Metalloproteinases and their inhibitors are associated with pulmonary arterial stiffness and ventricular function in pediatric pulmonary hypertension.

Disturbed balance between matrix metalloproteinases (MMPs) and their respective tissue inhibitors (TIMPs) is a well-recognized pathophysiological component of pulmonary arterial hypertension (PAH). Both classes of proteinases have been associated with clinical outcomes as well as with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. The purpose of this study was to evaluate the circulating levels of MMPs and TIMPs in children with PAH undergoing the same-day cardiac magnetic resonance imaging (MRI) and right heart catheterization. Children with PAH (n = 21) underwent a same-day catheterization, comprehensive cardiac MRI evaluation, and blood sample collection for proteomic analysis. Correlative analysis was performed between protein levels and 1) standard PAH indices from catheterization, 2) cardiac MRI hemodynamics, and 3) pulmonary arterial stiffness. MMP-8 was significantly associated with the right ventricular end-diastolic volume (R = 0.45, P = 0.04). MMP-9 levels were significantly associated with stroke volume (R = -0.49, P = 0.03) and pulmonary vascular resistance (R = 0.49, P = 0.03). MMP-9 was further associated with main pulmonary arterial stiffness evaluated by relative area change (R = -0.79, P < 0.01).TIMP-2 and TIMP-4 levels were further associated with the right pulmonary artery pulse wave velocity (R = 0.51, P = 0.03) and backward compression wave (R = 0.52, P = 0.02), respectively. MMPs and TIMPs warrant further clinically prognostic evaluation in conjunction with the conventional cardiac MRI hemodynamic indices.NEW & NOTEWORTHY Metalloproteinases have been associated with clinical outcomes in pulmonary hypertension and with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. In this study, we demonstrated that plasma circulating levels of metalloproteinases and their inhibitors are associated with standard cardiac MRI hemodynamic indices and with the markers of proximal pulmonary arterial stiffness. Particularly, MMP-9 and TIMP-2 were associated with several different markers of pulmonary arterial stiffness. These findings suggest the interplay between the extracellular matrix (ECM) remodeling and overall hemodynamic status in children with PAH might be assessed using the peripheral circulating MMP and TIMP levels.

Effect of phase of enhancement on texture analysis in renal masses evaluated with non-contrast-enhanced, corticomedullary, and nephrographic phase-enhanced CT images.

OBJECTIVE: To compare texture analysis (TA) features of solid renal masses on renal protocol (non-contrast enhanced [NECT], corticomedullary [CM], nephrographic [NG]) CT. MATERIALS AND METHODS: A total of 177 consecutive solid renal masses (116 renal cell carcinoma [RCC]; 51 clear cell [cc], 40 papillary, 25 chromophobe, and 61 benign masses; 49 oncocytomas, 12 fat-poor angiomyolipomas) with three-phase CT between 2012 and 2017 were studied. Two blinded radiologists independently assessed tumor heterogeneity (5-point Likert scale) and segmented tumors. TA features (N = 25) were compared between groups and between phases. Accuracy (area under the curve [AUC]) for RCC versus benign and cc-RCC versus other masses was compared. RESULTS: Subjectively, tumor heterogeneity differed between phases (p < 0.01) and between tumors within the same phase (p = 0.03 [NECT] and p < 0.01 [CM, NG]). Inter-observer agreement was moderate to substantial (intraclass correlation coefficient = 0.55-0.73). TA differed in 92.0% (23/25) features between phases (p < 0.05) except for GLNU and f6. More TA features differed significantly on CM (80.0% [20/25]) compared with NG (40.0% [10/25]) and NECT (16.0% [4/25]) (p < 0.01). For RCC versus benign, AUCs of texture features did not differ comparing CM and NG (p > 0.05), but were higher for 20% (5/25) and 28% (7/25) of features comparing CM and NG with NECT (p < 0.05). For cc-RCC versus other, 36% (9/25) and 40% (10/25) features on CM had higher AUCs compared with NECT and NG images (p < 0.05). CONCLUSION: Texture analysis of renal masses differs, when evaluated subjectively and quantitatively, by phase of CT enhancement. The corticomedullary phase had the highest discriminatory value when comparing masses and for differentiating cc-RCC from other masses. KEY POINTS: • Subjectively evaluated renal tumor heterogeneity on CT differs by phase of enhancement. • Quantitative CT texture analysis features in renal tumors differ by phases of enhancement with the corticomedullary phase showing the highest number and most significant differences compared with non-contrast-enhanced and nephrographic phase images. • For diagnosis of clear cell RCC, corticomedullary phase texture analysis features had improved accuracy of classification in approximately 40% of features studied compared with non-contrast-enhanced and nephrographic phase images.

18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial.

