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Purpose: To explore the feasibility of imaging amino-acid transport and PSMA molecular pathways in the detection of metastatic breast invasive lobular carcinoma (ILC) and if there is superior detection compared to standard-of-care imaging [computed tomography (CT)/bone scan, or 18 F-FDG positron-emission-tomography (PET)-CT]., Methods: 20 women with de-novo or suspected metastatic ILC underwent two PET-CT scans with 18 F-fluciclovine and 68 Ga-PSMA-11 on separate days. Uptake per patient and in 3 regions per patient - ipsilateral axillary lymph node (LN), extra-axillary LN (ipsilateral supraclavicular or internal mammary), or distant sites of disease - was compared to standard-of-care imaging (CT/bone scan in 13 patients and 18 F-FDG PET-CT in 7 patients). Results were correlated to a composite standard of truth. Confirmed detection rate (cDR) was compared using McNemar's test. Mean SUVmax of 18 F-fluciclovine and 68 Ga-PSMA-11 in the most avid lesion for each true positive metastatic region and intact primary lesion were compared by t-test., Results: The cDR for standard-of-care imaging was 5/20 patients in 5/60 regions. 68 Ga-PSMA-11 PET-CT detected metastasis in 7/20 patients in 7/60 regions. 18 F-fluciclovine PET-CT detected metastasis in 9/20 patients in 12/60 regions. The cDR for 18 F-fluciclovine PET-CT was significantly higher versus standard-of-care imaging on the patient and combined region levels, while there were no significant differences between 68 Ga-PSMA-11 and standard-of care imaging. 18 F-fluciclovine cDR was also significantly higher than 68 Ga-PSMA-11 on the combined region level. Mean SUVmax for true positive metastatic and primary lesions with 18 F-fluciclovine (n = 18) was significantly greater than for 68 Ga-PSMA-11 (n = 11) [5.5 ± 1.8 versus 3.5 ± 2.7 respectively, p = 0.021]., Conclusion: In this exploratory trial, 18 F-fluciclovine PET-CT has a significantly higher cDR for ILC metastases compared to standard-of-care imaging and to 68 Ga-PSMA-11. Mean SUVmax for true positive malignancy was significantly higher with 18 F-fluciclovine than for 68 Ga-PSMA-11. Exploratory data from this trial suggests that molecular imaging of amino acid metabolism in patients with ILC deserves further study., Clinical Trial Registration: Early phase (I-II) clinical trial (NCT04750473) funded by the National Institutes of Health (R21CA256280)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Whole-pelvis (WP) radiation therapy (radiation) improved biochemical relapse-free survival (bRFS) compared with prostate bed (PB)-only radiation in the Radiation Therapy Oncology Group 0534, but was performed in an era prior to positron emission tomography (PET) staging. Separately, 18F-fluciclovine PET/CT-guided postprostatectomy radiation improved 3-year bRFS versus radiation guided by conventional imaging alone. We hypothesized that patients who were changed from WP to PB-only radiation after PET would have bRFS that was: (a) no higher than patients initially planned for PB-only radiation; and (b) lower than patients planned for WP radiation without PET guidance., Methods and Materials: We conducted a post hoc analysis of a prospective, randomized trial comparing conventional (arm 1) versus PET-guided (arm 2) postprostatectomy radiation. In arm 2, pre-PET treatment field decisions were recorded and post-PET fields were defined per protocol; pathologic node negative (pN0) without pelvic or extrapelvic PET uptake received PB-only radiation. Three-year bRFS was compared in patients planned for WP with change to PB-only radiation (arm 2 [WP:PB]) vs arm 2 patients planned for PB-only with final radiation to PB-only (arm 2 [PB:PB]) and arm 1 pN0 patients treated with WP radiation (arm 1 [WP]) using the Z test and log-rank test. Demographics were compared using the chi-square test, Fisher exact test, or analysis of variance, as appropriate., Results: We identified 10 arm 2 (WP:PB), 31 arm 2 (PB:PB) and 11 arm 1 (WP) patients. Androgen deprivation was used in 50.0% of arm 2 (WP:PB) and 3.2% of arm 2 (PB:PB) patients, P < .01. Median preradiation prostate-specific antigen was higher in arm 2 (WP:PB) vs arm 2 (PB:PB) patients (0.4 vs 0.2 ng/mL, P = .03); however, there were no significant differences in T stage, Gleason score, or margin positivity. Three-year bRFS was 80% in arm 2 (WP:PB) vs 87.4% in arm 2 (PB:PB), P = .47, respectively. Arm 1(WP) patients had significantly worse 3-year (23%) bRFS vs arm 2 (WP:PB), P < .01., Conclusions: Patients initially planned for WP radiation with field decision change to PB-only radiation after PET showed (1) no significant difference in 3-year bRFS compared with patients initially planned for PB-only radiation; and (2) improved bRFS compared with patients receiving WP radiation without PET guidance. PET-guided volume de-escalation in selected patients may be 1 approach to mitigating toxicity without compromising outcomes., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Including poly(ADP-ribose) polymerase (PARP) inhibitors in managing patients with inoperable tumors has significantly improved outcomes. The PARP inhibitors hamper single-strand deoxyribonucleic acid (DNA) repair by trapping poly(ADP-ribose)polymerase (PARP) at sites of DNA damage, forming a non-functional "PARP enzyme-inhibitor complex" leading to cell cytotoxicity. The effect is more pronounced in the presence of PARP upregulation and homologous recombination (HR) deficiencies such as breast cancer-associated gene ( BRCA1/2 ). Hence, identifying HR-deficiencies by genomic analysis-for instance, BRCA1/2 used in triple-negative breast cancer-should be a part of the selection process for PARP inhibitor therapy. Published data suggest BRCA1/2 germline mutations do not consistently predict favorable responses to PARP inhibitors, suggesting that other factors beyond tumor mutation status may be at play. A variety of factors, including tumor heterogeneity in PARP expression and intrinsic and/or acquired resistance to PARP inhibitors, may be contributing factors. This justifies the use of an additional tool for appropriate patient selection, which is noninvasive, and capable of assessing whole-body in vivo PARP expression and evaluating PARP inhibitor pharmacokinetics as complementary to the currently available BRCA1/2 analysis. In this review, we discuss [ 18 F]Fluorine PARP inhibitor radiotracers and their potential in the imaging of PARP expression and PARP inhibitor pharmacokinetics. To provide context we also briefly discuss possible causes of PARP inhibitor resistance or ineffectiveness. The discussion focuses on TNBC, which is a tumor type where PARP inhibitors are used as part of the standard-of-care treatment strategy.

