Introduction:Targeted radionuclide therapy (TRT) and immune checkpoint inhibition (ICI) could be a highly effective combination treatment due to potential synergistic effects. In this study, we investigated two clinically relevant antibody-based radiopharmaceuticals labeled with lutetium-177: [177Lu]Lu-DOTA-hG250 targeting carbonic anhydrase IX (CAIX) and rosopatamab tetraxetan ([177Lu]Lu-DOTA-rosopatamab) targeting prostate-specific membrane antigen (PSMA). We aimed to assess whether ICI target and treatment timing influence the efficacy of TRT+ICI combinations across three syngeneic murine tumor models with distinct immunogenicity profiles. Understanding these factors is critical for optimizing combination strategies. Methods:C57BL6 hPSMA transgenic mice bearing subcutaneous MC38-hPSMA or B16F10-hPSMA tumors were injected with [177Lu]Lu-DOTA-rosopatamab. Balb/c mice bearing subcutaneous renca-hCAIX tumors were injected with [177Lu]Lu-DOTA-hG250. Tumor growth and overall survival were evaluated for different combination treatments of hPSMA-TRT or hCAIX-TRT with aPD-1, aCTLA-4, or dual-ICI (n = 10 per group). To evaluate the impact of timing on therapeutic outcomes, different concurrent and sequential treatment schedules were compared. Results:In the MC38-hPSMA model, a subtherapeutic [177Lu]Lu-DOTA-rosopatamab dose combined with aPD-1 resulted in robust anti-tumor activity. aCTLA-4 monotherapy was already curative, precluding detection of a combination effect under the conditions tested. In contrast, in the B16F10-hPSMA model, only minimal benefit was seen when combining the same radiopharmaceutical with dual-ICI. The renca-hCAIX model demonstrated differential outcomes, responding most strongly to a subtherapeutic dose of [177Lu]Lu-DOTA-hG250 combined with dual-ICI, while combining with aPD-1 provided moderate benefit and with aCTLA-4 had no therapeutic benefit. Lastly, exploring treatment timing in the MC38-hPSMA and renca-hCAIX models revealed only limited impact on therapeutic outcome under the assessed conditions. Discussion:These findings indicate that 177Lu-labeled antibodies can synergize with ICI at subtherapeutic activity levels in certain settings, supporting their potential to enhance efficacy while potentially reducing toxicity. Combination outcomes varied across tumor models and ICI targets and were likely influenced by both biological and experimental context. The impact of treatment timing appeared limited within the experimental conditions evaluated. These findings should be further explored in preclinical models incorporating mechanistic analyses, while the impact of treatment timing warrants additional investigation in clinically relevant settings. These insights highlight key factors for optimizing TRT+ICI strategies in future clinical studies.

OBJECTIVES:To evaluate the impact of the presence, extent and location of positive surgical margins (PSMs) on the risk of biochemical recurrence (BCR) and metastases in a nationwide cohort of patients who underwent radical prostatectomy (RP) and had 5 years of follow-up. METHODS:All patients diagnosed with prostate cancer in the Netherlands between October 2015 and April 2016 who underwent RP were included in a prospective cohort. Data on these patients from the Netherlands Cancer Registry and the PALGA pathology registry were analysed. BCR was defined as a prostate-specific antigen (PSA) level ≥0.1 ng/mL >28 days after RP. Exclusion criteria were (neo)adjuvant treatment, pN1 disease, and salvage therapy initiated at PSA <0.1 μg/L. Multivariable Cox regression analyses were performed to evaluate the impact of PSM presence, extent and location on the risk of BCR and metastases. RESULTS:Of 998 patients, 311 (31%) had PSMs (median length 5.0 mm). Over 5 years of follow-up, 36% of patients experienced BCR and 11% developed metastases. PSMs ≥3 mm were associated with a significantly increased risk of BCR (hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.58-2.64; P < 0.001) and metastases (HR 2.12, 95% CI 1.21-3.74; P = 0.009) compared to negative surgical margins. By contrast, PSMs <3 mm and PSM location did not significantly increase the risk of BCR or metastases. CONCLUSION:Our study showed that PSMs ≥3 mm appear to be independently associated with an increased risk of BCR and metastases after RP. Therefore, avoiding or limiting the extent of PSMs during RP remains essential.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is caused by heterozygous germline variants in the fumarate hydratase (FH) gene. Inheritance follows an autosomal dominant pattern. Loss of FH confers a predisposition for various benign and malignant neoplasms, including cutaneous leiomyomas, uterine fibroids and FH-deficient renal cell carcinoma. While benign, cutaneous and uterine manifestations have a relevant impact on quality of life and risk for complications, the vast majority of FH-deficient RCCs exhibit an aggressive behaviour with invasive growth and the potential for early metastatic spread. Additionally, pathogenic germline FH variants have been associated with other neoplasms, such as adrenal gland and Leydig cell tumours. The aggressive behaviour of FH-deficient RCC challenges nephron-sparing resection strategies, as a wide margin is recommended. Even after early nephrectomy for surgical removal of FH-deficient renal cell carcinomas, there is a relevant risk for distant metastasis as well as the remaining predisposition for de novo primary renal tumours in the other kidney. Active screening is central to HLRCC care since no preventative HLRCC-specific treatment exists. Vascular endothelial growth factor/epidermal growth factor receptor-directed treatment regimes, such as erlotinib/bevacizumab, demonstrate efficacy against HLRCC-associated RCC. This emphasizes the importance of establishing the correct diagnosis in HLRCC early on to guide therapeutic decisions. Morphologic criteria as well as specific immunohistochemical staining and molecular genetics allow the identification of FH-deficient RCC. Changes made in the recent 2022 World Health Organization classification impact the diagnosis of HLRCC in multiple ways. This commentary aims to discuss this impact and raise awareness among pathologists as well as clinicians involved in the care of patients with HLRCC.

