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Purpose: In patients with unresectable stage III non-small-cell lung cancer (NSCLC), durvalumab maintenance treatment after chemoradiotherapy (CRT) significantly improves survival. So far, however, metabolic changes of tumoral lesions and secondary lymphoid organs under durvalumab are unknown. Hence, we assessed changes on [ 18 F]FDG PET/CT in comparison to patients undergoing CRT alone., Methods: Forty-three patients with [ 18 F]FDG PET/CT both before and after standard CRT for unresectable stage III NSCLC were included, in 16/43 patients durvalumab maintenance treatment was initiated (CRT-IO) prior to the second PET/CT. Uptake of tumor sites and secondary lymphoid organs was compared between CRT and CRT-IO. Also, readers were blinded for durvalumab administration and reviewed scans for findings suspicious for immunotherapy-related adverse events (irAE)., Results: Initial uptake characteristics were comparable. However, under durvalumab, diverging metabolic patterns were noted: There was a significantly higher reduction of tumoral uptake intensity in CRT-IO compared to CRT, e.g. median decrease of SUV max -70.0% vs. -24.8%, p = 0.009. In contrast, the spleen uptake increased in CRT-IO while it dropped in CRT (median + 12.5% vs. -4.4%, p = 0.029). Overall survival was significantly longer in CRT-IO compared to CRT with few events (progression/death) noted in CRT-IO. Findings suggestive of irAE were present on PET/CT more often in CRT-IO (12/16) compared to CRT (8/27 patients), p = 0.005., Conclusion: Durvalumab maintenance treatment after CRT leads to diverging tumoral metabolic changes, but also increases splenic metabolism and leads to a higher proportion of findings suggestive of irAE compared to patients without durvalumab. Due to significantly prolonged survival with durvalumab, survival analysis will be substantiated in correlation to metabolic changes as soon as more clinical events are present., (© 2023. The Author(s).)

Despite intensive basic scientific, translational, and clinical efforts in the last decades, glioblastoma remains a devastating disease with a highly dismal prognosis. Apart from the implementation of temozolomide into the clinical routine, novel treatment approaches have largely failed, emphasizing the need for systematic examination of glioblastoma therapy resistance in order to identify major drivers and thus, potential vulnerabilities for therapeutic intervention. Recently, we provided proof-of-concept for the systematic identification of combined modality radiochemotherapy treatment vulnerabilities via integration of clonogenic survival data upon radio(chemo)therapy with low-density transcriptomic profiling data in a panel of established human glioblastoma cell lines. Here, we expand this approach to multiple molecular levels, including genomic copy number, spectral karyotyping, DNA methylation, and transcriptome data. Correlation of transcriptome data with inherent therapy resistance on the single gene level yielded several candidates that were so far underappreciated in this context and for which clinically approved drugs are readily available, such as the androgen receptor (AR). Gene set enrichment analyses confirmed these results, and identified additional gene sets, including reactive oxygen species detoxification, mammalian target of rapamycin complex 1 (MTORC1) signaling, and ferroptosis/autophagy-related regulatory circuits to be associated with inherent therapy resistance in glioblastoma cells. To identify pharmacologically accessible genes within those gene sets, leading edge analyses were performed yielding candidates with functions in thioredoxin/peroxiredoxin metabolism, glutathione synthesis, chaperoning of proteins, prolyl hydroxylation, proteasome function, and DNA synthesis/repair. Our study thus confirms previously nominated targets for mechanism-based multi-modal glioblastoma therapy, provides proof-of-concept for this workflow of multi-level data integration, and identifies novel candidates for which pharmacological inhibitors are readily available and whose targeting in combination with radio(chemo)therapy deserves further examination. In addition, our study also reveals that the presented workflow requires mRNA expression data, rather than genomic copy number or DNA methylation data, since no stringent correlation between these data levels could be observed. Finally, the data sets generated in the present study, including functional and multi-level molecular data of commonly used glioblastoma cell lines, represent a valuable toolbox for other researchers in the field of glioblastoma therapy resistance., (© 2023. The Author(s).)