BACKGROUND: National Comprehensive Cancer Network guidelines consider 18F-fluciclovine PET-CT for prostate cancer biochemical recurrence localisation after radical prostatectomy, whereas European Association of Urology guidelines recommend prostate-specific membrane antigen (PSMA) PET-CT. To the best of our knowledge, no prospective head-to-head comparison between these tests has been done so far. The aim of this study was to compare prospectively paired 18F-fluciclovine and PSMA PET-CT scans for localising biochemical recurrence of prostate cancer after radical prostatectomy in patients with low prostate-specific antigen (PSA) concentrations (<2·0 ng/mL). METHODS: This was a prospective, single-centre, open-label, single-arm comparative study done at University of California Los Angeles (Los Angeles, CA, USA). Patients older than 18 years of age with prostate cancer biochemical recurrence after radical prostatectomy and PSA levels ranging from 0·2 to 2·0 ng/mL without any prior salvage therapy and with a Karnofsky performance status of at least 50 were eligible. Patients underwent 18F-fluciclovine (reference test) and PSMA (index test) PET-CT scans within 15 days. Detection rate of biochemical recurrence at the patient level and by anatomical region was the primary endpoint. A statistical power analysis demonstrated that a sample size of 50 patients was needed to show a 22% difference in detection rates in favour of PSMA (test for superiority). Each PET scan was interpreted by three independent masked readers and a consensus majority interpretation was generated (two vs one) to determine positive findings. This study is registered with ClinicalTrials.gov, number NCT02940262, and is complete. FINDINGS: Between Feb 26, 2018, and Sept 20, 2018, 143 patients were screened for eligibility, of whom 50 patients were enrolled into the study. Median follow-up was 8 months (IQR 7-9). The primary endpoint was met; detection rates were significantly lower with 18F-fluciclovine PET-CT (13 [26%; 95% CI 15-40] of 50) than with PSMA PET-CT (28 [56%; 41-70] of 50), with an odds ratio (OR) of 4·8 (95% CI 1·6-19·2; p=0·0026) at the patient level; in the subanalysis of the pelvic nodes region (four [8%; 2-19] with 18F-fluciclovine vs 15 [30%; 18-45] with PSMA PET-CT; OR 12·0 [1·8-513·0], p=0·0034); and in the subanalysis of any extrapelvic lesions (none [0%; 0-6] vs eight [16%; 7-29]; OR non-estimable [95% CI non-estimable], p=0·0078). INTERPRETATION: With higher detection rates, PSMA should be the PET tracer of choice when PET-CT imaging is considered for subsequent treatment management decisions in patients with prostate cancer and biochemical recurrence after radical prostatectomy and low PSA concentrations (≤2·0 ng/mL). Further research is needed to investigate whether higher detection rates translate into improved oncological outcomes. FUNDING: None.

Erythema multiforme major in a patient with metastatic melanoma treated with nivolumab.

Nivolumab, a relatively novel immune checkpoint inhibitor with FDA approval in 2014, is gaining greater utilization due to its efficacy in treating metastatic melanoma. Many of the cutaneous immune-related adverse events (irAEs) being catalogued do not necessitate discontinuation of immunotherapy and are managed with supportive therapy. We present a case of erythema multiforme major secondary to nivolumab requiring hospitalization and discontinuation of treatment. This is only the second reported case of nivolumab-induced erythema multiforme in the literature we are aware of, and emphasizes the importance of oncologists working in conjunction with dermatologists for prompt diagnosis and management.

Emerging role of human basophil biology in health and disease.

Basophils have emerged in recent years as a small but potent subpopulation of leukocytes capable of bridging innate and adaptive immunity. They can be activated through IgE-dependent and IgE-independent mechanisms to release preformed mediators and to produce Th2 cytokines. In addition to their role in protective immunity to helminths, basophils are major participants in allergic reactions as diverse as anaphylaxis and immediate hypersensitivity reactions, late-phase hypersensitivity reactions, and delayed hypersensitivity reactions. Additionally, basophils have been implicated in the pathophysiology of autoimmune diseases such as lupus nephritis and rheumatoid arthritis, and the modulation of immune responses to bacterial infections, as well as being a feature of myelogenous leukemias. Distinct signals for activation, degranulation, transendothelial migration, and immune regulation are being defined, and demonstrate the important role of basophils in promoting a Th2 microenvironment. These mechanistic insights are driving innovative approaches for diagnostic testing and therapeutic targeting of basophils.

Visual and whole-body quantitative analyses of 68 Ga-DOTATATE PET/CT for prognosis of outcome after PRRT with 177Lu-DOTATATE.

