Metformin Regulates the miR-205/VEGFA Axis in Renal Cell Carcinoma Cells: Exploring a Clinical Synergism with Tyrosine Kinase Inhibitors.

INTRODUCTION: Metformin (MF) intake could be associated with a favorable outcome in sunitinib (SUT)- and axitinib (AX)-treated clear cell renal cell carcinoma (ccRCC) patients. Functionally, MF induces miR-205, a microRNA serving as a tumor suppressor in several cancers. METHODS: Real-time quantitative PCR, viability assays, and Western blotting analyzed MF and SUT/AX effects in RCC4 and 786-O cells. A tetracycline-inducible overexpression model was used to study the role of miR-205 and its known target gene, VEGFA. We analyzed miR-205 and VEGFA within a public and an in-house ccRCC cohort. Human umbilical vein endothelial cell (HUVEC) sprouting assays examined miR-205 effects on angiogenesis initiation. To determine the influence of the von Hippel-Lindau tumor suppressor (VHL), we examined VHLwt reexpressing RCC4 and 786-O cells. RESULTS: Viability assays confirmed a sensitizing effect of MF toward SUT/AX in RCC4 and 786-O cells. Overexpression of miR-205 diminished VEGFA expression - as did treatment with MF. Tumor tissue displayed a downregulation of miR-205 and an upregulation of VEGFA. Accordingly, miR-205 caused less and shorter vessel sprouts in HUVEC assays. Finally, VHLwt-expressing RCC4 and 786-O cells displayed higher miR-205 and lower VEGFA levels. CONCLUSION: Our results support the protective role of MF in ccRCC and offer functional insights into the clinical synergism with tyrosine kinase inhibitors.

Determinants of COVID-19 Disease Severity-Lessons from Primary and Secondary Immune Disorders including Cancer.

At the beginning of the COVID-19 pandemic, patients with primary and secondary immune disorders-including patients suffering from cancer-were generally regarded as a high-risk population in terms of COVID-19 disease severity and mortality. By now, scientific evidence indicates that there is substantial heterogeneity regarding the vulnerability towards COVID-19 in patients with immune disorders. In this review, we aimed to summarize the current knowledge about the effect of coexistent immune disorders on COVID-19 disease severity and vaccination response. In this context, we also regarded cancer as a secondary immune disorder. While patients with hematological malignancies displayed lower seroconversion rates after vaccination in some studies, a majority of cancer patients' risk factors for severe COVID-19 disease were either inherent (such as metastatic or progressive disease) or comparable to the general population (age, male gender and comorbidities such as kidney or liver disease). A deeper understanding is needed to better define patient subgroups at a higher risk for severe COVID-19 disease courses. At the same time, immune disorders as functional disease models offer further insights into the role of specific immune cells and cytokines when orchestrating the immune response towards SARS-CoV-2 infection. Longitudinal serological studies are urgently needed to determine the extent and the duration of SARS-CoV-2 immunity in the general population, as well as immune-compromised and oncological patients.

Aplastic Anemia as a Roadmap for Bone Marrow Failure: An Overview and a Clinical Workflow.

In recent years, it has become increasingly apparent that bone marrow (BM) failures and myeloid malignancy predisposition syndromes are characterized by a wide phenotypic spectrum and that these diseases must be considered in the differential diagnosis of children and adults with unexplained hematopoiesis defects. Clinically, hypocellular BM failure still represents a challenge in pathobiology-guided treatment. There are three fundamental topics that emerged from our review of the existing data. An exogenous stressor, an immune defect, and a constitutional genetic defect fuel a vicious cycle of hematopoietic stem cells, immune niches, and stroma compartments. A wide phenotypic spectrum exists for inherited and acquired BM failures and predispositions to myeloid malignancies. In order to effectively manage patients, it is crucial to establish the right diagnosis. New theragnostic windows can be revealed by exploring BM failure pathomechanisms.

Usability and diagnostic accuracy of different MRI/ultrasound-guided fusion biopsy systems for the detection of clinically significant and insignificant prostate cancer: a prospective cohort study.

