PSMA-Targeted Radiopharmaceuticals for Prostate Cancer Diagnosis and Therapy.

ABSTRACT: Prostate cancer (PCa) is the most common noncutaneous malignancy in men. Until recent years, accurate imaging of men with newly diagnosed PCa, or recurrent or low-volume metastatic disease, was limited. Further, therapeutic options for men with advanced, metastatic, castration-resistant disease were increasingly limited as a result of increasing numbers of systemic therapies being combined in the upfront metastatic setting. The advent of urea-based, small-molecule inhibitors of prostate-specific membrane antigen (PSMA) has partially addressed those shortcomings in diagnosis and therapy of PCa. On the diagnostic side, there are multiple pivotal phase III trials with several different agents having demonstrated utility in the initial staging setting, with generally modest sensitivity but very high specificity for determining otherwise-occult pelvic nodal involvement. That latter statistic drives the utility of the scan by allowing imaging interpreters to read with very high sensitivity while maintaining a robust specificity. Other pivotal phase III trials have demonstrated high detection efficiency in patients with biochemical failure, with high positive predictive value at the lesion level, opening up possible new avenues of therapy such as metastasis-directed therapy. Beyond the diagnostic aspects of PSMA-targeted radiotracers, the same urea-based chemical scaffolds can be altered to deliver therapeutic isotopes to PCa cells that express PSMA. To date, one such agent, when combined with best standard-of-care therapy, has demonstrated an ability to improve overall survival, progression-free survival, and freedom from skeletal events relative to best standard-of-care therapy alone in men with metastatic, castration-resistant PCa who are post chemotherapy. Within the current milieu, there are a number of important future directions including the use of artificial intelligence to better leverage diagnostic findings, further medicinal chemistry refinements to the urea-based structure that may allow improved tumor targeting and decreased toxicities, and the incorporation of new radionuclides that may better balance efficacy with toxicities than those nuclides that are available.

The cutting edge: Promising oncology radiotracers in clinical development.

Molecular imaging moves forward with the development of new imaging agents, and among these are new radiotracers for nuclear medicine applications, particularly positron emission tomography (PET). A number of new targets are becoming accessible for use in oncologic applications. In this review, major new radiotracers in clinical development are discussed. Prominent among these is the family of fibroblast-activation protein-targeted agents that interact with the tumor microenvironment and may show superiority to 2-deoxy-2-[18F]fluoro-d-glucose in a subset of different tumor histologies. Additionally, carbonic anhydrase IX (CAIX) inhibitors are directed at clear cell renal cell carcinoma, which has long lacked an effective PET imaging agent. Those CAIX agents may also have utility in hypoxic tumors. Pentixafor, which binds to a transmembrane receptor, may similarly allow for visualization by PET of low-grade lymphomas, as well as being a second agent for multiple myeloma that opens theranostic possibilities. There are new adrenergic agents aimed at providing a PET-visible replacement to the single-photon-emitting radiotracer meta-[123I]iodobenzylguanidine (MIBG). Finally, in response to a major development in oncologic chemotherapy, there are new radiotracers targeted at assessing the suitability or use of immunotherapeutic agents. All of these and the existing evidence for their utility are discussed.

Utility of PSMA PET/CT in Staging and Restaging of Renal Cell Carcinoma: A Systematic Review and Metaanalysis.