BACKGROUND: Somatostatin receptors (SSTR) represent an ideal target for nuclear theranostics applications in neuroendocrine tumors (NET). Studies suggest that high uptake on SSTR-PET is associated with response to SSTR peptide receptor radionuclide therapy (PRRT). The purpose of this study was to evaluate the role of baseline whole-body (WB) 68 Ga-DOTATATE PET/CT (SSTR-PET) quantitative parameters, and the presence of NET lesions without uptake on SSTR-PET, as outcome prognosticator in patients with NET treated with PRRT. METHODS: Patients with NET who underwent at least 4 177Lu-DOTATATE PRRT cycles between 07/2016 and 03/2021 were included in this retrospective analysis if they fulfilled the following inclusion criteria: SSTR-PET within 6 months of 1st PRRT cycle, follow-up CT and/or MRI performed > 6 months after the 4th cycle of PRRT. The SSTR-PET analysis consisted of a visual and a quantitative analysis done independently by two board-certified physicians. The visual analysis assessed the presence of NET lesions visible on the SSTR-PET co-registered CT. The quantitative analysis consisted in contouring all SSTR-avid lesions on SSTR-PET and extracting WB quantitative parameters: SUVmean (WB-SUVmean), SUVmax of the lesion with highest uptake (H-SUVmax), and tumor volume (WB-TV). WB-SSTR-PET parameters and the presence of SSTR-PET-negative lesions were correlated to radiologic response (assessed by RECIST 1.1 criteria) and progression-free survival (PFS). Fisher's exact test, Mann-Whitney's U test and Kaplan-Meier curves with Cox-regression analysis were used for the statistical analysis. RESULTS: Forty patients (F/M: 21/19; 34/40 with gastro-entero-pancreatic (GEP) NET, 6/40 with non-GEP NET) were included in the analysis. The median follow-up period after the 4th PRRT cycle was 25.7 months (range 15.2-59.1). Fourteen/40 (35%) patients showed radiologic response (RECIST PR). PFS event was observed in 17/40 (42.5%) patients. Thirteen/40 (32.5%) patients had SSTR-PET-negative lesions at baseline. Higher WB-SUVmean and H-SUVmax were associated with better response (p = 0.015 and 0.005, respectively). The presence of SSTR-PET-negative lesions and lower WB-SUVmean were associated with shorter PFS (p = 0.026 and 0.008, respectively). CONCLUSION: Visual and quantitative analyses of baseline SSTR-PET can yield valuable information to prognosticate outcomes after 177Lu-DOTATATE PRRT.

Efficacy and Toxicity of [177Lu]Lu-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: Results from the U.S. Expanded-Access Program and Comparisons with Phase 3 VISION Data.

The phase 3 VISION trial demonstrated that [177Lu]Lu-PSMA-617 prolonged progression-free survival and overall survival (OS) in prostate-specific membrane antigen [PSMA]-positive metastatic castration-resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor-signaling inhibitors (ARSIs). The U.S. expanded-access program (EAP; NCT04825652) was opened to provide access to [177Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. This study aimed to evaluate the efficacy and safety profile of [177Lu]Lu-PSMA-617 within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP at 4 institutions in the United States with available toxicity and outcome data were included. Outcome measures included OS, a prostate-specific antigen (PSA) response rate (RR) of at least 50%, and incidences of toxicity according to Common Terminology Criteria for Adverse Events version 5.0. Differences in baseline characteristics, outcome data, and toxicity between the EAP and VISION were evaluated using t testing of proportions and survival analyses. Results: In total, 117 patients with mCRPC who received [177Lu]Lu-PSMA-617 within the EAP between May 2021 and March 2022 were eligible and included in this analysis. Patients enrolled in the EAP were more heavily pretreated with ARSI (≥2 ARSI regimens: 70% vs. 46%; P < 0.001) and had worse performance status at baseline (Eastern Cooperative Oncology Group score ≥ 2: 19% vs. 7%; P < 0.001) than VISION patients. EAP and VISION patients had similar levels of grade 3 or higher anemia (18% vs. 13%; P = 0.15), thrombocytopenia (13% vs. 8%; P = 0.13), and neutropenia (3% vs. 3%; P = 0.85) and similar PSA RRs (42% vs. 46%; P = 0.50) and OS (median: 15.1 vs. 15.3 mo; P > 0.05). Conclusion: Patients with PSMA-positive mCRPC who received [177Lu]Lu-PSMA-617 within the EAP were later in their disease trajectory than VISION patients. Patients enrolled in the EAP achieved similar PSA RRs and OS and had a safety profile similar to that of the VISION trial patients.

Prognostic Value of End-of-Treatment PSMA PET/CT in Patients Treated with 177Lu-PSMA Radioligand Therapy: A Retrospective, Single-Center Analysis.

