[Emergencies in cancer immunotherapy]. / Notfälle in der Medikamentösen Tumortherapie.

BACKGROUND: Immunomodulatory therapies are becoming increasingly important in uro-oncology. For this reason, we will probably be increasingly confronted with side effects. In addition, there is an increasing number of combinations with other mechanisms of action. Immune-mediated side effects may occur as a consequence of this therapy. These are different from the side effects of chemotherapy and other targeted therapies and therefore require different treatment strategies. AIM: Based on the current literature, the data on graduation and stage-dependent management will be presented as well as illustrated with examples from practice. MATERIALS AND METHODS: Literature review on the detection and therapeutic management of adverse events mediated in the setting of immuno-oncologic therapy. RESULTS: Treatment-related events can in principle affect all organ systems. Toxicities in the area of the skin, such as rash or pruritus, hypo- or hyperthyreosis, arthritis, muscle pain and gastrointestinal symptoms are frequently seen. In terms of frequency, most side effects are grade 1 to 2, but grade 3 to 4 toxicities are also generally well treatable if detected early. Rare complications such as neurological toxicities, pneumonitis or carditis can develop a fulminant course if diagnosed too late. CONCLUSIONS: Even emergencies are manageable if we know the most important side effects and the therapeutic options. Immune-mediated side effects are of particular importance because they can affect any organ system. However, as long as we consider the possibility of toxicity from checkpoint inhibitors when the patient presents with symptoms, most side effects are easy to treat and therefore manageable.

Analysing the tumor transcriptome of prostate cancer to predict efficacy of Lu-PSMA therapy.

RATIONALE: 177Lu-PSMA ([177Lu]Lutetium-PSMA-617) therapy is an effective treatment option for patients with prostate specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, but still shows a non-responder rate of approximately 30%. Combination regimes of programmed death-ligand 1 (PD-L1) inhibition and concomitant 177Lu-PSMA therapy have been proposed to increase the response rate. However, the interplay of immune landscape and 177Lu-PSMA therapy efficacy is poorly understood. METHODS: Between March 2018 and December 2021, a total of 168 patients were referred to 177Lu-PSMA therapy in our department and received a mean total dose of 21.9 GBq (three cycles in mean). All patients received baseline PSMA positron emission tomography to assess the PSMA uptake. The histopathological specimen of the primary prostate tumor was available with sufficient RNA passing quality control steps for genomic analysis in n=23 patients. In this subset of patients, tumor RNA transcriptomic analyses assessed 74 immune-related features in total, out of which n=24 signatures were not co-correlated and investigated further for outcome prognostication. RESULTS: In the subset of patients who received 177Lu-PSMA therapy, PD-L1 was not significantly associated with OS (HR per SD change (95% CI) 0.74 (0.42 to 1.30); SD: 0.18; p=0.29). In contrast, PD-L2 signature was positively associated with longer OS (HR per SD change 0.46 (95% CI 0.29 to 0.74); SD: 0.24; p=0.001; median OS 17.2 vs 5.7 months in higher vs lower PD-L2 patients). In addition, PD-L2 signature correlated with PSA-response (ϱ=-0.46; p=0.04). The PD-L2 signature association with OS was significantly moderated by L-Lactatdehydrogenase (LDH) levels (Cox model interaction p=0.01). CONCLUSION: Higher PD-L2 signature might be associated with a better response to 177Lu-PSMA therapy and warrants further studies investigating additional immunotherapy. In contrast, PD-L1 was not associated with outcome. The protective effect of PD-L2 signature might be present only in men with lower LDH levels.

[Prostate cancer-multiparametric MRI and alternative approaches in intervention and therapy planning]. / Multiparametrische MRT und alternative Methoden in der Interventions- und Behandlungsplanung beim Prostatakarzinom.

BACKGROUND: In recent years, multiparametric magnetic resonance imaging (mpMRI) of the prostate has gained importance and plays a crucial role in both personalized diagnostics and increasingly in the treatment planning for patients with prostate cancer. OBJECTIVE: The aim of this study is to present established and innovative applications of MRI in the diagnosis and treatment of localized prostate cancer, evaluating their strengths and weaknesses. Furthermore, it will explore alternative approaches and compare them in a comprehensive manner. MATERIALS AND METHODS: A systematic literature review on the application of mpMRI for biopsy and therapy planning was conducted. RESULTS: The integration of modern imaging techniques, especially mpMRI, into the diagnostic algorithm has revolutionized prostate cancer diagnosis. MRI and MRI-guided biopsy detect more significant prostate cancer, with the potential to reduce unnecessary biopsies and the diagnosis of clinically insignificant carcinomas. In addition, MRI provides crucial information for risk stratification and treatment planning in prostate cancer patients, both before radical prostatectomy and during active surveillance. CONCLUSION: Multiparametric MRI offers significant added value for the diagnosis and treatment of localized prostate cancer. The advancement of MRI analysis, such as the implementation of artificial intelligence algorithms, holds the potential for further enhancing imaging diagnostics.

[Systematic or targeted fusion-guided biopsy]. / Systematische oder gezielte Fusionsbiopsie der Prostata.