Prostate-specific membrane antigen (PSMA) is expressed in the neovasculature of multiple solid tumors, including renal cell carcinoma (RCC). Studies have demonstrated promising results on the utility of PSMA-targeted PET/CT imaging in RCC. This report aims to provide a systematic review and metaanalysis on the utility and detection rate of PSMA PET/CT imaging in staging or evaluation of primary RCC and restaging of metastatic or recurrent RCC. Methods: Searches were performed in PubMed, Embase, and abstract proceedings (last updated, August 2023). Studies that provided a lesion-level detection rate of PSMA radiotracers in staging or restaging of RCC were included in the metaanalysis. The overall pooled detection rate with a 95% CI was estimated, and subgroup analysis was performed when feasible. Results: Nine studies comprising 152 patients (133 clear cell RCC [ccRCC], 19 other RCC subtypes) were included in the metaanalysis. The pooled detection rate of PSMA PET/CT in evaluation of primary or metastatic RCC was estimated to be 0.83 (95% CI, 0.67-0.92). Subgroup analysis showed a pooled PSMA detection rate of 0.74 (95% CI, 0.57-0.86) in staging or evaluation of primary RCC lesions and 0.87 (95% CI, 0.73-0.95) in restaging of metastatic or recurrent RCC. Analysis based on the type of radiotracer showed a pooled detection rate of 0.85 (95% CI, 0.62-0.95) for 68Ga-based PSMA tracers and 0.92 (95% CI, 0.76-0.97) for 18F-DCFPyL PET/CT. Furthermore, in metastatic ccRCC, the available data support a significantly higher detection rate for 18F-DCFPyL PET/CT than for conventional imaging modalities (2 studies). Conclusion: Our preliminary results show that PSMA PET/CT could be a promising alternative imaging modality for evaluating RCC, particularly metastatic ccRCC. Large prospective studies are warranted to confirm clinical utility in the staging and restaging of RCC.

Prostate-Specific Membrane Antigen PET Response Associates with Metastasis-Free Survival After Stereotactic Ablative Radiation in Oligometastatic Prostate Cancer.

Purpose: Emerging data suggest that metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease, and PSMA response has been proposed as a biomarker for treatment response. Herein, we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC. Methods and Materials: We performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation who underwent PSMA-PET/computed tomography (CT) before and after (median, 6.2 months; range, 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT maximum standardized uptake value (SUVmax) was measured for all lesions, and PSMA response was defined as the percent change in SUVmax of the least responsive lesion. PSMA response was both evaluated as a continuous variable and dichotomized into PSMA responders, with a complete/partial response (at least a 30% reduction in SUVmax), and PSMA nonresponders, with stable/progressive disease (less than a 30% reduction in SUVmax). PSMA response was correlated with conventional imaging-defined metastasis-free survival (MFS) via Kaplan-Meier and Cox regression analysis. Results: A total of 131 patients with 261 treated metastases were included in the analysis, with a median follow-up of 29 months (IQR, 18.5-41.3 months). After stereotactic ablative radiation, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated that PSMA response as a continuous variable was associated with a significantly worse MFS (hazard ratio = 1.003; 95% CI, 1.001-1.006; P = .016). Patients classified as PSMA responders were found to have a significantly improved median MFS of 39.9 versus 12 months (P = .001) compared with PSMA nonresponders. Our study is limited as it is a retrospective review of a heterogenous population. Conclusions: After stereotactic ablative radiation, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting.

Prostate-specific Membrane Antigen: Diagnostics.

Since its clinical introduction in May 2011, prostate-specific membrane antigen (PSMA)-PET/computed tomography has quickly gained worldwide recognition as a significant breakthrough in prostate cancer diagnostics. In the meantime, several new PSMA radioligands for PET imaging have been introduced into routine clinical practice. This article aims to introduce the most commonly used tracers and their key areas of application.

An Automated Deep Learning-Based Framework for Uptake Segmentation and Classification on PSMA PET/CT Imaging of Patients with Prostate Cancer.

