PURPOSE: Determining the frequency and distribution of pathogenic germline variants (PGVs) in Austrian prostate cancer (PCa) patients and to assess the accuracy of different clinical risk scores to correctly predict PGVs. METHODS: This cross-sectional study included 313 men with advanced PCa. A comprehensive personal and family history was obtained based on predefined questionnaires. Germline DNA sequencing was performed between 2019 and 2021 irrespective of family history, metastatic or castration status or age at diagnosis. Clinical risk scores for hereditary cancer syndromes were evaluated and a PCa-specific score was developed to assess the presence of PGVs. RESULTS: PGV presence was associated with metastasis (p = 0.047) and castration resistance (p = 0.011), but not with personal cancer history or with relatives with any type of cancer. Clinical risk scores (Manchester score, PREMM5 score, Amsterdam II criteria or Johns Hopkins criteria) showed low sensitivities (3.3-20%) for assessing the probability of PGV presence. A score specifically designed for PCa patients stratifying patients into low- or high-risk regarding PGV probability, correctly classified all PGV carriers as high-risk, whereas a third of PCa patients without PGVs was classified as low risk of the presence of PGVs. CONCLUSION: Application of common clinical risk scores based on family history are not suitable to identify PCa patients with high PGV probabilities. A PCa-specific score stratified PCa patients into low- or high-risk of PGV presence with sufficient accuracy, and germline DNA sequencing may be omitted in patients with a low score. Further studies are needed to evaluate the score.

• Klíčová slova
• DNA sequencing, Family history, Genetic testing criteria, Germline variants, Prostate cancer, Risk score,
• MeSH
• genetická predispozice k nemoci MeSH
• lidé MeSH
• nádory prostaty * genetika   patologie   MeSH
• průřezové studie MeSH
• rizikové faktory MeSH
• zárodečné buňky patologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Rakousko MeSH

BACKGROUND & AIMS: Patient-derived organoid cancer models are generated from epithelial tumor cells and reflect tumor characteristics. However, they lack the complexity of the tumor microenvironment, which is a key driver of tumorigenesis and therapy response. Here, we developed a colorectal cancer organoid model that incorporates matched epithelial cells and stromal fibroblasts. METHODS: Primary fibroblasts and tumor cells were isolated from colorectal cancer specimens. Fibroblasts were characterized for their proteome, secretome, and gene expression signatures. Fibroblast/organoid co-cultures were analyzed by immunohistochemistry and compared with their tissue of origin, as well as on gene expression levels compared with standard organoid models. Bioinformatics deconvolution was used to calculate cellular proportions of cell subsets in organoids based on single-cell RNA sequencing data. RESULTS: Normal primary fibroblasts, isolated from tumor adjacent tissue, and cancer associated fibroblasts retained their molecular characteristics in vitro, including higher motility of cancer associated compared with normal fibroblasts. Importantly, both cancer-associated fibroblasts and normal fibroblasts supported cancer cell proliferation in 3D co-cultures, without the addition of classical niche factors. Organoids grown together with fibroblasts displayed a larger cellular heterogeneity of tumor cells compared with mono-cultures and closely resembled the in vivo tumor morphology. Additionally, we observed a mutual crosstalk between tumor cells and fibroblasts in the co-cultures. This was manifested by considerably deregulated pathways such as cell-cell communication and extracellular matrix remodeling in the organoids. Thrombospondin-1 was identified as a critical factor for fibroblast invasiveness. CONCLUSION: We developed a physiological tumor/stroma model, which will be vital as a personalized tumor model to study disease mechanisms and therapy response in colorectal cancer.

