68Ga-PSMA-11 PET/CT (PSMA PET/CT) is used for staging advanced prostate cancer (PCa); however, its role in initial cancer detection and guiding localized treatment remains uncertain. The primary objective of this study was to assess the impact of upfront PSMA PET/CT on treatment decision-making based on imaging and biopsy-derived information. Methods: In this prospective, phase 2 interventional trial, 230 biopsy- and imaging-naïve men with suspected PCa underwent PSMA PET/CT and multiparametric MRI (mpMRI) before targeted ultrasound fusion and systematic biopsy. Randomized assessor teams independently reviewed histopathology and imaging data from either the mpMRI or the combined mpMRI plus PSMA PET/CT pathway and formulated treatment plans accordingly. Patient recruitment was conducted between 2021 and 2023. Results: Among 137 patients with PCa (9% low-, 35% intermediate-, and 15% high-risk disease), PSMA PET/CT altered management plans in 34% of patients, primarily modifying local treatment strategies, including lymph node dissection (16%), a nerve-sparing procedure (18%), and radiation field adjustments (28%). Systemic therapy escalation was rare (1%). In addition, 2% of patients initiated active treatment, 5% received adjunctive hormone therapy, and 7% underwent metastasis-directed therapy. Upfront PSMA PET/CT prompted treatment intensification at comparable rates in both intermediate-risk (31%) and high-risk (30%) PCa with high interrater agreement (Cohen κ, 0.71; 95% CI, 0.61-0.80). Prostate-specific antigen density of at least 0.15 ng/mL3 (odds ratio, 2.48; 95% CI, 1.22-5.06) and abnormal digital rectal examination (odds ratio, 2.12; 95% CI, 1.03-4.33) predicted PSMA PET/CT-driven changes. Conclusion: Early PSMA PET/CT staging altered treatment strategies for up to one third of patients with intermediate- and high-risk PCa by enhancing metastasis detection and local tumor characterization. Its effect on oncologic and functional outcomes warrants further investigation.

OBJECTIVES:Accurate assessment of extraprostatic extension (EPE) in prostate cancer is essential for surgical planning. This study aimed to compare the diagnostic performance of biparametric (bpMRI) and multiparametric MRI (mpMRI) for detecting EPE using histopathology as the reference standard. MATERIALS AND METHODS:Biopsy-naïve men that underwent mpMRI followed by radical prostatectomy were included retrospectively. Four radiologists independently evaluated bpMRI (T2-weighted, diffusion-weighted) and mpMRI (addition of DCE). PI-RADS, pseudocapsular (PC) bulging, PC irregularity, MRI-visible PC breach, and PC tumor contact length were assessed. Histopathological prostatectomy specimens served as reference. Sensitivities and specificities were calculated using generalized estimating equations. A scoring system, integrating these morphological characteristics with MRI-visible PC breach and tumor contact length weighted double, was evaluated by calculating the area-under-the-curve (AUC) and Youden-Index. RESULTS:90 men (mean age: 64 ± 6) were included. 86 (95.6%) patients had clinically significant prostate cancer (ISUP ≥ 2). bpMRI and mpMRI had no significant difference regarding morphological characteristics, for instance, MRI-visible PC breach (sensitivity: 0.22 [95% CI: 0.15, 0.31] versus 0.23 [95% CI: 0.16, 0.31], p = 0.87; specificity: 0.99 [95% CI: 0.96, 0.99] versus 0.99 [95% CI: 0.96, 0.99], p = 1.00). The AUC for the scoring system was similar between bpMRI and mpMRI (mean AUC: 0.80 [95% CI: 0.69, 0.90] versus 0.79 [95% CI: 0.69, 0.90], p = 0.77) with an optimal score of 2/6 points for both protocols. CONCLUSION:Diagnostic accuracy for detecting EPE did not differ between bpMRI and mpMRI, thus supporting bpMRI as an alternative for local prostate cancer staging.