Uptake segmentation and classification on PSMA PET/CT are important for automating whole-body tumor burden determinations. We developed and evaluated an automated deep learning (DL)-based framework that segments and classifies uptake on PSMA PET/CT. We identified 193 [18F] DCFPyL PET/CT scans of patients with biochemically recurrent prostate cancer from two institutions, including 137 [18F] DCFPyL PET/CT scans for training and internally testing, and 56 scans from another institution for external testing. Two radiologists segmented and labelled foci as suspicious or non-suspicious for malignancy. A DL-based segmentation was developed with two independent CNNs. An anatomical prior guidance was applied to make the DL framework focus on PSMA-avid lesions. Segmentation performance was evaluated by Dice, IoU, precision, and recall. Classification model was constructed with multi-modal decision fusion framework evaluated by accuracy, AUC, F1 score, precision, and recall. Automatic segmentation of suspicious lesions was improved under prior guidance, with mean Dice, IoU, precision, and recall of 0.700, 0.566, 0.809, and 0.660 on the internal test set and 0.680, 0.548, 0.749, and 0.740 on the external test set. Our multi-modal decision fusion framework outperformed single-modal and multi-modal CNNs with accuracy, AUC, F1 score, precision, and recall of 0.764, 0.863, 0.844, 0.841, and 0.847 in distinguishing suspicious and non-suspicious foci on the internal test set and 0.796, 0.851, 0.865, 0.814, and 0.923 on the external test set. DL-based lesion segmentation on PSMA PET is facilitated through our anatomical prior guidance strategy. Our classification framework differentiates suspicious foci from those not suspicious for cancer with good accuracy.

Axicabtagene ciloleucel versus standard of care in second-line large B-cell lymphoma: outcomes by metabolic tumor volume.

Metabolic tumor volume (MTV) assessed using 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography, a measure of tumor burden, is a promising prognostic indicator in large B-cell lymphoma (LBCL). This exploratory analysis evaluated relationships between baseline MTV (categorized as low [≤median] vs high [>median]) and clinical outcomes in the phase 3 ZUMA-7 study (NCT03391466). Patients with LBCL relapsed within 12 months of or refractory to first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel (axi-cel; autologous anti-CD19 chimeric antigen receptor [CAR] T-cell therapy) or standard care (2-3 cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). All P values are descriptive. Within high and low MTV subgroups, event-free survival (EFS) and progression-free survival (PFS) were superior with axi-cel vs standard care (all HR ≤0.523; P<.01). EFS in patients with high MTV (vs low MTV) was numerically shorter with axi-cel (HR, 1.448; P=.06) and was significantly shorter with standard care (HR, 1.486; P=.02). PFS was shorter in patients with high MTV vs low MTV in both the axi-cel (HR,1.660; P=.02) and standard-care (HR, 1.635; P=.02) arms, and median MTV was lower in patients in ongoing response at data cutoff vs others (both P≤.01). Median MTV was higher in axi-cel-treated patients who experienced grade ≥3 neurologic events or cytokine release syndrome (CRS) than in patients with grade 1/2 or no neurologic events or CRS, respectively (both P≤.03). Baseline MTV ≤median was associated with better clinical outcomes in patients receiving axi-cel or standard care for second-line LBCL.

Longitudinal improvements in clinical and functional outcomes following initiation of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis.

Background: Use of elexacaftor/tezacaftor/ivacaftor (ETI) for treatment of cystic fibrosis (CF) has resulted in unprecedented clinical improvements necessitating development of outcome measures for monitoring disease course. Intranasal micro-optical coherence tomography (µOCT) has previously helped detect and characterize mucociliary abnormalities in patients with CF. This study was done to determine if µOCT can define the effects of ETI on nasal mucociliary clearance and monitor changes conferred to understand mechanistic effects of CFTR modulators beyond CFTR activation. Methods: 26 subjects, with at least 1 F508del mutation were recruited and followed at baseline (visit 1), +1 month (visit 2) and +6 months (visit 4) following initiation of ETI therapy. Clinical outcomes were computed at visits 1, 2 and 4. Intranasal µOCT imaging and functional metrics analysis including mucociliary transport rate (MCT) estimation were done at visits 1 and 2. Results: Percent predicted forced expiratory volume in 1 s (ppFEV1) showed a significant increase of +10.9 % at visit 2, which sustained at visit 4 (+10.6 %). Sweat chloride levels significantly decreased by -36.6 mmol/L and -41.3 mmol/L at visits 2 and 4, respectively. µOCT analysis revealed significant improvement in MCT rate (2.8 ± 1.5, visit 1 vs 4.0 ± 1.5 mm/min, visit 2; P = 0.048). Conclusions: Treatment with ETI resulted in significant and sustained clinical improvements over 6 months. Functional improvements in MCT rate were evident within a month after initiation of ETI therapy indicating that µOCT imaging is sensitive to the treatment effect of HEMT and suggests improved mucociliary transport as a probable mechanism of action underlying the clinical benefits.