Score chart with predicted probability (%) to remain on WW at 12 months This model was based on the number of IMDC Risk factors (0, 1, 2), the number or involved organ sites (0 - 4) and the geometric mean [¹⁸F]FDG SUVmax as a continuous variable. The underlying formula is 100*(exp(-0.531)^exp(0.198*[IMDC score] + 0.039*[No of affected organ sites] + 0.170*[geometric mean [¹⁸F]FDG SUVmax] - 1.09))

Anatomic imaging of renal masses provides limited information on the histology or likely aggressiveness of the tumor, leading to the use of invasive procedures such as renal mass biopsy or empiric partial or radical nephrectomy. Molecular imaging can assist in risk stratification of indeterminate renal masses, potentially contributing to optimal patient decision-making. Two primary approaches have been explored for renal mass molecular imaging. The first is the use of agents that target carbonic anhydrase IX (CAIX), a cell-surface protein that is over-expressed on clear cell renal cell carcinoma (ccRCC) and generally not expressed on other renal tumors. A recent phase III trial (ZIRCON) is widely believed to have laid the groundwork for United States Food and Drug Administration approval of the CAIX monoclonal antibody 89Zr-girentuximab. The second approach is the use of mitochondrial imaging agents, most notably 99mTc-sestamibi, which are lipophilic cations that accumulate in tumors with an abundance of mitochondria with negative charge potential (e.g., oncocytomas and other benign/indolent lesion) and do not accumulate in tumors with multidrug resistance pumps (e.g., ccRCC). The complementary information from 89Zr-girentuximab and 99mTc-sestamibi can provide improved risk stratification. Further, emerging new targeted radiotracers and techniques such as imaging biomarker discovery with artificial intelligence will bolster those concepts. In this manual, we synthesize key data into a recommended approach.

Flow-chart patients according to RECIST-defined PD. *All patients had clinical disease progression; no CT-imaging was performed before initiation of systemic treatment ** In total 7 patients choose best supportive care. Three other patients underwent radiotherapy or surgery of all target lesions.