Our objective was to evaluate the prognostic value of end-of-treatment prostate-specific membrane antigen (PSMA) PET/CT (PSMA-PET) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA radioligand therapy (PSMA-RLT). Methods: This was a single-center retrospective study. mCRPC patients who underwent PSMA-RLT with available baseline PSMA-PET (bPET) and end-of-treatment PSMA-PET (ePET) within 6 mo of the last PSMA-RLT cycle were eligible. Overall survival (OS) and prostate-specific antigen (PSA) progression status at the time of ePET (by Prostate Cancer Clinical Trials Working Group 3 criteria) were collected. PSMA-PET tumor segmentation was performed to obtain whole-body PSMA tumor volume (PSMA-VOL) and define progressive (≥20% increase) versus nonprogressive disease. Pairs of bPET and ePET were interpreted for appearance of new lesions. Response Evaluation Criteria in PSMA-PET/CT (RECIP) 1.0 were also applied to define progressive versus nonprogressive disease. The associations between changes in PSMA-VOL, new lesions, RECIP 1.0, and PSA progression status at the time of ePET with OS were evaluated by Kaplan-Meier analysis. Results: Twenty mCRPC patients were included. The median number of treatment cycles was 3.5 (interquartile range [IQR], 2-4). The median time between bPET and cycle 1 of PSMA-RLT was 1.0 mo (IQR, 0.7-1.8 mo). The median time between the last cycle of PSMA-RLT and ePET was 1.9 mo (IQR, 1.2-3.5 mo). Twelve of 20 patients (60%) had died at the last follow-up. The median follow-up time from ePET for survivors was 31.2 mo (IQR, 6.8-40.7 mo). The median OS from ePET was 11.4 mo (IQR, 6.8-30.7 mo). Patients with new lesions on ePET had shorter OS than those without new lesions (median OS, 10.7 mo [95% CI, 9.2-12.2] vs. not reached; P = 0.002). Patients with progressive PSMA-VOL had shorter OS than those with nonprogressive PSMA-VOL (median OS, 10.7 mo [95% CI: 9.7-11.7 mo] vs. not reached; P = 0.007). Patients with progressive RECIP had shorter OS than those with nonprogressive RECIP (median OS, 10.7 mo [95% CI, 9.7-11.7 mo] vs. not reached; P = 0.007). PSA progression at the time of ePET was associated with shorter OS (median, 10.9 mo [95% CI, 9.4-12.4 mo] vs. not reached; P = 0.028). Conclusion: In this retrospective study of 20 mCRPC patients treated with PSMA-RLT, progression on ePET by the appearance of new lesions, changes in PSMA-VOL, and RECIP 1.0 was prognostic for OS. Validation in larger, prospective multicentric clinical trials is warranted.

Associations of quantitative whole-body PSMA-PET metrics with PSA progression status under long-term androgen deprivation therapy in prostate cancer patients: a retrospective single-center study.

PURPOSE: To evaluate whether quantitative whole-body (WB) PSMA-PET metrics under long-term androgen deprivation therapy (ADT) and/or androgen receptor signaling inhibitors (ARSi) are associated with PSA progression. METHODS: Patients who underwent at least 2 68Ga-PSMA-11 PET/CT scans between October 2016 and April 2021 (n = 372) and started a new line of ADT ± ARSi between PET1 and PET2 were retrospectively screened for inclusion. We investigated the association between PCWG3-defined PSA progression status at PET2 and the following PSMA-PET parameters: appearance of new lesions on PET2, ≥ 20% increase in WB-PSMA tumor volume (WB-PSMA-VOL), progression of disease (PD) by RECIP 1.0, and ≥ 30% increase in WB-PSMA-SUVmean from PET1 to PET2. Spearman's rank correlation coefficients and Fisher's exact test were used to evaluate the associations. RESULTS: Thirty-five patients were included: 12/35 (34%) were treated with ADT only and 23/35 (66%) with ARSi ± ADT. The median time between PET1 and PET2 was 539 days. Changes (%) in median PSA levels, WB-PSMA-SUVmean, and WB-PSMA-VOL from PET1 to PET2 were -86%, -23%, and -86%, respectively. WB-PSMA-VOL ≥ 20%, new lesions, RECIP-PD, and WB-PSMA-SUVmean ≥ 30% were observed in 5/35 (14%), 9/35 (26%), 5/35 (14%), and 4/35 (11%) of the whole cohort, in 3/9 (33%), 7/9 (78%), 3/9 (33%), and 2/9 (22%) of patients with PSA progression at PET2, and in 2/26 (8%), 2/26 (8%), 2/26 (8%), and 2/26 (8%) of patients without PSA progression at PET2 (p = 0.058, p < 0.001, p = 0.058, p = 0.238, respectively). Changes in PSA were correlated to percent changes in WB-PSMA-VOL and WB-PSMA-SUVmean (Spearman ρ: 0.765 and 0.633, respectively; p < 0.001). CONCLUSION: Changes in PSA correlated with changes observed on PSMA-PET, although discordance between PSA and PSMA-PET changes was observed. Further research is necessary to evaluate if PSMA-PET parameters can predict progression-free survival and overall survival and serve as novel endpoints in clinical trials.

68Ga-PSMA PET/CT-Based Atlas for Prostate Bed Recurrence After Radical Prostatectomy: Clinical Implications for Salvage Radiation Therapy Contouring Guidelines.

