Publications by authors named "Peter Choyke"

726 Publications

Positive Multifocal PSMA PET/CT in a Patient With Prostate Cancer and Follicular Lymphoma.

Clin Nucl Med 2021 Jul 26. Epub 2021 Jul 26.

From the Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National, Institutes of Health, Bethesda, MD Department of Nuclear Medicine, University Hospital Düsseldorf, Düsseldorf Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center Translational Lung Research Center Heidelberg, German Center for Lung Research National Center for Tumor Diseases, Heidelberg, Germany.

Abstract: Prostate-specific membrane antigen (PSMA) PET/CT is a highly reliable nuclear tracer for diagnostic imaging of prostate cancer. However, PSMA is also expressed by some nonprostatic tissues such as benign tumors, inflammatory processes, and malignant neoplasms. This case presents a patient with prostate cancer and follicular lymphoma undergoing PSMA PET/CT. Remarkably, both tumor entities were clearly detected in the scan. Yet, the 2 malignancies demonstrated rather different ranges in terms of SUVmax uptake values and therefore still enabled precise and accurate discrimination of prostate cancer and follicular lymphoma.
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http://dx.doi.org/10.1097/RLU.0000000000003828DOI Listing
July 2021

Competitive blocking of salivary gland [F]DCFPyL uptake via localized, retrograde ductal injection of non-radioactive DCFPyL: a preclinical study.

EJNMMI Res 2021 Jul 21;11(1):66. Epub 2021 Jul 21.

Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, NIH, NCI/NIH, Building 10, Room # B3B69F, Bethesda, MD, 20892, USA.

Background: PSMA-targeted radionuclide therapy (TRT) is a promising treatment for prostate cancer (PCa), but dose-limiting xerostomia can severely limit its clinical adaptation, especially when using alpha-emitting radionuclides. With [F]DCFPyL as a surrogate for PSMA-TRT, we report a novel method to selectively reduce salivary gland (SG) uptake of systemically administered [F]DCFPyL by immediate prior infusion of non-radioactive standard of [F]DCFPyL (DCFPyL) directly into the SG via retrograde cannulation.

Methods: A dose-finding cohort using athymic nude mice demonstrated proof of principle that SG uptake can be selectively blocked by DCFPyL administered either locally via cannulation (CAN group) or systemically (SYS group). The experiments were repeated in a validation cohort of 22RV1 tumor-bearing mice. Submandibular glands (SMG) of CAN mice were locally blocked with either saline or DCFPyL (dose range: 0.01× to 1000× molar equivalent of the radioactive [18F]DCFPyL dose). The radioactive dose of [18F]DCFPyL was administered systemically 10 min later and the mice euthanized after 1 h for biodistribution studies. Toxicity studies were done at up to 1000× dose.

Results: In the dose-finding cohort, the SYS group showed a dose-dependent 12-40% decrease in both the SMG T/B and the kidney (tumor surrogate). Mild blocking was observed at 0.01× , with maximal blocking reached at 1× with no additional blocking up to 1000× . In the CAN group, blocking at the 0.1× and 1× dose levels resulted in a similar 42-53% decrease, but without the corresponding decrease in kidney uptake as seen in the SYS group. Some evidence of "leakage" of DCFPyL from the salivary gland into the systemic circulation was observed. However, experiments in 22RV1 tumor-bearing mice at the 0.1× and 1× dose levels confirm that, at the appropriate blocking dose, SG uptake of [18F]DCFPyL can be selectively reduced without affecting tumor uptake and with no toxicity.

Conclusion: Our results suggest that direct retrograde instillation of DCFPyL into the SG could predictably and selectively decrease salivary uptake of systemically administered [F]DCFPyL without altering tumor uptake, if given at the appropriate dose. This novel approach is easily translatable to clinical practice and has the potential to mitigate xerostomia, without compromising the therapeutic efficacy of the PSMA-TRT.
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http://dx.doi.org/10.1186/s13550-021-00803-9DOI Listing
July 2021

Metabolic reprogramming in prostate cancer.

Br J Cancer 2021 Jul 14. Epub 2021 Jul 14.

Molecular Imaging Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Although low risk localised prostate cancer has an excellent prognosis owing to effective treatments, such as surgery, radiation, cryosurgery and hormone therapy, metastatic prostate cancer remains incurable. Existing therapeutic regimens prolong life; however, they are beset by problems of resistance, resulting in poor outcomes. Treatment resistance arises primarily from tumour heterogeneity, altered genetic signatures and metabolic reprogramming, all of which enable the tumour to serially adapt to drugs during the course of treatment. In this review, we focus on alterations in the metabolism of prostate cancer, including genetic signatures and molecular pathways associated with metabolic reprogramming. Advances in our understanding of prostate cancer metabolism might help to explain many of the adaptive responses that are induced by therapy, which might, in turn, lead to the attainment of more durable therapeutic responses.
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http://dx.doi.org/10.1038/s41416-021-01435-5DOI Listing
July 2021

The Risk of Prostate Cancer Progression in Active Surveillance Patients With Bilateral Disease Detected by Combined MRI-Fusion and Systematic Biopsy.

J Urol 2021 Jun 28:101097JU0000000000001941. Epub 2021 Jun 28.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Purpose: To evaluate whether bilateral prostate cancer detected at Active Surveillance (AS) enrollment is associated with progression to Grade Group ≥2 (GG2) and to compare the efficacy of combined targeted biopsy plus systematic biopsy (CBx) versus systematic biopsy (Sbx) or targeted biopsy (Tbx) alone to detect bilateral disease.

Methods: A prospectively-maintained database of patients referred to our institution from 2007-2020 was queried. The study cohort included all AS patients with GG1 on confirmatory Cbx and follow-up of at least one year. Cox proportional hazard analysis identified baseline characteristics associated with progression to GG ≥2 at any point throughout follow-up.

Results: Of 579 patients referred, 103 patients had GG1 on Cbx and were included in the study. 49/103 (47.6%) patients progressed to ≥GG2, with 30/72 (41.7%) patients with unilateral disease progressing and 19/31 (61.3%) patients with bilateral disease progressing. Median time to progression was 68 months vs. 52 months for unilateral and bilateral disease, respectively (p=0.006). Both PSA Density (HR 1.72, p=0.005) and presence of bilateral disease (HR 2.21, p=0.012) on confirmatory biopsy were associated with AS progression. At time of progression, GG and risk group were significantly higher in patients with bilateral versus unilateral disease. Cbx detected 16% more patients with bilateral disease than Sbx alone.