With the heterogeneous use and interpretation of next-generation molecular imaging and approval of new treatment strategies, therapeutic decision-making for de novo metastatic hormone-sensitive prostate cancer (mHSPC) is becoming increasingly challenging. It is conceivable that patients are treated differently in another country, hospital or by another clinician. Here, we aim to provide insights into the clinical practices, challenges, and unmet needs in the management of de novo mHSPC.In this explorative mixed-method study, a survey was sent to urologists and oncologists in 13 Dutch hospitals from the TripleAiM1 network. Additionally, four patient cases were discussed in multi-disciplinary team consultations in four of these hospitals. Results from the survey and patient cases were then discussed in focus group sessions. Three sessions were held with the same expert panel, comprising urologists, medical oncologists, a nuclear medicine physician and radiation oncologist. Major themes were identified and analysed using the Matrix method. Of the 91 surveys distributed, 27 urologists and 19 oncologists responded. Patients with low-volume (LV) disease showed most practice variation; ranging from curative to palliative intent and from single to triplet therapies. Reasons given for this variation include the heterogeneous aspect of LV disease, ambiguous definitions, varying interpretations of study data, lead-time in adoption of novel treatment strategies, and guideline gaps. Adding to this divergence are differences in interpretation of metastatic volume. As the majority of physicians (36/46) use PSMA-PET/CT for staging, while LV and high-volume per CHAARTED criteria are defined on conventional imaging. On a scale of 0-10, metastatic volume (8.5), performance score (8.6), and patient preferences (9.0) were considered the most important factors for selecting treatments. This did not differ significantly between specialties, but showed large dispersion within specialties, suggesting variation at the individual physician level. In conclusion, this study provides insights into clinical practices and challenges in the management of de novo mHSPC. By elucidating the perspectives of Dutch physicians, our findings contribute to a better understanding of the complexities involved in treatment decision-making. Moving forward, there is a need for consensus on definitions, imaging modalities for staging, and treatment selection given the altered diagnostic and therapeutic landscape.

Background Androgen receptor targeted therapies (ART) play a major role in the treatment of metastatic castration-resistant prostate cancer (mCRPC). In recent years consensus has been reached that treatment with a second ART should be avoided due to low response rates. The aim of this study was to investigate if new scientific insights led to changes in clinical daily practice in the Netherlands. Methods Patients included in the Dutch CAPRI-3 prostate cancer registry, currently encompassing 19 hospitals, and treated with at least 1 ART (ie, abiraterone or enzalutamide) were included. Patients were stratified based on start date of first ART (ART1) according to standard of care between 2016-2017, 2018-2019 and 2020-2021. Second ART (ART2) was defined as either direct (ART1>ART2) or at any given time (any ART2). Results Between the first and last ART1 group, the prevalence of ART1>ART2 declined from 14.3% to 6.5% (P = .001) and the prevalence of any ART2 from 27.6% to 10.7% (P < .001). The decline was observed before recommendations were included in European guidelines. The use of other life-prolonging drugs (LPDs) after ART1 (ART1>LPD) increased. Patients who were selected for ART1>ART2 instead of ART1>LPD were older, less frequently treated with taxane-based chemotherapy for mHSPC and had a longer time to development of mCRPC. Conclusions New scientific insights were incorporated into clinical daily practice, with a significant decline in in the prevalence of sequential ART treatment, even before recommendations were included in European guidelines.

Hier is alweer het volgende abstractnummer van het Tijdschrift voor Urologie. Deze keer van de voorjaarsvergadering van de NVU in Groningen. Martiniplaza is de plek waar veel urologen, arts-assistenten en arts-onderzoekers naartoe zullen gaan.

Flow diagram of patient enrolment. * Four patients were unfit for systemic treatment due to clinical deterioration resulting from rapid disease progression (n=3) or comorbidity and age (n=1). Three other patients did not wat systemic treatment.

Voor u ligt het abstractnummer van de najaarsvergadering van de Nederlandse Vereniging voor Urologie in ‘s-Hertogenbosch op 8 november 2024.

BACKGROUND: The role of active surveillance (AS) has been recognized as a management strategy for localized small renal masses (SRMs). The EAU guidelines suggest AS can be offered to frail and/or comorbid patients diagnosed with SRM due to the low cancer-specific-mortality (CSM) and higher competing-cause mortality. As specific cut-offs defining the characteristics of frail and comorbid patients who may benefit from AS remain less clear, our objective is to conduct a systematic review aiming to identify potential characteristics that could assist physicians in shared decision-making. METHODS: The systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Two authors independently screened the literature according to the PICOs criteria previously outlined in our registered review protocol (via Pubmed, Embase, and the Cochrane Central Register of Controlled Trials), extracted data, and assessed the risk of bias, using Newcastle-Ottawa Scale. Studies that analyzed differences in patient’s tumor-related and molecular characteristics associated with any differences in growth rate (GR), overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS), were considered eligible. RESULTS: Nineteen studies comprising a total of 5105 patients were analyzed. Patient-specific factors such as age and cardiovascular index, which demonstrated a predominant impact on OS, exhibited a high degree of consistency across the analyzed studies. Less concordance was found when exploring GR, with the main predictors being ethnicity, age, sex, comorbidity, symptoms, and eGFR. The analysis of tumor-related characteristics, such as tumor size, nephrometry score, and mass histology, among others, yielded contradictory outcomes concerning their impact on GR and CSS. CONCLUSION: Age, cardiovascular index, and chronic kidney disease have shown to be reliable predictors of OS. Nonetheless, significant debates persist regarding tumor characteristics or molecular markers that may influence survival and GR. Further research is awaited to shed light on the potential to identify prognostic factors. This would aid in pinpointing the subgroup of patients who could experience additional benefits from AS, potentially leading to a reduced risk of progression. It is imperative to standardize approaches to AS and reporting of results, as this will be pivotal for future quantitative analyses.