New magnetic resonance imaging (MRI) gradient technology enables the acquisition of ultrahigh b-value diffusion-weighted imaging (DWI). We assessed its impact on image quality and Prostate Imaging Reporting and Data System (PI-RADS) scores in prostate MRI. Participants with cancer suspicion prospectively underwent 3-T prostate MRI (maximum gradient strength 200 mT/m). Sequences with b-values of 0/800, 1,500, 2,500, 3,500, and 4,500 s/mm² were acquired. Lesion conspicuity was rated from 1 (non-diagnostic) to 5 (excellent). Apparent signal-to-noise ratios (aSNR) and acquisition times were determined. Cumulative link mixed-effects models, repeated measures ANOVA, and Cohen/Fleiss κ statistics were used. A total of 107 participants, aged 67 ± 8 years (mean ± standard deviation), were included. Compared to DWI(b1500), the DWI(b2500), DWI(b3500), and DWI(b4500) acquisitions were worse regarding both lesion conspicuity (median score, 5 [interquartile interval 4–5] versus 4 [3–4] versus 2 [2–3] versus 2 [1–2], respectively; all p < 0.001) and aSNR (19.0 ± 7.5 versus 12.7 ± 4.8 versus 11.8 ± 4.1 versus 11.4 ± 2.6, respectively; all p < 0.001). Acquisition times increased from DWI(b1500) (107 ± 9 s) to DWI(b4500) (329 ± 26 s). Cohen κ for PI-RADS score agreement was good to moderate (DWI(b2500): 0.87 [confidence interval 0.81, 0.94]; DWI(b3500): 0.75 [0.65, 0.84]; DWI(4500): 0.61 [0.49, 0.72]). Acquired ultrahigh gradient DWI sequences with ultrahigh b-values in prostate MRI had worse image quality than standard b-values, while PI-RADS agreement between DWI(b1500) and DWI(b2500) was good. However, diagnostic estimates for clinically significant prostate carcinoma remained limited due to a small biopsy sample size (50/107 patients). Ultrahigh b-value DWI showed no improved diagnostic performance in comparison to standard b-value DWI regarding the identification of potential prostate cancer. Ultrahigh b-value should not replace standard high b-values (1,500 s/mm²) for imaging workup of patients with suspicion for prostate cancer.

IMPORTANCE Progressive disease (PD) in patients treated with immune checkpoint inhibitors (ICIs) varies widely in outcomes according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Efforts to modify RECIST for ICI treatment have not resolved the heterogeneity in PD patterns, posing a clinical challenge. OBJECTIVE To develop and validate a modified PD classification based on PD patterns and evaluate its association with postprogression survival (PPOS) in patients treated with the programmed cell death protein ligand 1 antibody atezolizumab across various solid tumors. DESIGN, SETTING, AND PARTICIPANTS This study analyzed data from 5 phase 3 trials (IMmotion151, IMvigor211, OAK, Impower133, and IMspire150) involving patients treated with atezolizumab for renal cell carcinoma (RCC), urothelial carcinoma, small cell lung cancer, non-small cell lung cancer, and melanoma. This post hoc analysis was conducted from March to September 2024. EXPOSURE Treatment with atezolizumab. MAIN OUTCOMES AND MEASURES The primary outcome was the association of PD patterns with PPOS. Seven PD patterns were identified based on the enlargement of target and nontarget lesions or new lesions and their combinations. RESULTS A total of 1377 patients were analyzed across the 5 trials. In RCC, 7 PD patterns significantly affected prognosis. The 6-month PPOS probability ranged from 26% for progression in target and nontarget lesions plus new lesions to 90% for progression in either target or nontarget lesions alone. A modified PD classification was developed that categorized PD into 3 risk levels: low risk (progression of existing lesions), intermediate risk (new lesions without progression of existing lesions), and high risk (progression of existing lesions plus new lesions). This score was associated with PPOS in ICI-treated RCC, with hazard ratios of 0.23(95% CI, 0.13-0.41; P < .001) and 0.39 (95% CI, 0.23-0.66; P < .001) for low-risk and intermediate-risk PD compared with high-risk PD, respectively. Validation in additional trials confirmed the score's applicability across various tumors. CONCLUSIONS AND RELEVANCE In this study, a survival score was developed based on PD patterns. The risk classification was associated with PPOS across various solid tumors treated with immunotherapy and may therefore enhance prognostication and clinical decision-making, potentially providing a valuable tool for treating patients with PD who are receiving immunotherapy.

