

Should routine risk reduction procedures for the prevention and control of pandemics become a standard in all oncological outpatient clinics? The prospective COVID-19 cohort study: protect-CoV.

Limited knowledge exists on the effectiveness of preventive preparedness plans for the care of outpatient cancer patients during epidemics or pandemics. To ensure adequate, timely and continuous clinical care for this highly vulnerable population, we propose the establishment of preventive standard safety protocols providing effective early phase identification of outbreaks at outpatient cancer facilities and communicating adapted standards of care. The prospective cohort study Protect-CoV conducted at the LMU Klinikum from mid-March to June 2020 investigated the effectiveness of a rapid, proactive and methodical response to protect patients and interrupt SARS-CoV-2 transmission chains during the first pandemic wave. The implemented measures reduced the risk of infection of individual cancer patients and ensured safe adjunctive infusion therapy in an outpatient setting during the early COVID-19 pandemic. In addition to the immediate implementation of standard hygiene procedures, our results underscore the importance of routine PCR testing for the identification of asymptomatic or pre-symptomatic COVID-19 cases and immediate tracing of positive cases and their contacts. While more prospective controlled studies are needed to confirm these results, our study illustrates the importance of including preventative testing and tracing measures in the standard risk reduction procedures at all out patient cancer centers.

Optimizing the Analytical Value of Oncology-Related Data Based on an In-Memory Analysis Layer: Development and Assessment of the Munich Online Comprehensive Cancer Analysis Platform.

BACKGROUND: Many comprehensive cancer centers incorporate tumor documentation software supplying structured information from the associated centers' oncology patients for internal and external audit purposes. However, much of the documentation data included in these systems often remain unused and unknown by most of the clinicians at the sites. OBJECTIVE: To improve access to such data for analytical purposes, a prerollout of an analysis layer based on the business intelligence software QlikView was implemented. This software allows for the real-time analysis and inspection of oncology-related data. The system is meant to increase access to the data while simultaneously providing tools for user-friendly real-time analytics. METHODS: The system combines in-memory capabilities (based on QlikView software) with innovative techniques that compress the complexity of the data, consequently improving its readability as well as its accessibility for designated end users. Aside from the technical and conceptual components, the software's implementation necessitated a complex system of permission and governance. RESULTS: A continuously running system including daily updates with a user-friendly Web interface and real-time usage was established. This paper introduces its main components and major design ideas. A commented video summarizing and presenting the work can be found within the Multimedia Appendix. CONCLUSIONS: The system has been well-received by a focus group of physicians within an initial prerollout. Aside from improving data transparency, the system's main benefits are its quality and process control capabilities, knowledge discovery, and hypothesis generation. Limitations such as run time, governance, or misinterpretation of data are considered.

Dynamic Survival Analysis Using In-Memory Technology.

In the field of oncology, survival analysis is one of the most important tools in terms of measuring therapy success, evaluating risk or prognostic factors. Within this work, a variety of common survival analyses were embedded into a real-time analysis platform based on a comprehensive oncological dataset. The analysis platform utilizes an in-memory database, therefore allowing spontaneous adjustments of the survival curves to selections and stratifications. In contrast to classical statistics, where individual scripts have to be formulated for every possible request, the running system allows the deduction of instantaneous results.

Tri-country translation, cultural adaptation, and validity confirmation of the Scored Patient-Generated Subjective Global Assessment.

PURPOSE: The Scored Patient-Generated Subjective Global Assessment (PG-SGA) is the only malnutrition (risk) assessment tool that combines patient-generated measures with professional-generated (medical) factors. We aimed to apply international standards to produce a high quality, validated, translation and cultural adaptation of the original PG-SGA for the Austrian, German, and Swiss setting. METHODS: Analogue to methodology used for the Dutch, Portuguese, and Thai versions of PG-SGA, the ten steps of the International Society for Pharmacoeconomics and Outcomes Research's principles of good practice for translation and cultural adaptation were followed. Comprehensibility and difficulty of the translation were assessed in 103 patients and 104 healthcare professionals recruited from all three German-speaking countries. Content validity of the translation was assessed among healthcare professionals (HCP). Item and scale indices were calculated for content validity (I-CVI; S-CVI), comprehensibility (I-CI; S-CI), and difficulty (I-DI; S-DI). RESULTS: Patients' perceived comprehensibility and difficulty of the PG-SGA fell within the range considered to be excellent (S-CI = 0.90, S-DI = 0.90), HCP-perceived content validity (S-CVI = 0.90) was also excellent, while HCP-perceived comprehensibility fell within the high range of acceptable (S-CI = 0.87). The professional component of the PG-SGA was perceived as below acceptable (S-DI = 0.72) with the physical exam being rated the most difficult (I-DI=0.29-0.75). CONCLUSIONS: The systematic approach resulted in a high-quality validation of the German language version of the PG-SGA, that is internationally comparable, comprehensible, easy to complete, and considered relevant for use in Austria, Germany and Switzerland.

Impaired endothelial shear stress induces podosome assembly via VEGF up-regulation.