PURPOSE: To explore the usability and diagnostic accuracy for prostate cancer of three multiparametric magnetic resonance imaging (mpMRI)/transrectal ultrasound (TRUS)-guided fusion biopsy systems operated by the same urologists. METHODS: We performed a prospective, observational study including patients that underwent prostate biopsy due to a visible lesion in mpMRI (PI-RADS ≥ 3). We consecutively assessed two platforms with a rigid image registration (BioJet, D&K Technologies and UroNav, Invivo Corporation) and one with an elastic registration (Trinity, KOELIS). Four urologists evaluated each fusion system in terms of usability based on the System Usability Scale and diagnostic accuracy based on the detection of prostate cancer. RESULTS: We enrolled 60 consecutive patients that received mpMRI/TRUS-guided prostate biopsy with the BioJet (n = 20), UroNav (n = 20) or Trinity (n = 20) fusion system. Comparing the rigid with the elastic registration systems, the rigid registration systems were more user-friendly compared to the elastic registration systems (p = 0.012). Similarly, the prostate biopsy with the rigid registration systems had a shorter duration compared to the elastic registration system (p < 0.001). Overall, 40 cases of prostate cancer were detected. Of them, both the BioJet and UroNav fusion systems detected 13 prostate cancer cases, while the Trinity detected 14. No significant differences were demonstrated among the three fusion biopsy systems in terms of highest ISUP Grade Group (p > 0.99). CONCLUSIONS: Rigid fusion biopsy systems are easier to use and provide shorter operative time compared to elastic systems, while both types of platforms display similar detection rates for prostate cancer. Still, further high-quality, long-term results are mandatory.

68Ga-PSMA I&T PET/CT for primary staging of prostate cancer.

PURPOSE: The present study is based on a retrospective analysis of Gallium-68 (68Ga)-labelled prostate-specific membrane antigen (68Ga-PSMA I&T) PET/CT performed in newly diagnosed, treatment-naïve prostate cancer (PCa) patients prior to definitive treatment. METHODS: A total of 82 men were included in the study and were imaged with 68Ga-PSMA I&T PET/CT to assess the distribution of PSMA-avid disease for staging purposes (11 with low-risk, 32 with intermediate-risk, and 39 with high-risk PCa). Forty patients (20 with intermediate- and 20 with high-risk disease) underwent subsequent radical prostatectomy with extended pelvic lymph node dissection which allowed for correlation of imaging findings with histopathologic data. RESULTS: PSMA-positive disease was detected in 83% of patients with 66/82 (80.5%) primary tumours being visualized. PSMA-avid lymph nodes were recorded in 17/82 patients (20.7%, 3 with intermediate-risk and 14 with high-risk PCa); distant disease was found in 14/82 subjects (17.1%, 2 with intermediate-risk and 12 with high-risk PCa). No extraprostatic disease was found in low-risk PCa. SUVmax of primary tumours showed a weak but significant correlation with serum PSA values (r = 0.51, p < 0.001) and Gleason scores (GSC; r = 0.35, p = 0.001), respectively. In correlation with histopathology, calculated per-region sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for detection of lymph node metastases were 35.0%, 98.4%, 63.6%, 95.0%, and 93.0%, respectively. CONCLUSIONS: In patients with initial diagnosis of intermediate- and high-risk prostate cancer, 68Ga-PSMA I&T PET/CT emerges as a relevant staging procedure by identifying nodal and/or distant metastases. Due to the low prevalence of extraprostatic disease, its value seems to be limited in low-risk disease.

The Role of Magnetic Resonance Imaging in the Diagnosis of Penile Fracture in Real-Life Emergency Settings: Comparative Analysis with Intraoperative Findings.

PURPOSE: We evaluated the role of magnetic resonance imaging of the penis in the diagnosis of penile fracture and/or concomitant urethral lesions in real-life emergency settings compared with intraoperative findings. MATERIALS AND METHODS: A total of 43 patients presented with suspicion of penile fracture between January 2006 and December 2016. Magnetic resonance imaging was performed in 28 patients prior to surgical treatment in the emergency setting. Surgery was done in all patients via a subcoronal, circumferential degloving approach. We calculated sensitivity, specificity, and positive and negative predictive values as well as likelihood ratios of the positive and negative results of the agreement between magnetic resonance imaging and intraoperative findings. RESULTS: Intraoperatively penile fracture was confirmed in 19 of 28 patients (67.9%) and a concomitant urethral lesion was observed in 5 of 28 (17.9%). Magnetic resonance imaging findings were highly associated with intraoperative findings of tunical rupture, including 100% sensitivity (95% CI 98.5-100), 77.8% specificity (95% CI 50.6-100), 90.5% positive predictive value (95% CI 78-100), 100% negative predictive value (95% CI 97.6-100) and a positive result likelihood ratio of 4.5. Magnetic resonance imaging had lower accuracy for urethral lesions with 60% sensitivity (95% CI 17.1-100), 78.3% specificity (95% CI 61.5-95.1), 37.5% positive predictive value (95% CI 4-71), 90% negative predictive value (95% CI 76.9-100) and a positive result likelihood ratio of 2.76. CONCLUSIONS: Magnetic resonance imaging may be applicable in the emergency setting if the goal is to treat all men who warrant intervention. It has high sensitivity and negative predictive value for tunical rupture and concomitant urethral lesions. Therefore, it could help avoid unnecessary surgery by excluding the diagnosis. However, solitary magnetic resonance imaging is not sufficient for diagnosis and it should not replace clinical assessment or delay surgical exploration.

miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo.

BACKGROUND: Despite latest advances in prostate cancer (PCa) therapy, PCa remains the third-leading cause of cancer-related death in European men. Dysregulation of microRNAs (miRNAs), small non-coding RNA molecules with gene expression regulatory function, has been reported in all types of epithelial and haematological cancers. In particular, miR-221-5p alterations have been reported in PCa. METHODS: miRNA expression data was retrieved from a comprehensive publicly available dataset of 218 PCa patients (GSE21036) and miR-221-5p expression levels were analysed. The functional role of miR-221-5p was characterised in androgen- dependent and androgen- independent PCa cell line models (C4-2 and PC-3M-Pro4 cells) by miR-221-5p overexpression and knock-down experiments. The metastatic potential of highly aggressive PC-3M-Pro4 cells overexpressing miR-221-5p was determined by studying extravasation in a zebrafish model. Finally, the effect of miR-221-5p overexpression on the growth of PC-3M-Pro4luc2 cells in vivo was studied by orthotopic implantation in male Balb/cByJ nude mice and assessment of tumor growth. RESULTS: Analysis of microRNA expression dataset for human primary and metastatic PCa samples and control normal adjacent benign prostate revealed miR-221-5p to be significantly downregulated in PCa compared to normal prostate tissue and in metastasis compared to primary PCa. Our in vitro data suggest that miR-221-5p overexpression reduced PCa cell proliferation and colony formation. Furthermore, miR-221-5p overexpression dramatically reduced migration of PCa cells, which was associated with differential expression of selected EMT markers. The functional changes of miR-221-5p overexpression were reversible by the loss of miR-221-5p levels, indicating that the tumor suppressive effects were specific to miR-221-5p. Additionally, miR-221-5p overexpression significantly reduced PC-3M-Pro4 cell extravasation and metastasis formation in a zebrafish model and decreased tumor burden in an orthotopic mouse model of PCa. CONCLUSIONS: Together these data strongly support a tumor suppressive role of miR-221-5p in the context of PCa and its potential as therapeutic target.

Cognitive Status and Functional Dexterity as Outcome Predictors Following Urinary Diversion: A Combined Retrospective and Prospective Observational Study.

PURPOSE: The study aimed to evaluate the impact of the validated functional dexterity test and the Mini-Mental Status test on subjective functional outcomes, medical care situation, and health-related quality of life (HRQoL) after urinary diversion (UD). PATIENTS AND METHODS: A total of 106 patients (n = 26 ileal conduits, n = 29 neobladders, and n = 51 ileocecal pouches) were included in this combined retrospective (n = 77) and prospective (n = 29) observational study. All patients performed the 2 tests mentioned above and filled out self-designed questionnaires with diversion and HRQoL items. In the prospective cohort, the tests were performed preoperatively and the questionnaires were filled out preoperatively as well as 3 and 6 months after surgery. RESULTS: Reduced dexterity and cognitive skills were significantly associated with increased patient age and subjective constraints in stoma care of ileal conduits, self-catheterization in ileocecal pouches, and continence in neobladders. Overall HRQoL, however, was not affected by dexterity or cognitive measures. CONCLUSIONS: Assessing the cognitive status and functional dexterity of patients undergoing UD might provide a useful objective clinical tool to aid in decision-making regarding the type of UD and postoperative medical care situation. Further prospective data are needed to confirm these findings and further simplify the methods used here.

Preoperative C-Reactive Protein Values as a Potential Component in Outcome Prediction Models of Metastasized Renal Cell Carcinoma Patients Receiving Cytoreductive Nephrectomy.