Abstract Objectives Although biomarkers predicting therapy response in first‐line metastatic renal carcinoma (mRCC) therapy remain to be defined, C‐reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. Here, we aimed to assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real‐world first‐line mRCC cohort. Methods Metastatic renal carcinoma patients treated with IO‐based first‐line therapy within 5 years were retrospectively included in this multicentre study. According to Fukuda et al., patients were defined as ‘CRP flare‐responder’, ‘CRP responder’ and ‘non‐CRP responder’; according to Ishihara et al., patients were defined as ‘normal’, ‘normalised’ and ‘non‐normalised’ based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression‐free survival (PFS), including multivariable Cox regression analyses. Results Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare‐ (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non‐CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalised patients had a significantly longer PFS and OS, compared with non‐normalised group. Conclusion Different early CRP kinetics may predict therapy response in first‐line mRCC therapy in a large real‐world cohort. However, further research regarding the optimal timing and frequency of measurement is needed.

Abstract Objectives To implement and evaluate a super-fast and high-quality biparametric MRI (bpMRI) protocol for prostate imaging acquired at a new ultra-high gradient 3.0-T MRI system. Methods Participants with clinically suspected prostate cancer prospectively underwent a multiparametric MRI (mpMRI) on a new 3.0-T MRI scanner (maximum gradient strength: 200 mT/m, maximum slew rate: 200 T/m/s). The bpMRI protocol was extracted from the full mpMRI protocol, including axial T2-weighted and diffusion-weighted (DWI) sequences (b0/800, b1500). Overall image quality was rated by two readers on a five-point Likert scale from (1) non-diagnostic to (5) excellent. PI-RADS 2.1 scores were assessed by three readers separately for the bpMRI and mpMRI protocols. Cohen’s and Fleiss’ κ were calculated for PI-RADS agreement between protocols and interrater reliability between readers, respectively. Results Seventy-seven male participants (mean age, 66 ± 8 years) were included. Acquisition time of the bpMRI protocol was reduced by 62% (bpMRI: 5 min, 33 ± 21 s; mpMRI: 14 min, 50 ± 42 s). The bpMRI protocol showed excellent overall image quality for both the T2-weighted (median score both readers: 5 [IQR: 4–5]) and DWI (b1500) sequence (median score reader 1: 4 [IQR: 4–5]; reader 2: 4 [IQR: 4–4]). PI-RADS score agreement between protocols was excellent (Cohen’s κ range: 0.91–0.95 [95% CI: 0.89, 0.99]) with an overall good interrater reliability (Fleiss’ κ, 0.86 [95% CI: 0.80, 0.92]). Conclusion Ultra-high gradient MRI allows the establishment of a high-quality and rapidly acquired bpMRI with high PI-RADS agreement to a full mpMRI protocol. Trials registration Clinicaltrials.gov, NCT06244680, Registered 06 February 2024, retrospectively registered, https://classic.clinicaltrials.gov/ct2/show/NCT06244680. Critical relevance statement A novel 3.0-Tesla MRI system with an ultra-high gradient performance enabled high-quality biparametric prostate MRI in 5.5 min while achieving excellent PI-RADS agreement with a standard multiparametric protocol. Key Points Multi- and biparametric prostate MRIs were prospectively acquired utilizing a maximum gradient of 200 mT/m. Super-fast biparametric MRIs showed excellent image quality and had high PI-RADS agreement with multiparametric MRIs. Implementation of high gradient MRI in clinical routine allows accelerated and high-quality biparametric prostate examinations. Graphical Abstract