OBJECTIVES:It is assumed that neuroplasticity plays a central role in the effect of electroconvulsive therapy (ECT) on patients with major depressive disorder. We carried out an explorative study to map out the extent in which gray matter volume changes could be found directly after ECT treatment and after follow-up. METHODS:Initially, 12 patients with treatment-resistant depression were recruited from the Radboud Medical Center. Magnetic resonance imaging scans were conducted at the following 3 time points: before ECT (n = 12), after ECT (n = 10), and at 3-month follow-up (n = 8). Subcortical volume, hippocampal subfield volume, and cortical thickness were analyzed using FreeSurfer. RESULTS:The extensive, generalized changes in gray matter volume are largely transient after treatment with ECT, with the noted exceptions being a sustained increase in volume of the right amygdala and a part of the left cornu ammonis. Post hoc testing revealed no significant correlation with clinical response. DISCUSSION:Our results suggest that the neuroplastic effects of ECT may not be mediators of clinical response and could be transient epiphenomena.

BACKGROUND:With limitations of conventional imaging and biopsy, accurate, non-invasive techniques to detect clear-cell renal cell carcinoma in patients with renal masses remain an unmet need. 89Zr-labelled monoclonal antibody ([89Zr]Zr-girentuximab) has high affinity for carbonic anhydrase 9, a tumour antigen highly expressed in clear-cell renal cell carcinoma. We aimed to evaluate [89Zr]Zr-girentuximab PET-CT imaging for detection and characterisation of clear-cell renal cell carcinoma. METHODS:ZIRCON was a prospective, open-label, multicentre, phase 3 trial conducted at 36 research hospitals and practices across nine countries (the USA, Australia, Canada, the UK, Türkiye, Belgium, the Netherlands, Spain, and France). Patients aged 18 years or older with an indeterminate renal mass 7 cm or smaller (cT1) suspicious for clear-cell renal cell carcinoma and scheduled for nephrectomy received a single dose of [89Zr]Zr-girentuximab (37 MBq ±10%; 10 mg girentuximab) intravenously followed by abdominal PET-CT imaging 5 days (±2 days) later. Surgery was performed no later than 90 days after administration of [89Zr]Zr-girentuximab. Blinded central review, conducted by three independent readers, determined the histology from surgical samples. The coprimary endpoints, determined for each individual reader, were the sensitivity and specificity of [89Zr]Zr-girentuximab PET-CT imaging to detect clear-cell renal cell carcinoma, with histopathological confirmation as standard of truth. Analyses were on the full analysis set of patients, defined as patients who had evaluable PET-CT imaging and a confirmed histopathological diagnosis. The trial is registered with ClinicalTrials.gov, NCT03849118, and EUDRA Clinical Trials Register, 2018-002773-21, and is closed to enrolment. FINDINGS:Between Aug 14, 2019, and July 8, 2022, 371 patients were screened for eligibility, 332 of whom were enrolled. 300 patients received [89Zr]Zr-girentuximab (214 [71%] male and 86 [29%] female). 284 (95%) evaluable patients were included in the primary analysis. The mean sensitivity was 85·5% (95% CI 81·5-89·6) and mean specificity was 87·0% (81·0-93·1). No safety signals were observed. Most adverse events were not or were unlikely to be related to [89Zr]Zr-girentuximab, with most (193 [74%] of 261 events) occurring during or after surgery. The most common grade 3 or worse adverse events were post-procedural haemorrhage (in six [2%] of 261 patients), urinary retention (three [1%]), and hypertension (three [1%]). In 25 (8%) of 300 patients, 52 serious adverse events were reported, of which 51 (98%) occurred after surgery. There were no treatment-related deaths. INTERPRETATION:Our results suggest that [89Zr]Zr-girentuximab PET-CT has a favourable safety profile and is a highly accurate, non-invasive imaging modality for the detection and characterisation of clear-cell renal cell carcinoma, which has the potential to be practice changing. FUNDING:Telix Pharmaceuticals.