• Klíčová slova
• Cancer, Co-cultures, Colorectal Cancer, Fibroblasts, Organoids,
• MeSH
• fibroblasty asociované s nádorem * metabolismus   MeSH
• fibroblasty metabolismus   MeSH
• kokultivační techniky MeSH
• kolorektální nádory * patologie   MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• organoidy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Prostate-specific membrane antigen (PSMA) targeted molecular imaging using positron emission tomography (PET) has significantly improved the diagnosis and treatment of prostate cancer (PCA). OBJECTIVE: To assess the feasibility and compare the diagnostic accuracy of [68Ga]Ga-PSMA-11 PET images taken at baseline, before the initiation of systemic treatment and preoperative images, using histopathology after cytoreductive surgery as reference. DESIGN SETTING AND PARTICIPANTS: We identified 20 patients in our prospectively maintained database with primary oligometastatic PCA who underwent cytoreductive radical prostatectomy and superextended pelvic lymph node dissection after systemic therapy, who had baseline and preoperative [68Ga]Ga-PSMA-11 PET imaging available. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed a region-based analysis to determine the diagnostic accuracy of imaging, using pathology as a reference. Regions were predefined as prostate, internal iliac left/right, obturator left/right, external iliac left/right, common iliac left/right, and presacral. RESULTS AND LIMITATIONS: Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and diagnostic effectiveness were, respectively, 95.65%, 78.22%, 98.39%, 57.89%, and 83.00% for baseline [68Ga]Ga-PSMA-11 PET, compared to 56.52%, 98.05%, 88.30%, 89.66%, and 88.50% for preoperative [68Ga]Ga-PSMA-11 PET. On a receiver operating characteristic analysis, the diagnostic accuracy of baseline [68Ga]Ga-PSMA-11 PET with an area under the curve (AUC) of 0.87 (95% confidence interval [CI] 0.83-0.92) was significantly better than that of preoperative [68Ga]Ga-PSMA-11 PET after systemic therapy with an AUC of 0.77 (95% CI 0.70-0.85, p = 0.01). CONCLUSIONS: Baseline imaging, [68Ga]Ga-PSMA-11 PET has significantly better diagnostic accuracy, sensitivity, and NPV than images obtained preoperatively, in systemically pretreated patients. If a patient is suitable for local treatment and complete resection of the residual tumor is intended, [68Ga]Ga-PSMA-11 PET images taken prior to systemic therapy are significantly more accurate in selecting the relevant lymph nodes for resection. PATIENT SUMMARY: We found that prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging used early, before hormonal therapy or chemotherapy, provides more accurate information about the spread of the disease, than if used immediately before surgery but after hormonal therapy or chemotherapy. Early use of PSMA-PET has the potential to improve therapy also at later stages of the disease.

• Klíčová slova
• Cytoreductive surgery, Hormone therapy, Prostate cancer, Prostate-specific membrane antigen, Radical prostatectomy,
• Publikační typ
• časopisecké články MeSH

• MeSH
• epigeneze genetická MeSH
• epigenomika metody   MeSH
• lidé MeSH
• management nemoci MeSH
• metylace DNA * MeSH
• náchylnost k nemoci MeSH
• nádorové biomarkery * MeSH
• nádory prostaty rezistentní na kastraci krev   diagnóza   genetika   terapie   MeSH
• prognóza MeSH
• stanovení celkové genové exprese MeSH
• tekutá biopsie * metody   MeSH
• výpočetní biologie metody   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové biomarkery * MeSH