Theranostics with radioligands (radiotheranostics) has played a pivotal role in oncology. Radiotheranostics explores the molecular targets expressed on tumor cells to target them for imaging and therapy. In this way, radiotheranostics entails non-invasive demonstration of the in vivo expression of a molecular target of interest through imaging followed by the administration of therapeutic radioligand targeting the tumor-expressed molecular target. Therefore, radiotheranostics ensures that only patients with a high likelihood of response are treated with a particular radiotheranostic agent, ensuring the delivery of personalized care to cancer patients. Within the last decades, a couple of radiotheranostics agents, including Lutetium-177 DOTATATE ( 177 Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen ( 177 Lu-PSMA), were shown to prolong the survival of cancer patients compared to the current standard of care leading to the regulatory approval of these agents for routine use in oncology care. This recent string of successful approvals has broadened the interest in the development of different radiotheranostic agents and their investigation for clinical translation. In this work, we present an updated appraisal of the literature, reviewing the recent advances in the use of established radiotheranostic agents such as radioiodine for differentiated thyroid carcinoma and Iodine-131-labeled meta-iodobenzylguanidine therapy of tumors of the sympathoadrenal axis as well as the recently approved 177 Lu-DOTATATE and 177 Lu-PSMA for differentiated neuroendocrine tumors and advanced prostate cancer, respectively. We also discuss the radiotheranostic agents that have been comprehensively characterized in preclinical studies and have shown some clinical evidence supporting their safety and efficacy, especially those targeting fibroblast activation protein (FAP) and chemokine receptor 4 (CXCR4) and those still being investigated in preclinical studies such as those targeting poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor 2., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Actinium-225 ( 225 Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225 Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world., Methods: This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225 Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 ( 177 Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival., Findings: Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225 Ac-PSMA RLT (median two cycles, IQR 2-4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6-519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177 Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0-17·5). The median overall survival was 15·5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225 Ac-PSMA RLT. All patients who received more than seven cycles of 225 Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded., Interpretation: 225 Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events., Funding: None., Competing Interests: Declaration of interests MMS reports grants or contracts from Novartis; payment or honoraria from Bayer, Johnson & Johnson, NTP, and Sanofi; support for attending meetings from the International Atomic Energy Agency; and receipt of equipment or materials from POINT Biopharma. ME reports grants or contracts from Blue Earth Diagnostics; royalties from patent on radiohybrid PSMA; consulting fees from Novartis, Point Biopharma, payment from Novartis; payment for expert testimony from Novartis, Bayer, Telix, and Blue Earth Diagnostics; support for attending meetings from Blue Earth Diagnostics; and patent ownership on radiohybrid PSMA. TH reports grants or contracts from Siemens. CK reports patent ownership. NPL reports contracts from Telix, Ipsen/Ariceum, and Clarity; receipt of educational material from Telix; support for attending meetings from Telix; participation on the advisory board of Telix; and family stock ownership at Clarity. ASi reports support for attending meetings from Telix International, Australia and participation on Data Safety Monitoring Borad for Telix International. RT reports payment or honoraria from Astella, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck, MSD, Novartis, Orion, Pfizer, Roche, and Sanofi; support for attending meetings from Bayer, Janssen, Orion, Pfizer, and Roche; participation on Data Safety Monitoring Board or Advisory Board of Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisei, EUSA, IPSEN, Janssen, Merck, MSD, Novartis, Orion, Pfizer, Philogen, Roche, and Sanofi; stock ownership at Bayer; and financial or non-financial interests at Thieme compliance and Elsevier. AM reports patents owning a patent for treatment of PSMA-expressing cancers. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Breast cancer is the most frequently diagnosed cancer and leading cause of cancer-related deaths worldwide. Timely decision-making that enables implementation of the most appropriate therapy or therapies is essential for achieving the best clinical outcomes in breast cancer. While clinicopathologic characteristics and immunohistochemistry have traditionally been used in decision-making, these clinical and laboratory parameters may be difficult to ascertain or be equivocal due to tumor heterogeneity. Tumor heterogeneity is described as a phenomenon characterized by spatial or temporal phenotypic variations in tumor characteristics. Spatial variations occur within tumor lesions or between lesions at a single time point while temporal variations are seen as tumor lesions evolve with time. Due to limitations associated with immunohistochemistry (which requires invasive biopsies), whole-body molecular imaging tools such as standard-of-care [ 18 F]FDG and [ 18 F]FES PET/CT are indispensable in addressing this conundrum. Despite their proven utility, these standard-of-care imaging methods are often unable to image a myriad of other molecular pathways associated with breast cancer. This has stimulated interest in the development of novel radiopharmaceuticals targeting other molecular pathways and processes. In this review, we discuss validated and potential roles of these standard-of-care and novel molecular approaches. These approaches' relationships with patient clinicopathologic and immunohistochemical characteristics as well as their influence on patient management will be discussed in greater detail. This paper will also introduce and discuss the potential utility of novel PARP inhibitor-based radiopharmaceuticals as non-invasive biomarkers of PARP expression/upregulation.

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed in the majority of prostate cancer (PCa). PSMA has an enzymatic function that makes metabolic substrates such as folate available for utilization by PCa cells. Intracellular folate availability drives aggressive tumor phenotype. PSMA expression is, therefore, a marker of aggressive tumor biology. The large extracellular domain of PSMA is available for targeting by diagnostic and therapeutic radionuclides, making it a suitable cellular epitope for theranostics. PET imaging of radiolabeled PSMA ligands has several prognostic utilities. In the prebiopsy setting, intense PSMA avidity in a prostate lesion correlate well with clinically significant PCa (csPCa) on histology. When used for staging, PSMA PET imaging outperforms conventional imaging for the accurate staging of primary PCa, and findings on imaging predict post-treatment outcomes. The biggest contribution of PSMA PET imaging to PCa management is in the biochemical recurrence setting, where it has emerged as the most sensitive imaging modality for the localization of PCa recurrence by helping to guide salvage therapy. PSMA PET obtained for localizing the site of recurrence is prognostic, such that a higher lesion number predicts a less favorable outcome to salvage radiotherapy or surgical intervention. Systemic therapy is given to patients with advanced PCa with distant metastasis. PSMA PET is useful for predicting response to treatments with chemotherapy, first- and second-line androgen deprivation therapies, and PSMA-targeted radioligand therapy. Artificial intelligence using machine learning algorithms allows for the mining of information from clinical images not visible to the human eyes. Artificial intelligence applied to PSMA PET images, therefore, holds great promise for prognostication in PCa management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53 , FLT4 , EYA1 , NCOR2 , CSMD3 , and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1 , CSMD3 , FLT4 , NCOR2 , and PCDH15 and found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer.

Abstract: 68 Ga-prostate-specific membrane antigen (PSMA) PET/CT is a valuable tool for staging and restaging of prostate cancer. Prostate-specific membrane antigen expression is not specific to prostate cancer, as it is expressed in normal tissues as well as in neoplastic and nonneoplastic processes. Awareness of the broad possibility of lesions with PSMA avidity is necessary to recognize normal variants and avoid potential pitfalls in image interpretation. We present a series of cases showing physiologic focal PSMA avidity in hepatic segment IVb. We correlate this uptake with aberrant hepatic vasculature. The awareness of this variant is important for accurate image interpretation to prevent additional invasive procedures, undue treatment escalation, and denial of curative treatment to patients., Competing Interests: Conflicts of interest and sources of funding: none declared. Telix Pharmaceuticals (US) Inc provided the prostate-specific membrane antigen cold kits used in the trial. The EMPIRE-2 trial is funded by NIH (R01CA226992). The authors have no conflicts to report., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Hypoxia leads to changes in tumor microenvironment (upregulated CAFs) with resultant aggressiveness. A key factor in the physiological response to hypoxia is hypoxia-inducible factor-1alpha (HIF-1α). [ 68 Ga]Ga-FAPI PET imaging has been demonstrated in various cancer types. We hypothesized that [ 68 Ga]Ga-FAPI PET may be used as an indirect tracer for mapping hypoxia by correlating the image findings to pathological analysis of HIF-1α expression. The [ 68 Ga]Ga-FAPI PET/CT scans of women with cancer of the cervix were reviewed and the maximum and mean standardized uptake value (SUVmax and SUVmean) and FAPI tumor volume (FAPI-TV) were documented. Correlation analysis was performed between PET-derived parameters and immunohistochemical staining as well as between PET-derived parameters and the presence of metastasis. Ten women were included. All patients demonstrated tracer uptake in the primary site or region of the primary. All patients had lymph node metastases while only six patients had distant visceral or skeletal metastases. The mean SUVmax, SUVmean, and FAPI-TV was 18.89, 6.88, and 195.66 cm 3 , respectively. The average FAPI-TV for patients with additional sites of metastases was higher than those without. Immunohistochemistry revealed varying intensities of HIF-1α expression in all tested samples. There was a positive correlation between the presence of skeletal metastases and staining for HIF-1α (r=0.80;p=0.017). The presence of skeletal metastasis was correlated to the HIF-1⍺ staining (percentage distribution). Furthermore, the FAPI-TV was a better predictor of metastatic disease than the SUVmax.

Purpose: 225 Ac-PSMA-617 has demonstrated good anti-tumor effect as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) patients. No study has previously assessed treatment outcome and survival following 225 Ac-PSMA-617 treatment of de novo metastatic hormone-sensitive prostate carcinoma (mHSPC) patients. Based on the potential side effects that are known and explained to the patients by the oncologist, some of the patients refused the standard treatment and are seeking alternative therapies. Thus, we report our preliminary findings in a retrospective series of 21 mHSPC patients that refused standard treatment options and were treated with 225 Ac-PSMA-617., Methods: We retrospectively reviewed patients with histologically confirmed de novo treatment-naïve bone ± visceral mHSPC that were treated with 225 Ac-PSMA-617 radioligand therapy (RLT). Inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, treatment-naive bone ± visceral mHSPC, and patients refusal for ADT ± docetaxel, abiraterone acetate, or enzalutamide. We evaluated the response to treatment using prostate-specific antigen (PSA) response and the progression-free survival (PFS) and overall survival (OS) as well as the toxicities., Results: Twenty-one mHSPC patients were included in this preliminary work. Following treatment, twenty patients (95%) had any decline in PSA and eighteen patients (86%) presented with a PSA decline of ≥ 50% including 4 patients in whom PSA became undetectable. A lower percentage decrease in PSA following treatment was associated with increased mortality and shorter progression-free survival. Overall, administration of 225 Ac-PSMA-617 was well tolerated. The commonest toxicity seen was grade I/II dry mouth observed in 94% of patients., Conclusions: Given these favorable results, randomized prospective multicenter trials assessing the clinical value of 225 Ac-PSMA-617 as a therapeutic agent for mHSPC administered either as monotherapy or administered concomitant with ADT are of interest., (© 2023. The Author(s).)