RECIP 1.0 Predicts Progression-Free Survival After [177Lu]Lu-PSMA Radiopharmaceutical Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer.

Response Evaluation Criteria in Prostate-Specific Membrane Antigen Imaging (RECIP) 1.0 is an evidence-based framework to evaluate therapeutic efficacy in metastatic prostate cancer using prostate-specific membrane antigen (PSMA) PET/CT. This study aimed to evaluate the associations of interim PSMA PET/CT by RECIP 1.0 with short-term outcome after radiopharmaceutical treatment. Methods: This multicenter retrospective study included patients with metastatic castration-resistant prostate cancer who underwent [177Lu]Lu-PSMA radiopharmaceutical therapy at 3 academic centers and received PSMA PET/CT at baseline and at 12 wk. Pairs of PSMA PET/CT images were assessed by 5 readers for visual RECIP 1.0. The primary outcome was the association of RECIP with prostate-specific antigen progression-free survival (PSA-PFS) by Kaplan-Meier analysis. Results: In total, 124 of 287 screened patients met the inclusion criteria, with 0 (0%), 29 (23%), 54 (44%), and 41 (33%) of those 124 patients having complete response, partial response, stable disease, or progressive disease (PD) by visual RECIP 1.0, respectively. Patients with visual RECIP PD had a significantly shorter PSA-PFS than those with RECIP stable disease or with RECIP partial response (2.6 vs. 6.4 vs. 8.4 mo; P < 0.001). The median PSA-PFS among patients with RECIP PD versus those with non-RECIP PD was 2.6 versus 7.2 mo (hazard ratio, 13.0; 95% CI, 7.0-24.1; P < 0.001). Conclusion: PSMA PET/CT by RECIP 1.0 after 2 cycles of [177Lu]Lu-PSMA is prognostic for PSA-PFS. PSMA PET/CT by RECIP 1.0 may be used in earlier stages of prostate cancer to evaluate drug efficacy and to predict progression-free survival.

Erdheim-Chester Disease Occult on Radiographs and CT but Visible on MRI and PET.

BACKGROUND Erdheim-Chester disease (ECD) is a rare neoplasm of histiocytes that is characterized by prominent involvement of the long bones. Approximately 1500 cases have been reported since the disease was first described in 1930. The imaging appearance of ECD can be highly variable given the numerous systems it can affect. In this case report we discuss a patient whose ECD was occult on multiple imaging modalities. CASE REPORT We report the case of a 60-year-old woman who presented with sub-acute left knee and calf pain that led to an MRI. She was found to have innumerable marrow-replacing lesions in the axial and appendicular skeleton visualized on the initial MRI, as well as on an ¹8F-FDG PET/CT scan. The patient did not have extraosseous abnormal uptake on the PET/CT. Subsequently, a lesion from the left iliac bone was histologically confirmed as ECD on the basis of positive staining for CD68 and CD163 and negative staining for CD1a. Osseous lesions in ECD have a distinct imaging appearance and are typically detected by radiography and bone scintigraphy, among other modalities; however, the lesions in this case were unexpectedly absent from those studies. CONCLUSIONS If there is a high degree of suspicion for ECD, 18F-FDG PET/CT and/or MRI may be necessary for adequate visualization of bone lesions, given that those lesions can have an infiltrative nature that may be difficult to image with other anatomic imaging modalities. Use of 18F-FDG PET/CT and/or MRI may also lead to adequate guidance of confirmatory biopsy.

Prognostic Performance of RECIP 1.0 Based on [18F]PSMA-1007 PET in Prostate Cancer Patients Treated with [177Lu]Lu-PSMA I&T.

In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on 68Ga- and 18F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean, SUVmax, PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 (P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression.

Implementation of PSMA PET/CT and alignment of ordering to SNMMI appropriate use criteria in a large network system.