BACKGROUND AND AIMS: [177Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT) is a new therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). However, identification of reliable prognostic factors is hampered by heterogeneous treatment regimens applied in previous studies. Hence, we sought clinical factors able to predict response and survival to PSMA-RLT in a homogenous group of patients, all receiving 7400 MBq every 4 weeks. PATIENTS AND METHODS: Data of 61 patients (mean age 71.6 ± 6.9 years, median basal PSA 70.7 [range 1.0-4890 μg/L]), pretreated with abiraterone/enzalutamide (75.4%) and docetaxel/cabazitaxel (68.9%), received three cycles of PSMA-RLT (mean 7321 ± 592 MBq) at four weekly intervals and were analyzed retrospectively. General medical conditions and laboratory parameters of every patients were regularly assessed. Response to therapy was based on PSA levels 1 month after the 3rd cycle. Binary logistic regression test and Kaplan-Meier estimates were used to evaluate predictors and overall survival (OS). RESULTS: Forty-nine (80.3%) patients demonstrated a therapy response in terms of any PSA decline, while 21 (19.7%) patients showed increase or no changes in their PSA levels. Baseline hemoglobin (Hb) significantly predicted PSA reductions of ≥ 50% 4 weeks after receiving the 3rd PSMA-RLT (P = 0.01, 95% CI: 1.09-2.09) with an AUC of 0.68 (95% CI: 0.54-0.81). The levels of basal Hb and basal PSA were able to predict survival of patients, both P < 0.05 (relative risk 1.51 and 0.79, 95% CI: 1.09-2.09 and 0.43-1.46), respectively. In comparison to patients with reduced basal Hb, patients with normal basal Hb levels lived significantly longer (median survival not reached vs. 89 weeks, P = 0.016). Also, patients with basal PSA levels ≤ 650 μg/L had a significantly longer survival than patients with basal PSA levels > 650 μg/L (median survival not reached vs. 97 weeks, P = 0.031). Neither pretreatments with abiraterone/enzalutamide or docetaxel/cabazitaxel nor distribution of metastasis affected survival and rate of response to PSMA-RLT. CONCLUSION: Basal Hb level is an independent predictor for therapy response and survival in patients receiving PSMA-RLT every 4 weeks. Both baseline PSA ≤ 650 μg/L and normal Hb levels were associated with longer survival.

• Klíčová slova
• PSA, PSMA-RLT, Response prediction, Survival prediction, mCRPC,
• MeSH
• dipeptidy * terapeutické užití   MeSH
• heterocyklické sloučeniny monocyklické * terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lutecium MeSH
• nádory prostaty rezistentní na kastraci * farmakoterapie   radioterapie   MeSH
• prostatický specifický antigen MeSH
• radiofarmaka MeSH
• retrospektivní studie MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 177Lu-PSMA-617 MeSH Prohlížeč
• dipeptidy * MeSH
• heterocyklické sloučeniny monocyklické * MeSH
• lutecium MeSH
• prostatický specifický antigen MeSH
• PSMA-617 MeSH Prohlížeč
• radiofarmaka MeSH

Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3'-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences show a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRα/TRβ) in target tissues. We show in our study that low CRYM expression levels in PCa patients are associated with early biochemical recurrence and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in positron emission tomography/magnetic resonance imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3- and androgen-mediated signaling in PCa. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.

• Klíčová slova
• PSMA-PET, androgen receptor, prostate cancer, thyroid hormone receptor, μ-Crystallin,
• MeSH
• androgenní receptory genetika   metabolismus   MeSH
• buňky PC-3 MeSH
• cholin aplikace a dávkování   analogy a deriváty   MeSH
• čipová analýza tkání MeSH
• down regulace * MeSH
• kohortové studie MeSH
• krystaliny genetika   metabolismus   MeSH
• lidé MeSH
• metabolomika MeSH
• mu-krystaliny MeSH
• nádorové buněčné linie MeSH
• nádory prostaty diagnostické zobrazování   genetika   metabolismus   patologie   MeSH
• PET/CT MeSH
• prognóza MeSH
• receptory thyreoidních hormonů genetika   MeSH
• regulace genové exprese u nádorů MeSH
• sekvenční analýza RNA MeSH
• signální transdukce * MeSH
• staging nádorů MeSH
• stanovení celkové genové exprese MeSH
• trijodthyronin antagonisté a inhibitory   metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• androgenní receptory MeSH
• AR protein, human MeSH Prohlížeč
• cholin MeSH
• CRYM protein, human MeSH Prohlížeč
• fluoromethylcholine MeSH Prohlížeč
• krystaliny MeSH
• mu-krystaliny MeSH
• receptory thyreoidních hormonů MeSH
• trijodthyronin MeSH