Background: Metastatic prostate cancer (mPCA) poses challenges in treatment response assessment, particularly in cases where prostate-specific antigen (PSA) levels do not reliably indicate a response. Liquid biopsy, focusing on circulating cell-free DNA (ccfDNA) methylation analysis as a proxy for circulating tumor DNA, offers a non-invasive and cost-effective approach. This study explores the potential of two methylation markers, short stature homeobox 2 (SHOX2) and Septin 9 (SEPT9), as on-mPCA-treatment biomarkers. Methods: Plasma samples were collected from 11 mPCA patients undergoing various treatments. Quantitative assessment of hypermethylated SHOX2 (mSHOX2) and SEPT9 (mSEPT9) levels in ccfDNA was conducted through methylation-specific real-time PCR. Early and overall dynamics of PSA, mSHOX2, and mSEPT9 were analyzed. Statistical evaluation employed Wilcoxon tests. Results: mSHOX2 demonstrated a significant decline post-treatment in patients with a radiographic treatment response as well as in an early treatment setting. mSEPT9 and PSA exhibited non-significant declines. In individual cases, biomarker dynamics revealed unique patterns compared to PSA. Discussion: mSHOX2 and mSEPT9 exhibit dynamics on mPCA treatment. This proof-of-concept study lays the groundwork for further investigation into these markers as valuable additions to treatment response monitoring in mPCA. Further validation in larger cohorts is essential for establishing clinical utility.

Introduction: A large number of patients with non-small cell lung cancer (NSCLC) on immune checkpoint inhibition (ICI) achieve stable disease (SD) as the best overall response, which is associated with heterogeneous outcomes. In this context, complementary biomarkers that improve outcome prediction are needed. We have recently demonstrated that measuring the on-treatment modified Glasgow prognostic score (mGPS), which is based on the two serum markers C-reactive protein (CRP) and albumin, can improve outcome prediction complementary to radiological staging in metastatic renal cell carcinoma. However, this concept has not been assessed for patients with NSCLC on ICI. Methods: We assessed the prognostic and predictive value of on-treatment mGPS at week six in patients with NSCLC treated with atezolizumab or docetaxel in the phase 3 OAK trial (NCT02008227) comprising n = 750 patients and validated the findings in the phase 2 BIRCH (NCT02031458, n = 560). Results: On-treatment mGPS assessed at week six demonstrated valuable prognostic information (Hazard Ratio (HR) for mGPS low-risk vs intermediate risk 2.34 (95 % CI 1.76-3.11, p < 0.001) and vs high risk 3.56, (95 % CI 2.57-4.91, p < 0.001) in the atezolizumab-treated subgroup. On-treatment mGPS predicted overall survival more accurately than imaging using RECIST criteria (concordance index: on-treatment mGPS 0.646 (95 % CI 0.615-0.677) vs RECIST 0.606 (95 % CI 0.575-0.637)). On-treatment mGPS provides additional prognostic information to imaging-assessed treatment response at first staging, especially for the patient subgroup with SD. These findings were validated in the BIRCH trial. Conclusions: We highlight the novel concept of integrating on-treatment mGPS for improved outcome prediction in conjunction with radiological imaging for patients with NSCLC on ICI.