Purpose: We aimed to evaluate the impact of 18 F-fluciclovine PET/CT imaging on failure-free survival (FFS) post-salvage radiotherapy (SRT) for prostate cancer (PCa) recurrence., Methods: Seventy-nine patients were recruited in a phase 2/3 clinical trial to undergo 18 F-fluciclovine PET/CT before SRT for PCa. Four patients with extrapelvic disease were excluded. All patients were followed up at regular intervals up to 48 months. Treatment failure was defined as a serum prostate-specific antigen level of ≥0.2 ng/mL above the nadir after SRT, confirmed with an additional measurement, requiring systemic treatment or clinical progression. Failure-free survival was computed and compared between patients grouped according to 18 F-fluciclovine PET/CT imaging findings., Results: Eighty percent (60/75) of patients had a positive finding on 18 F-fluciclovine PET/CT, of which 56.7% (34/60) had prostate bed-only uptake, whereas 43.3% (26/60) had pelvic nodal ± bed uptake. Following SRT, disease failure was detected in 36% (27/75) of patients. There was a significant difference in FFS between patients who had a positive versus negative scan (62.3% vs 92.9% [ P < 0.001] at 36 months and 59.4% vs 92.9% [ P < 0.001] at 48 months). Similarly, there was a significant difference in FFS between patients with uptake in pelvic nodes ± bed versus prostate bed only at 36 months (49.8% vs 70.7%; P = 0.003) and at 48 months (49.8% vs 65.6%; P = 0.040). Failure-free survival was also significantly higher in patients with either negative PET/CT or prostate bed-only disease versus those with pelvic nodal ± prostate bed disease at 36 (78% vs 49.8%, P < 0.001) and 48 months (74.4% vs 49.8%, P < 0.001)., Conclusions: Findings on pre-SRT 18 F-fluciclovine PET/CT imaging, even when acted upon to optimize the treatment decisions and treatment planning, are predictive of post-SRT FFS in men who experience PCa recurrence after radical prostatectomy. A negative 18 F-fluciclovine PET/CT is most predictive of a lower risk of failure, whereas the presence of pelvic nodal recurrence portends a higher risk of SRT failure., Competing Interests: Conflicts of interest and sources of funding: A.B.J. reports personal fees from Blue Earth Diagnostics for advisory board services outside the submitted work. M.G. is entitled to a royalty derived from sale of products related to the research described in this report. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. The research consent forms state that he is entitled to a share of sales royalty received by Emory University from Nihon MediPhysics under that agreement. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. D.M.S. participates through the Emory University Office of Sponsored Projects in sponsored grants including those funded or partially funded by Blue Earth Diagnostics, Nihon MediPhysics, Telix Pharmaceuticals (US), Advanced Accelerator Applications, FUJIFILM Pharmaceuticals USA, and Amgen. D.M.S. also reports consultant fees outside the submitted work from Syncona, AIM Specialty Health, Global Medical Solutions Taiwan, and Progenics Pharmaceuticals. The other authors declare no competing interests. The EMPIRE-1 trial received funding from the National Institutes of Health/National Cancer Institute (R01 CA16918), Blue Earth Diagnostics, Ltd, and the Winship Cancer Institute of Emory University., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The EMPIRE-1 (Emory Molecular Prostate Imaging for Radiotherapy Enhancement 1) trial reported a survival advantage in recurrent prostate cancer salvage radiotherapy (SRT) guided by 18 F-fluciclovine PET/CT versus conventional imaging. We performed a post hoc analysis of the EMPIRE-1 cohort stratified by protocol-specified criteria, comparing failure-free survival (FFS) between study arms. Methods: EMPIRE-1 randomized patients to SRT planning via either conventional imaging only (bone scanning plus abdominopelvic CT or MRI) (arm A) or conventional imaging plus 18 F-fluciclovine PET/CT (arm B). Randomization was stratified by prostate-specific antigen (PSA) level (<2.0 vs. ≥ 2.0 ng/mL), adverse pathology, and androgen-deprivation therapy (ADT) intent. We subdivided patients in each arm using the randomization stratification criteria and compared FFS between patient subgroups across study arms. Results: Eighty-one and 76 patients received per-protocol SRT in study arms A and B, respectively. The median follow-up was 3.5 y (95% CI, 3.0-4.0). FFS was 63.0% and 51.2% at 36 and 48 mo, respectively, in arm A and 75.5% at both 36 and 48 mo in arm B. Among patients with a PSA of less than 2 ng/mL (mean, 0.42 ± 0.42 ng/mL), significantly higher FFS was seen in arm B than arm A at 36 mo (83.2% [95% CI, 70.0-91.0] vs. 66.5% [95% CI, 51.6-77.8], P < 0.001) and 48 mo (83.2% [95% CI, 70.0-91.0] vs. 56.2% [95% CI, 40.5-69.2], P < 0.001). No significant difference in FFS between study arms in patients with a PSA of at least 2 ng/mL was observed. Among patients with adverse pathology, significantly higher FFS was seen in arm B than arm A at 48 mo (68.9% [95% CI, 52.1-80.8] vs. 42.8% [95% CI, 26.2-58.3], P < 0.001) though not at the 36-mo follow-up. FFS was higher in patients without adverse pathology in arm B versus arm A (90.2% [95% CI, 65.9-97.5] vs. 73.1% [95% CI, 42.9-89.0], P = 0.006) at both 36 and 48 mo. Patients in whom ADT was intended in arm B had higher FFS than those in arm A, with the difference reaching statistical significance at 48 mo (65.2% [95% CI, 40.3-81.7] vs. 29.1 [95% CI, 6.5-57.2], P < 0.001). Patients without ADT intent in arm B had significantly higher FFS than patients in arm A at 36 mo (80.7% [95% CI, 64.9-90.0] vs. 68.0% [95% CI, 51.1-80.2]) and 48 mo (80.7% [95% CI, 64.9-90.0] vs. 58.6% [95% CI, 41.0-72.6]). Conclusion: The survival advantage due to the addition of 18 F-fluciclovine PET/CT to SRT planning is maintained regardless of the presence of adverse pathology or ADT intent. Including 18 F-fluciclovine PET/CT to SRT leads to survival benefits in patients with a PSA of less than 2 ng/mL but not in patients with a PSA of 2 ng/mL or higher., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Abstract: A 62-year-old woman with right-sided invasive lobular breast carcinoma completed external beam radiotherapy 6 weeks before undergoing a 68 Ga-PSMA PET/CT and 18 F-fluciclovine PET/CT scan as part of an ongoing clinical trial (NCT04750473) assessing the performance of these molecular imaging modalities in invasive lobular breast carcinoma. The 68 Ga-PSMA PET/CT demonstrated a band-like area of increased radiotracer uptake in the dome of the right lobe of the liver anteriorly, whereas 18 F-fluciclovine PET/CT done a day later revealed photopenia in the corresponding area of the liver. The external beam radiotherapy plan confirmed that the radiotherapy field overlaid the region of the hepatic discordant radiotracer uptake on the PET/CT scans., Competing Interests: Conflicts of interest and sources of funding: Fluciclovine doses were provided by Blue Earth Diagnostics, Inc. PSMA-11 cold kits were provided by Telix Pharmaceuticals (US) Inc. Study funded by NIH R21CA256280., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Despite the introduction of many novel diagnostic techniques and newer treatment agents, tuberculosis (TB) remains a major cause of death from an infectious disease worldwide. With about a quarter of humanity harboring Mycobacterium tuberculosis, the causative agent of TB, the current efforts geared towards reducing the scourge due to TB must be sustained. At the same time, newer alternative modalities for diagnosis and treatment response assessment are considered. Molecular imaging entails the use of radioactive probes that exploit molecular targets expressed by microbes or human cells for imaging using hybrid scanners that provide both anatomic and functional features of the disease being imaged. Fluorine-18 fluorodeoxyglucose (FDG) is the most investigated radioactive probe for TB imaging in research and clinical practice. When imaged with positron emission tomography interphase with computed tomography (PET/CT), FDG PET/CT performs better than sputum conversion for predicting treatment outcome. At the end of treatment, FDG PET/CT has demonstrated the unique ability to identify a subset of patients declared cured based on the current standard of care but who still harbor live bacilli capable of causing disease relapse after therapy discontinuation. Our understanding of the pathogenesis and evolution of TB has improved significantly in the last decade, owing to the introduction of FDG PET/CT in TB research. FDG is a non-specific probe as it targets the host inflammatory response to Mycobacterium tuberculosis, which is not specifically different in TB compared with other infectious conditions. Ongoing efforts are geared towards evaluating the utility of newer probes targeting different components of the TB granuloma, the hallmark of TB lesions, including hypoxia, neovascularization, and fibrosis, in TB management. The most exciting category of non-FDG PET probes developed for molecular imaging of TB appears to be radiolabeled anti-tuberculous drugs for use in studying the pharmacokinetic characteristics of the drugs. This allows for the non-invasive study of drug kinetics in different body compartments concurrently, providing an insight into the spatial heterogeneity of drug exposure in different TB lesions. The ability to repeat molecular imaging using radiolabeled anti-tuberculous agents also offers an opportunity to study the temporal changes in drug kinetics within the different lesions during treatment., (Published by Elsevier Inc.)