PURPOSE: To validate preoperative C-reactive protein (CRP) levels as a prognostic marker for survival in a metastasized renal cell carcinoma (mRCC) patient cohort receiving cytoreductive nephrectomy (CN). PATIENTS AND METHODS: By chart review, 146 mRCC patients receiving CN at our tertiary referral centre from 1997 to 2015 were identified retrospectively. All relevant clinicopathological features including laboratory parameters were collected and correlated to overall survival, progression-free survival and cancer-specific survival (CSS). The mean follow-up was 23 months (range 1-168 months). RESULTS: Besides the already established scoring systems like the MSKCC criteria, an elevated preoperative CRP level (≥0.5 mg/dL) was an independent predictor of CSS in our study group including the chosen postoperative adjuvant therapies (TKI vs. immunotherapy vs. others). With regard to morbidity, patients with a good performance status, small tumour size and adequate renal function/haematopoiesis experienced less complication rates, thereby profiting more from CN. CONCLUSIONS: Our data provide indication that preoperative CRP levels should be implemented in nomograms regarding the outcome prediction in mRCC to identify candidates likely to profit from CN.

Diagnosis and Clinical Management of Ruptured Ileocecal Pouches for Continent Cutaneous Urinary Diversion.

BACKGROUND AND OBJECTIVES: The study aimed to report on pouch ruptures in 5 patients with ileocecal reservoirs for continent cutaneous urinary diversion. PATIENTS AND METHODS: Five male patients aged 48-89 were referred to our department between 2000 and 2016 with a ruptured ileocecal pouch 16-175 months postoperatively. RESULTS: With an incidence of 0.95% in our series (5 ruptures in 529 pouch patients out of a pool of 1,182 radical cystectomies) a rupture of the ileocecal pouch is a rare but severe complication. In all the cases, the rupture was supported by the over-distension of the reservoir, while a traumatic self-catheterization was reported in 2 patients. The rupture occurred on the right lateral wall of the ileocecal pouch in 4 out of 5 cases and led to acute abdominal pain and inflammation. Pouchography was performed in all the patients and revealed a leakage in 4 of them. The rupture was verified intraoperatively in 1 patient. Open surgical exploration, drainage and repair were successfully performed in all 5 cases. CONCLUSIONS: Early diagnosis and immediate intervention are mandatory in the cases of pouch rupture to manage this severe complication, which is often related to reduction in patient compliance. Consequently, it is essential to raise awareness of this potentially life-threatening complication in patients with ileocecal pouches.

Long-Term Outcome of Nephron-Sparing Surgery Compared to Radical Nephrectomy for Renal Cell Carcinoma ≥4 cm - A Matched-Pair Single Institution Analysis.

PURPOSE: We investigated the long-term oncological and functional outcome of nephron-sparing surgery/partial nephrectomy (PN) versus radical nephrectomy (RN) for any renal cell carcinoma (RCC) ≥4 cm. PATIENTS AND METHODS: Between 1997 and 2013, we identified 128 patients undergoing PN for RCC ≥4 cm and matched this collective to 128 patients undergoing RN. We then compared overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS) and functional parameters in both groups. The median follow-up time was 58 months (3-210 months). RESULTS: Compared to RN, patients with a PN showed a significantly higher 10-year OS (77.0 vs. 63.0%, p = 0.04), CSS (90.6 vs. 71.7%, p = 0.002) and PFS (82.9 vs. 57.4%, p ≤ 0.001). Renal function preservation was better in the PN group (24 months estimated glomerular filtration rate: 68.2 ml/min for PN vs. 40.6 ml/min for RN, p ≤ 0.01) with significantly less new onset chronic kidney diseases. Total complication rate was comparable, whereas PN procedures showed more Clavien-Dindo grade I + II complications, portraying the technical challenge of PN in larger RCCs. CONCLUSIONS: Whenever feasible, PN should be considered for renal masses ≥4 cm, as this technique shows better long-term results regarding disease-specific survival and renal function preservation in our study group.

Metformin-Derived Growth Inhibition in Renal Cell Carcinoma Depends on miR-21-Mediated PTEN Expression.

