Background: The recent phase III VISION-trial confirms the treatment efficacy of radioligand therapy with [¹⁷⁷Lu]PSMA-617 (PSMA-RLT) in metastatic castration-resistant prostate cancer (mCRPC). In PSMA-RLT, the relatively low absorbed bone marrow dose allows for multiple therapy cycles with relatively low risk of haematological adverse events (hAE). However, as disease progression itself may be a cause of bone marrow impairment, the aim of this study was to assess potential relations between impairment of haematological status and response to PSMA-RLT. Methods: In this retrospective analysis, haematological parameters (HP) of 64 patients with mCRPC were systematically acquired over two cycles (12–16 weeks) of PSMA-RLT from baseline to restaging. Changes in HP were analysed qualitatively (CTCAE 5.0) and quantitatively. The HP changes from baseline were compared to quantitative and qualitative biochemical and imaging response, using PCWG3 and PROMISE criteria. Results: All grade 3/4 hAE observed were associated with disseminated or diffuse bone involvement as well as biochemical non-response at restaging. Quantitatively, at baseline, HP inversely correlated with biochemical and volumetric (on PET) tumour burden as well as bone involvement pattern (p ≤ 0.043). Among patients with disseminated or diffuse bone involvement, percentage changes in HP (%HP) at restaging inversely correlated with serological and imaging tumour burden (p ≤ 0.017). Biochemical non-responders showed a significant decrease in %HP (p ≤ 0.001) while HP in biochemical responders remained stable (p ≥ 0.079). Conclusion: During early cycles of PSMA-RLT, qualitative and quantitative bone marrow impairment appears to be closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events, showing a significant decline of haematological parameters. This implies that in patients with advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles. German Clinical Trial Register DRKS00013665. Registered 28 December 2017, retrospectively registered (www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013665)

Introduction: Quantitative evaluation of prostate-specific membrane antigen (PSMA)- targeting positron emission tomography/computer tomography (PSMA PET/CT) remains challenging but is urgently needed for the use of standardized PET-based response criteria, such as the PSMA PET/CT consensus statement or RECIP 1.0. A recent study evaluated the prognostic value of whole-body tumor volume using a semiautomatical method relying on a 50% threshold of maximum lesion standardized uptake value (PSMA_TV50). In the present study, we analyzed the suitability of this approach comparing ¹⁸F-PSMA-1007 to ⁶⁸Ga-PSMA-11 PET/CT scans and the potential of PSMA_TV50 for the prediction of overall survival (OS) in patients before ¹⁷⁷Lu-PSMA-radioligand therapy (PSMA RLT). Moreover, PSMA_TV50 was integrated into the PSMA PET/CT consensus statement as well as RECIP 1.0 and the prognostic value of these response classification systems was compared. Methods: This retrospective study included 70 patients with metastatic castration-resistant prostate cancer undergoing PSMA RLT. 33 patients were monitored by ⁶⁸Ga-PSMA-11 PET/CT and 37 patients by ¹⁸F-PSMA-1007 PET/CT. PET/CT scans before (baseline) and at the end of PSMA RLT after 2-4 cycles (follow-up) were separately analyzed by two readers. PSMA_TV50 at baseline and its change to follow-up (ΔPSMA_TV50; expressed as a ratio) were correlated with OS using Cox proportional hazard regression. The results of both subgroups were compared. The integration of ΔPSMA_TV50 in existing response classification systems was evaluated. To assess and compare the discriminatory strength of these classification systems, Gönen & Heller concordance probability estimates (CPE) were calculated. Results: PSMA_TV50-determination was technically feasible in all examinations. A higher PSMA_TV50 at baseline and a higher ΔPSMA_TV50 were strongly associated with a shorter OS for both ⁶⁸Ga-PSMA-11 (PSMA_TV50: HR 1.29 [1.05 – 1.55], p=0.009; ΔPSMA_TV50: HR 1.83 [1.08 – 3.09], p=0.024) and ¹⁸F-PSMA-1007 (PSMA_TV50: HR 1.84 [1.13 – 2.99], p=0.014; ΔPSMA_TV50: HR 1.23 [1.04 – 1.51], p=0.03). Response assessment provided high discriminatory power for OS for the PSMA PET/CT consensus statement (CPE 0.73) as well as RECIP 1.0 (CPE 0.74). Conclusion: PSMA_TV50 and ΔPSMA_TV50 proved to be predictive of OS not only for ⁶⁸Ga-PSMA-11 but also for ¹⁸F-PSMA-1007 PET/CT scans. Subsequent integration of ΔPSMA_TV50 into the PSMA PET/CT consensus statement and RECIP 1.0 provided equally high prognostic value for both classification systems.