Over the last decades, the population at risk for invasive fungal disease (IFD) has increased because of medical therapy advances and diseases compromising patients' immune systems. The high morbidity and mortality associated with invasive fungal disease in the immunocompromised present the challenge of early diagnosis of the IFD and the need to closely monitor the infection during treatment. The definitive diagnosis of invasive fungal disease based on culture or histopathological methods often has reduced diagnostic accuracy in the immunocompromised and may be very invasive. Less invasive and indirect evidence of the fungal infection by serology and imaging has been used for the early diagnosis of fungal infection before definitive results are available or when the definitive methods of diagnosis are suboptimal. Imaging in invasive fungal disease is a non-invasive biomarker that helps in the early diagnosis of invasive fungal disease but helps follow-up the infection during treatment. Different imaging modalities are used in the workup to evaluate fungal disease. The different imaging modalities have advantages and disadvantages at different sites in the body and may complement each other in the management of IFD. Positron emission tomography integrated with computed tomography with [18F]Fluorodeoxyglucose (FDG PET/CT) has helped manage IFD. The combined functional data from PET and anatomical data from the CT from almost the whole body allows noninvasive evaluation of IFD and provides a semiquantitative means of assessing therapy. FDG PET/CT adds value to anatomic-based only imaging modalities. The nonspecificity of FDG uptake has led to the evaluation of other tracers in the assessment of IFD. However, these are mainly still at the preclinical level and are yet to be translated to humans. FDG PET/CT remains the most widely evaluated radionuclide-based imaging modality in IFD management. The limitations of FDG PET/CT must be well understood, and more extensive prospective studies in uniform populations are needed to validate its role in the management of IFD that can be international guidelines., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Abstract: A 41-year-old woman with invasive lobular carcinoma of the breast underwent sequential 68Ga-PSMA-11 PET/CT and 18F-fluciclovine PET/CT as part of an ongoing clinical trial (NCT04750473). 68Ga-PSMA PET/CT showed increased radiotracer uptake in the uterine endometrium and left adnexa. 18F-fluciclovine PET/CT showed increased radiotracer uptake in a leiomyomatous uterus. A clinical 18F-FDG PET/CT demonstrated radiotracer uptake in the endometrium and a circumferential area of uptake in the left adnexa, a pattern more similar to the 68Ga-PSMA uptake pattern. This case highlights the discordance in the uptake pattern of 2 radiotracers approved for prostate cancer imaging but increasingly used in non-prostate malignancies imaging., Competing Interests: Conflicts of interest and sources of funding: The authors declare that they have no conflicts of interest. Fluciclovine doses were provided by Blue Earth Diagnostics, Inc. PSMA-11 cold kits were provided by Telix Pharmaceuticals (US) Inc. The study was funded by NIH R21CA256280., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

225 Ac-PSMA-617, targeting the prostate-specific membrane antigen (PSMA), which is overexpressed on prostate cancer cells, has shown a remarkable therapeutic efficacy in heavily pretreated patients with metastatic castration-resistant prostate carcinoma (mCRPC). Here, we report on treatment outcome and survival using this novel treatment modality in a series of 53 patients with mCRPC directly after their androgen deprivation treatment (ADT). Methods: 225 Ac-PSMA-617 was administered to 53 such patients. 68 Ga-PSMA PET/CT was obtained at baseline, before every treatment cycle, and on follow-up to select patients for treatment, determine the activity to be administered, and assess their response. Serial prostate-specific antigen (PSA) measurements were obtained for response assessment. Results: The median age of the patients was 63.4 y (range, 45-83 y). In total, 167 cycles were administered (median, 3; range, 1-7). Forty-eight patients (91%) had a PSA decline of at least 50%, and 51 patients (96%) had any decline in PSA. 68 Ga-PSMA PET findings became negative in 30 patients. In the multivariate analysis, a PSA decline of at least 50% proved predictive of both progression-free survival (PFS) and overall survival (OS), and platelet count also proved predictive for PFS. The median estimated OS was 9 mo for patients with a PSA decline of less than 50% but was not yet reached at the latest follow-up (55 mo) for patients with a PSA decline of 50% or more. The estimated median PFS was 22 mo for patients with a PSA decline of at least 50% and 4 mo for patients with a PSA decline of less than 50%. No severe hematotoxicity was noted, and only 3 patients had grade III-IV nephrotoxicity. The commonest toxicity seen was grade I-II xerostomia, observed in 81% of patients. Conclusion: In 91% of 53 patients with mCRPC, treatment with 225 Ac-PSMA-617 immediately after ADT resulted in at least a 50% decrease in PSA level. Furthermore, a PSA decline of at least 50% proved the single most important factor predicting PFS and OS after 225 Ac-PSMA-617 treatment. Of interest, median OS in patients with a PSA decline of at least 50% was not yet reached at the latest follow-up (55 mo). These favorable results suggest that it would be of major clinical relevance to perform a prospective randomized study comparing 225 Ac-PSMA-617 with current standard-of-care treatment options such as enzalutamide, abiraterone acetate, and docetaxel after ADT., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Actinium-225-labeled prostate-specific membrane antigen ([ 225 Ac]Ac-PSMA-617) is safe and effective in the treatment of metastatic castration-resistant prostate cancer (mCRPC). No study has specifically assessed its safety in patients with extensive skeletal metastases of mCRPC. We aimed to investigate the hematologic toxicity and efficacy of [ 225 Ac]Ac-PSMA-617 therapy in patients with extensive skeletal metastases of mCRPC., Methods: We retrospectively reviewed the medical record of patients treated with [ 225 Ac]Ac-PSMA-617 for mCRPC. We included patients with a superscan pattern of skeletal metastases and those with 20 or more multifocal sites of skeletal metastases on baseline [ 68  Ga]Ga-PSMA-11 PET/CT. We reviewed the levels of hemoglobin, white blood cell (WBC), and platelet prior to each cycle of treatment and determined the presence of impaired bone marrow function at baseline and the grade of toxicity in the hematologic parameters induced by treatment. We evaluated the predictors of hematologic toxicity using binary logistic regression analysis. We also determined the presence of renal dysfunction before or during treatment. We assessed response to treatment using prostate-specific antigen response and the progression-free survival (PFS) and overall survival (OS)., Results: A total of 106 patients were included. Skeletal metastasis was in the superscan pattern in 34 patients (32.1%) and multifocal in 72 patients (67.9%). The median treatment cycle was 4 (range = 1-9). Ninety-eight patients (92.5%) had abnormal baseline hematologic parameters. One patient had grade 4 thrombocytopenia. Grade 3 anemia, leukopenia, and thrombocytopenia were seen in 1 (0.9%), 3 (2.8%), and 2 (1.9%) patients, respectively. Age, the number of treatment cycles, and the presence of renal dysfunction were significant predictors of hematologic toxicity. Eighty-five patients (80.2%) achieved PSA response. The median PFS and OS of the study population were 14:00 (95%CI: 8.15-19.86) months and 15.0 (95%CI: 12.8-17.2) months, respectively., Conclusions: [ 225 Ac]Ac-PSMA-617 induces a good anti-tumor effect in about 80% of patients with extensive skeletal metastases of mCRPC with a rare incidence of severe hematologic toxicity. Age, number of treatment cycles, and the presence of renal dysfunction were significant risk factors for hematologic toxicity of [ 225 Ac]Ac-PSMA-617 therapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: This study aimed to determine the correlation of [ 68 Ga]Ga-NODAGA ZOL uptake in atherosclerotic plaques and the cardiovascular risk profile of patients imaged with positron emission tomography (PET), wherein quantification of uptake was determined by atherosclerotic plaque maximum target-to-background ratio (TBRmax). We also correlated uptake with a history of cardiovascular events., Methods: We included patients who underwent PET/CT imaging post-injection of [ 68 Ga] Ga-NODAGA ZOL . We documented the number of atherosclerotic plaques found in the major arteries on CT and the cardiovascular risks in each patient. We quantified the intensity of tracer uptake in atherosclerotic plaque in the major arteries using the maximum standardized uptake value (SUVmax). The SUVmax of the most tracer-avid plaque was documented as representative of the individual arterial bed. We determined background vascular tracer activity using the mean standardized uptake value (SUVmean) obtained from the lumen of the superior vena cava. The maximum target-to-background ratio (TBRmax) was calculated as a ratio of the SUVmax to the SUVmean. The TBRmax was correlated to the number of atherogenic risk factors and history of cardiovascular events., Results: Thirty-four patients (M: F 31:3; mean age ± SD: 63 ± 10.01 years) with ≥ 2 cardiovascular risk factors were included. Statistically significant correlation between TBRmax and the number of cardiovascular risk factors was noted in the right carotid (r = 0.50; p < 0.05); left carotid (r = 0. 649; p < 0.05); ascending aorta (r = 0.375; p < 0.05); aortic arch (r = 0.483; p < 0.05); thoracic aorta (r = 0.644; p < 0.05); left femoral (r = 0.552; p < 0.05) and right femoral arteries (r = 0.533; p < 0.05). TBRmax also demonstrated a positive correlation to history of cardiovascular event in the right carotid (U = 26.00; p < 0.05); left carotid (U = 11.00; p < 0.05); ascending aorta (U = 49.00; p < 0.05); aortic arch (U = 37.00; p < 0.05); thoracic aorta (U = 16.00; p < 0.05); left common iliac (U = 49.500; p < 0.05), right common iliac (U = 43.00; p < 0.05), left femoral (U = 40.500; p < 0.05) and right femoral (U = 37.500; p < 0.05)., Conclusion: In this cohort of patients, a positive correlation was noted between atherosclerotic plaque uptake of [ 68 Ga]Ga-NODAGA ZOL and the number of atherogenic risk factors which translates to the risk of atherosclerosis and cardiovascular risk factors., (© 2022. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Severe acute respiratory coronavirus-2 (SARS-Co-2) is the causative agent of coronavirus disease-2019 (COVID-19). COVID-19 is a disease with highly variable phenotypes, being asymptomatic in most patients. In symptomatic patients, disease manifestation is variable, ranging from mild disease to severe and critical illness requiring treatment in the intensive care unit. The presence of underlying cardiovascular morbidities was identified early in the evolution of the disease to be a critical determinant of the severe disease phenotype. SARS-CoV-2, though a primarily respiratory virus, also causes severe damage to the cardiovascular system, contributing significantly to morbidity and mortality seen in COVID-19. Evidence on the impact of cardiovascular disorders in disease manifestation and outcome of treatment is rapidly emerging. The cardiovascular system expresses the angiotensin-converting enzyme-2, the receptor used by SARS-CoV-2 for binding, making it vulnerable to infection by the virus. Systemic perturbations including the so-called cytokine storm also impact on the normal functioning of the cardiovascular system. Imaging plays a prominent role not only in the detection of cardiovascular damage induced by SARS-CoV-2 infection but in the follow-up of patients' clinical progress while on treatment and in identifying long-term sequelae of the disease., (© 2022. The Author(s).)