The aim of this study was to analyze the patterns of prostate bed (PB) recurrence in prostate cancer patients experiencing prostate-specific antigen (PSA) persistence (BCP) or biochemical recurrence (BCR) after radical prostatectomy using 68Ga-PSMA-11 PET/CT (68Ga-PSMA PET) in relation to the Radiation Therapy Oncology Group (RTOG) clinical target volumes (CTVs). Methods: This single-center, retrospective analysis included patients with BCP or BCR after radical prostatectomy and PB recurrence on 68Ga-PSMA PET. The PB recurrences were delineated by nuclear medicine physicians, the CTVs by radiation oncologists contouring guidelines on the 68Ga-PSMA PET, respectively, masked from each other. The coverage of the 68Ga-PSMA PET recurrence was categorized as PSMA recurrence completely covered, partially covered, or not covered by the RTOG-based CTV. Further, we evaluated the differences in PSMA recurrence patterns among patients with different 68Ga-PSMA PET staging (miTNM). Mann-Whitney U tests, the chi-square test, and Spearman (ρ) correlation analysis were used to investigate associations between CTV coverage and 68Ga-PSMA PET-based tumor volume, serum PSA levels, miTNM, and rectal/bladder involvement. Results: A total of 226 patients were included in the analysis; 127 patients had PSMA recurrence limited to the PB (miTrN0M0), 30 had pelvic nodal disease (miTrN1M0), 32 had extrapelvic disease (miTrN0M1), and 37 had both pelvic nodal disease and extrapelvic disease (miTrN1M1). In the miTrN0M0 cohort, the recurrence involved the rectal and bladder walls in 12 of 127 (9%) and 4 of 127 (3%), respectively. The PSMA-positive PB recurrences were completely covered by the CTV in 68 of 127 patients (53%), partially covered in 43 of 127 (34%), and not covered in 16 of 127 (13%). Full coverage was associated with a smaller tumor volume (P = 0.043), a lack of rectal/bladder wall involvement (P = 0.03), and lower miTNM staging (P = 0.035) but not with lower serum PSA levels (P = 0.979). Conclusion: Our study suggests that 68Ga-PSMA PET can be a valuable tool for guiding salvage radiation therapy (SRT) planning directed to the PB in the setting of postoperative BCR or BCP. These data should be incorporated into the redefinition of PB contouring guidelines.

Lung and Heart Biology of the Dp16 Mouse Model of down Syndrome: Implications for Studying Cardiopulmonary Disease.

(1) Background: We sought to investigate the baseline lung and heart biology of the Dp16 mouse model of Down syndrome (DS) as a prelude to the investigation of recurrent respiratory tract infection. (2) Methods: In controls vs. Dp16 mice, we compared peripheral blood cell and plasma analytes. We examined baseline gene expression in lungs and hearts for key parameters related to susceptibility of lung infection. We investigated lung and heart protein expression and performed lung morphometry. Finally, and for the first time each in a model of DS, we performed pulmonary function testing and a hemodynamic assessment of cardiac function. (3) Results: Dp16 mice circulate unique blood plasma cytokines and chemokines. Dp16 mouse lungs over-express the mRNA of triplicated genes, but not necessarily corresponding proteins. We found a sex-specific decrease in the protein expression of interferon α receptors, yet an increased signal transducer and activator of transcription (STAT)-3 and phospho-STAT3. Platelet-activating factor receptor protein was not elevated in Dp16 mice. The lungs of Dp16 mice showed increased stiffness and mean linear intercept and contained bronchus-associated lymphoid tissue. The heart ventricles of Dp16 mice displayed hypotonicity. Finally, Dp16 mice required more ketamine to achieve an anesthetized state. (4) Conclusions: The Dp16 mouse model of DS displays key aspects of lung heart biology akin to people with DS. As such, it has the potential to be an extremely valuable model of recurrent severe respiratory tract infection in DS.

Developing a Patient-Reported Outcome Measure for Radionuclide Therapy for Prostate Cancer.

The field of radionuclide therapy (RNT) for prostate cancer (PC) is growing rapidly, with recent Food and Drug Administration approval of the first 177Lu-PSMA ligand. We aimed to develop the first patient-reported outcome (PRO) measure for PC patients receiving RNT. Methods: We identified relevant symptoms and toxicities by reviewing published trials and interviews with PC patients receiving RNT (n = 29), caregivers (n = 14), and clinicians (n = 11). Second, we selected items for measure inclusion. Third, we refined the item list with input from experts in RNTs and PROs. Fourth, we finalized the Functional Assessment of Cancer Therapy-Radionuclide Therapy (FACT-RNT) with patient input. Results: This multistep process yielded a brief 15-item measure deemed by key stakeholders to be relevant and useful in the context of RNT for PC. Conclusion: The FACT-RNT is a new standardized tool to monitor relevant symptoms and toxicities among PC patients in RNT trials and real-world settings.

Presurgical 68Ga-PSMA-11 Positron Emission Tomography for Biochemical Recurrence Risk Assessment: A Follow-up Analysis of a Multicenter Prospective Phase 3 Imaging Trial.