Conclusion: Bilateral disease and PSA Density at confirmatory Cbx conferred greater risk of earlier AS progression. Cbx was superior to Sbx for identifying bilateral disease. AS risk-stratification protocols may benefit from including presence of bilateral disease and should use Cbx to detect bilateral disease.
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http://dx.doi.org/10.1097/JU.0000000000001941DOI Listing
June 2021

Real-Time insight into in vivo redox status utilizing hyperpolarized [1-C] N-acetyl cysteine.

Sci Rep 2021 Jun 9;11(1):12155. Epub 2021 Jun 9.

Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Drastic sensitivity enhancement of dynamic nuclear polarization is becoming an increasingly critical methodology to monitor real-time metabolic and physiological information in chemistry, biochemistry, and biomedicine. However, the limited number of available hyperpolarized C probes, which can effectively interrogate crucial metabolic activities, remains one of the major bottlenecks in this growing field. Here, we demonstrate [1-C] N-acetyl cysteine (NAC) as a novel probe for hyperpolarized C MRI to monitor glutathione redox chemistry, which plays a central part of metabolic chemistry and strongly influences various therapies. NAC forms a disulfide bond in the presence of reduced glutathione, which generates a spectroscopically detectable product that is separated from the main peak by a 1.5 ppm shift. In vivo hyperpolarized MRI in mice revealed that NAC was broadly distributed throughout the body including the brain. Its biochemical transformation in two human pancreatic tumor cells in vitro and as xenografts differed depending on the individual cellular biochemical profile and microenvironment in vivo. Hyperpolarized NAC can be a promising non-invasive biomarker to monitor in vivo redox status and can be potentially translatable to clinical diagnosis.
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http://dx.doi.org/10.1038/s41598-021-90921-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190077PMC
June 2021

Endoscopic near-infrared photoimmunotherapy in an orthotopic head and neck cancer model.

Cancer Sci 2021 Jun 8. Epub 2021 Jun 8.

Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Near-infrared photoimmunotherapy (NIR-PIT) is a cell selective cancer therapy that uses an antibody-photoabsorber (IRDye700DX, IR700) conjugate (APC) and NIR light. NIR-PIT targeting epidermal growth factor receptor (EGFR) in head and neck cancer (HNC) was conditionally approved in Japan in 2020. APC-bound tumors can be detected using endoscopic fluorescence imaging, whereas NIR light can be delivered using endoscopic fiber optics. The aims of this study were: (1) to assess the feasibility of endoscopic NIR-PIT in an orthotopic HNC model using a CD44-expressing MOC2-luc cell line; and (2) to evaluate quantitative fluorescence endoscopic imaging prior to and during NIR-PIT. The results were compared in 3 experimental groups: (1) untreated controls, (2) APC injection without light exposure (APC-IV), and (3) APC injection followed by NIR light exposure (NIR-PIT). APC injected groups showed significantly higher fluorescence signals for IR700 compared with the control group prior to therapeutic NIR light exposure, and the fluorescence signal significantly decreased in the NIR-PIT group after light exposure. After treatment, the NIR-PIT group showed significantly attenuated bioluminescence compared with the control and the APC-IV groups. Histology demonstrated diffuse necrotic death of the cancer cells in the NIR-PIT group alone. In conclusion, endoscopically delivered light combined with quantitative fluorescence imaging can be used to "see and treat" HNC. This method could also be applied to other types of cancer approachable with endoscopy.
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http://dx.doi.org/10.1111/cas.15013DOI Listing
June 2021

Near Infrared Photoimmunotherapy; A Review of Targets for Cancer Therapy.

Cancers (Basel) 2021 May 21;13(11). Epub 2021 May 21.

Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that uses an antibody-photoabsorber (IRDye700DX) conjugate (APC) that is activated by NIR light irradiation. In September 2020, the first APC and laser system were conditionally approved for clinical use in Japan. A major benefit of NIR-PIT is that only APC-bound cancer cells that are exposed to NIR light are killed by NIR-PIT; thus, minimal damage occurs in adjacent normal cells. These early trials have demonstrated that in addition to direct cell killing, there is a significant therapeutic host immune response that greatly contributes to the success of the therapy. Although the first clinical use of NIR-PIT targeted epidermal growth factor receptor (EGFR), many other targets are suitable for NIR-PIT. NIR-PIT has now been applied to many cancers expressing various cell-surface target proteins using monoclonal antibodies designed to bind to them. Moreover, NIR-PIT is not limited to tumor antigens but can also be used to kill specific host cells that create immune-permissive environments in which tumors grow. Moreover, multiple targets can be treated simultaneously with NIR-PIT using a cocktail of APCs. NIR-PIT can be used in combination with other therapies, such as immune checkpoint inhibitors, to enhance the therapeutic effect. Thus, NIR-PIT has great potential to treat a wide variety of cancers by targeting appropriate tumor cells, immune cells, or both, and can be augmented by other immunotherapies.
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http://dx.doi.org/10.3390/cancers13112535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196790PMC
May 2021

and Comparison of 3,2-HOPO Versus Deferoxamine-Based Chelation of Zirconium-89 to the Antimesothelin Antibody Anetumab.

Cancer Biother Radiopharm 2021 May;36(4):316-325

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

[Th]Th-3,2-HOPO-MSLN-mAb, a mesothelin (MSLN)-targeted thorium-227 therapeutic conjugate, is currently in phase I clinical trial; however, direct PET imaging using this conjugate is technically challenging. Thus, using the same MSLN antibody, we synthesized 3,2-HOPO and deferoxamine (DFO)-based zirconium-89 antibody conjugates, [Zr]Zr-3,2-HOPO-MSLN-mAb and [Zr]Zr-DFO-MSLN-mAb, respectively, and compared them and . [Zr]Zr-3,2-HOPO-MSLN-mAb and [Zr]Zr-DFO-MSLN-mAb were evaluated to determine binding affinity and immunoreactivity in HT29-MSLN and PDX (NCI-Meso16, NCI-Meso21) cells. For both the zirconium-89 conjugates, studies (biodistribution/imaging) were performed at days 1, 3, and 6, from which tissue uptake was determined. Both the conjugates demonstrated a low nanomolar binding affinity for MSLN and >95% immunoreactivity. In all the three tumor types, biodistribution of [Zr]Zr-DFO-MSLN-mAb resulted in higher tumor uptake(15.88-28-33%ID/g) at all time points compared with [Zr]Zr-3,2-HOPO-MSLN-mAb(7-13.07%ID/g). [Zr]Zr-3,2-HOPO-MSLN-mAb femur uptake was always higher than [Zr]Zr-DFO-MSLN-mAb, and imaging results concurred with the biodistribution studies. Even though the conjugates exhibited a high binding affinity for MSLN, [Zr]Zr-DFO-MSLN-mAb showed a higher tumor and lower femur uptake than [Zr]Zr-3,2-HOPO-MSLN-mAb. Nevertheless, [Zr]Zr-3,2-HOPO-MSLN-mAb could be used to study organ distribution and lesion uptake with the caveat of detecting MSLN-positive bone lesions. Clinical trial (NCT03507452).
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http://dx.doi.org/10.1089/cbr.2020.4492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161658PMC
May 2021

MRI-guided focal laser ablation of prostate cancer: a prospective single-arm, single-center trial with 3 years of follow-up.