Purpose: Radioligand therapy with [¹⁷⁷Lu]PSMA-617 (PSMA-RLT) is a promising therapeutic option for metastatic castration-resistant prostate cancer (mCPRP). This study assessed the prognostic value of early PSA measurements during PSMA-RLT. Methods: 27 patients with mCRPC scheduled for PSMA-RLT were prospectively enrolled for a serial short-interval PSA-assessment. Change in PSA (∆%PSA) during two treatment cycles was correlated with biochemical response (BR) and change in tumor volume on PET (TV) after 16 weeks (w16), as well as overall survival (OS). PCWG3 criteria and the recently recommended threshold of ∆%PSA ≤ −30% were assessed for their predictive value. Results: ∆%PSA first correlated with BR, TV and OS after 4 weeks (c1w4). At c1w4, ∆%PSA ≤ −30% was associated with the biochemical response at w16 (p = 0.003) and a longer median OS (p = 0.025), whereas the PCWG3-derived threshold of ∆%PSA ≤ −50% showed no such correlation. In contrast, ∆%PSA ≥ 25% at c1w4 was associated with biochemical progression at w16 (p = 0.003) and a shorter median OS (p < 0.001). Conclusion: PSA changes as early as four weeks after PSMA-RLT allow a significant prediction of later biochemical and PET-based imaging response, as well as OS. At this early time point, a more lenient threshold for a PSA decrease of at least 30% appears better-suited for the prediction of a positive biochemical response and longer OS. In contrast, the PCWG3-derived threshold for PSA increase (+25%) reliably anticipates biochemical progression and shorter OS.

Background/Objectives: Purinergic signaling, which involves extracellular ATP (eATP), its metabolites, purinergic receptors and ectonucleotidases, plays a pivotal role in the tumor microenvironment (TME), impacting tumor progression and the antineoplastic immune response. In this study, the CD39, CD73, P2X4, and P2X7 expression in NSCLC tumor cells and the surrounding stroma of 139 resected patients was examined. Methods: The study included tissue samples from 139 NSCLC patients. Tissue microarrays (TMAs) were constructed using 1.0 mm cores from annotated tumor regions. Immunohistochemical staining for CD39, CD73, P2X4, and P2X4 was performed on 2 µm sections. TMA slides were digitized and analyzed with QuPath, where staining intensity was evaluated using a semi-quantitative H-score. Statistical analysis, including survival analysis, was performed using R, to assess the impact of biomarker expression on patient outcomes. Results: High CD39 expression in both tumor and stromal cells was significantly associated with prolonged PFS (respectively: p = 0.0058 and p = 0.0067), particularly in adenocarcinoma (ADC) patients (respectively: p = 0.01 and p = 0.023). In the multivariable Cox model, low CD73 expression in tumor cells correlated with longer PFS (HR: 0.47; 95% CI: [0.28, 0.8], p = 0.005), while low CD73 expression in stromal cells was linked to increased progression risk (HR: 4.81; 95% CI: [1.61, 14.4], p = 0.001). Neither P2X7 nor P2X4 demonstrated a consistent effect on PFS in univariable analyses; however, multivariable analyses suggested that P2X4 might play a prognostic role in NSCLCs (HR: 0.37; 95% CI: [0.19, 0.73], p = 0.003). Conclusions: These findings underscore the importance of purinergic signaling in NSCLC prognosis and highlight the role of the ectonucleotidases CD39 and CD73 as potential therapeutic targets to enhance antineoplastic immune responses.

A 58-year-old man with progressive dyspnea and recurrent extensive left-sided pleural effusion underwent pulmonary ventilation/perfusion SPECT/CT, which showed a pronounced mismatched perfusion deficit of the entire, normally ventilated left lung. As unilateral perfusion deficits of an entire lobe are generally not due to pulmonary embolism, further CT angiography and cardiac MRI were conducted. These examinations revealed high-grade left pulmonary vein stenosis (PVS) caused by pulmonary vein isolation performed for atrial fibrillation 3 and 4 years earlier. Thus, in addition to, for example, neoplastic processes or pulmonary congenital vascular abnormalities, PVS must be considered as a differential diagnosis and possible pitfall in ventilation/perfusion SPECT/CT in dyspneic patients with prior pulmonary vein isolation.