BACKGROUND: In the initial staging of patients with high-risk prostate cancer (PCa), prostate-specific membrane antigen positron emission tomography (PSMA-PET) has been established as a front-line imaging modality. The increasing number of PSMA-PET scans performed in the primary staging setting might be associated with decreases in biochemical recurrence (BCR)-free survival (BCR-FS). OBJECTIVE: To assess the added prognostic value of presurgical PSMA-PET for BCR-FS compared with the presurgical Cancer of the Prostate Risk Assessment (CAPRA) and postsurgical CAPRA-Surgery (CAPRA-S) scores in patients with intermediate- to high-risk PCa treated with radical prostatectomy (RP) and pelvic lymph node dissection. DESIGN, SETTING, AND PARTICIPANTS: This is a follow-up study of the surgical cohort evaluated in the multicenter prospective phase 3 imaging trial (n = 277; NCT03368547, NCT02611882, and NCT02919111). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Each 68Ga-PSMA-11-PET scan was read by three blinded independent readers. PSMA-PET prostate uptake (low vs high), PSMA-PET extraprostatic disease (N1/M1), and CAPRA and CAPRA-S scores were used to assess the risk of BCR. Patients were followed after RP by local investigators using electronic medical records. BCR was defined by a prostate-specific antigen (PSA) level increasing to ≥0.2 ng/ml after RP or initiation of PCa-specific secondary treatment (>6 mo after surgery). Univariate and multivariable Cox models, and c-statistic index were performed to assess the prognostic value of PSMA-PET and for a comparison with the CAPRA and CAPRA-S scores. RESULTS AND LIMITATIONS: From December 2015 to December 2019, 277 patients underwent surgery after PSMA-PET. Clinical follow-up was obtained in 240/277 (87%) patients. The median follow-up after surgery was 32.4 (interquartile range 23.3-42.9) mo. Of 240 BCR events, 91 (38%) were observed. PSMA-PET N1/M1 was found in 41/240 (17%) patients. PSMA-PET prostate uptake, PSMA-PET N1/M1, and CAPRA and CAPRA-S scores were significant univariate predictors of BCR. The addition of PSMA-PET N1/M1 status to the presurgical CAPRA score improved the risk assessment for BCR significantly in comparison with the presurgical CAPRA score alone (c-statistic 0.70 [0.64-0.75] vs 0.63 [0.57-0.69]; p < 0.001). The C-index of the postsurgical model utilizing the postsurgical CAPRA-S score alone was not significantly different from the presurgical model combining the presurgical CAPRA score and PSMA-PET N1/M1 status (p = 0.19). CONCLUSIONS: Presurgical PSMA-PET was a strong prognostic biomarker improving BCR-FS risk assessment. Its implementation in the presurgical risk assessment with the CAPRA score improved the performance and reduced the difference with the reference standard (postsurgical CAPRA-S score). PATIENT SUMMARY: The use prostate-specific membrane antigen positron emission tomography improved the assessment of biochemical recurrence risk in patients with intermediate- and high-risk prostate cancer who were treated with radical prostatectomy and pelvic lymph node dissection.

A Comprehensive Assessment of 68Ga-PSMA-11 PET in Biochemically Recurrent Prostate Cancer: Results from a Prospective Multicenter Study on 2,005 Patients.

We prospectively investigated the performance of the prostate-specific membrane antigen (PSMA) ligand 68Ga-PSMA-11 for detecting prostate adenocarcinoma in patients with elevated levels of prostate-specific antigen (PSA) after initial therapy. Methods:68Ga-PSMA-11 hybrid PET was performed on 2,005 patients at the time of biochemically recurrent prostate cancer after radical prostatectomy (RP) (50.8%), definitive radiation therapy (RT) (19.7%), or RP with postoperative RT (PORT) (29.6%). The presence of prostate cancer was assessed qualitatively (detection rate = positivity rate) and quantitatively on a per-patient and per-region basis, creating a disease burden estimate from the presence or absence of local (prostate/prostate bed), nodal (N1: pelvis), and distant metastatic (M1: distant soft tissue and bone) disease. The primary study endpoint was the positive predictive value (PPV) of 68Ga-PSMA-11 PET/CT confirmed by histopathology. Results: After RP, the scan detection rate increased significantly with rising PSA level (44.8% at PSA < 0.25%-96.2% at PSA > 10 ng/mL; P < 0.001). The detection rate significantly increased with rising PSA level in each individual region, overall disease burden, prior androgen deprivation, clinical T-stage, and Gleason grading from the RP specimen (P < 0.001). After RT, the detection rate for in-gland prostate recurrence was 64.0%, compared with 20.6% prostate bed recurrence after RP and 13.3% after PORT. PSMA-positive pelvic nodal disease was detected in 42.7% after RP, 40.8% after PORT, and 38.8% after RT. In patients with histopathologic validation, the PPV per patient was 0.82 (146/179). The SUVmax of histologically proven true-positive lesions was significantly higher than that of false-positive lesions (median, 11.0 [interquartile range, 6.3-22.2] vs. 5.1 [interquartile range, 2.2-7.4]; P < 0.001). Conclusion: We confirmed a high PPV for 68Ga-PSMA-11 PET in biochemical recurrence and the PSA level as the main predictor of scan positivity.

Tumor Sink Effect in 68Ga-PSMA-11 PET: Myth or Reality?