PURPOSE: Metformin (MF) acts as a tumour-suppressor in renal cell carcinoma (RCC) by inhibiting the AKT/mTOR pathway via AMPK activation. Here, we explore the influence of miR-21 and its target gene PTEN on MF effects in CAKI-1 and CAKI-2 cells. METHODS: Proliferation assays (MTS) and qRT-PCR after transient transfection with pre- and anti-miR-21 and MF treatment were conducted. AMPK-dependency was assessed via transfection of siAMPK. The expression of PTEN, AKT and miR-21 after transient pre-miR-21 transfection and MF treatment was analysed. RESULTS: We demonstrate that CAKI-1 cells, which were found to be less sensitive towards MF, showed a significant higher miR-21 and lower PTEN expression than CAKI-2. This was confirmed in a primary RCC collective (n = 28): miR-21 and PTEN expression correlated negatively. MF treatment lowered miR-21 AMPK-dependently and increased PTEN expression in the cell lines. Ectopic miR-21 regulation modulated MF sensitivity. Western blot analysis showed that pre-miR-21 transfection and MF treatment regulated PTEN expression with impact on pAKT levels in the cells. CONCLUSIONS: We show that differing MF sensitivity in RCC cells is associated with and mediated through the regulation of miR-21/PTEN expression with an impact on subsequent AKT signalling. This provides imaginable clinical implications regarding MF therapy of RCC patients for the future.

The WERA cancer center matrix: Strategic management of patient access to precision oncology in a large and mostly rural area of Germany.

PURPOSE: Providing patient access to precision oncology (PO) is a major challenge of clinical oncologists. Here, we provide an easily transferable model from strategic management science to assess the outreach of a cancer center. METHODS: As members of the German WERA alliance, the cancer centers in Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact. Specifically, we examined the provenance of patients from WERA´s molecular tumor boards (MTBs) between 2020 and 2022 (n = 2243). As second dimension, we added the provenance of patients receiving general cancer care by WERA. Clustering our catchment area along these two dimensions set up a four-quadrant matrix consisting of postal code areas with referrals towards WERA. These areas were re-identified on a map of the Federal State of Bavaria. RESULTS: The WERA matrix overlooked an active screening area of 821 postal code areas - representing about 50 % of Bavaria´s spatial expansion and more than six million inhabitants. The WERA matrix identified regions successfully connected to our outreach structures in terms of subsidiarity - with general cancer care mainly performed locally but PO performed in collaboration with WERA. We also detected postal code areas with a potential PO backlog - characterized by high levels of cancer care performed by WERA and low levels or no MTB representation. CONCLUSIONS: The WERA matrix provided a transparent portfolio of postal code areas, which helped assessing the geographical impact of our PO program. We believe that its intuitive principle can easily be transferred to other cancer centers.

MiR-205 is progressively down-regulated in lymph node metastasis but fails as a prognostic biomarker in high-risk prostate cancer.

The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the prognostic potential of miR-205 in HRPCa study and validation cohorts, setting defined clinical endpoints for both. We demonstrate miR-205 to be significantly down-regulated in over 70% of the HRPCa samples analysed and that reconstitution of miR-205 causes inhibition of proliferation and invasiveness in prostate cancer (PCa) cell lines. Additionally, miR-205 is increasingly down-regulated in lymph node metastases compared to the primary tumour indicating that miR-205 plays a role in migration of PCa cells from the original location into extraprostatic tissue. Nevertheless, down-regulation of miR-205 in primary PCa was not correlated to the synchronous presence of metastasis and failed to predict the outcome for HRPCa patients. Moreover, we found a tendency for miR-205 up-regulation to correlate with an adverse outcome of PCa patients suggesting a pivotal role of miR-205 in tumourigenesis. Overall, we showed that miR-205 is involved in the development and metastasis of PCa, but failed to work as a useful clinical biomarker in HRPCa. These findings might have implications for the use of miR-205 as a prognostic or therapeutic target in HRPCa.

[New forms of immunotherapy in uro-oncology : HLA-independent therapeutic approaches with bispecific antibodies and CAR T cells]. / Neue Formen der Immuntherapie für die Uroonkologie : HLA-unabhängige Therapieansätze mit bispezifischen Antikörpern und CAR-T-Zellen.

Immunotherapies using bispecific antibodies and chimeric antigen receptor (CAR) T cells do not depend on previous activation of T cells by the human leukocyte antigen (HLA) system. These HLA-independent approaches displayed groundbreaking clinical results in hematological malignancies-leading to drug approvals for diseases like acute lymphocytic leukemia (ALL), B-cell Non-Hodgkin's lymphoma and multiple myeloma. Currently, several phase I/II trials are investigating the transferability of these results to solid tumors-especially prostate cancer. Compared to established immune checkpoint blockade, bispecific antibodies and CAR T cells have novel and heterogenous side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Treating these side effects and identifying suitable trial participants requires an interdisciplinary treatment approach.