Background: To compare the rate, time and, pattern of recurrence of cervical cancer between patients with and without HIV infection and to determine factors predicting cervical cancer recurrence in patients evaluated by 18 F-FDG-PET/CT., Methods: We reviewed the 18 F-FDG-PET/CT images of patients with histologically proven cervical carcinoma who were presenting with suspected recurrence. We extracted epidemiologic data, previous treatment, histologic subtype, HIV status, viral load and CD4 counts from the electronic laboratory database and the referral form for the 18 F-FDG-PET/CT study., Results: We studied 303 women including 112 HIV-infected patients. FIGO stage III disease was present in 131 patients. Of 198 patients with recurrence, 74 were HIV-infected while 124 were not (P=0.849). HIV infected patients were younger (41.99±9.30 years) compared to HIV-uninfected (50.19±11.09), P<0.001. Local recurrence was present in 125 patients while 100 patients had a distant recurrence. Recurrence occurred at a single site in 88 patients and two or more sites in 110 patients. No significant difference in the recurrent patterns between HIV-infected and uninfected patients. Median time to recurrence was 10.50 months (range: 6.00-156.00) among HIV-infected versus 12.00 months (IQR:7.00-312.00) among the uninfected, P=0.065. FIGO stage III (P=0.042) and the presence of histological sub-types other than SCC (P=0.005) were significant predictors of recurrence. HIV infection by itself was not significant in predicting recurrence (P=0.843)., Conclusions: HIV infection has no significant impact on the rate, time or pattern of recurrence in women with suspected cervical carcinoma recurrence. Advanced disease and histological variant other than SCC are predictive of recurrence.

Traditional medicine is typically the most accessible primary healthcare for a large proportion of the people in Nigeria. However, its potential remains under-explored, especially with regards to their documentation. This research investigated and documented the use of medicinal plants in the management of various health conditions/diseases among local populations in Lagos State. This study was conducted in five (5) locations of Lagos State i.e., Alimosho, Badagry, Eti-Osa, and Epe (including Ijebu and Imota). Ethnobotanical information from 100 participants was obtained using semi-structured questionnaires. Frequency of citation (FC), relative frequency of citation (RFC), fidelity level (FL), and informant consensus factor (ICF) were used to assess the importance of plants utilised for various health conditions/diseases. We identified 183 plants from 61 plant families with the highest number (24) of plants belonging to Fabaceae. Based on the high FC, the top-five popular plants used for managing health conditions/diseases in the study areas were Mangifera indica (95%), Waltheria indica (93%), Zingiber officinale (87%), Alchornea cordifolia (83%) and Ipomoea involucrata (81%). Furthermore, Rauvolfia vomitoria , Urena lobata and Waltheria indica were recognised as the most adaptable plants, as they were used to treat five different health conditions/diseases. The most commonly used life-forms were herbs (34%) and woody species (shrubs; 30%, and trees; 22%). The most regularly used plant parts were leaves. The calculated RFC values for all medicinal plant species ranged from 0.01 to 0.95, while FL values ranged from 7.14 to 100%. We found 14 health conditions/diseases, with ICF values ranging from 0.88 to 0.95. Insomnia, insanity, convulsion, nervousness, and muscle relaxants had the lowest (ICF = 0.88) agreement, while malaria/fevers, stomach, and respiratory-related diseases had the most (ICF = 0.95) agreement. The documented therapeutic uses of the plants provide basic data for further research aimed at pharmacological and conservation studies of the most important flora existing in the study areas.

Patients who complete a standard course of anti-tuberculous treatment (ATT) for pulmonary tuberculosis and are declared cured according to the current standard of care commonly have residual metabolic activity (RMA) in their lungs on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PER/CT) imaging. RMA seen in this setting has been shown to be associated with relapse of tuberculosis. The routine clinical use of FDG PET/CT imaging for treatment response assessment in tuberculosis is hindered by cost and availability. CT is a more readily available imaging modality. We sought to determine the association between CT features suggestive of active tuberculosis and RMA on FDG PET/CT obtained in patients who completed a standard course of ATT for pulmonary tuberculosis. We prospectively recruited patients who completed a standard course of ATT and declared cured based on negative sputum culture. All patients had FDG PET/CT within 2 weeks of completing ATT. We determined the presence of RMA on FDG PET images. Among the various lung changes seen on CT, we considered the presence of lung nodule, consolidation, micronodules in tree-in-bud pattern, FDG-avid chest nodes, and pleural effusion as suggestive of active tuberculosis. We determine the association between the presence of RMA on FDG PET and the CT features of active tuberculosis. We include 75 patients with a mean age of 36.09 ± 10.49 years. Forty-one patients (54.67%) had RMA on their FDG PET/CT while 34 patients (45.33%) achieved complete metabolic response to ATT. There was a significant association between four of the five CT features of active disease, p < 0.05 in all cases. Pleural effusion (seen in two patients) was the only CT feature of active disease without a significant association with the presence of RMA. This suggests that CT may be used in lieu of FDG PET/CT for treatment response assessment of pulmonary tuberculosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lawal, Mokoala, Mathebula, Moagi, Popoola, Moeketsi, Nchabeleng, Hikuam, Ellner, Hatherill, Fourie and Sathekge.)