PURPOSE: [177Lu]Lu-PSMA-617 radio-ligand therapy (PSMA-RLT) is emerging in patients with an advanced metastatic castration-resistant prostate cancer (mCRPC). Here, we aimed to estimate the results of PSMA-RLT in terms of response, progression-free survival (PFS), and overall survival (OS) in patients receiving a highly standardized treatment regimen due to mCRPC. The toxicity of PSMA-RLT has also been evaluated. PATIENTS AND METHODS: Fifty-four patients (mean age 72 ± 7 years, median PSA at time of initial therapy 66 [range 1.0-4890 μg/L]), receiving three PSMA-RLT cycles (mean 7315 ± 573 MBq) at four weekly intervals, were included in this retrospective analysis. Hematological and biochemical parameters were regularly determined in every patient. Kaplan-Meier estimates were used to assess PFS and OS and a Cox proportional hazard model was used to analyze significant associations. Treatment response was based on PSA measurements 4 weeks after the 3rd treatment. RESULTS: The majority of patients were previously treated with abiraterone/enzalutamide (69%) and docetaxel/cabazitaxel (67%). In total, 79% of the patients showed a decrease in PSA (median PSA decrease from 66 to 19.8, range 0.7-4563 μg/L, P < 0.001) 1 month after the 3rd therapy cycle. Among them, 58% and 35% demonstrated a PSA-decline of > 50% and > 80%, respectively. Median OS was 119 weeks; median PFS was 25 weeks. Patients presenting with a PSA decline had significantly longer PFS (27 vs. 15 weeks, P < 0.0001) and OS (median survival not reached vs. 52 weeks, P < 0.001) than patients with no PSA reduction. Moreover, patients with reduction in PSA levels ≥ 50% (median survival not reached vs. 52 weeks, P < 0.0001) and ≥ 80% (median survival not reached vs. 87 weeks, P = 0.008) lived significantly longer. While hemoglobin did not change during treatment, levels of platelets (236 ± 71 g/L vs. 193 ± 67 g/L) and leucocytes (6.5, range 2.9-13.7 g/L vs. 4.8, range 1.5-12.3 g/L) decreased significantly, both P < 0.001. Two grade 3 leukocytopenia and one grade 3 anemia were observed. CONCLUSION: Intense PSMA-RLT regime with four weekly intervals between the cycles is well-tolerated and offers favorable response rates, PFS, and survival rates for patients with mCRPC.

• Klíčová slova
• PSA response, PSMA PET, PSMA therapy, Prostate cancer, mCRPC,
• MeSH
• dipeptidy MeSH
• heterocyklické sloučeniny monocyklické terapeutické užití   MeSH
• lidé MeSH
• nádory prostaty rezistentní na kastraci * radioterapie   MeSH
• prostatický specifický antigen MeSH
• retrospektivní studie MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dipeptidy MeSH
• heterocyklické sloučeniny monocyklické MeSH
• prostatický specifický antigen MeSH
• PSMA-617 MeSH Prohlížeč

Ectopic lipid accumulation in skeletal muscle and liver drives the pathogenesis of diabetes mellitus type 2 (DMT2). Mild hyperbilirubinaemia has been repeatedly suggested to play a role in the prevention of DMT2 and is known for its capacity to shape an improved lipid phenotype in humans and in animals. To date, the effect of bilirubin on lipid accumulation in tissues that are prone to ectopic lipid deposition is unclear. Therefore, we analyzed the effect of bilirubin on lipid accumulation in skeletal muscle and liver cell lines. C2C12 skeletal mouse muscle and HepG2 human liver cells were treated with physiological concentrations of free fatty acids (FFA) (0.5 mM and 1 mM) and unconjugated bilirubin (UCB) (17.1 and 55 µM). The intracellular presence of UCB upon exogenous UCB administration was confirmed by HPLC and the lipid accumulation was assessed by using Nile red. Exposure of both cell lines to UCB significantly reduced lipid accumulation by up to 23% (p ≤ 0.001) in HepG2 and by up to 17% (p ≤ 0.01) in C2C12 cells at 0.5 and 5 h under hypoglycaemic conditions. Simultaneously, UCB slightly increased FFA uptake in HepG2 cells after 0.5 and 5 h and in C2C12 cells after 12 h as confirmed by gas chromatographic analyses of the remaining FFA content in the incubation media. The effects of UCB on lipid accumulation and uptake were abolished in the presence of higher glucose concentrations. Monitoring the uptake of a radiolabeled glucose analogue [18F]FDG: (2-deoxy-2-[18F]fluoro-D-glucose) into both cell types further indicated higher glucose consumption in the presence of UCB. In conclusion, our findings show that UCB considerably decreases lipid accumulation in skeletal muscle and liver cells within a short incubation time of max. 5 h which suggests that mildly elevated bilirubin levels could lower ectopic lipid deposition, a major key element in the pathogenesis of DMT2.

