Diagnostic Performance of 99mTc-iPSMA SPECT/CT in the Initial Staging of Patients with Unfavorable Intermediate-, High-, and Very High-Risk Prostate Cancer: A Comparative Analysis with 18F-PSMA-1007 PET/CT.

Prostate cancer is a leading cause of cancer death in men worldwide. Imaging plays a key role in disease detection and initial staging. Emerging data has shown the superiority of PSMA imaging with PET/CT over conventional imaging for primary diagnoses. Single photon emission computed tomography is more available worldwide, and the imaging agent is low in cost. The aim of this study is to compare the diagnostic accuracy of 99mTc-EDDA/HYNIC-iPSMA SPECT/CT to 18F-PSMA-1007 PET/CT in the primary diagnosis of prostate cancer and the impact on clinical staging. METHODS: In this prospective controlled study, 18 patients with histologically confirmed prostate cancer with unfavorable intermediate-, high-, and very high-risk characteristics were recruited to undergo 18F-PSMA-PET/CT and 99mTc-iPSMA SPECT/CT. The median age of the patients was 71 years old, and the median PSA level was 23.3 ng/mL. Lesions were divided into the prostate, seminal vesicles, lymph nodes, bone, and visceral metastases. Volumetric analysis was also performed between the two imaging modalities and correlated with PSA levels. RESULTS: A total of 257 lesions were detected on 18F-PSMA-PET/CT: prostate (n = 18), seminal vesicles (n = 12), locoregional lymph nodes (n = 62), non-locoregional (n = 67), bone (n = 90), and visceral (n = 8). Of these, 99mTc-iPSMA-SPECT/CT detected 229 lesions, while both reviewers detected 100% of the lesions in the prostate (18/18), seminal vesicles (12/12), and visceral (8/8); LN LR (56/62; 90%), NLR (57/67; 85%), and bone (78/90; 86%). There were no statistically significant differences between volumetric parameters (t = -0.02122; p = 0.491596). CONCLUSIONS: 99mTc-iPSMA SPECT/CT is useful in the primary diagnosis of prostate cancer. Despite it showing a slightly lower lesion detection rate compared to 18F-PSMA PET/CT, it exhibited no impact on clinical staging and, consequently, the initial treatment intention.

Multitarget Molecular Imaging in Metastatic Castration Resistant Adenocarcinoma Prostate Cancer with Therapy Induced Neuroendocrine Differentiation.

Neuroendocrine differentiation of prostate cancer (NEDPC) includes de novo presentation and secondary to epigenetic changes, referred as therapy-induced neuroendocrine prostate cancer (t-NEPC). Molecular imaging with prostate-specific membrane antigen (PSMA) and somatostatin analogues positron emission tomography (PET/CT) in NEDPC have not been validated. 18F-FDG (fluorodeoxyglucose) PET/CT has numerous limitations in prostate cancer (PCa) and the utility in NEDPC has only been reported in a few series of cases. The objective of this study is to compare the lesions detection rate of the three radiotracers in metastatic t-NEPC patients. (1) Material and Methods: Retrospective evaluation of patients with prostate adenocarcinoma treated with androgen deprivation therapy, chemotherapy, a novel androgen receptor pathway inhibitor or a combination of them and a second tumour biopsy confirming t-NEPC was made. All patients underwent 18F PSMA-1007, 18F AlF-NOTA-Octreotide, and 18F-FDG PET/CT. Evaluation of positive lesions was determined and SUVmax of each radiotracer was estimated and correlated with computer tomography (CT) findings. (2) Results: A total of eight patients were included. The mean time from diagnosis of prostate adenocarcinoma to t-NEPC was 28.2 months, with a mean serum specific prostate antigen (PSA) of 16.6 ng/dl at the time of NEPC diagnosis. All patients were treated with antiandrogen therapy and 87.5% with chemotherapy. A total of 273 lesions were identified by CT from which 182 were detected by 18F-FDG PET/CT, 174 lesions by 18F PSMA-1007, and 59 by 18F AlF-NOTA-Octreotide. An interpatient analysis of the lesions was performed and dual tracer 18F-FDG PET/CT and 18F PSMA-1007 PET/CT detected a total of 270/273 lesions (98.9%). (3) Conclusions: NEDPC patients demonstrated wide inter and intrapatient molecular imaging heterogeneity within the three radiotracers. 18F-FDG detected most lesions in t-NEPC among all radiotracers, especially in visceral sites; 18F PSMA-1007 detected more bone lesions. 18F AlF-NOTA-Octreotide showed no significant utility.