Hypoxia in cervical cancer has been associated with a poor prognosis. Over the years 68 Ga labelled nitroimidazoles have been studied and have shown improved kinetics. We present our initial experience of hypoxia Positron Emission Tomography (PET) imaging in cervical cancer with 68 Ga-Nitroimidazole derivative and the correlation with 18 F-FDG PET/CT and immunohistochemistry. Twenty women with cervical cancer underwent both 18 F-FDG and 68 Ga-Nitroimidazole PET/CT imaging. Dual-point imaging was performed for 68 Ga-Nitroimidazole PET. Immunohistochemical analysis was performed with hypoxia inducible factor-1α (HIF-1α). We documented SUVmax, SUVmean of the primary lesions as well as tumor to muscle ratio (TMR), tumor to blood (TBR), metabolic tumor volume (MTV) and hypoxic tumor volume (HTV). There was no significant difference in the uptake of 68 Ga-Nitroimidazole between early and delayed imaging. Twelve patients had uptake on 68 Ga-Nitroimidazole PET. Ten patients demonstrated varying intensities of HIF-1α expression and six of these also had uptake on 68 Ga-Nitroimidazole PET. We found a strong negative correlation between HTV and immunohistochemical staining (r = -0.660; p = 0.019). There was no correlation between uptake on PET imaging and immunohistochemical analysis with HIF-1α. Two-thirds of the patients demonstrated hypoxia on 68 Ga-Nitroimidazole PET imaging.

Purpose: This review discusses the current state of prostate-specific membrane antigen (PSMA)-based alpha therapy of metastatic castration-resistant prostate cancer (mCRPC). With this in-depth discussion on the growing field of PSMA-based alpha therapy (PAT), we aimed to increase the interactions between basic scientists and physician-scientists in order to advance the field., Methods: To achieve this, we discuss the potential, current status, and opportunities for alpha therapy and strategies, attempted to date, and important questions that need to be addressed. The paper reviews important concepts, including whom to treat, how to treat, what to expect regarding treatment outcome, and toxicity, and areas requiring further investigations., Results: There is much excitement about the potential of this field. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other conventional therapies., Conclusion: A better understanding of the strengths and limitations of PAT may help in creating an effective therapy for mCRPC and design a rational combinatorial approach to treatment by targeting different tumor pathways., (© 2021. The Author(s).)

Invasive fungal disease (IFD) leads to increased mortality, morbidity, and costs of treatment in patients with immunosuppressive conditions. The definitive diagnosis of IFD relies on the isolation of the causative fungal agents through microscopy, culture, or nucleic acid testing in tissue samples obtained from the sites of the disease. Biopsy is not always feasible or safe to be undertaken in immunocompromised hosts at risk of IFD. Noninvasive diagnostic techniques are, therefore, needed for the diagnosis and treatment response assessment of IFD. The available techniques that identify fungal-specific antigens in biological samples for diagnosing IFD have variable sensitivity and specificity. They also have limited utility in response assessment. Imaging has, therefore, been applied for the noninvasive detection of IFD. Morphologic imaging with computed tomography (CT) and magnetic resonance imaging (MRI) is the most applied technique. These techniques are neither sufficiently sensitive nor specific for the early diagnosis of IFD. Morphologic changes evaluated by CT and MRI occur later in the disease course and during recovery after successful treatment. These modalities may, therefore, not be ideal for early diagnosis and early response to therapy determination. Radionuclide imaging allows for targeting the host response to pathogenic fungi or specific structures of the pathogen itself. This makes radionuclide imaging techniques suitable for the early diagnosis and treatment response assessment of IFD. In this review, we aimed to discuss the interplay of host immunity, immunosuppression, and the occurrence of IFD. We also discuss the currently available radionuclide probes that have been evaluated in preclinical and clinical studies for their ability to detect IFD.

Objectives: We aimed to describe the clinical characteristics and the response to radioactive iodine (RAI) treatment of immune reconstitution inflammatory syndrome-associated Graves disease (IRIS-GD) in comparison to Graves disease (GD) seen in HIV-uninfected patients., Methods: We retrospectively reviewed the medical records of patients treated with RAI for GD. We obtained clinical, biochemical and HIV-related information of patients from their medical records. We compared patient characteristics and response to RAI treatment between patients with IRIS-GD and GD seen in HIV-uninfected patients., Results: A total of 253 GD patients, including 51 patients with IRIS-GD, were included. Among IRIS-GD patients, CD4 cell nadir was 66 cells/µL (range: 37-103) with a peak HIV viral load of 60 900 copies/mL (range: 36 542-64 500). At the time of diagnosis of IRIS-GD, all patients had a completely suppressed HIV viraemia with a CD4 cell count of 729 cells/µL (range: 350-1279). The median interval between the commencement of HIV treatment and the onset of GD was 63 months. At 3 months follow-up, the proportion of patients with IRIS-GD achieving a successful RAI treatment outcome (euthyroid/hypothyroid state) was lower than that of HIV-uninfected patients (35.3% vs. 63.4%, respectively; p < 0.001). The response rate remained lower (60.8%) among patients with IRIS GD than among HIV-uninfected GD patients (80.2%, p = 0.004) at 6 months follow-up. After correcting for differences in age, gender and pre-treatment thyroid-stimulating hormone level, there was no significant difference in RAI treatment response between the two groups., Conclusions: After correcting for possible confounders, the response to RAI treatment was not different between patients with IRIS-GD and GD in HIV-uninfected patients., (© 2021 British HIV Association.)

The progression of coronavirus disease 2019 (COVID-19), resulting from a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may be influenced by both genetic and environmental factors. Several viruses hijack the host genome machinery for their own advantage and survival, and similar phenomena might occur upon SARS-CoV-2 infection. Severe cases of COVID-19 may be driven by metabolic and epigenetic driven mechanisms, including DNA methylation and histone/chromatin alterations. These epigenetic phenomena may respond to enhanced viral replication and mediate persistent long-term infection and clinical phenotypes associated with severe COVID-19 cases and fatalities. Understanding the epigenetic events involved, and their clinical significance, may provide novel insights valuable for the therapeutic control and management of the COVID-19 pandemic. This review highlights different epigenetic marks potentially associated with COVID-19 development, clinical manifestation, and progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kgatle, Lawal, Mashabela, Boshomane, Koatale, Mahasha, Ndlovu, Vorster, Rodrigues, Zeevaart, Gordon, Moura-Alves and Sathekge.)

Cancer of the cervix is the fourth commonest malignancy in women worldwide and it also ranks fourth as the cause of cancer related mortality in women. Hypoxia is a common characteristic of solid tumours and cervical cancer is no exception. Hypoxia is associated with increased aggressiveness, risk of invasion and metastasis. Tumour hypoxia also results in resistance to both radiation therapy and chemotherapy leading to a poorer prognosis. In-vivo measurement of tumour hypoxia is vital in oncologic practice because it can predict outcome and identify patients with a worse prognosis. Mapping of tumour hypoxia may also help select patients that may benefit from applicable treatments. While traditional methods of measuring hypoxia such as the Eppendorf probe is considered the gold standard, it is invasive and technically demanding. Non-invasive methods of measuring tumourhypoxia are ideal. Positron emission tomography/computed tomography (PET/CT) imaging with nitro-imidazole-based tracers is a highly sensitive nuclear imaging technique that is suited for non-invasive in vivo monitoring of hypoxia. Over the years various hypoxia specific PET tracers have been investigated in various malignancies including cancer of the cervix. Several fluorine-18 ( 18 F)-based tracers have been studied and although most had small patient numbers, the results are promising and generally demonstrate an associate between the presence of hypoxia and treatment outcome. The need for an onsite cyclotron and specialized radiopharmacy skills make these tracers unattractive and largely unavailable for routine clinical applications. With the increase in availability of the gallium-68 ( 68 Ga) generator this makes the 68 Ga-labelled nitroimidazole derivatives attractive because 68 Ga is available from a generator with a shelf life of almost a year. The chemistry of 68 Ga makes for easy labelling with several peptides and molecules. Pre-clinical work has demonstrated the feasibility of using these tracers for imaging hypoxia and has laid the groundwork for further human studies with these tracers.The aim of this review is to discuss hypoxia and its impact in cancer of the cervix as well as to look into the progress made in hypoxia imaging in cancer of the cervix. This will focus on the tracers studied thus far and some of the challenges of hypoxia imaging.