Diagn Interv Radiol 2021 May;27(3):394-400

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose: We aimed to assess post-interventional and 36-month follow-up results of a single-center, single-arm, in-bore phase I trial of focal laser ablation (FLA) guided by multiparametric magnetic resonance imaging (mpMRI).

Methods: FLA procedures were done in-bore MRI using a transperineal approach. Primary endpoints were feasibility and safety expressed as lack of grade 3 complications. Secondary endpoints were changes in international prostate symptom score (IPSS), sexual health inventory for men (SHIM), quality of life (QoL) scores, and serum prostate specific antigen (PSA) levels. Treatment outcomes were assessed by combined mpMRI-ultrasound fusion-guided and extended sextant systematic biopsy after 12, 24, and optionally after 36 months.

Results: Fifteen participants were included. Seven patients (46.67%) had Gleason 3+3 and 8 patients (53.33%) had Gleason 3+4 cancer. All patients tolerated the procedure well, and no grade 3/4 complications occurred. All grade 1 and 2 complications were transient and resolved completely. There was no significant change in mean IPSS from baseline (-1, p = 0.460) and QoL (0, p = 0.441) scores following FLA but there was a significant drop in mean SHIM scores (-2, p = 0.010) compared to pretreatment baselines. Mean PSA significantly decreased after FLA (-2.5, p < 0.001). Seven out of 15 patients (46.67%) had residual cancer in, adjacent, or in close proximity to the treatment area (1 × 4+3=7, 1 × 3+4=7, and 5 × 3+3=6). Four out of 15 patients (26.67%) underwent salvage therapy (2 repeat FLA, 2 radical prostatectomy).

Conclusion: After 3 years of follow-up we conclude focal laser ablation is safe and feasible without significant complications.
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http://dx.doi.org/10.5152/dir.2021.20095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136525PMC
May 2021

Local Depletion of Immune Checkpoint Ligand CTLA4 Expressing Cells in Tumor Beds Enhances Antitumor Host Immunity.

Adv Ther (Weinh) 2021 May 24;4(5). Epub 2021 Feb 24.

Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA.

Near-infrared photoimmunotherapy (NIR-PIT) is a cancer treatment that utilizes antibody-photoabsorber (IR700) conjugates to selectively kill target cells by exposing them to NIR light. Cytotoxic T-lymphocyte antigen 4 (CTLA4) is a major immune checkpoint ligand mediating antitumor immune suppression. Local depletion of CTLA4 expressing cells in the tumor bed with NIR-PIT could enhance antitumor immune responses by both blocking the CTLA4-axis and depleting immune suppressive cells. The aim of this study is to evaluate the antitumor efficacy of CTLA4-targeted NIR-PIT using four murine tumor models, MC38-luc, LL/2-luc, MOC2-luc, and MOC2. The CTLA4-targeted NIR-PIT depletes intratumoral CTLA4 expressing cells which are mostly regulatory T cells. CTLA4-targeted NIR-PIT yields complete responses in 80% of MC38-luc, 70% of LL/2-luc and 40% of MOC2-luc tumors prolonging survival in all cases. After CTLA4-targeted NIR-PIT, activation and infiltration of CD8 T cells within the tumor microenvironment is observed. In conclusion, CTLA4-targeted NIR-PIT can effectively treat tumors by blocking the CTLA4-axis as well as by eliminating CTLA4-expressing immune suppressor cells, resulting in T cell mediated antitumor immunity. Local CTLA4-expressing cell depletion in tumor beds using NIR-PIT could be a promising new cancer immunotherapy for safely treating a variety of tumor types.
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http://dx.doi.org/10.1002/adtp.202000269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115697PMC
May 2021

Ga-FAPI-PET/CT improves diagnostic staging and radiotherapy planning of adenoid cystic carcinomas - Imaging analysis and histological validation.

Radiother Oncol 2021 07 1;160:192-201. Epub 2021 May 1.

Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany.

Background: Adenoid cystic carcinomas (ACCs) are rare epithelial tumors mostly situated in the head and neck region and characterized by infiltrative growth. The tumor stroma of ACCs includes cancer-associated fibroblasts (CAFs) expressing Fibroblast Activation Protein (FAP), a new target for positron emission tomography (PET) imaging. Here we describe the value of PET/ computed tomography (PET/CT) imaging using Ga-labelled FAP-Inhibitors (Ga-FAPI-PET/CT) and their clinical potential for staging and radiotherapy planning in 12 ACC patients (7 primary, 5 recurrent).

Patients And Methods: Patients underwent contrast enhanced staging CT (ceCT) and magnetic resonance imaging (ceMRI) before Ga-FAPI - PET/CT. PET-scans were acquired 10, 60 and 180 minutes after administration of 150-250 MBq of Ga-labelled FAPI tracers. SUV and SUV values of ACCs and healthy organs were obtained using a 60% of maximum iso-contour. FAP and alpha smooth muscle actin (α-SMA) immunohistochemistry was performed in 13 cases (3 with and 10 without Ga FAPI-PET/CT). Staging and radiotherapy planning based on Ga-FAPI-PET/CT versus ceCT/MRI alone were compared.

Results: We observed elevated tracer uptake in all ACCs. Immunohistochemistry showed FAP-expressing CAFs in the tumor. Compared to conventional staging, Ga-FAPI-PET/CT led to upstaging in 2/12 patients and to detection of additional metastases in 3 patients, thus in total 42% of patients had their staging altered. Moreover, Ga-FAPI PET improved the accuracy of target volume delineation for radiotherapy, as compared to CT and MRI.

Conclusion: Ga-FAPI-PET/CT is a promising imaging modality for ACC, increasing the accuracy of staging exams and radiotherapy planning volumes, as compared conventional to CT and MRI.
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http://dx.doi.org/10.1016/j.radonc.2021.04.016DOI Listing
July 2021

Near-infrared photoimmunotherapy targeting human-EGFR in a mouse tumor model simulating current and future clinical trials.

EBioMedicine 2021 May 29;67:103345. Epub 2021 Apr 29.

Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address:

Background: near-infrared photoimmunotherapy (NIR-PIT) is a cancer treatment that uses antibody-photoabsorber (IRDye700DX, IR700) conjugates (APCs) which bind to target cells and are photoactivated by NIR light inducing rapid necrotic cell death. NIR-PIT targeting human epidermal growth factor receptor (hEGFR) has been shown to destroy hEGFR expressing human tumor cells and to be effective in immunodeficient mouse models. NIR-PIT can also be targeted to cells in the tumor microenvironment, for instance, CD25-targeted NIR-PIT can be used to selectively deplete regulatory T cells (Tregs) within a tumor. The aim of this study was to evaluate the combined therapeutic efficacy of hEGFR and CD25-targeted NIR-PIT in a newly established hEGFR expressing murine oropharyngeal cell line (mEERL-hEGFR).

Methods: panitumumab conjugated with IR700 (pan-IR700) was used as the cancer cell-directed component of NIR-PIT and anti-CD25-F(ab')-IR700 was used as the tumor microenvironment-directed component of NIR-PIT. Efficacy was evaluated using tumor-bearing mice in four groups: (1) non-treatment group (control), (2) pan-IR700 based NIR-PIT (pan-PIT), (3) anti-CD25-F(ab')-IR700 based NIR-PIT (CD25-PIT), (4) combined NIR-PIT with pan-IR700 and anti-CD25- F(ab')-IR700 (combined PIT).

Findings: the combined PIT group showed the greatest inhibition of tumor growth. Destruction of cancer cells likely leads to an immune response which is amplified by the loss of Tregs in the tumor microenvironment.

Interpretation: combined hEGFR and CD25-targeted NIR-PIT is a promising treatment for hEGFR expressing cancers in which Treg cells play an immunosuppressive role.
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http://dx.doi.org/10.1016/j.ebiom.2021.103345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102756PMC
May 2021

Monitoring PSMA Responses to ADT in Prostate Cancer Patient-Derived Xenograft Mouse Models Using [F]DCFPyL PET Imaging.

Mol Imaging Biol 2021 Apr 23. Epub 2021 Apr 23.

Molecular Imaging Program, NCI/NIH, Center for Cancer Research, National Cancer Institute, Building 10, Room B3B406, Bethesda, MD, 20892, USA.

Purpose: PSMA overexpression has been associated with aggressive prostate cancer (PCa). However, PSMA PET imaging has revealed highly variable changes in PSMA expression in response to ADT treatment ranging from increases to moderate decreases. To better understand these PSMA responses and potential relationship to progressive PCa, the PET imaging agent, [F]DCFPyL, was used to assess changes in PSMA expression in response to ADT using genomically characterized LuCaP patient-derived xenograft mouse models (LuCaP-PDXs) which were found to be sensitive to ADT (LuCaP73 and LuCaP136;CS) or resistant (LuCaP167;CR).

Methods: [F]DCFPyL (2-(3-{1-carboxy-5-[(6-[F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) was used to assess PSMA in vitro (saturation assays) in LuCaP tumor membrane homogenates and in vivo (imaging/biodistribution) in LuCaP-PDXs. Control and ADT-treated LuCaPs were imaged before ADT (0 days) and 2-, 7-, 14-, and 21-days post-ADT from which tumor:muscle ratios (T:Ms) were determined and concurrently tumor volumes were measured (caliper). After the 21-day imaging, biodistributions and histologic/genomic (PSMA, AR) analysis were done.

Results: [F]DCFPyL exhibited high affinity for PSMA and distinguished different levels of PSMA in LuCaP tumors. Post-ADT CS LuCaP73 and LuCaP136 tumor volumes significantly decreased at day 7 or 14 respectively vs controls, whereas the CR LuCaP167 tumor volumes were minimally changed. [F]DCFPyL imaging T:Ms were increased 3-5-fold in treated LuCaP73 tumors vs controls, while treated LuCaP136 T:Ms remained unchanged which was confirmed by day 21 biodistribution results. For treated LuCaP167, T:Ms were decreased (~ 45 %) vs controls but due to low T:M values (<2) may not be indicative of PSMA level changes. LuCaP73 tumor PSMA histologic/genomic results were comparable to imaging/biodistribution results, whereas the results for other tumor types varied.

Conclusion: Tumor responses to ADT varied from sensitive to resistant among these LuCaP PDXs, while only the high PSMA expressing LuCaP model exhibited an increase in PSMA levels in response to ADT. These models may be useful in understanding the clinical relevance of PSMA PET responses to ADT and potentially the relationship to disease progression as it may relate to the genomic signature.
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http://dx.doi.org/10.1007/s11307-021-01605-0DOI Listing
April 2021

Changes in Magnetic Resonance Imaging Using the Prostate Cancer Radiologic Estimation of Change in Sequential Evaluation Criteria to Detect Prostate Cancer Progression for Men on Active Surveillance.

Eur Urol Oncol 2021 Apr 21;4(2):227-234. Epub 2020 Oct 21.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: The ability of serial magnetic resonance imaging (MRI) to capture pathologic progression during active surveillance (AS) remains in question.

Objective: To determine whether changes in MRI are associated with pathologic progression for patients on AS.

Design, Setting, And Participants: From July 2007 through January 2020, we identified all patients evaluated for AS at our institution. Following confirmatory biopsy, a total of 391 patients who underwent surveillance MRI and biopsy at least once were identified (median follow-up of 35.6 mo, interquartile range 19.7-60.6).

Outcome Measurements And Statistical Analysis: All MRI intervals were scored using the "Prostate Cancer Radiologic Estimation of Change in Sequential Evaluation" (PRECISE) criteria, with PRECISE scores =4 considered a positive change in MRI. A generalized estimating equation-based logistic regression analysis was conducted for all intervals with a PRECISE score of <4 to determine the predictors of Gleason grade group (GG) progression despite stable MRI.

Results And Limitations: A total of 621 MRI intervals were scored by PRECISE and validated by biopsy. The negative predictive value of stable MRI (PRECISE score <4) was greatest for detecting GG1 to?=?GG3 disease (0.94 [0.91-0.97]). If 2-yr surveillance biopsy were performed exclusively for a positive change in MRI, 3.7% (4/109) of avoided biopsies would have resulted in missed progression from GG1 to?=?GG3 disease. Prostate-specific antigen (PSA) density (odds ratio 1.95 [1.17-3.25], p?=? 0.01) was a risk factor for progression from GG1 to =GG3 disease despite stable MRI.

Conclusions: In patients with GG1 disease and stable MRI (PRECISE score <4) on surveillance, grade progression to?=?GG3 disease is not common. In patients with grade progression detected on biopsy despite stable MRI, elevated PSA density appeared to be a risk factor for progression to?=?GG3 disease.

Patient Summary: For patients with low-risk prostate cancer on active surveillance, the risk of progressing to grade group 3 disease is low with a stable magnetic resonance image (MRI) after 2?yr. Having higher prostate-specific antigen density increases the risk of progression, despite having a stable MRI.
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http://dx.doi.org/10.1016/j.euo.2020.09.004DOI Listing
April 2021

Editorial Comment.