Importance:In the era of immuno-oncology, imaging alone seems to be insufficient to capture treatment responses, as patients with stable disease treated with immunotherapy have a wide range of clinical outcomes. There is an unmet need for complementary (ideally cost-efficient) markers that enable assessment of therapy response and outcomes in conjunction with imaging.Objectives:To examine whether longitudinal changes in the modified Glasgow prognostic score (mGPS), which is based on C-reactive protein and albumin, can predict responses and outcomes in patients with metastatic renal cell carcinoma (mRCC).Design, Setting, and Participants:This post hoc analysis, conducted from October 2022 to April 2023, evaluated the prognostic and predictive performance of on-treatment mGPS in patients with mRCC being treated with atezolizumab (plus bevacizumab) or sunitinib in 2 randomized clinical trials: the phase 3 IMmotion151 study (discovery cohort) and the phase 2 IMmotion150 study (validation cohort).Main Outcomes and Measures:Outcomes were investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and overall survival (OS) for survival analyses. To compare the prognostic value of the on-treatment mGPS with radiologic staging, we used RECIST assessed by the Independent Review Committee (IRC-RECIST) to ensure high data quality.Results:Of the 915 patients with mRCC in the IMmotion151 discovery cohort, baseline mGPS was available for 861 patients and on-treatment mGPS for 691. The IMmotion150 validation cohort included 305 patients with mRCC, and on-treatment mGPS could be evaluated for 199. In the IMmotion150 study, on-treatment mGPS predicted outcomes as early as 6 weeks following therapy initiation, thereby opening a window for early therapy adjustments. In both clinical trials, on-treatment mGPS provided valuable prognostic information regardless of imaging-assessed treatment response at first staging. Of note, in the disease control subgroup, on-treatment mGPS exhibited superior and independent prognostic information compared with IRC-RECIST (available for 611 patients; C-index, 0.651 [95% CI, 0.588-0.714] for the mGPS during treatment vs 0.574 [95% CI, 0.528-0.619] for IRC-RECIST).Conclusions and Relevance:These data support the concept of integrating on-treatment mGPS for more holistic and patient-centered therapy monitoring in addition to radiologic staging to improve clinical care at a low cost for patients with mRCC.

Collectively, urological malignancies account for a considerable proportion of cancer cases worldwide [...].

METTL3 is the major writer of N6-Methyladenosine (m6A) and has been associated with controversial roles in cancer. This is best illustrated in urothelial carcinoma of the bladder (UCB), where METTL3 was described to have both oncogenic and tumor-suppressive functions. Here, we reinvestigated the role of METTL3 in UCB. METTL3 knockout reduced the oncogenic phenotype and m6A levels of UCB cell lines. However, complete depletion of METTL3/m6A was not achieved due to selection of cells expressing alternative METTL3 isoforms. Systematic vulnerability and inhibitor response analyses suggested that uroepithelial cells depend on METTL3 for viability. Furthermore, expression and survival analyses of clinical data revealed a complex role for METTL3 in UCB, with decreased m6A mRNA levels in UCB tumors. Our results suggest that METTL3 expression may be a suitable diagnostic UCB biomarker, as the enzyme promotes UCB formation. However, the suitability of the enzyme as a therapeutic target should be evaluated carefully.

AbstractPurpose:The antibody–drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET).Experimental Design:Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4–negative/weak (H-score 0–99) versus moderate/strong (H-score 100–300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9–induced polyclonal NECTIN-4 knockouts.Results:In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0–140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001).Conclusions:Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV.See related commentary by Aggen et al., p. 1377