[99mTc]Tc-iFAP/SPECT Tumor Stroma Imaging: Acquisition and Analysis of Clinical Images in Six Different Cancer Entities.

Fibroblast activation protein (FAP) is highly expressed on the cancer-associated fibroblasts (CAF) of the tumor stroma. Recently, we reported the preclinical evaluation and clinical biokinetics of a novel 99mTc-labeled FAP inhibitor radioligand ([99mTc]Tc-iFAP). This research aimed to evaluate [99mTc]Tc-iFAP for the tumor stroma imaging of six different cancerous entities and analyze them from the perspective of stromal heterogeneity. [99mTc]Tc-iFAP was prepared from freeze-dried kits with a radiochemical purity of 98 ± 1%. The study included thirty-two patients diagnosed with glioma (n = 5); adrenal cortex neuroendocrine tumor (n = 1); and breast (n = 21), lung (n = 2), colorectal (n = 1) and cervical (n = 3) cancer. Patients with glioma had been evaluated with a previous cranial MRI scan and the rest of the patients had been involved in a [18F]FDG PET/CT study. All oncological diagnoses were corroborated histopathologically. The patients underwent SPECT/CT brain imaging (glioma) or thoracoabdominal imaging 1 h after [99mTc]Tc-iFAP administration (i.v., 735 ± 63 MBq). The total lesions (n = 111) were divided into three categories: primary tumors (PT), lymph node metastases (LNm), and distant metastases (Dm). [99mTc]Tc-iFAP brain imaging was positive in four high-grade WHO III-IV gliomas and negative in one treatment-naive low-grade glioma. Both [99mTc]Tc-iFAP and [18F]FDG detected 26 (100%) PT, although the number of positive LNm and Dm was significantly higher with [18F]FDG [82 (96%)], in comparison to [99mTc]Tc-iFAP imaging (35 (41%)). Peritoneal carcinomatosis lesions in a patient with recurrent colorectal cancer were only visualized with [99mTc]Tc-iFAP. In patients with breast cancer, a significant positive correlation was demonstrated among [99mTc]Tc-iFAP uptake values (Bq/cm3) of PT and the molecular subtype, being higher for subtypes HER2+ and Luminal B HER2-enriched. Four different CAF subpopulations have previously been described for LNm of breast cancer (from CAF-S1 to CAF-S4). The only subpopulation that expresses FAP is CAF-S1, which is preferentially detected in aggressive subtypes (HER2 and triple-negative), confirming that FAP+ is a marker for poor disease prognosis. The results of this pilot clinical research show that [99mTc]Tc-iFAP SPECT imaging is a promising tool in the prognostic assessment of some solid tumors, particularly breast cancer.

The impact of the extent of the bone involvement on overall survival and toxicity in mCRPC patients receiving [177Lu]Lu-PSMA-617: a WARMTH multicentre study.