Objective: Accurate early assessment of biochemical recurrence is essential in determining the correct treatment plan for patients with prostate cancer. Gallium-68-prostate-specific membrane antigen-11 ( 68 Ga-PSMA-11) targeting PSMA has been at the forefront of imaging in biochemical recurrence however the emergence of fluorine-18 ( 18 F)-PSMA-1007 may prove to be advantageous over the 68 Ga-PSMA-11 molecule due to its physical and physiologic al attributes. The aim of our study was to assess the diagnostic performance of 18 F-PSMA-1007 as compared to that of 68 Ga-PSMA-11 in the same patients who presented with biochemical recurrence., Material and Methods: Twenty-one patients with biochemical recurrence prostate cancer were prospectively enrolled into the study. Fluorine-18-PSMA-1007 positron emission tomography/computed tomography (PET/CT) was performed on the same patient after 68 Ga-PSMA-11 PET/CT had been performed. Recurrence diagnosed on each of these studies was compared against a final diagnosis based on clinical follow-up and histological correlation where available., Results: Gallium-68-PSMA-11 identified fifteen (71,4%) patients as being negative for recurrence whilst five (23.8%) were identified as positive and one (4.8%) as uncertain. In comparison 18 F-PSMA-1007 identified eight (38.1%) as being positive with thirteen (61.9%) patients' scans identified as negative for recurrence. No scans were classified as uncertain for the 18 F-PSMA-1007 group. Fluorine-18-PSMA-1007 identified 8 lesions as positive for disease recurrence whilst only 6 lesions were identified on 68 Ga-PSMA-11. Of the 8 patients identified as having recurrence on 18 F-PSMA-1007 4 of those demonstrated local prostatic recurrence. The rest demonstrated local nodal recurrence and skeletal metastases. Fluorine-18-PSMA-1007 demonstrated a sensitivity, specificity, positive and negative predictive value of 88.9%, 100%, 100%, and 92.3% respectively whilst 68 Ga-PSMA-11 demonstrated a sensitivity, specificity, positive and negative predictive value of 44.4%, 83.3%, 80%, and 66.6%, respectively., Conclusion: In our pilot study 18 F-PSMA-1007 was able to detect more sites of recurrence as compared to 68 Ga-PSMA-11 which were mainly within the prostate and surrounding pelvic structures.

Imaging plays a vital role in detecting the recurrence of prostate cancer (PCa) to guide the choice of salvage therapy. Gallium-68 prostate-specific membrane antigen positron-emission tomography/computed tomography ( 68 Ga-PSMA-11 PET/CT) is useful for detecting PCa recurrence. We assessed the pattern of PCa recurrence stratified by serum prostate-specific antigen level and type of primary local treatment in men with biochemical recurrence (BCR) after primary local therapy with radical prostatectomy or external beam radiotherapy (EBRT) using 68 Ga-PSMA-11 PET/CT. We reviewed patients imaged with 68 Ga-PSMA-11 PET/CT for the localization of the site of PCa recurrence. We determined the site and number of lesions due to PCa recurrence at different PSA levels. A total of 247 men (mean age of 65.72 ± 7.51 years and median PSA of 2.70 ng/mL (IQR = 0.78-5.80)) were included. 68 Ga-PSMA-11 PET/CT detected the site of recurrence in 81.4% of patients with a median number of lesions per patient of 1 (range = 1-5). 68 Ga-PSMA-11 PET/CT positivity was 43.6%, 75.7%, 83.3%, 90.0%, and 95.8% at PSA levels of <0.5, 0.5-1.0., 1.1-2.0, 2.1-5.0, and 5.0-10.0, respectively. The most common site of recurrence was in the prostate gland/bed at all PSA levels. Pelvic, extra-pelvic, and combined pelvic and extra-pelvic sites of recurrence were seen in 118, 50, and 33 patients, respectively. The risk of extra-pelvic recurrence increases with rising PSA levels. 68 Ga-PSMA-11 PET/CT has a high lesion detection rate for biochemical recurrence of PCa in patients previously treated with primary local therapy.

Background: The cardiovascular committee of the European Association of Nuclear Medicine (EANM) recently published recommendations on imaging conditions to be observed during 18 F-FDG PET imaging of vascular inflammation. This study aimed to evaluate the impact of applying these optimized imaging conditions on PET quantification of arterial 18 F-FDG uptake., Methods and Results: Fifty-seven patients were prospectively recruited to undergo an early 18 F-FDG PET/CT imaging at 60 minutes and repeat delayed imaging at ≥ 120 minutes post tracer injection. Routine oncologic 18 F-FDG PET protocol was observed for early imaging, while delayed imaging parameters were optimized for vascular inflammation imaging as recommended by the EANM. Aortic SUVmax of the ascending aorta and SUVmean from the lumen of the superior vena cava (SVC SUVmean) were obtained on early and delayed imaging. Target-to-background ratio (TBR) was obtained for the early and delayed imaging. Aortic SUVmax increased by a mean of 70%, while SVC SUVmean decreased by a mean of 52% between early and delayed imaging (P < 0.001). TBR increased by 122% following delayed imaging. TBR increased, while SVC SUVmean declined across all time-points from 120 to > 180 minutes. Aortic SUVmax significantly increased at imaging time-points between 120 and 180 minutes. No significant improvement in aortic SUVmax was seen at imaging time-points beyond 180 minutes., Conclusions: 18 F-FDG PET imaging conditions optimized for vascular inflammation imaging lead to an improved quantification through an increase in the quantified vascular tracer uptake and decrease in blood-pool background activity., (© 2019. American Society of Nuclear Cardiology.)

Purpose: The aim of this study was to assess the impact of 18F-FDG PET/CT metabolic parameters obtained at initial staging of vulva carcinoma on survival in women with and without HIV infection., Patients and Methods: 18F-FDG PET/CT images of women with vulva cancer who are planned for definitive therapy were analyzed. SUVmax, SUVmean, MTV, and total lesion glycolysis (TLG) as well as whole-body MTV and whole-body TLG were computed., Results: Twenty-five women were included with a mean age of 43.44 ± 10.32. The majority of the patients were HIV infected with a median CD4 count of 444.00 cells/mm3. The HIV-infected women are younger at diagnosis than their HIV-uninfected counterparts. All patients presented with inguinofemoral lymph node involvement, whereas half the patients had pelvic nodal metastasis. All the patients with distant visceral or skeletal metastasis were HIV infected. The lungs were the most common site of distant metastasis. When comparing the SUVmax, SUVmean, MTV, TLG, wbMTV, and wbTLG between HIV-infected and HIV-uninfected patients, we did not find statistical differences. Twelve patients (48%) were upstaged to metastatic disease. Seven patients had died at the time of analysis. The wbMTV and wbTLG were significantly higher in nonsurvivors than survivors., Conclusions: 18F-FDG PET/CT improves initial staging of squamous cell carcinoma among women with and without HIV infection. The whole-body tumor burden assessed by 18F-FDG PET metabolic metrics did not differ between HIV-infected and HIV-uninfected women. A higher whole-burden tumor burden is associated with a higher risk of mortality among women with vulva cancer., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.