Background Deep learning (DL) reconstructions can enhance image quality while decreasing MRI acquisition time. However, DL reconstruction methods combined with compressed sensing for prostate MRI have not been well studied. Purpose To use an industry-developed DL algorithm to reconstruct low-resolution T2-weighted turbo spin-echo (TSE) prostate MRI scans and compare these with standard sequences. Materials and Methods In this prospective study, participants with suspected prostate cancer underwent prostate MRI with a Cartesian standard-resolution T2-weighted TSE sequence (T2C) and non-Cartesian standard-resolution T2-weighted TSE sequence (T2NC) between August and November 2022. Additionally, a low-resolution Cartesian DL-reconstructed T2-weighted TSE sequence (T2DL) with compressed sensing DL denoising and resolution upscaling reconstruction was acquired. Image sharpness was assessed qualitatively by two readers using a five-point Likert scale (from 1 = nondiagnostic to 5 = excellent) and quantitatively by calculating edge rise distance. The Friedman test and one-way analysis of variance with post hoc Bonferroni and Tukey tests, respectively, were used for group comparisons. Prostate Imaging Reporting and Data System (PI-RADS) score agreement between sequences was compared by using Cohen κ. Results This study included 109 male participants (mean age, 68 years ± 8 [SD]). Acquisition time of T2DL was 36% and 29% lower compared with that of T2C and T2NC (mean duration, 164 seconds ± 20 vs 257 seconds ± 32 and 230 seconds ± 28; P < .001 for both). T2DL showed improved image sharpness compared with standard sequences using both qualitative (median score, 5 [IQR, 4-5] vs 4 [IQR, 3-4] for T2C and 4 [IQR, 3-4] for T2NC; P < .001 for both) and quantitative (mean edge rise distance, 0.75 mm ± 0.39 vs 1.15 mm ± 0.68 for T2C and 0.98 mm ± 0.65 for T2NC; P < .001 and P = .01) methods. PI-RADS score agreement between T2NC and T2DL was excellent (κ range, 0.92-0.94 [95% CI: 0.87, 0.98]). Conclusion DL reconstruction of low-resolution T2-weighted TSE sequences enabled accelerated acquisition times and improved image quality compared with standard acquisitions while showing excellent agreement with conventional sequences for PI-RADS ratings. Clinical trial registration no. NCT05820113 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Turkbey in this issue.

Static biomarkers like programmed death-ligand 1 (PD-L1) are insufficient to accurately predict response to immune checkpoint inhibition. Therefore, on-treatment biomarkers, which measure immediate therapy-associated changes, are currently shifting into the focus of immuno-oncology. A prime example of a simple predictive on-treatment biomarker is the early C-reactive protein (CRP) kinetics with its predictive CRP flare-response phenomenon. Here, we were able to confirm the predictive value of CRP flare-response kinetics in the pivotal phase III OAK trial (NCT02008227), which compared atezolizumab with docetaxel in patients with non-small cell lung cancer. Of note, CRP flare-response predicted favorable outcomes only in the immune checkpoint inhibition-treated subgroup, which suggests that it is an immunotherapy-specific phenomenon. In conclusion, we have for the first time validated the high predictive value of early CRP kinetics in a pivotal phase III trial, justifying the broad use of this cost-effective and easy-to-implement on-treatment biomarker to optimize therapy monitoring for patients with non-small cell lung cancer.