J Urol 2021 07 15;206(1):60-61. Epub 2021 Apr 15.

Genitourinary Malignancy Branch, National Cancer Institute, Bethesda, Maryland.

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http://dx.doi.org/10.1097/JU.0000000000001698.01DOI Listing
July 2021

Prognostic Features of Biochemical Recurrence of Prostate Cancer Following Radical Prostatectomy Based on Multiparametric MRI and Immunohistochemistry Analysis of MRI-guided Biopsy Specimens.

Radiology 2021 06 13;299(3):613-623. Epub 2021 Apr 13.

From the Clinical Research Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute (S.A.H.); Molecular Imaging Branch (S.A.H., S.M., Y.M., T.S., J.S., P.L.C., B.T.), Laboratory of Pathology (M.J.M.), Center for Interventional Oncology (B.J.W.), and Urologic Oncology Branch (S.M., P.A.P.), National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room B3B85, Bethesda, Md 20892; Center for Prostate Disease Research, John P. Murtha Cancer Center, Department of Surgery, Uniformed Services University of the Health Sciences (W.G., D.Y., J.C., I.L.R., S.S., A.D., I.A.S.) and Urology Service (I.L.R.), Walter Reed National Military Medical Center, Bethesda, Md; and Department of Genitourinary Pathology, Joint Pathology Center, Silver Spring, Md (I.A.S.).

Background Although prostate MRI is routinely used for the detection and staging of localized prostate cancer, imaging-based assessment and targeted molecular sampling for risk stratification are an active area of research. Purpose To evaluate features of preoperative MRI and MRI-guided biopsy immunohistochemistry (IHC) findings associated with biochemical recurrence (BCR) of prostate cancer after surgery. Materials and Methods In this retrospective case-control study, patients underwent multiparametric MRI before MRI-guided biopsy followed by radical prostatectomy between 2008 and 2016. Lesions were retrospectively scored with the Prostate Imaging Reporting and Data System (PI-RADS) (version 2) by radiologists who were blinded to the clinical-pathologic results. The IHC staining, including stains for the ETS-related gene, phosphatase and tensin homolog, androgen receptor, prostate specific antigen, and p53, was performed with targeted biopsy specimens of the index lesion (highest suspicion at MRI and pathologic grade) and scored by pathologists who were blinded to clinical-pathologic outcomes. Cox proportional hazards regression analysis was used to evaluate associations with recurrence-free survival (RFS). Results The median RFS was 31.7 months (range, 1-101 months) for 39 patients (median age, 62 years; age range, 47-76 years) without BCR and 14.6 months (range, 1-61 months) for 40 patients (median age, 59 years; age range, 47-73 years) with BCR. MRI features that showed a significant relationship with the RFS interval included an index lesion with a PI-RADS score of 5 (hazard ratio [HR], 2.10; 95% CI: 1.05, 4.21; = .04); index lesion burden, defined as ratio of index lesion volume to prostate volume (HR, 1.55; 95% CI: 1.2, 2.1; = .003); and suspicion of extraprostatic extension (EPE) (HR, 2.18; 95% CI: 1.1, 4.2; = .02). Presurgical multivariable analysis indicated that suspicion of EPE at MRI (adjusted HR, 2.19; 95% CI: 1.1, 4.3; = .02) and p53 stain intensity (adjusted HR, 2.22; 95% CI: 1.0, 4.7; = .04) were significantly associated with RFS. Conclusion MRI features, including Prostate Imaging Reporting and Data System score, index lesion burden, extraprostatic extension, and preoperative guided biopsy p53 immunohistochemistry stain intensity are associated with biochemical relapse of prostate cancer after surgery. © RSNA, 2021 . See also the editorial by Costa in this issue.
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http://dx.doi.org/10.1148/radiol.2021202425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165944PMC
June 2021

Using Prostate Imaging-Reporting and Data System (PI-RADS) Scores to Select an Optimal Prostate Biopsy Method: A Secondary Analysis of the Trio Study.

Eur Urol Oncol 2021 Apr 10. Epub 2021 Apr 10.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: While magnetic resonance imaging (MRI)-targeted biopsy (TBx) results in better prostate cancer (PCa) detection relative to systematic biopsy (SBx), the combination of both methods increases clinically significant PCa detection relative to either Bx method alone. However, combined Bx subjects patients to higher number of Bx cores and greater detection of clinically insignificant PCa.

Objective: To determine if prebiopsy prostate MRI can identify men who could forgo combined Bx without a substantial risk of missing clinically significant PCa (csPC).

Design, Setting, And Participants: Men with MRI-visible prostate lesions underwent combined TBx plus SBx.

Outcome Measurements And Statistical Analysis: The primary outcomes were detection rates for grade group (GG) ≥2 and GG ≥3 PCa by TBx and SBx, stratified by Prostate Imaging-Reporting and Data System (PI-RADS) score.

Results And Limitations: Among PI-RADS 5 cases, nearly all csPCs were detected by TBx, as adding SBx resulted in detection of only 2.5% more GG ≥2 cancers. Among PI-RADS 3-4 cases, however, SBx addition resulted in detection of substantially more csPCs than TBx alone (7.5% vs 8%). Conversely, TBx added little to detection of csPC among men with PI-RADS 2 lesions (2%) relative to SBx (7.8%).

Conclusions: While combined Bx increases the detection of csPC among men with MRI-visible prostate lesions, this benefit was largely restricted to PI-RADS 3-4 lesions. Using a strategy of TBx only for PI-RADS 5 and combined Bx only for PI-RADS 3-4 would avoid excess biopsies for men with PI-RADS 5 lesions while resulting in a low risk of missing csPC (1%).

Patient Summary: Our study investigated an optimized strategy to diagnose aggressive prostate cancer in men with an abnormal prostate MRI (magnetic resonance imaging) scan while minimizing the risk of excess biopsies. We used a scoring system for MRI scan images called PI-RADS. The results show that MRI-targeted biopsies alone could be used for men with a PI-RADS score of 5, while men with a PI-RADS score of 3 or 4 would benefit from a combination of MRI-targeted biopsy and systematic biopsy. This trial is registered at ClinicalTrials.gov as NCT00102544.
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http://dx.doi.org/10.1016/j.euo.2021.03.004DOI Listing
April 2021

Nascent Prostate Cancer Heterogeneity Drives Evolution and Resistance to Intense Hormonal Therapy.

Eur Urol 2021 Mar 27. Epub 2021 Mar 27.

Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA. Electronic address:

Background: Patients diagnosed with high risk localized prostate cancer have variable outcomes following surgery. Trials of intense neoadjuvant androgen deprivation therapy (NADT) have shown lower rates of recurrence among patients with minimal residual disease after treatment. The molecular features that distinguish exceptional responders from poor responders are not known.

Objective: To identify genomic and histologic features associated with treatment resistance at baseline.

Design, Setting, And Participants: Targeted biopsies were obtained from 37 men with intermediate- to high-risk prostate cancer before receiving 6 mo of ADT plus enzalutamide. Biopsy tissues were used for whole-exome sequencing and immunohistochemistry (IHC).

Outcome Measurements And Statistical Analysis: We assessed the relationship of molecular features with final pathologic response using a cutpoint of 0.05 cm for residual cancer burden to compare exceptional responders to incomplete and nonresponders. We assessed intratumoral heterogeneity at the tissue and genomic level, and compared the volume of residual disease to the Shannon diversity index for each tumor. We generated multivariate models of resistance based on three molecular features and one histologic feature, with and without multiparametric magnetic resonance imaging estimates of baseline tumor volume.

Results And Limitations: Loss of chromosome 10q (containing PTEN) and alterations to TP53 were predictive of poor response, as were the expression of nuclear ERG on IHC and the presence of intraductal carcinoma of the prostate. Patients with incompletely and nonresponding tumors harbored greater tumor diversity as estimated via phylogenetic tree reconstruction from DNA sequencing and analysis of IHC staining. Our four-factor binary model (area under the receiver operating characteristic curve [AUC] 0.89) to predict poor response correlated with greater diversity in our cohort and a validation cohort of 57 Gleason score 8-10 prostate cancers from The Cancer Genome Atlas. When baseline tumor volume was added to the model, it distinguished poor response to NADT with an AUC of 0.98. Prospective use of this model requires further retrospective validation with biopsies from additional trials.

Conclusions: A subset of prostate cancers exhibit greater histologic and genomic diversity at the time of diagnosis, and these localized tumors have greater fitness to resist therapy.

Patient Summary: Some prostate cancer tumors do not respond well to a hormonal treatment called androgen deprivation therapy (ADT). We used tumor volume and four other parameters to develop a model to identify tumors that will not respond well to ADT. Treatments other than ADT should be considered for these patients.
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http://dx.doi.org/10.1016/j.eururo.2021.03.009DOI Listing
March 2021

Risk of adverse pathology at prostatectomy in the era of MRI and targeted biopsies; rethinking active surveillance for intermediate risk prostate cancer patients.

Urol Oncol 2021 Mar 15. Epub 2021 Mar 15.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany. Electronic address:

Purpose: Men with intermediate risk (IR) prostate cancer (CaP) are often excluded from active surveillance (AS) due to higher rates of adverse pathology (AP). We determined our rate of AP in men who underwent multiparametric MRI (MpMRI) with combined biopsy (CB) consisting of targeted biopsy (TB) and systematic biopsy (SB) prior to radical prostatectomy (RP).

Methods: A retrospective review was conducted of men with Gleason Grade Group (GG) 2 disease who underwent RP after SB alone or after preoperative MRI with CB. AP was defined as either pathologic stage T3a (AP ≥ T3a) or pathologic stage T3b (AP ≥ T3b) and/or GG upgrading. Rates of AP were determined for both groups and those who fit the National Comprehensive Cancer Network (NCCN) definition of favorable IR (FIR) or the low volume IR (LVIR) criteria. Multivariable logistic regression was used to determine predictive factors.

Results: The overall rate of AP ≥ T3b was 21.2% in the SB group vs. 8.6% in the MRI with CB group, P = 0.006. This rate was lowered to 6.8% and 5.6% when men met the definition of NCCN FIR or LVIR, respectively. Suspicion for extraprostatic extension (EPE) (OR 7.65, 95% CI 1.77-33.09, P = 0.006) and positive cores of GG 2 on SB (OR 1.43, 95% CI 1.05-1.96, P = 0.023) were significant for predicting AP ≥ T3b.

Conclusions: Rates of AP at RP after MRI with CB are lower than studies prior to the adoption of this technology, suggesting that more men with IR disease may be considered for AS. However, increasing cores positive on SB and MRI findings suggestive of EPE remain unsafe.
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http://dx.doi.org/10.1016/j.urolonc.2021.02.018DOI Listing
March 2021

Pilot study of gadoxetate disodium-enhanced mri for localized and metastatic prostate cancers.

Sci Rep 2021 Mar 11;11(1):5662. Epub 2021 Mar 11.

Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. Gadoxetate disodium is a substrate of OATP1B3, and its uptake has been shown to correlate with OATP1B3 expression in other cancers. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. A single center open-label non-randomized pilot study recruited men with (1) localized, and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3, NCTP and OATP1B1 was conducted. The mCRPC subgroup (n = 9) demonstrated significant enhancement compared to pre-contrast images at 20-, 40- and 60-min timepoints (p < 0.0078). The localized cancer subgroup (n = 11) demonstrated earlier enhancement compared to the mCRPC group, but no retention over time (p > 0.05). OATP1B3 expression on IHC trended higher contrast enhancement between 20-40 min (p ≤ 0.064) and was associated with contrast enhancement at 60 min (p = 0.0422). OATP1B1 haplotype, with N130D and V174A substitutions, impacted enhancement at 40-60 min (p ≤ 0.038). mCRPC lesions demonstrate enhancement after injection of gadoxetate disodium on MRI and retention over 60 min. As inter-individual variability in OATP1B3 expression and function has both predictive and prognostic significance, gadoxetate disodium has potential as a biomarker in prostate cancer.
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http://dx.doi.org/10.1038/s41598-021-84960-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952731PMC
March 2021

Reply by Authors.

J Urol 2021 05 11;205(5):1359-1360. Epub 2021 Mar 11.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1097/JU.0000000000001547.03DOI Listing
May 2021

Phase 1 study of Z-endoxifen in patients with advanced gynecologic, desmoid, and hormone receptor-positive solid tumors.

Oncotarget 2021 Feb 16;12(4):268-277. Epub 2021 Feb 16.

Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA.

Background: Differential responses to tamoxifen may be due to inter-patient variability in tamoxifen metabolism into pharmacologically active Z-endoxifen. Z-endoxifen administration was anticipated to bypass these variations, increasing active drug levels, and potentially benefitting patients responding sub-optimally to tamoxifen.

Materials And Methods: Patients with treatment-refractory gynecologic malignancies, desmoid tumors, or hormone receptor-positive solid tumors took oral Z-endoxifen daily with a 3+3 phase 1 dose escalation format over 8 dose levels (DLs). Safety, pharmacokinetics/pharmacodynamics, and clinical outcomes were evaluated.