Cardiac and vascular infection is an arising cause of mortality and morbidity in the adult population. Diagnosis based on culture and anatomic imaging are frequently inconclusive. Radiolabeled leucocyte scintigraphy plays a useful role in the diagnosis and management of these serious infectious conditions. In this paper, we present an update on the diagnostic performance of single- photon emission tomographic (SPECT) techniques using different radionuclides in the management of patients with cardiac and vascular infections. We performed a thorough search of recent literature on the topic. We present a discussion on the clinical utility of different SPECT tracers in cardiac and vascular infections, including infective endocarditis, cardiac implantable electronic device (CIED) infections, left ventricular assist device infection, and vascular graft infection. Radionuclide technique using SPECT tracers is a useful imaging modality in the diagnosis of cardiac infection. Among the different SPECT tracers for infection imaging, radiolabeled leucocyte scintigraphy is currently the most useful tool in the diagnosis and management of patients with suspected cardiac and vascular infection. Radiolabeled leucocyte scintigraphy has a high specificity, a result of the ability of the leucocytes to accumulate as sites of pyogenic infection but not at sites of sterile inflammation such as seen in the early post-operative period or in response to the presence of a prosthetic cardiac or vascular material. Limited experience with radiotracers for in vivo labelling of leucocytes such as 99m Tc-sulesomab and 99m Tc-besilesomab show acceptable diagnostic performance without the need for the tedious process of ex-vivo labeling. 67 Ga scintigraphy used to be popular for cardiac and vascular infection imaging. Its use has run out of favor following the availability of more effective molecular imaging methods. SPECT techniques with radiolabeled leucocyte scintigraphy has a high diagnostic performance in the evaluation of patients with suspected cardiac or vascular infection. It is able to confirm or reject the presence of infection when results of anatomic imaging or culture remain inconclusive. Its diagnostic performance is not compromised by sterile inflammation occurring in the early post-operative period or in response to implanted prosthetic materials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Prostate cancer (PCa) commonly metastasizes to the bones. There are several radionuclide techniques for imaging PCa skeletal metastases. We aimed to compare the lesion detection rate of [ 68 Ga]Ga-PSMA-11 PET/CT, [ 68 Ga]Ga-NODAGA-zoledronate ([ 68 Ga]Ga-NODAGA ZOL ) PET/CT, and [ 99m Tc]Tc-MDP bone scan in the assessment of bone metastases in patients with advanced PCa., Methods: We prospectively recruited two cohorts of patients (staging and re-staging cohorts) with advanced prostate cancer. The staging cohort was treatment-naïve PCa patients who showed skeletal metastases on bone scan. These patients were subsequently imaged with [ 68 Ga]Ga-PSMA-11 PET/CT and [ 68 Ga]Ga-NODAGA ZOL PET/CT. Re-staging cohort was patients who were previously treated with PSMA-based radioligand therapy and were experiencing PSA progression. The re-staging cohort was imaged with [ 68 Ga]Ga-PSMA-11 PET/CT and [ 68 Ga]Ga-NODAGA ZOL PET/CT. We performed a per-patient and per-lesion analysis of skeletal metastases in both cohorts and made a comparison between scan findings., Results: Eighteen patients were included with a median age of 68 years (range = 48-80) and a median Gleason score of 8. There were ten patients in the staging cohort with a median PSA of 119.26 ng/mL (range = 4.63-18,948.00) and eight patients in the re-staging cohort with a median PSA of 48.56 ng/mL (range = 6.51-3175.00). In the staging cohort, skeletal metastases detected by [ 68 Ga]Ga-PSMA-11 PET/CT, [ 68 Ga]Ga-NODAGA ZOL PET/CT, and bone scan were 322, 288, and 261, respectively, p = 0.578. In the re-staging cohort, [ 68 Ga]Ga-PSMA-11 PET/CT and [ 68 Ga]Ga-NODAGA ZOL PET/CT detected 152 and 191 skeletal metastases, respectively, p = 0.529. In two patients with negative [ 68 Ga]Ga-PSMA-11 PET/CT findings, [ 68 Ga]Ga-NODAGA ZOL detected one skeletal metastasis in one patient and 12 skeletal metastases in the other., Conclusion: In patients with advanced prostate cancer, [ 68 Ga]Ga-PSMA-11 PET/CT may detect more lesions than [ 68 Ga]Ga-NODAGA ZOL PET/CT and [ 99m Tc]Tc-MDP bone scan for the staging of skeletal metastases. In patients who experience PSA progression on PSMA-based radioligand therapy, [ 68 Ga]Ga-NODAGA PET/CT is a more suitable imaging modality for the detection of skeletal lesions not expressing PSMA. In the setting of re-staging, [ 68 Ga]Ga-NODAGA ZOL PET/CT may detect more lesions than [ 68 Ga]Ga-PSMA-11 PET/CT.

People living with human immunodeficiency virus (PLHIV) have excess risk of atherosclerotic cardiovascular disease (ASCVD). Arterial inflammation is the hallmark of atherogenesis and its complications. In this study we aimed to perform a head-to-head comparison of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG PET/CT) and Gallium-68 pentixafor positron emission tomography/computed tomography [ 68 Ga]Ga-pentixafor PET/CT for quantification of arterial inflammation in PLHIV. We prospectively recruited human immunodeficiency virus (HIV)-infected patients to undergo [ 18 F]FDG PET/CT and [ 68 Ga]Ga-pentixafor PET/CT within two weeks of each other. We quantified the levels of arterial tracer uptake on both scans using maximum standardized uptake value (SUVmax) and target-background ratio. We used Bland and Altman plots to measure the level of agreement between tracer quantification parameters obtained on both scans. A total of 12 patients were included with a mean age of 44.67 ± 7.62 years. The mean duration of HIV infection and mean CD+ T-cell count of the study population were 71.08 ± 37 months and 522.17 ± 260.33 cells/µL, respectively. We found a high level of agreement in the quantification variables obtained using [ 18 F]FDG PET and [ 68 Ga]Ga-pentixafor PET. There is a good level of agreement in the arterial tracer quantification variables obtained using [ 18 F]FDG PET/CT and [ 68 Ga]Ga-pentixafor PET/CT in PLHIV. This suggests that [ 68 Ga]Ga-pentixafor may be applied in the place of [ 18 F]FDG PET/CT for the quantification of arterial inflammation.

Objective:  To assess the patterns of recurrence of vulva cancer on 18 F-FDG PET/CT and to compare the 18 F-FDG PET metabolic metrics in patients with and without Human Immunodeficiency Virus (HIV)., Methods:  Maximum standardized uptake value (SUV max ), mean standardized uptake value (SUV mean ), metabolic tumour volume (MTV and total lesion glycolysis (TLG) were obtained on Flourine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography ( 18 F-FDG PET/CT) images of women referred with suspected or confirmed vulva cancer recurrence. We compared HIV-infected and HIV-uninfected patients regarding pattern disease recurrence, age at diagnosis, and the PET-derived metabolic indices., Results:  We analyzed 33 patients with a mean age 50.76 ± 15.78 including 21 HIV-infected women. The majority of patients (94 %) had squamous cell carcinoma and 84.85 % were Blacks. Of the HIV-infected individuals, the median CD4 count was 526.0 cells/mm3 (IQR: 379.0-729.0). HIV infected patients were younger than the HIV uninfected at the time of diagnosis: 40.50 ± 8.87 vs 66.54 ± 9.71 respectively, p < 0.001. We found a local (vulvar) recurrence rate of 75.8 %. Nodal pelvic recurrences were higher in the HIV-infected patients than in the HIV uninfected patients (70 % vs 30 %, p = 0.027). Three patients had distant metastasis and all three were HIV-infected. There was a higher whole-body MTV and TLG among HIV-infected women compared with HIV-uninfected women, 103.39 vs 17.58 and 852.64 vs 101.79, respectively (p < 0.05 for both)., Conclusion:  HIV-infected women are diagnosed with vulva cancer at a younger age. HIV-infected patients had a higher rate of pelvic lymph node recurrence. There is a higher tumor burden at vulva cancer recurrence among women with HIV infection., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

To evaluate arterial fluorodeoxyglucose (FDG) uptake as a marker of arterial inflammation in multiple vascular beds in patients treated with anthracycline-based chemotherapy for Hodgkin lymphoma (HL).We used maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) to quantify arterial FDG uptake in the carotid artery, ascending aorta, abdominal aorta, and femoral artery obtained on positron emission tomography/computed tomography (PET/CT) imaging performed at baseline before chemotherapy and after completion of chemotherapy in patients with HL treated with an anthracycline-containing regimen. We compared the SUVmax and TBR obtained at baseline with that obtained post-chemotherapy for each arterial bed to evaluate the effect of anthracycline-based chemotherapy. We evaluated the effect of cardiovascular risk factors such as human immunodeficiency virus (HIV) infection, smoking, hypertension, and diabetes on the changes in SUVmax and TBR seen in the different arterial beds after anthracycline-based chemotherapy.Fifty-two patients were included with a mean age of 34.56 ± 10.19 years. There were 33 males, and 18 patients were HIV-infected. The mean interval between completion of chemotherapy and follow-up flourine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan was 65 weeks. We found no significant difference in arterial FDG uptake measured by SUVmax and TBR in all arterial beds between the pre- and post-chemotherapy FDG PET/CT. There was no significant impact of HIV infection, smoking, and hypertension on the changes in arterial FDG uptake following treatment with anthracycline-based chemotherapy.In patients with HL who were treated with anthracycline-based chemotherapy, we found no significant increase in arterial inflammation measured by FDG PET/CT after an average follow-up period of about 65 weeks since completion of chemotherapy.