Breaking through Multiple Myeloma: A Paradigm for a Comprehensive Tumor Ecosystem Targeting.

Multiple myeloma (MM) is a cancerous condition characterized by the proliferation of plasma cells within the hematopoietic marrow, resulting in multiple osteolytic lesions. MM patients typically experience bone pain, kidney damage, fatigue due to anemia, and infections. Historically, MM was an incurable disease with a life expectancy of around three years after diagnosis. However, over the past two decades, the development of novel therapeutics has significantly improved patient outcomes, including response to treatment, remission duration, quality of life, and overall survival. These advancements include thalidomide and its derivatives, lenalidomide and pomalidomide, which exhibit diverse mechanisms of action against the plasma cell clone. Additionally, proteasome inhibitors such as bortezomib, ixazomib, and carfilzomib disrupt protein degradation, proving specifically toxic to cancerous plasma cells. Recent advancements also involve monoclonal antibodies targeting surface antigens, such as elotuzumab (anti-CS1) and daratumumab (anti-CD38), bispecific t-cell engagers such as teclistamab (anti-BCMA/CD3) and Chimeric antigen receptor T (CAR-T)-based strategies, with a growing focus on drugs that exhibit increasingly targeted action against neoplastic plasma cells and relevant effects on the tumor microenvironment.

Critical Evaluation of a microRNA-Based Risk Classifier Predicting Cancer-Specific Survival in Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava.

(1) Background: Clear cell renal cell carcinoma extending into the inferior vena cava (ccRCCIVC) represents a clinical high-risk setting. However, there is substantial heterogeneity within this patient subgroup regarding survival outcomes. Previously, members of our group developed a microRNA(miR)-based risk classifier-containing miR-21-5p, miR-126-3p and miR-221-3p expression-which significantly predicted the cancer-specific survival (CSS) of ccRCCIVC patients. (2) Methods: Examining a single-center cohort of tumor tissue from n = 56 patients with ccRCCIVC, we measured the expression levels of miR-21, miR-126, and miR-221 using qRT-PCR. The prognostic impact of clinicopathological parameters and miR expression were investigated via single-variable and multivariable Cox regression. Referring to the previously established risk classifier, we performed Kaplan-Meier analyses for single miR expression levels and the combined risk classifier. Cut-off values and weights within the risk classifier were taken from the previous study. (3) Results: miR-21 and miR-126 expression were significantly associated with lymphonodal status at the time of surgery, the development of metastasis during follow-up, and cancer-related death. In Kaplan-Meier analyses, miR-21 and miR-126 significantly impacted CSS in our cohort. Moreover, applying the miR-based risk classifier significantly stratified ccRCCIVC according to CSS. (4) Conclusions: In our retrospective analysis, we successfully validated the miR-based risk classifier within an independent ccRCCIVC cohort.

Predicting Microenvironment in CXCR4- and FAP-Positive Solid Tumors-A Pan-Cancer Machine Learning Workflow for Theranostic Target Structures.

(1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database-representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets.

Does medication-related osteonecrosis of the jaw affect survival of patients with Multiple Myeloma?: Exploring a large single center database using artificial intelligence.

In addition to randomized clinical trials, consideration of Real-World Evidence is necessary for mirroring clinical reality. However, processing such evidence for large numbers of patients often requires considerable time and effort. This is particularly true for rare tumor diseases such as multiple myeloma (MM) or for adverse effects that occur even more rarely. In such cases, artificial intelligence is able to efficiently detect patients with rare conditions. One of these rare adverse events, and the most discussed, following bone protective treatment in MM is medication-related osteonecrosis of the jaw (MRONJ). The association of bone protective treatment to MM outcome has been intensively studied. However, the impact of MRONJ resulting from such treatment on MM prognosis and outcome is poorly understood. In this retrospective study, we therefore investigated the long-term effects of MRONJ. We used natural language processing (NLP) to screen individual data of 2389 MM patients to find 50 out of 52 patients with MRONJ matching our inclusion criteria. To further improve data quality, we then performed propensity score matching. In comparison to MM patients without MRONJ, we found a significantly longer overall survival (median 126 vs. 86 months) despite slightly worse clinical features.