Results: Thirty-four of 40 patients were evaluable. No maximum tolerated dose was established. DL8, 360 mg/day, was used for the expansion phase and is higher than doses administered in any previous study; it also yielded higher plasma Z-endoxifen concentrations. Three patients had partial responses and 8 had prolonged stable disease (≥ 6 cycles); 44.4% (8/18) of patients at dose levels 6-8 achieved one of these outcomes. Six patients who progressed after tamoxifen therapy experienced partial response or stable disease for ≥ 6 cycles with Z-endoxifen; one with desmoid tumor remains on study after 62 cycles (nearly 5 years).

Conclusions: Evidence of antitumor activity and prolonged stable disease are achieved with Z-endoxifen despite prior tamoxifen therapy, supporting further study of Z-endoxifen, particularly in patients with desmoid tumors.
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http://dx.doi.org/10.18632/oncotarget.27887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899551PMC
February 2021

Sodium Fluoride-18 and Radium-223 Dichloride Uptake Colocalize in Osteoblastic Mouse Xenograft Tumors.

Cancer Biother Radiopharm 2021 Mar 25;36(2):133-142. Epub 2021 Feb 25.

Molecular Imaging Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Patients with osteoblastic bone metastases are candidates for radium-223 (RaCl) therapy and may undergo sodium fluoride-18 (F-NaF) positron emission tomography-computed tomography imaging to identify bone lesions. F-NaF has been shown to predict RaCl uptake, but intratumor distributions of these two agents remain unclear. In this study, the authors evaluate the spatial distribution and relative uptakes of F-NaF and RaCl in Hu09-H3 human osteosarcoma mouse xenograft tumors at macroscopic and microscopic levels to better quantify their correlation. F-NaF and RaCl were co-injected into Hu09-H3 xenograft tumor severe combined immunodeficient mice. Tumor content was determined from biodistributions and visualized by PET, single photon emission computed tomography, and CT imaging. Intratumor distributions were visualized by quantitative autoradiography of tumor tissue sections and compared to histology of the same or adjacent sections. F and Ra accumulated in proportional amounts in whole Hu09-H3 tumors ( = 0.82) and in microcalcified regions within these tumors ( = 0.87). Intratumor distributions of F and Ra were spatially congruent in these microcalcified regions. F-NaF and RaCl uptake are strongly correlated in heterogeneously distributed microcalcified regions of Hu09-H3 xenograft tumors, and thus, tumor accumulation of F is predictive of Ra accumulation. Hu09-H3 xenograft tumors appear to possess certain histopathological features found in patients with metastatic bone disease and may be useful in clarifying the relationship between administered Ra dose and therapeutic effect.
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http://dx.doi.org/10.1089/cbr.2020.4068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994428PMC
March 2021

Rapid Depletion of Intratumoral Regulatory T Cells Induces Synchronized CD8 T- and NK-cell Activation and IFNγ-Dependent Tumor Vessel Regression.

Cancer Res 2021 Jun 11;81(11):3092-3104. Epub 2021 Feb 11.

Molecular Imaging Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Regulatory T cells (Tregs) are known to inhibit antitumor immunity, yet the specific mechanism by which intratumoral Tregs promote tumor growth remains unclear. To better understand the roles of intratumoral Tregs, we selectively depleted tumor-infiltrating Tregs using anti-CD25-F(ab') near-infrared photoimmunotherapy. Depletion of tumor-infiltrating Tregs induced transient but synchronized IFNγ expression in CD8 T and natural killer (NK) cells. Despite the small fraction of CD8 T and NK cells contained within examined tumors, IFNγ produced by these CD8 T and NK cells led to efficient and rapid tumor vessel regression, intratumoral ischemia, and tumor necrosis/apoptosis and growth suppression. IFNγ receptor expression on vascular endothelial cells was required for these effects. Similar findings were observed in the early phase of systemic Treg depletion in tumor-bearing mice; combination with IL15 therapy further inhibited tumor growth and achieved increased complete regression. These results indicate the pivotal roles of intratumoral Tregs in maintaining tumor vessels and tumor growth by suppressing CD8 T and NK cells from producing IFNγ, providing insight into the mechanism of Treg-targeting therapies. SIGNIFICANCE: Intratumoral Treg depletion induces synchronized intratumoral CD8 T- and NK-cell activation, IFNγ-dependent tumor vessel regression, and ischemic tumor necrosis/apoptosis, indicating the roles of intratumoral Tregs to support the tumor vasculature. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/3092/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178213PMC
June 2021

Pattern of failure in prostate cancer previously treated with radical prostatectomy and post-operative radiotherapy: a secondary analysis of two prospective studies using novel molecular imaging techniques.

Radiat Oncol 2021 Feb 10;16(1):32. Epub 2021 Feb 10.

Molecular Imaging Program, National Cancer Institute, 10 Center Drive Magnuson Clinical Center, Room B3B69F, Bethesda, MD, 20892, USA.

Background: Prostate Membrane Specific Antigen (PSMA) positron emission tomography (PET) and multiparametric MRI (mpMRI) have shown high accuracy in identifying recurrent lesions after definitive treatment in prostate cancer (PCa). In this study, we aimed to outline patterns of failure in a group of post-prostatectomy patients who received adjuvant or salvage radiation therapy (PORT) and subsequently experienced biochemical recurrence, using F-PSMA PET/CT and mpMRI.

Methods: PCa patients with biochemical failure post-prostatectomy, and no evident site of recurrence on conventional imaging, were enrolled on two prospective trials of first and second generation F-PSMA PET agents (F-DCFBC and F-DCFPyL) in combination with MRI between October 2014 and December 2018. The primary aim of our study is to characterize these lesions with respect to their location relative to previous PORT field and received dose.

Results: A total of 34 participants underwent F-PSMA PET imaging for biochemical recurrence after radical prostatectomy and PORT, with 32/34 found to have F-PSMA avid lesions. On F-PSMA, 17/32 patients (53.1%) had metastatic disease, 8/32 (25.0%) patients had locoregional recurrences, and 7/32 (21.9%) had local failure in the prostate fossa. On further exploration, we noted 6/7 (86%) of prostate fossa recurrences were in-field and were encompassed by 100% isodose lines, receiving 64.8-72 Gy. One patient had marginal failure encompassed by the 49 Gy isodose.

Conclusions: F-PSMA PET imaging demonstrates promise in identifying occult PCa recurrence after PORT. Although distant recurrence was the predominant pattern of failure, in-field recurrence was noted in approximately 1/5th of patients. This should be considered in tailoring radiotherapy practice after prostatectomy. Trial registration www.clinicaltrials.gov , NCT02190279 and NCT03181867. Registered July 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02190279 and June 8 2017, https://clinicaltrials.gov/ct2/show/NCT03181867 .
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http://dx.doi.org/10.1186/s13014-020-01733-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874470PMC
February 2021

Avelumab, a PD-L1 Inhibitor, in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma.