Objectives The aim of this study was to compare a new compressed sensing (CS) method for T2-weighted propeller acquisitions (T2CS) with conventional T2-weighted propeller sequences (T2conv) in terms of achieving a higher image quality, while reducing the acquisition time. Materials and Methods Male participants with a clinical suspicion of prostate cancer were prospectively enrolled and underwent prostate magnetic resonance imaging at 3 T. Axial and sagittal images of the T2conv sequence and the T2CS sequence were acquired. Sequences were qualitatively assessed by 2 blinded radiologists concerning artifacts, image-sharpness, lesion conspicuity, capsule delineation, and overall image quality using 5-point Likert items ranging from 1 (nondiagnostic) to 5 (excellent). The apparent signal-to-noise ratio and apparent contrast-to-noise ratio were evaluated. PI-RADS scores were assessed for both sequences. Statistical analysis was performed by using Wilcoxon signed rank test and paired samples t test. Intrarater and interrater reliability of qualitative image evaluation was assessed using intraclass correlation coefficient (ICC) estimates. Results A total of 29 male participants were included (mean age, 66 ± 8 years). The acquisition time of the T2CS sequence was respectively 26% (axial plane) and 24% (sagittal plane) shorter compared with the T2conv sequence (eg, axial: 171 vs 232 seconds; P < 0.001). In the axial plane, the T2CS sequence had fewer artifacts (4 [4–4.5] vs 4 [3–4]; P < 0.001), better image-sharpness (4 [4–4.5] vs 3 [3–3.5]; P < 0.001), better capsule delineation (4 [3–4] vs 3 [3–3.5]; P < 0.001), and better overall image quality (4 [4–4] vs 4 [3–4]; P < 0.001) compared with the T2conv sequence. The ratings of lesion conspicuity were similar (4 [4–4] vs 4 [3–4]; P = 0.166). In the sagittal plane, the T2CS sequence outperformed the T2conv sequence in the categories artifacts (4 [4–4] vs 3 [3–4]; P < 0.001), image sharpness (4 [4–5] vs 4 [3–4]; P < 0.001), lesion conspicuity (4 [4–4] vs 4 [3–4]; P = 0.002), and overall image quality (4 [4–4] vs 4 [3–4]; P = 0.002). Capsule delineation was similar between both sequences (3 [3–4] vs 3 [3–3]; P = 0.07). Intraobserver and interobserver reliability for qualitative scoring were good (ICC intra: 0.92; ICC inter: 0.86). Quantitative analysis revealed a higher apparent signal-to-noise ratio (eg, axial: 52.2 ± 9.7 vs 22.8 ± 3.6; P < 0.001) and a higher apparent contrast-to-noise ratio (eg, axial: 44.0 ± 9.6 vs 18.6 ± 3.7; P ≤ 0.001) of the T2CS sequence. PI-RADS scores were the same for both sequences in all participants. Conclusions CS-accelerated T2-weighted propeller acquisition had a superior image quality compared with conventional T2-weighted propeller sequences while significantly reducing the acquisition time.

We analyzed real-world clinical outcomes of sequential α-/β-emitter therapy for metastatic castration-resistant prostate cancer (mCRPC). Methods: We assessed safety and overall survival in 26 patients who received 177Lu-prostate-specific membrane antigen ligand (177Lu-PSMA) after 223Ra in the ongoing noninterventional REASSURE study (223Ra α-Emitter Agent in Nonintervention Safety Study in mCRPC Population for Long-Term Evaluation; NCT02141438). Results: Patients received 223Ra for a median of 6 injections and subsequent 177Lu-PSMA for a median of 3.5 mo (≥ the fourth therapy in 69%). The median time between 223Ra and 177Lu-PSMA treatment was 8 mo (range, 1-31 mo). Grade 3 hematologic events occurred in 9 of 26 patients (during or after 177Lu-PSMA treatment in 5/9 patients; 8/9 patients had also received docetaxel). Median overall survival was 28.0 mo from the 223Ra start and 13.2 mo from the 177Lu-PSMA start. Conclusion: Although the small sample size precludes definitive conclusions, these preliminary data, especially the 177Lu-PSMA treatment duration, suggest that the use of 177Lu-PSMA after 223Ra is feasible in this real-world setting.