INTRODUCTION: Prostate-specific membrane antigen (PSMA)-based radioligand therapy (RLT) showed in a multicentre WARMTH (World Association of Radiopharmaceutical and Molecular Therapy) study that the presence of bone metastases is a negative prognosticator for the survival. The current multicentre retrospective analysis aims to evaluate the response rate to RLT, the overall survival (OS) of patients and the safety of the treatment according to the extent of bone involvement. METHODS: The study included patients with progressive metastatic castration-resistant prostate cancer (mCRPC), who underwent RLT with [177Lu]Lu-PSMA-617 and a follow-up of at least 6 months. Tumour burden in the bone was classified prior to RLT as follows: less than 6 lesions, 6-20 lesions, more than 20 lesions and diffuse involvement. The response rate was evaluated using changes of the prostate-specific antigen (PSA) after the first treatment cycle. Overall survival was calculated from the date of the first treatment. Haematological adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. RESULTS: A total of 319 males were included in the analysis. The extent of bone metastases and PSA response did not correlate significantly. Any PSA decline was observed in 73% patients; 44% showed a decline of ≥50%. The median OS of patient in the different subgroups was 18 months (less than 6 lesions), 13 months (6-20 lesions), 11 months (more than 20 lesions) and 8 months (diffuse involvement), respectively (p < 0.0001). Patients with prior Ra-223-therapy showed longer OS in all subgroups, especially in the subgroups with 6-20 lesions (OS: 16 vs. 12 months; p = 0.038) as well as diffuse involvement (OS: 11 vs. 7 months; p = 0.034). Significant negative prognosticators of OS were the existence of liver metastases in all subgroups and prior chemotherapy in patients with <6 bone lesions. Anaemia and thrombocytopenia correlated positively with the extent of bone metastases: p < 0.0001 and 0.005, respectively. No patient showed a high grade leukopenia. CONCLUSION: The extent of bone involvement correlated negatively with the OS after RLT; however, it showed no relevant correlation with the PSA response rate. Prior therapy with Ra-223 may have a positive impact on OS. Haematotoxicity was higher in patients with more than 20 bone lesions; nevertheless, the majority of these patients did not show a relevant haematotoxicity.

Prior therapies as prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients treated with [177Lu]Lu-PSMA-617. A WARMTH multicenter study (the 617 trial).

INTRODUCTION: The impact of prior therapies, especially chemotherapy, on overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) receiving [177Lu]Lu-PSMA-617 therapy has been the subject of controversy. Therefore, WARMTH decided to plan a multicenter retrospective analysis (the "617 trial") to evaluate response rate and OS as well as the impact of prior therapies on OS in more than 300 patients treated with 177Lu-PSMA-617. MATERIALS AND METHODS: The data of 631 metastatic CRPC (mCRPC) patients from 11 different clinics were evaluated. According to the inclusion and exclusion criteria, all patients had to have received at least abiraterone or enzalutamide prior to [177Lu]Lu-PSMA-617 therapy. The patients were divided into three groups: patients who had received prior chemotherapy, patients who avoided chemotherapy, and patients for whom a chemotherapy was contraindicated. RESULTS: The analysis included the data of 416 patients, with a median age of 71.9 years. At the time of analysis, 87 patients (20,9%) were still alive. A total of 53.6% of patients had received both abiraterone and enzalutamide; 75.5% and 26.4% had a history of chemotherapy with docetaxel and cabazitaxel, respectively. A total of 20.4% had had Ra-223. The median OS was 11.1 months. Prior chemotherapy, the existence of bone and liver metastases, as well as Eastern Cooperative Oncology Group (ECOG) status, were significant prognosticators of worse overall survival in both univariate and multivariate analyses. Patients without any prior chemotherapy showed a significantly longer OS (14.6 months). The median OS in patients who received one or two lines of chemotherapy with docetaxel or docetaxel followed by cabazitaxel, respectively, was 10.9 months and 8.9 months. There was no difference in OS between patients who had not received chemotherapy and patients for whom chemotherapy was contraindicated. The other prior therapies did not have any significant impact on OS. CONCLUSION: In the present multicenter analysis, chemotherapy-naïve mCRPC patients receiving [177Lu]Lu-PSMA-617 therapy had a significantly longer OS than patients with a history of chemotherapy. This remained independent in the multivariate analysis besides presence of bone and liver metastases as negative prognosticators for survival, whereas an ECOG of 0-1 is associated with a longer OS.

Head-to-Head Comparison of 68Ga-PSMA-11 and 131I in the Follow-Up of Well-Differentiated Metastatic Thyroid Cancer: A New Potential Theragnostic Agent.