• Klíčová slova
• C2C12 skeletal muscle cells, HepG2 cells, [18F]FDG uptake, bilirubin, ectopic lipid accumulation, insulin resistance, lipid accumulation, mild hyperbilirubinaemia,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: To assess which parameters of [68 Ga]Ga-PSMA-11 positron emission tomography (PSMA-PET) predict response to systemic therapies in metastatic (m) castration-resistant prostate cancer (CRPC). In addition, to investigate which of these factors are associated with overall survival (OS). METHODS: We retrospectively assessed the following PSMA-PET parameters in 43 patients before and after systemic therapies for mCRPC: PSMA total tumor volume (TTV), mean standardized uptake value (SUVmean), SUVmax, and SUVpeak. prostate-specific antigen (PSA) levels and PSMA-PET/CT(magnetic resonance imaging [MRI]) imaging were both performed within 8 weeks before and 6 weeks after systemic therapy. PSMA-PET and CT (MRI) images were reviewed according to the modified PET Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Results were compared to PSA response. Univariable survival analyses were performed. RESULTS: Overall, 43 patients undergoing 67 systemic therapies were included (9 patients radium-223, 12 cabazitaxel, 22 docetaxel, 6 abiraterone, and 18 enzalutamide). Median serum PSA level before any therapy was 11.3 ng/mL (interquartile range [IQR] = 3.3, 30.1). Delta (d) PSA after systemic therapies was -41%, dTTV 10.5%, dSUVmean -7.5%, dSUVmax -13.3%, dSUVpeak -12%, and dRECIST -13.3%. Overall, 31 patients had dPSA response (46.3%), 12 stable disease (17.9%), and 24 progressive disease (35.8%). All observed PET parameters, as well as the RECIST evaluation, were significantly associated with PSA response (dTTV P = .003, dSUVmean P = .003, dSUVmax P = .011, dSUVpeak P < 0001, dRECIST P = .012), while RECIST assessment was applicable in 37 out of 67 patients (55.2%). Within a median follow-up of 33 months (IQR = 26, 38), 10 patients (23.3%) died of PC. On univariable survival analyses, neither the investigated PET parameters nor PSA level or RECIST criteria were associated with OS. CONCLUSION: PSMA-PET provides reliable parameters for prediction of response to systemic therapies for mCRPC. These parameters, if confirmed, could enhance RECIST criteria, specifically concerning its limitations for sclerotic bone lesions.

• Klíčová slova
• PET/CT, PET/MRI, PSMA ligand, hybrid imaging, metastatic prostate cancer,
• MeSH
• EDTA analogy a deriváty   MeSH
• izotopy gallia MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory prostaty rezistentní na kastraci diagnostické zobrazování   farmakoterapie   radioterapie   terapie   MeSH
• oligopeptidy * MeSH
• pozitronová emisní tomografie metody   MeSH
• radiofarmaka MeSH
• radioizotopy galia MeSH
• retrospektivní studie MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• EDTA MeSH
• gallium 68 PSMA-11 MeSH Prohlížeč
• izotopy gallia MeSH
• oligopeptidy * MeSH
• radiofarmaka MeSH
• radioizotopy galia MeSH