Biomarkers for predicting response to anti-programmed death-1 (PD-1) immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) remain in demand. Since anti-tumor immune activation is a process, early dynamic changes of the acute-phase reactant C reactive protein (CRP) may serve as a predictive on-treatment biomarker. In a retrospective (N=105) and prospective (N=108) ICB-treated NSCLC cohort, early CRP kinetics were stratified after the start of immunotherapy until weeks 4, 6, and 12 as follows: an early doubling of baseline CRP followed by a drop below baseline (CRP flare-responder), a drop of at least 30% below baseline without prior flare (CRP responders), or those who remained as CRP non-responders. In our study, we observed characteristic longitudinal changes of serum CRP concentration after the initiation of ICB. In the prospective cohort, N=40 patients were defined as CRP non-responders, N=39 as CRP responders, and N=29 as CRP flare-responders with a median progression-free survival (PFS) of 2.4, 8.1, and 14.3 months, respectively, and overall survival (OS) of 6.6, 18.6, and 32.9 months (both log-rank p<0.001). Of note, CRP flare-responses, characterized by a sharp on-treatment CRP increase in the first weeks after therapy initiation, followed by a decrease of CRP serum level below baseline, predict ICB response as early as 4 weeks after therapy initiation. Of note, early CRP kinetics showed no predictive value for chemoimmunotherapy or when steroids were administered concurrently. On-treatment CRP kinetics had a predictive value for both major histological NSCLC subtypes, adenocarcinoma and squamous cell carcinoma. The results were verified in an independent retrospective cohort of 105 patients. In conclusion, CRP flare predicted anti-PD-1 monotherapy response and survival in two independent cohorts including a total of 213 patients with NSCLC, regardless of histology. Due to its wide clinical availability, early CRP kinetics could become an easily determined, cost-efficient, and non-invasive biomarker to predict response to checkpoint inhibitors in NSCLC within the first month.

Prostate cancer (PCa) is reported as the most common malignancy and second leading cause of death in America. In Europe, PCa is considered the leading type of tumour in 28 European countries. The costs of treating PCa are currently increasing more rapidly than those of any other cancer. Corresponding economic burden is enormous, due to an overtreatment of slowly developing disease on one hand and underestimation/therapy resistance of particularly aggressive PCa subtypes on the other hand. The incidence of metastatic PCa is rapidly increasing that is particularly characteristic for young adults. PCa is a systemic multi-factorial disease resulting from an imbalanced interplay between risks and protective factors. Sub-optimal behavioural patterns, abnormal stress reactions, imbalanced antioxidant defence, systemic ischemia and inflammation, mitochondriopathies, aberrant metabolic pathways, gene methylation and damage to DNA, amongst others, are synergistically involved in pathomechanisms of PCa development and progression. To this end, PCa-relevant systemic effects are reflected in liquid biopsies such as blood patterns which are instrumental for predictive diagnostics, targeted prevention and personalisation of medical services (PPPM/3P medicine) as a new paradigm in the overall PCa management. This strategic review article highlights systemic effects in prostate cancer development and progression, demonstrates evident challenges in PCa management and provides expert recommendations in the framework of 3P medicine.

BACKGROUND:Canonical androgen receptor (AR) signaling regulates a network of DNA repair genes in prostate cancer (PCA). Experimental and clinical evidence indicates that androgen deprivation not only suppresses DNA repair activity but is often synthetically lethal in combination with PARP inhibition. The present study aimed to elucidate the impact of AR splice variants (AR-Vs), occurring in advanced or late-stage PCA, on DNA repair machinery. METHODS:Two hundred and seventy-three tissue samples were analyzed, including primary hormone-naïve PCA, primary metastases, hormone-sensitive PCA on androgen deprivation therapy (ADT) and castration refractory PCA (CRPC group). The transcript levels of the target genes were profiled using the nCounter platform. Experimental support for the findings was gained in AR/AR-V7-expressing LNCaP cells subjected to ionizing radiation. RESULTS:AR-Vs were present in half of hormone-sensitive PCAs on androgen deprivation therapy (ADT) and two-thirds of CRPC samples. The presence of AR-Vs is highly correlated with increased activity in the AR pathway and DNA repair gene expression. In AR-V-expressing CRPC, the DNA repair score increased by 2.5-fold as compared to AR-V-negative samples. Enhanced DNA repair and the deregulation of DNA repair genes by AR-V7 supported the clinical data in a cell line model. CONCLUSIONS:The expression of AR splice variants such as AR-V7 in PCA patients following ADT might be a reason for reduced or absent therapy effects in patients on additional PARP inhibition due to the modulation of DNA repair gene expression. Consequently, AR-Vs should be further studied as predictive biomarkers for therapy response in this setting.