Introduction: Thyroid cancer is the main endocrine neoplasia worldwide, for which 131I therapy is the cornerstone treatment. One of the main problems of follow up in patients with this type of cancer, is the need for thyroglobulin stimulation, not to mention the poor availability of 123I or 124I, to perform studies with a higher degree of sensitivity. Prostatic Specific Membrane Antigen (PSMA) PET/CT has demonstrated to be quite useful in a diversified number of neoplasms, on behalf of its capacity of evaluating the extent of type II carboxypeptidase expression in vascular endothelium. The end point of this article is to assess whether this novel image method possesses applicability in thyroid neoplasms follow up, for diagnostic and potentially therapeutic purposes. Methods: We retrospectively evaluated well differentiated metastatic thyroid cancer patients, who underwent a post therapeutic 131I dose whole body scan (WBS) and complementary SPECT/CT, as well as 68Ga-PSMA-11 PET/CT. Results: Ten patients with differentiated thyroid cancer were included, of whom 80% were women and 20% men, mean age was 58 years old (± 11.6). Sixty-four metastatic lesions were analyzed, 67.19% had papillary histology and 32.81% were follicular type, the most affected site of metastases was bone in 57.81%, followed by lung 17.19%, lymph nodes 7.81%, postoperative thyroid bed 4.69%, brain 4.69% and others 7.81%. 68Ga PSMA-11 PET/CT detected 64/64 lesions, all of them also identified by computed tomography (CT), whereas 131I SPECT/CT detected 55/64 lesions. Discrepant lesions were localized in lung 44.4%, brain 22.2%, postoperative thyroid bed 11.1%, lymph nodes 11.1% and bone 11.1%. The degree of correspondence among observers was outstanding for both radiotracers, but close upon perfect for PSMA-11 (κ = 0.98; 95% CI, 0.80 - 0.91), as opposed to 131 I (κ = 0.86; 95% CI, 0.71 - 0.76). Conclusions: 68Ga-PSMA PET/CT showed an utterly superior capability for metastatic lesion detection when compared to 131I SPECT/CT. These findings suggest that PSMA PET/CT could possibly and precociously identify radioiodine refractoriness. PSMA uptake values not only expedite diagnosis, but also award it the ability to be used for therapeutic intents.

A dedicated phantom design for positron emission mammography performance evaluation.

A standard protocol for performance evaluation of positron emission mammography (PEM) systems has not yet been established. In this work we propose a methodology based on the design of specific phantoms for this imaging modality with component dimensions in accordance with typical breast lesion sizes together with the adaptation of current international protocols designed for clinical and preclinical positron emission tomographs (PET) systems. This methodology was used to evaluate the performance of the Flex Solo II PEM scanner in terms of spatial resolution, uniformity and contrast lesion detectability, recovery coefficients and spill-over ratios. Positron range effects were studied with 18F and 68Ga, which have very different energy spectra. Our results indicate that in-plane spatial resolution of the system is around 3.0 mm and 4.4 mm for 18F and 68Ga, respectively. Lesion detectability tests with sphere diameters between 4 and 10 mm confirmed that the PEM system can resolve all the spheres (hot or cold). Percent contrast values for 18F lie between 6%-38% and 34%-51% for hot- and cold- spheres, respectively; the corresponding intervals for 68Ga are lower, 4%-25% and 32%-44%. Regarding uniformity quantification, the system shows percentage standard deviations within 4.9%-5.7%, while the percent background variability measurements ranged between 6.7% and 10.9% for both radionuclides. Recovery coefficients measured with hot rod diameters between 1.5 and 9 mm, have values between 0.2-1.05 and 0.17-0.69 for 18F and 68Ga, respectively. Spill-over ratios have large values (0.22 in average) for both radionuclides. Our results indicate that the phantoms and the methodology developed in this work can serve as the basis for establishing an image quality protocol for the systematic evaluation of PEM systems, with a potential extension for performance evaluation of dedicated breastPET scanners.

Evaluation of non-small cell lung cancer by PET/CT with 64CuCl2: initial experience in humans.