INTRODUCTION: The Society of Nuclear Medicine and Molecular Imaging (SNMMI) provides appropriate use criteria (AUC) for prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) which include guidance on imaging in newly diagnosed prostate cancer and in patients with biochemically recurrent (BCR) disease. This study aims to examine trends in PSMA implementation and the prevalence and outcomes of scans ordered in scenarios deemed rarely appropriate or not meeting SNMMI AUC. METHODS: We retrospectively identified patients who were diagnosed with presumptive National Comprehensive Cancer Network unfavorable intermediate, high, or very high risk prostate cancer, patients who underwent staging for BCR, and all patients staged with PSMA between July 2021 and March 2023. Positivity was validated by adherence to a predetermined reference standard. RESULTS: The frequency of PSMA use increased in initial staging from 24% to 80% and work-up of BCR from 91% to 99% over our study period. In addition, 5% (17/340) of PSMA scans ordered for initial staging did not meet AUC and 3% (15/557) of posttreatment scans were deemed rarely appropriate. Initial staging orders not meeting SNMMI AUC resulted in no positivity (0/17), while rarely appropriate posttreatment scans were falsely positive in 75% (3/4) of cases. Urologists (53%, 17/32) comprised the largest ordering specialty in rarely appropriate use. CONCLUSION: The frequency of PSMA use rose across the study period. A significant minority of patients received PSMA PET/CT in rarely appropriate scenarios yielding no positivity in initial staging and significant false positivity post-therapy. Further education of providers and electronic medical record-based interventions could help limit the rarely appropriate use of PET imaging.

Comparison of a novel potentiator of CFTR channel activity to ivacaftor in ameliorating mucostasis caused by cigarette smoke in primary human bronchial airway epithelial cells.

Background: Cystic Fibrosis causing mutations in the gene CFTR , reduce the activity of the CFTR channel protein, and leads to mucus aggregation, airway obstruction and poor lung function. A role for CFTR in the pathogenesis of other muco-obstructive airway diseases such as Chronic Obstructive Pulmonary Disease (COPD) has been well established. The CFTR modulatory compound, Ivacaftor (VX-770), potentiates channel activity of CFTR and certain CF-causing mutations and has been shown to ameliorate mucus obstruction and improve lung function in people harbouring these CF-causing mutations. A pilot trial of Ivacaftor supported its potential efficacy for the treatment of mucus obstruction in COPD. These findings prompted the search for CFTR potentiators that are more effective in ameliorating cigarette-smoke (CS) induced mucostasis. Methods: A novel small molecule potentiator (SK-POT1), previously identified in CFTR binding studies, was tested for its activity in augmenting CFTR channel activity using patch clamp electrophysiology in HEK-293 cells, a fluorescence-based assay of membrane potential in Calu-3 cells and in Ussing chamber studies of primary bronchial epithelial cultures. Addition of cigarette smoke extract (CSE) to the solutions bathing the apical surface of Calu-3 cells and primary bronchial airway cultures was used to model COPD. Confocal studies of the velocity of fluorescent microsphere movement on the apical surface of CSE exposed airway epithelial cultures, were used to assess the effect of potentiators on CFTR-mediated mucociliary movement. Results: We showed that SK-POT1, like VX-770, was effective in augmenting the cyclic AMP-dependent channel activity of CFTR. SK-POT-1 enhanced CFTR channel activity in airway epithelial cells previously exposed to CSE and ameliorated mucostasis on the surface of primary airway cultures. Conclusion: Together, this evidence supports the further development of SK-POT1 as an intervention in the treatment of COPD.

Alterations in the fecal microbiota in patients with advanced cystic fibrosis liver disease after 6 months of elexacaftor/tezacaftor/ivacaftor.