We aimed to systematically determine the impact of tumor burden on 68Ga-prostate-specific membrane antigen-11 (68Ga-PSMA) PET biodistribution by the use of quantitative measurements. Methods: This international multicenter, retrospective analysis included 406 men with prostate cancer who underwent 68Ga-PSMA PET/CT. Of these, 356 had positive findings and were stratified by quintiles into a very low (quintile 1, ≤25 cm3), low (quintile 2, 25-189 cm3), moderate (quintile 3, 189-532 cm3), high (quintile 4, 532-1,355 cm3), or very high (quintile 5, ≥1,355 cm3) total PSMA-positive tumor volume (PSMA-VOL). PSMA-VOL was obtained by semiautomatic segmentation of total tumor lesions using qPSMA software. Fifty prostate cancer patients with no PSMA-positive lesions (negative scan) served as a control group. Normal organs, which included salivary glands, liver, spleen, and kidneys, were semiautomatically segmented using 68Ga-PSMA PET images, and SUVmean was obtained. Correlations between the SUVmean of normal organs and PSMA-VOL as continuous and categoric variables by quintiles were evaluated. Results: The median PSMA-VOL was 302 cm3 (interquartile range [IQR], 47-1,076 cm3). The median SUVmean of salivary glands, kidneys, liver, and spleen was 10.0 (IQR, 7.7-11.8), 26.0 (IQR, 20.0-33.4), 3.7 (IQR, 3.0-4.7), and 5.3 (IQR, 4.0-7.2), respectively. PSMA-VOL showed a moderate negative correlation with the SUVmean of the salivary glands (r = -0.44, P < 0.001), kidneys (r = -0.34, P < 0.001), and liver (r = -0.30, P < 0.001) and a weak negative correlation with the spleen SUVmean (r = -0.16, P = 0.002). Patients with a very high PSMA-VOL (quintile 5, ≥1,355 cm3) had a significantly lower PSMA uptake in the salivary glands, kidneys, liver, and spleen than did the control group, with an average difference of -38.1%, -40.0%, -43.2%, and -34.9%, respectively (P < 0.001). Conclusion: Tumor sequestration affects 68Ga-PSMA biodistribution in normal organs. Patients with a very high tumor load showed a significantly lower uptake of 68Ga-PSMA in normal organs, confirming a tumor sink effect. As similar effects might occur with PSMA-targeted radioligand therapy, these patients might benefit from increased therapeutic activity without exceeding the radiation dose limit for organs at risk.

Identifying the Best Candidates for Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography as the Primary Staging Approach Among Men with High-risk Prostate Cancer and Negative Conventional Imaging.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is an emerging imaging modality with greater sensitivity and specificity over conventional imaging for prostate cancer (PCa) staging. Using data from two prospective trials (NCT03368547 and NCT04050215), we explored predictors of overall upstaging (nodal and metastatic) by PSMA PET/CT among patients with cN0M0 National Comprehensive Cancer Network high-risk PCa on conventional imaging (n = 213). Overall, 21.1%, 8.9%, and 23.9% of patients experienced nodal, metastatic, and overall upstaging, respectively, without histologic confirmation. On multivariable analysis, Gleason grade group (GG) and percent positive core (PPC) on systematic biopsy significantly predict overall upstaging (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.33-3.45; p = 0.002; and OR 1.03, 95% CI 1.01-1.04; p < 0.001). Overall upstaging was significantly more frequent among men with GG 5 disease (33.0% vs. 17.6%; p = 0.0097) and PPC ≥50% (33.0% vs 15.0%; p = 0.0020). We constructed a nomogram that predicts overall upstaging using initial prostate-specific antigen, PPC, GG, and cT stage, with coefficients estimated from a standard logistic regression model (using maximum likelihood estimation). It is internally validated with a tenfold cross-validated area under the receiver operating characteristic curve estimated at 0.74 (95% CI 0.67-0.82). In our cohort, 90% of patients who had a nomogram-estimated risk below the cutoff of 22% for overall upstaging could have been spared PSMA PET/CT as our model correctly predicted no upstaging. In other words, the predictive model only missed 10% of patients who would otherwise have benefitted from PSMA PET/CT. PATIENT SUMMARY: We analyzed predictors of overall upstaging (lymph node or/and metastasis) by prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) from conventional imaging in men with high-risk prostate cancer undergoing initial staging deemed free of disease in the lymph nodes and distant metastasis by conventional imaging techniques. We found that the pathologic grade and disease burden in a prostate biopsy are associated with upstaging. We also developed a tool that predicts the probability of upstaging according to an individual patient's characteristics. Our study may help in defining patient groups who are most likely to benefit from the addition of a PSMA PET/CT scan.

Mast Cells Promote Nitrogen Mustard-Mediated Toxicity in the Lung Associated With Proinflammatory Cytokine and Bioactive Lipid Mediator Production.

Sulfur mustard (SM) has been widely used as a chemical warfare agent including most recently in Syria. Mice exposed to SM exhibit an increase in pro-inflammatory cytokines followed by immune cell infiltration in the lung, however, the mechanisms leading to these inflammatory responses has not been completely elucidated. Mast cells are one of the first responding innate immune cells found at the mucosal surfaces of the lung and have been reported to be activated by SM in the skin. Therefore, we hypothesized that nitrogen mustard (NM: a surrogate for SM) exposure promotes activation of mast cells causing chronic respiratory inflammation. To assess the role of mast cells in NM-mediated pulmonary toxicity, we compared the effects of NM exposure between C57BL/6 and B6.Cg-KitW-sh/HNihrJaeBsmJ (KitW-sh; mast cell deficient) mice. Lung injury was observed in C57BL/6J mice following NM exposure (0.125 mg/kg) at 72 h, which was significantly abrogated in KitW-sh mice. Although both strains exhibited damage from NM, C57BL/6J mice had higher inflammatory cell infiltration and more elevated prostaglandin D2 (PGD2) present in bronchoalveolar lavage fluid compared with KitW-sh mice. Additionally, we utilized murine bone marrow-derived mast cells to assess NM-induced early and late activation. Although NM exposure did not result in mast cell degranulation, we observed an upregulation in PGD2 and IL-6 levels following exposure to NM. Results suggest that mast cells play a prominent role in lung injury induced by NM and may contribute to the acute and potentially long-term lung injury observed caused by SM.