Podosomes are dynamic cytoskeletal membrane structures with local adhesive and proteolytic activity. They are critically involved in angiogenesis and vascular adaptive growth. Here, we studied in HUVECs and murine small vessels whether shear stress controls podosome assembly and local proteolytic activity. Podosomes were characterized by immunohistochemistry, and their proteolytic activity was assessed as degradation imprints in fluorescent gelatin that was used as growth substrate. Compared with controls (10 dyn/cm(2)), the number of podosomes formed per time was doubled when cells were exposed to low shear stress (0.3 dyn/cm(2)) or even increased 5-fold under static conditions. This was a result of an enhanced expression of VEGF after reduction of shear stress. Consequently, enhanced podosome formation could be prevented by a VEGF receptor antagonist as well by interruption of VEGF signaling via inhibition of PI3K, Src, or p38. Increase of podosome assembly went along with significantly augmented cell motility. In vivo experiments in mouse arteries confirmed increased endothelial podosome numbers when shear stress was abolished by vessel occlusion. We conclude that shear stress, by reducing VEGF release, inhibits podosome assembly. Hence, endothelial cell-mediated matrix proteolysis and migratory activity are inhibited, thereby stabilizing the structure of the vessel wall.-Fey, T., Schubert, K. M., Schneider, H., Fein, E., Kleinert, E., Pohl, U., Dendorfer, A. Impaired endothelial shear stress induces podosome assembly via VEGF up-regulation.

AMPK Dilates Resistance Arteries via Activation of SERCA and BKCa Channels in Smooth Muscle.

The protective effects of 5'-AMP-activated protein kinase (AMPK) on the metabolic syndrome may include direct effects on resistance artery vasomotor function. However, the precise actions of AMPK on microvessels and their potential interaction are largely unknown. Thus, we set to determine the effects of AMPK activation on vascular smooth muscle tone and the underlying mechanisms. Resistance arteries isolated from hamster and mouse exhibited a pronounced endothelium-independent dilation on direct pharmacological AMPK activation by 2 structurally unrelated compounds (PT1 and A769662). The dilation was associated with a decrease of intracellular-free calcium [Ca(2+)]i in vascular smooth muscle cell. AMPK stimulation induced activation of BKCa channels as assessed by patch clamp studies in freshly isolated hamster vascular smooth muscle cell and confirmed by direct proof of membrane hyperpolarization in intact arteries. The BKCa channel blocker iberiotoxin abolished the hyperpolarization but only partially reduced the dilation and did not affect the decrease of [Ca(2+)]i. By contrast, the sarcoplasmic/endoplasmic Ca(2+)-ATPase (SERCA) inhibitor thapsigargin largely reduced these effects, whereas combined inhibition of SERCA and BKCa channels virtually abolished them. AMPK stimulation significantly increased the phosphorylation of the SERCA modulator phospholamban at the regulatory T17 site. Stimulation of smooth muscle AMPK represents a new, potent vasodilator mechanism in resistance vessels. AMPK directly relaxes vascular smooth muscle cell by a decrease of [Ca(2+)]i. This is achieved by calcium sequestration via SERCA activation, as well as activation of BKCa channels. There is in part a mutual compensation of both calcium-lowering mechanisms. However, SERCA activation which involves an AMPK-dependent phosphorylation of phospholamban is the predominant mechanism in resistance vessels.

Knockout of mitochondrial thioredoxin reductase stabilizes prolyl hydroxylase 2 and inhibits tumor growth and tumor-derived angiogenesis.

AIMS: Mitochondrial thioredoxin reductase (Txnrd2) is a central player in the control of mitochondrial hydrogen peroxide (H2O2) abundance by serving as a direct electron donor to the thioredoxin-peroxiredoxin axis. In this study, we investigated the impact of targeted disruption of Txnrd2 on tumor growth. RESULTS: Tumor cells with a Txnrd2 deficiency failed to activate hypoxia-inducible factor-1α (Hif-1α) signaling; it rather caused PHD2 accumulation, Hif-1α degradation and decreased vascular endothelial growth factor (VEGF) levels, ultimately leading to reduced tumor growth and tumor vascularization. Increased c-Jun NH2-terminal Kinase (JNK) activation proved to be the molecular link between the loss of Txnrd2, an altered mitochondrial redox balance with compensatory upregulation of glutaredoxin-2, and elevated PHD2 expression. INNOVATION: Our data provide compelling evidence for a yet-unrecognized mitochondrial Txnrd-driven, regulatory mechanism that ultimately prevents cellular Hif-1α accumulation. In addition, simultaneous targeting of both the mitochondrial thioredoxin and glutathione systems was used as an efficient therapeutic approach in hindering tumor growth. CONCLUSION: This work demonstrates an unexpected regulatory link between mitochondrial Txnrd and the JNK-PHD2-Hif-1α axis, which highlights how the loss of Txnrd2 and the resulting altered mitochondrial redox balance impairs tumor growth as well as tumor-related angiogenesis. Furthermore, it opens a new avenue for a therapeutic approach to hinder tumor growth by the simultaneous targeting of both the mitochondrial thioredoxin and glutathione systems.