BACKGROUND: Cystic fibrosis associated liver disease (CFLD) carries a significant disease burden with no effective preventive therapies. According to the gut-liver axis hypothesis for CFLD pathogenesis, dysbiosis and increased intestinal inflammation and permeability permit pathogenic bacterial translocation into the portal circulation, leading to hepatic inflammation and fibrosis. Evaluating the effect of CFTR (cystic fibrosis transmembrane conductance regulator) modulation with elexacaftor/tezacaftor/ivacaftor (ETI) may help determine the role of CFTR in CFLD and increase understanding of CFLD pathogenesis, which is critical for developing therapies. We aimed to characterize the fecal microbiota in participants with CF with and without advanced CFLD (aCFLD) before and after ETI. METHODS: This is an ancillary analysis of stool samples from participants ages ≥12 y/o enrolled in PROMISE (NCT04038047). Included participants had aCFLD (cirrhosis with or without portal hypertension, or non-cirrhotic portal hypertension) or CF without liver disease (CFnoLD). Fecal microbiota were defined by shotgun metagenomic sequencing at baseline and 1 and 6 months post-ETI. RESULTS: We analyzed 93 samples from 34 participants (11 aCFLD and 23 CFnoLD). Compared to CFnoLD, aCFLD had significantly higher baseline relative abundances of potential pathogens Streptococcus salivarius and Veillonella parvula. Four of 11 aCFLD participants had an initially abnormal fecal calprotectin that normalized 6 months post-ETI, correlating with a significant decrease in S. salivarius and a trend towards decreasing V. parvula. CONCLUSIONS: These results support an association between dysbiosis and intestinal inflammation in CFLD with improvements in both post-ETI, lending further support to the gut-liver axis in aCFLD.

Deep Semisupervised Transfer Learning for Fully Automated Whole-Body Tumor Quantification and Prognosis of Cancer on PET/CT.

Automatic detection and characterization of cancer are important clinical needs to optimize early treatment. We developed a deep, semisupervised transfer learning approach for fully automated, whole-body tumor segmentation and prognosis on PET/CT. Methods: This retrospective study consisted of 611 18F-FDG PET/CT scans of patients with lung cancer, melanoma, lymphoma, head and neck cancer, and breast cancer and 408 prostate-specific membrane antigen (PSMA) PET/CT scans of patients with prostate cancer. The approach had a nnU-net backbone and learned the segmentation task on 18F-FDG and PSMA PET/CT images using limited annotations and radiomics analysis. True-positive rate and Dice similarity coefficient were assessed to evaluate segmentation performance. Prognostic models were developed using imaging measures extracted from predicted segmentations to perform risk stratification of prostate cancer based on follow-up prostate-specific antigen levels, survival estimation of head and neck cancer by the Kaplan-Meier method and Cox regression analysis, and pathologic complete response prediction of breast cancer after neoadjuvant chemotherapy. Overall accuracy and area under the receiver-operating-characteristic (AUC) curve were assessed. Results: Our approach yielded median true-positive rates of 0.75, 0.85, 0.87, and 0.75 and median Dice similarity coefficients of 0.81, 0.76, 0.83, and 0.73 for patients with lung cancer, melanoma, lymphoma, and prostate cancer, respectively, on the tumor segmentation task. The risk model for prostate cancer yielded an overall accuracy of 0.83 and an AUC of 0.86. Patients classified as low- to intermediate- and high-risk had mean follow-up prostate-specific antigen levels of 18.61 and 727.46 ng/mL, respectively (P < 0.05). The risk score for head and neck cancer was significantly associated with overall survival by univariable and multivariable Cox regression analyses (P < 0.05). Predictive models for breast cancer predicted pathologic complete response using only pretherapy imaging measures and both pre- and posttherapy measures with accuracies of 0.72 and 0.84 and AUCs of 0.72 and 0.76, respectively. Conclusion: The proposed approach demonstrated accurate tumor segmentation and prognosis in patients across 6 cancer types on 18F-FDG and PSMA PET/CT scans.

CD38-Specific Gallium-68 Labeled Peptide Radiotracer Enables Pharmacodynamic Monitoring in Multiple Myeloma with PET.