BACKGROUND: Early detection of prostate cancer (PCa) is associated with a high risk for detecting low-risk disease. In the primary biopsy indication, systematic biopsy leads to an increased detection of clinically insignificant PCa, and significant prostate cancers are not detected with sufficient sensitivity, especially without prior magnetic resonance imaging (MRI). Similar data have recently become available for PCa screening. OBJECTIVES: In light of the current literature, this article aims to discuss the data on systematic and combined targeted and systematic multiparametric MRI (mpMRI)-guided fusion biopsy to improve PCa diagnosis in clinically suspected cancer even in screening using multivariable risk stratification. MATERIALS AND METHODS: Literature review on mpMRI and MRI/TRUS fusion biopsy (TRUS: transrectal ultrasonography) for tumor detection in suspected prostate cancer and PCa screening was performed. RESULTS: Multiparametric MRI as a reflex test after prostate-specific antigen (PSA) determination (PSA cut-off 4 ng/ml) in combination with targeted biopsy alone reduces the detection of clinically nonsignificant tumors in early detection by half. On the other hand, in the form of a target saturation or in combination with a systematic biopsy, the sensitivity for the detection of cancers of International Society of Urogenital Pathology (ISUP) grade groups 2 or higher can be improved. Similar results are also shown in PCa screening with a PSA cut-off of 3 ng/ml. CONCLUSIONS: The evidence for performing a targeted fusion biopsy alone is currently insufficient. Therefore, the combination of mpMRI-guided targeted and systematic biopsy continues to be the recommended standard for prostate cancer diagnosis.

High fibroblast-activation-protein expression in castration-resistant prostate cancer supports the use of FAPI-molecular theranostics.

PURPOSE: To evaluate fibroblast-activation-protein (FAP) expression in different clinical stages of prostate cancer (PC) with regards to utility of [68 Ga]Ga-FAPI-04 PET/CT imaging in patients with castration-resistant PC (CRPC). METHODS: Tissue microarrays (TMAs) were constructed from prostatic tissue from 94 patients at different stages of PC (primary PC, patients undergoing neoadjuvant androgen deprivation therapy, CRPC, and neuroendocrine PC (NEPC)) and were stained with anti-FAP monoclonal antibody. A positive pixel count algorithm (H-Index) was used to compare FAP expression between the groups. Additionally, three men with advanced CRPC or NEPC underwent [68 Ga]Ga-FAPI-04 PET/CT, and PET positivity was analyzed. RESULTS: The mean H-index for benign tissue, primary PC, neoadjuvant androgen deprivation therapy before radical prostatectomy, CRPC, and NEPC was 0.018, 0.031, 0.042, 0.076, and 0.051, respectively, indicating a significant rise in FAP expression with advancement of disease. Corroborating these findings [68 Ga]Ga-FAPI-04 PET/CT was highly positive in men with advanced CRPC. CONCLUSION: Increased FAP tissue expression supports the use of FAP inhibitor (FAPI)-molecular theranostics in CRPC.

Immunological and behavioral responses to in vivo lipopolysaccharide administration in young and healthy obese and normal-weight humans.

Obesity is associated with an increase prevalence of neuropsychiatric symptoms and diseases, such as depression. Based on the facts that pro-inflammatory cytokines are able to modulate behavior, and that obesity is characterized by a chronic low-grade inflammatory state, inflammation has been hypothesized to contribute to the neuropsychiatric comorbidity in obese individuals. However, a causal link between inflammation and the development of neuropsychiatric symptoms is hard to establish in humans. Here, we used an inflammatory stimulus, i.e. the intravenous injection of lipopolysaccharide (LPS), in a double-blind placebo-controlled design, to determine the vulnerability of obese individuals to inflammation-induced behavioral changes. The hypothesis was that obese individuals would show heightened behavioral response compared to normal-weight subjects for the same inflammatory stimulus, reflecting an increased sensitivity to the behavioral effects of pro-inflammatory cytokines. LPS (dose 0.8 ng/kg body weight, adjusted for estimated blood volume in obese subjects) and placebo (saline) were intravenously injected in 14 obese healthy subjects and 23 normal-weight healthy subjects in a within-subject, randomized, crossover design. LPS administration induced, in both groups, an acute increase in blood concentrations of cytokines (interleukin-6, tumor necrosis factor-α, and IL-10), as well as in body temperature, cortisol, norepinephrine, sickness symptoms, fatigue, negative mood, and state anxiety. There were little differences in the immune and behavioral responses to LPS between obese and normal-weight subjects, but the cortisol response to LPS was strongly attenuated in obese individuals. Higher percentage of body fat was related to a lower cortisol response to LPS. Taken together, the population of young and healthy obese individuals in this study did not exhibit an increased behavioral sensitivity to cytokines, but an attenuated cortisol response to the immune challenge. Future studies will need to determine whether additional physiological and psychological factors interact with the state of obesity to increase the risk for inflammation-induced neuropsychiatric symptoms.

Acute inflammation and psychomotor slowing: Experimental assessment using lipopolysaccharide administration in healthy humans.

Data from clinical and cross-sectional studies suggest that inflammation contributes to psychomotor slowing and attentional deficits found in depressive disorder. However, experimental evidence is still lacking. The aim of this study was to clarify the effect of inflammation on psychomotor slowing using an experimental and acute model of inflammation, in which twenty-two healthy volunteers received an intravenous injection of lipopolysaccharide (LPS, dose: 0.8 â€‹ng/kg body weight) and of placebo, in a randomized order following a double-blind within-subject crossover design. A reaction time test and a go/no-go test were conducted 3 â€‹h after the LPS/placebo injection and interleukin (IL)-6 and tumor necrosis factor (TNF)-α concentrations were assessed. No effect of experimental inflammation on reaction times or errors for either test was found. However, inflammation was related to worse self-rated performance and lower effort put in the tasks. Exploratory analyses indicated that reaction time fluctuated more over time during acute inflammation. These data indicate that acute inflammation has only modest effects on psychomotor speed and attention in healthy subjects objectively, but alters the subjective evaluation of test performance. Increased variability in reaction time might be the first objective sign of altered psychomotor ability and would merit further investigation.