The Impact of Monosodium Glutamate on 68Ga-PSMA-11 Biodistribution in Men with Prostate Cancer: A Prospective Randomized, Controlled Imaging Study.

The prostate-specific membrane antigen (PSMA) has been targeted for PET imaging and radioligand therapy (RLT) in patients with prostate cancer. Xerostomia is a common side effect of RLT because of the high salivary gland uptake of PSMA radioligands. Here, we aimed to determine the impact of monosodium glutamate (MSG) administration on PSMA-radioligand biodistribution within healthy organs and tumor lesions by using 68Ga-PSMA-11 PET imaging. Methods: Sixteen men with prostate cancer were randomized (1:1) into oral ingestion and oral topical application ("swishing") arms. Each subject underwent 2 68Ga-PSMA-11 PET/CT scans within 14 d under baseline and MSG conditions. The salivary glands and whole-body tumor lesions were segmented using qPSMA software. We quantified tracer uptake via SUVmean and SUVmax and compared parameters within each patient. Results: For the oral ingestion arm, salivary gland SUVmean and SUVmax decreased on average from the control scan to the MSG scan by 45% ± 15% (P = 0.004) and 53% ± 11% (P < 0.001), respectively. Tumor lesion SUVmean and SUVmax also decreased by 38% (interquartile range, -67% to -33%) and -52% (interquartile range, -70% to -49%), respectively (P = 0.018). Swishing had no significant effect on 68Ga-PSMA-11 accumulation in normal organs or tumor lesions. Conclusion: Oral ingestion but not topical application of MSG reduced 68Ga-PSMA-11 uptake in salivary glands. Tumor uptake also declined; therefore, the clinical application of MSG is unlikely to be useful in the framework of RLT.

Safety of PSMA-Targeted Molecular Radioligand Therapy with 177Lu-PSMA-617: Results from the Prospective Multicenter Phase 2 Trial RESIST-PC (NCT03042312).

The purpose of this analysis was to report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results: The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of 177Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion:177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.

Prospective phase 2 trial of PSMA-targeted molecular RadiothErapy with 177Lu-PSMA-617 for metastatic castration-reSISTant Prostate Cancer (RESIST-PC): efficacy results of the UCLA cohort.

The objective of this study was to determine prospectively the efficacy profile of 2 activity regimens of 177Lu-PSMA therapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC): 6.0 vs. 7.4 GBq. Methods: RESIST-PC (NCT03042312) was a prospective multicenter phase 2 trial. Patients with progressive mCRPC after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, and sufficient PSMA expression by PSMA PET were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq) and received up to 4 cycles every 8 wk. The primary endpoint was the efficacy of 177Lu-PSMA measured by the prostate-specific antigen (PSA) response rate (RR) after 2 cycles (≥50% decline from baseline). Secondary endpoints included the PSA RR (≥50% decline) at any time (best response), and overall survival (OS). Results: The study was closed at enrollment of 71/200 planned patients because of sponsorship transfer. We report here the efficacy of the University of California Los Angeles cohort results only (n = 43). The PSA RRs after 2 cycles and at any time were 11/40 (28%, 95% CI 15-44), 6/13 (46%, 95% CI 19-75), and 5/27 (19%, 95% CI 6-38), and 16/43 (37%, 95% CI 23-53), 7/14 (50%, 95% CI 23-77), and 9/29 (31%, 95% CI 15-51) in the whole cohort, the 6.0-GBq group, and the 7.4-GBq group, respectively (P = 0.12 and P = 0.31). The median OS was 14.0 mo (95% CI 10.1-17.9), 15.8 (95% CI 11.8-19.4), and 13.5 (95% CI 10.0-17.0) in the whole cohort, the 6.0-GBq group, and the 7.4 GBq group, respectively (P = 0.87). OS was longer in patients who experienced a PSA decline ≥ 50% at any time than in those who did not: median, 20.8 versus 10.8 mo (P = 0.005). Conclusion: In this prospective phase 2 trial of 177Lu-PSMA for mCRPC, the median OS was 14 mo. Despite the heterogeneous study population and the premature study termination, the efficacy profile of 177Lu-PSMA appeared to be favorable and comparable with both activity regimens (6.0 vs. 7.4 GBq). Results justify confirmation with real-world data matched-pair analysis and further clinical trials to refine and optimize the 177Lu-PSMA therapy administration scheme to improve tumor radiation dose delivery and efficacy.