Background: Inherent resistance to radio/chemotherapy is one of the major reasons for early recurrence, treatment failure, and dismal prognosis of glioblastoma. Thus, the identification of resistance driving regulators as prognostic and/or predictive markers as well as potential vulnerabilities for combined modality treatment approaches is of pivotal importance., Methods: We performed an integrative analysis of treatment resistance and DNA damage response regulator expression in a panel of human glioblastoma cell lines. mRNA expression levels of 38 DNA damage response regulators were analyzed by qRT-PCR. Inherent resistance to radiotherapy (single-shot and fractionated mode) and/or temozolomide treatment was assessed by clonogenic survival assays. Resistance scores were extracted by dimensionality reduction and subjected to correlation analyses with the mRNA expression data. Top-hit candidates with positive correlation coefficients were validated by pharmacological inhibition in clonogenic survival assays and DNA repair analyses via residual γH2AX/53BP1-foci staining., Results: Inherent resistance to single-shot and similarly also to fractionated radiotherapy showed strong positive correlations with mRNA expression levels of known vulnerabilities of GBM, including PARP1, NBN, and BLM, as well as ATR and LIG4-two so far underestimated targets. Inhibition of ATR by AZD-6738 resulted in robust and dose-dependent radiosensitization of glioblastoma cells, whereas LIG4 inhibition by L189 had no noticeable impact. Resistance against temozolomide showed strong positive correlation with mRNA expression levels of MGMT as to be expected. Interestingly, it also correlated with mRNA expression levels of ATM, suggesting a potential role of ATM in the context of temozolomide resistance in glioblastoma cells. ATM inhibition exhibited slight sensitization effects towards temozolomide treatment in MGMT low expressing glioblastoma cells, thus encouraging further characterization., Conclusions: Here, we describe a systematic approach integrating clonogenic survival data with mRNA expression data of DNA damage response regulators in human glioblastoma cell lines to identify markers of inherent therapy resistance and potential vulnerabilities for targeted sensitization. Our results provide proof-of-concept for the feasibility of this approach, including its limitations. We consider this strategy to be adaptable to other cancer entities as well as other molecular data qualities, and its upscaling potential in terms of model systems and observational data levels deserves further investigation., (© 2022. The Author(s).)

Prospect theory is among the most influential frameworks in behavioural science, specifically in research on decision-making under risk. Kahneman and Tversky's 1979 study tested financial choices under risk, concluding that such judgements deviate significantly from the assumptions of expected utility theory, which had remarkable impacts on science, policy and industry. Though substantial evidence supports prospect theory, many presumed canonical theories have drawn scrutiny for recent replication failures. In response, we directly test the original methods in a multinational study (n = 4,098 participants, 19 countries, 13 languages), adjusting only for current and local currencies while requiring all participants to respond to all items. The results replicated for 94% of items, with some attenuation. Twelve of 13 theoretical contrasts replicated, with 100% replication in some countries. Heterogeneity between countries and intra-individual variation highlight meaningful avenues for future theorizing and applications. We conclude that the empirical foundations for prospect theory replicate beyond any reasonable thresholds.

Objective: We report our initial experience in the treatment of prostate cancer (PCa) with high-intensity focused ultrasound (HIFU) using the Focal-One ® device., Material and Methods: Retrospective review of the prospectively populated database. Between June 2014 to October 2015, 85 patients underwent HIFU (focal/whole-gland) treatment for localized PCa. Preoperative cancer localization was done with multiparametric magnetic resonance imaging (mpMRI) and transperineal mapping biopsies. Treatment was carried out using the Focal-One ® device under general anesthesia. Oncological follow-up: PSA measurement and control biopsy with mpMRI according to protocol. Questionnaire-based functional outcome assessment was done. Complications were reported using Clavien classification., Results: The median PSA was 7.79ng/ml (IQR 6.32-9.16), with a median prostate volume of 38cc (IQR: 33-49.75). Focal and whole-gland therapy was performed in 64 and 21 patients respectively. Ten patients received salvage HIFU. Complications were encountered in 15% of cases, all Clavien 2 graded. Mean hospital stay was 1.8 days (0-7) and bladder catheter was removed on day 2 (1-6). Mean percentage reduction of PSA was 54%. Median follow-up was 3 months (IQR: 2-8). Functional outcomes: All patients were continents at 3 months and potency was maintained in 83% of the preoperatively potent., Conclusions: Focal-One ® HIFU treatment appears to be a safe procedure with few complications. Functional outcomes proved no urinary incontinence and sexual function were maintained in 83%., (Copyright © 2016. Publicado por Elsevier España, S.L.U.)