Objective: Changes in microbial composition are observed in various psychiatric disorders, but their specificity to certain symptoms or processes remains unclear. This study explores the associations between the gut microbiota composition and the Research Domain Criteria (RDoC) domains of functioning, representing symptom domains, specifically focusing on stress-related and neurodevelopmental disorders in patients with and without psychiatric comorbidity. Methods: The gut microbiota was analyzed in 369 participants, comprising 272 individuals diagnosed with a mood disorder, anxiety disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, and/or substance use disorder, as well as 97 psychiatrically unaffected individuals. The RDoC domains were estimated using principal component analysis (PCA) with oblique rotation on a range of psychiatric, psychological, and personality measures. Associations between the gut microbiota and the functional domains were assessed using multiple linear regression and permanova, adjusted for age, sex, diet, smoking, medication use and comorbidity status. Results: Four functional domains, aligning with RDoC's negative valence, social processes, cognitive systems, and arousal/regulatory systems domains, were identified. Significant associations were found between these domains and eight microbial genera, including associations of negative valence with the abundance of the genera Sellimonas, CHKCI001, Clostridium sensu stricto 1, Oscillibacter, and Flavonifractor; social processes with Sellimonas; cognitive systems with Sporobacter and Hungatella; and arousal/regulatory systems with Ruminococcus torques (all P-FDR < 0.05). Conclusion: Our findings demonstrate associations between the gut microbiota and the domains of functioning across patients and unaffected individuals, potentially mediated by immune-related processes. These results open avenues for microbiota-focused personalized interventions, considering psychiatric comorbidity. However, further research is warranted to establish causality and elucidate mechanistic pathways.

To evaluate the effectiveness of extended (e-PLND) and super-extended pelvic lymph node dissection (se-PLND) during robot-assisted radical prostatectomy (RARP) by examining lymph node (LN) yield, complications, LN metastasis, and biochemical recurrence (BCR) incidence. Between January 2016 and January 2020, 354 consecutive patients with > 5

tonen aan dat een kwart van de MRI's voor een consult niet nodig is op basis van de risicoscore.We gaan eigenlijk weer heen en weer, want wat doen we nu eerst tijdens het eerste bezoek van een patiënt met een verdenking op prostaatkanker?Het verhaal is nog niet afgerond en het zal nog wel verder aan bod komen tijdens de NVU-vergaderingen en in dit tijdschrift.Opvallend was het grote aantal deelnemers aan de NVU-vergadering in IJmuiden, maar ook hoeveel arts-assistenten en vooral ook arts-onderzoekers en zelfs coassistenten daar een podium kregen.De vergadering was zowel wetenschappelijk als sociaal een enorm succes -met dank aan de wetenschappelijke commissie, de Kennemer urologen en het bureau van de NVU.

Microarray and Single-Molecule Molecular Inversion Probe (smMIP)-based targeted RNA sequencing are two RNA profiling platforms for identifying disease-associated biomarkers. The microarray uses a GeneChip array with oligonucleotide probes to measure expression levels across thousands of genes, while smMIPs capture and quantify RNA transcripts and transcript variants via next-generation sequencing. To evaluate the strengths and weaknesses of both platforms, a comparative gene expression profiling study was conducted using RNA samples from 52 prostate tissues (normal, benign prostatic hyperplasia (BPH) and various prostate cancer (PCa) grades). Of all genes covered by both platforms, only 35% of the expression levels aligned, with 45% showing discrepancies. Both platforms identified the same 17 genes as potential PCa biomarkers. Microarray analysis identified an additional 253 genes that were not covered or not identified by smMIP technology, while smMIP technology identified eight markers not covered or not identified in the microarray core gene analysis, including fusion genes and splice variants. For high-grade prostate cancer (HG-PCa), the smMIP-method identified 8 markers, and the microarray identified 17 markers, with FOLH1, FAP and CLDN3 being common across both platforms. The choice of RNA expression analysis technology depends on research objectives; microarray technology is useful for the evaluation of a wide range of genes but has low throughput. In contrast, smMIP-based RNA sequencing enables sensitive analysis with minimal RNA in a medium- to high-throughput setting.