Oncologist 2021 04 10;26(4):288-e541. Epub 2021 Mar 10.

Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Lessons Learned: Despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma, subsequent clinical studies have been disappointing. Preclinical studies have suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T-cell exhaustion or senescence; however, in this small data set, radiotherapy with checkpoint inhibition did not appear to activate the antitumor immune response.

Background: Extramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof-of-principle pilot study to evaluate the synergy between the combination of the anti-PD-L1, avelumab, and concomitant hypofractionated radiotherapy.

Methods: This was a single-arm phase II Simon two-stage single center study that was prematurely terminated because of the COVID-19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect.

Results: At a median potential follow-up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression-free survival (PFS) was 5.3 months (95% confidence interval [CI]: 2.5-7.1 months), and no deaths occurred. There were no grade ≥3 and five grade 1-2 treatment-related adverse events.

Conclusion: Avelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens.
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http://dx.doi.org/10.1002/onco.13712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018315PMC
April 2021

Diagnostic imaging in near-infrared photoimmunotherapy using a commercially available camera for indocyanine green.

Cancer Sci 2021 Mar 5;112(3):1326-1330. Epub 2021 Feb 5.

Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Near-infrared photoimmunotherapy (NIR-PIT) is a new type of cancer treatment, which was recently approved in Japan for patients with inoperable head and neck cancer. NIR-PIT utilizes antibody-IRDye700DX (IR700) conjugates and NIR light at a wavelength of 690 nm. NIR light exposure leads to physicochemical changes in the antibody-IR700 conjugate cell receptor complex, inducing rapid necrotic cell death. Just as fluorescence guided surgery is useful for surgeons to resect tumors completely, real-time information of tumor locations would help clinicians irradiate NIR light more precisely. IR700 is a fluorescence dye that emits at 702 nm; however, there is no clinically available device optimized for detecting this fluorescence. On the other hand, many indocyanine green (ICG) fluorescence imaging devices have been approved for clinical use. Therefore, we investigated whether LIGHTVISION, one of the clinically available ICG cameras, could be employed for tumor detection. We hypothesized that irradiation with even low-power 690-nm laser light, attenuated by 99% with a neutral-density filter, could be detected with LIGHTVISION without fluorescence decay or therapeutic effect because of the long emission tail of IR700 beyond 800 nm (within the detection range of LIGHTVISION). We demonstrated that the LIGHTVISION camera, originally designed for ICG detection, can detect the tail of IR700 fluorescence in real time, thus enabling the visualization of target tumors.
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http://dx.doi.org/10.1111/cas.14809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935778PMC
March 2021

Federated learning improves site performance in multicenter deep learning without data sharing.

J Am Med Inform Assoc 2021 06;28(6):1259-1264

Department of Radiological Sciences, University of California, Los Angeles, Los Angeles, California, USA.

Objective: To demonstrate enabling multi-institutional training without centralizing or sharing the underlying physical data via federated learning (FL).

Materials And Methods: Deep learning models were trained at each participating institution using local clinical data, and an additional model was trained using FL across all of the institutions.

Results: We found that the FL model exhibited superior performance and generalizability to the models trained at single institutions, with an overall performance level that was significantly better than that of any of the institutional models alone when evaluated on held-out test sets from each institution and an outside challenge dataset.

Discussion: The power of FL was successfully demonstrated across 3 academic institutions while avoiding the privacy risk associated with the transfer and pooling of patient data.

Conclusion: Federated learning is an effective methodology that merits further study to enable accelerated development of models across institutions, enabling greater generalizability in clinical use.
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http://dx.doi.org/10.1093/jamia/ocaa341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200268PMC
June 2021

Fluorescence Imaging of Tumor-Accumulating Antibody-IR700 Conjugates Prior to Near-Infrared Photoimmunotherapy (NIR-PIT) Using a Commercially Available Camera Designed for Indocyanine Green.

Mol Pharm 2021 03 27;18(3):1238-1246. Epub 2021 Jan 27.

Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.

Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that uses antibody-IRDye700DX (IR700) conjugates and was recently approved in Japan for patients with inoperable head and neck cancer. Exposure of the tumor with NIR light at a wavelength of 690 nm leads to physicochemical changes in the antibody-IR700 conjugate-cell receptor complex, resulting in increased hydrophobicity and damage to the integrity of the cell membrane. However, it is important that the tumor be completely exposed to light during NIR-PIT, and thus, a method to provide real-time information on tumor location would help clinicians direct light more accurately. IR700 is a fluorophore that emits at 702 nm; however, there is no clinically available device optimized for detecting this fluorescence. On the other hand, many indocyanine green (ICG) fluorescence imaging devices have been approved for clinical use in operating rooms. Therefore, we investigated whether LIGHTVISION, one of the clinically available ICG cameras, could be employed for NIR-PIT target tumor detection. Due to the limited benefits of adding IR700 molecules, the additional conjugation of IRDye800CW (IR800) or ICG-EG4-Sulfo-OSu (ICG-EG4), which has an overlapping spectrum with ICG, to trastuzumab-IR700 conjugates was performed. Conjugation of second NIR dyes did not interfere the efficacy of NIR-PIT. The dual conjugation of IR800 and IR700 to trastuzumab clearly visualized target tumors with LIGHTVISION by detecting emission light of IR800. We demonstrated that the conjugation of second NIR dyes enables us to provide a real-time feedback of tumor locations prior to NIR-PIT.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c01107DOI Listing
March 2021

Tuberous Sclerosis Complex (TSC): Renal and Extrarenal Imaging.

Acad Radiol 2021 Jan 21. Epub 2021 Jan 21.

Department of Abdominal Imaging, Unit 1473, University of Texas MD Anderson Cancer Center; 1515 Holcombe Blvd, Houston, TX.; Department of Cancer Systems Imaging, Unit 1473, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX.

Tuberous sclerosis complex is a multiorgan syndrome manifesting with several benign and malignant tumors. Complications arising from renal abnormalities are a leading cause of death in patients with tuberous sclerosis complex. Renal cell carcinoma is relatively uncommon, occurring in 2%-4% of patients with tuberous sclerosis complex syndrome, but nonetheless can significantly contribute to morbidity and mortality. Extrarenal manifestations of tuberous sclerosis complex, including within the chest, abdomen and central nervous system, aid in diagnosis. Pathogenesis and management are also discussed, including the importance of the types of renal masses found in these patients.
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http://dx.doi.org/10.1016/j.acra.2020.12.019DOI Listing
January 2021
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