Objective: The aim of this study was to determine the incidence of acute renal failure secondary to rhabdomyolysis (ARFSR) as a complication of major urological surgery (MUS), as well as to describe the clinical characteristics and identify possible risk and protective factors., Subjects and Methods: Cases of ARFSR due to MUS between January 1997 and August 2011 were identified using the institutional database. The incidence was estimated and the clinical characteristics were analyzed using simple scatterplot graphs to identify possible risk and protective factors., Results: In this period, 14,337 MUS procedures were performed, in which 4 cases suffered from ARFSR (the incidence rate was 0.03%). The incidence rates after radical cystectomy and urethroplasty were 0.26% (3/1,175 cases) and 0.15% (1/651 cases), respectively. No case of rhabdomyolysis was reported among the patients who underwent other major surgical procedures. Two patients required dialysis, and all 4 patients recovered to their baseline renal function at an average of 11 days (7-17) with the appropriate treatment. Male gender, younger age, lower ASA score, prolonged operative time, high body mass index, elevated preoperative serum creatinine and estimated blood loss were possible risk factors for developing ARFSR due to MUS. We found that a higher intraoperative administered volume was a possible protective factor. The operative position and type of surgery seemed to play minor roles. Early diagnosis and treatment possibly leads to an improved outcome., Conclusion: In our study, ARFSR due to MUS was a rare entity and had a good prognosis. It was more frequent as a complication of radical cystectomy. Further studies are required to confirm our findings., (© 2016 S. Karger AG, Basel.)

Aim: Despite standard treatment with transurethral resection (TURBT) and adjuvant therapy, many bladder cancers (BCs) recur and some progress. Based on a review of the literature, we aimed to establish the optimal current approach for the early diagnosis and management of non-muscle-invasive bladder cancer (NMIBC)., Methods: A Medline® search was conducted to identify the published literature relating to early identification and treatment of NMIBC. Particular attention was paid to factors such as quality of TURBT, importance of second TUR, substaging, and carcinoma in situ. In addition, studies on urinary markers, photodynamic diagnosis, predictive clinical and molecular factors for recurrence and progression after BCG, and best management practice were analyzed., Results: Good quality of TUR and the implementation of photodynamic diagnosis in selected cases provide a more accurate diagnosis and reduce the risk of residual tumor in bladder cancer. Although insufficient evidence is available to warrant the use of new urinary molecular markers in isolation, their use in conjunction with cytology and cystoscopy can improve early diagnosis and follow-up. BCG plus maintenance for at least one year remains the standard adjuvant treatment in high-risk BC. Moreover, there is enough evidence to consider the implementation of new specific risk tables for patients treated with BCG., Conclusion: In high-risk patients with poor prognostic factors after TUR, early cystectomy should be considered.

Objectives: Sickle cell disease is one of the most common hereditary diseases, and migration trends and cross breeding have increased its incidence in Europe. While much has been published about the disease, there are few reviews in the literature dealing with its manifestations in the genitourinary system., Methods: We conducted a comprehensive review, using as our main instrument the PubMed online database, on recent advances in knowledge of the pathophysiology and urological, nephrological, and andrological manifestations of the disease., Results: Manifestations include sickle cell nephropathy, enuresis, nocturia, hematuria, priapism, renal medullary carcinoma, and infarctions and necrosis in various organs of the genitourinary system., Conclusions: The characteristics of this important disease and the multisystemic spectrum it covers make knowledge of its genitourinary manifestations necessary.