Human copper transporter 1 (hCtr1) is the main transporter of copper which has been involved as an essential cofactor in biological processes and mechanisms of action for cisplatin and its analogues. Although expression of hCtr1 is present in all tissues that require copper, several studies have showed that levels of expression are highly variable between normal and neoplastic tissues. We evaluated the potential diagnostic of the 64CuCl2-PET/CT in patients with wild type non-small cell lung cancer (NSCLC). Eleven patients were included. Baseline 18F-FDG-PET/CT and 64CuCl2-PET/CT performed before to initiate treatment with platinum-based chemotherapy. 18F-FDG-PET/CT detected a total of 68 lesions in different corporal sites: lung (24), regional lymph node (30), distant non-bone metastases (17) and bone metastases (14). Of total, 73% demonstrated high focal uptake of 64CuCl2-PET/CT: 36% in primary tumor and 27% in lymph-nodes metastases. The detection-rates (DRs) was lower with 64CuCl2 PET/CT compared to 18F-FDG-PET/CT, however, these was not statistically significant (P = 0.108). A complete match was found in 2 patients. All patients were treated with platinum-based chemotherapy. According to RECIST 1.1 and PERCIST 1.0 criteria, most patients with highest uptake 64CuCl2-PET/CT presented partial response (mean 3 cycles) corroborated with 18F-FDG PET/CT. On the other hand, patients with very low uptake or faint uptake have progressive disease (3/16 patients). To our knowledge, this is the first study with 64CuCl2-PET/CT in-human in patients with NSCLC chemo-naïve. Our results may represent that 64CuCl2-PET/CT had a good ability for detect lesions. In addition, the 64CuCl2 uptake is based on the expression of Ctr1 transporters seeking to differentiate between those patients who may benefit from platinum-based therapy. More studies are necessary for confirm these findings.

Head to head comparison performance of 99mTc-EDDA/HYNIC-iPSMA SPECT/CT and 68Ga-PSMA-11 PET/CT a prospective study in biochemical recurrence prostate cancer patients.

Positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) has found widespread use for the diagnosis of biochemical recurrence of prostate cancer (PCa). Unfortunately, PET/CT is not as widely available; thus a PSMA-targeting compound for scintigraphy is of special interest. The aim of this study was to compare 99mTc-EDDA/HYNIC-iPSMA and 68Ga-PSMA-11 PET/CT qualitatively and semi-quantitatively. Twenty-three patients with metastatic PCa were underwent 99mTc-EDDA/HYNIC-iPSMA SPECT/CT followed by 68Ga-PSMA-11 PET/CT. Gleason score in all patients was obtained. Maximal standardized uptake value (SUVmax) and counts per organ, including the primary and metastatic tumor, were normalized and compared using Pearson's correlation test. Sites considered as positive have increased SUVmax and tumor-to-background ratio (TBR) in comparison with non-diseased organs/tissues (SUVmax =25.2±4.7, 18.4±1.6, 11.4±1.2 (P=0.037) from prostate, bone and lymph nodes versus TBR =35.9±45.2, 15.4±18.9, 19.1±51.7 (P=0.035) for prostate, bone and lymph nodes. 99mTc-HYNIC-iPSMA and 68Ga-PSMA-11 uptake values in the evaluation of the affected nodes were very similar, although their ranges ranged from 5-21 mm (12±7.6). Correlation coefficient was normalized between SUVmax and TBR, demonstrating r values for prostate of r2=0.731; for bone of r2=0.720; and lymph nodes of r2=0.864 (P<0.05 in all cases). Values and confidence interval at the 95% are supporting the equivalency of both parameters in primary tumor and metastases (prostate 95% CI=4.61, 4.38; bone tissue 95% CI=-2.21, 3.41 and lymph node 95% CI=4.67). We conclude that 68Ga-PSMA-11 PET/CT and 99mTc-EDDA/HYNIC-iPSMA SPECT/CT were comparable, supporting the use of 99mTc-EDDA/HYNIC-iPSMA in patients with progressive metastatic castration-resistant PCa.