The limited availability of molecularly targeted low-molecular-weight imaging agents for monitoring multiple myeloma (MM)-targeted therapies has been a significant challenge in the field. In response, a first-in-class peptide-based radiotracer, [68Ga]Ga-AJ206, is developed that can be seamlessly integrated into the standard clinical workflow and is specifically designed to noninvasively quantify CD38 levels and pharmacodynamics by positron emission tomography (PET). A bicyclic peptide, AJ206, is synthesized and exhibits high affinity to CD38 (KD: 19.1 ± 0.99 × 10-9 m) by surface plasmon resonance. Further, [68Ga]Ga-AJ206-PET shows high contrast within 60 min and suitable absorbed dose estimates for clinical use. Additionally, [68Ga]Ga-AJ206 detects CD38 expression in cell line-derived xenografts, patient-derived xenografts (PDXs), and disseminated disease models in a manner consistent with flow cytometry and immunohistochemistry findings. Moreover, [68Ga]Ga-AJ206-PET successfully quantifies CD38 pharmacodynamics in PDXs, revealing increased CD38 expression in the tumor following all-trans retinoic acid (ATRA) therapy. In conclusion, [68Ga]Ga-AJ206 exhibits the salient features required for clinical translation, providing CD38-specific high-contrast images in multiple models of MM. [68Ga]Ga-AJ206-PET could be useful for quantifying total CD38 levels and pharmacodynamics during therapy to evaluate approved and new therapies in MM and other diseases with CD38 involvement.

The effect of discontinuing hypertonic saline or dornase alfa on mucociliary clearance in elexacaftor/tezacaftor/ivacaftor treated people with cystic fibrosis: The SIMPLIFY-MCC Study.

Many people with CF (pwCF) desire a reduction in inhaled treatment burden after initiation of elexacaftor/tezacaftor/ivacaftor. The randomized, open-label SIMPLIFY study showed that discontinuing hypertonic saline (HS) or dornase alfa (DA) was non-inferior to continuation of each treatment with respect to change in lung function over a 6-week period. In this SIMPLIFY substudy, we used gamma scintigraphy to determine whether discontinuation of either HS or DA was associated with deterioration in the rate of in vivo mucociliary clearance (MCC) in participants ≥12 years of age. While no significant differences in MCC endpoints were associated with HS discontinuation, significant improvement in whole and peripheral lung MCC was observed after discontinuing DA. These results suggest that pwCF on ETI with mild lung disease do not experience a subclinical deterioration in MCC that could later impact health outcomes after discontinuing HS, and in fact may benefit from improved MCC after stopping DA treatment.

Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma.

Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from that cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response. We found that nivolumab durably induces a pro-inflammatory state within the primary tumor, and baseline immune infiltration within the primary tumor correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. These findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations.

Positron Emission Tomography/Computed Tomography Transformation of Oncology: Multiple Myeloma.

This article provides a comprehensive review of the role of 2-deoxy-2-[18F]fluoro-d-glucose (18F FDG) positron emission tomography/computed tomography (PET/CT) in multiple myeloma (MM) and related plasma cell disorders. MM is a hematologic malignancy characterized by the neoplastic proliferation of plasma cells. 18F FDG PET/CT integrates metabolic and anatomic information, allowing for accurate localization of metabolically active disease. The article discusses the use of 18F FDG PET/CT in initial diagnosis, staging, prognostication, and assessing treatment response. Additionally, it provides valuable insights into the novel imaging targets including chemokine receptor C-X-C motif 4 and CD38.

PET/Computed Tomography Transformation of Oncology: Kidney and Urinary Tract Cancers.

Renal cell carcinoma (RCC) and urothelial carcinoma (UC) are two of the most common genitourinary malignancies. 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) can play an important role in the evaluation of patients with RCC and UC. In addition to the clinical utility of 18F-FDG PET to evaluate for metastatic RCC or UC, the shift in molecular imaging to focus on specific ligand-receptor interactions should provide novel diagnostic and therapeutic opportunities in genitourinary malignancies. In combination with the rise of artificial intelligence, our ability to derive imaging biomarkers that are associated with treatment selection, response assessment, and overall patient prognostication will only improve.