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PURPOSE: It is well-established that the lack of accurate diagnostic modalities for prostate cancer (PCa) leads to overdiagnosis and overtreatments. Accordingly, this study aimed to assess the value of urine-derived exosomal prostate-specific membrane antigen (PSMA) as a biomarker for the diagnosis of PCa and clinically significant prostate cancer (csPCa). METHODS: A total of 284 urine samples were collected from patients after the digital rectal examination (DRE). Urinary exosomes were extracted using commercial kits, and urine-derived exosomal PSMA was determined via enzyme-linked immunosorbent assay (ELISA). Evaluation of diagnostic accuracy of PSMA was performed via receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and waterfall plots. RESULTS: We found that urine-derived exosomal PSMA was significantly higher in PCa and csPCa than in benign prostatic hyperplasia (BPH) and BPH + non-aggressive prostate cancer (naPCa) groups (P < 0.001). Furthermore, the urine-derived exosome PSMA yielded area under the ROC curve (AUC) values of 0.876 and 0.826 for detecting PCa and csPCa, respectively, suggesting better performance than traditional clinical biomarkers. Besides, when the cutoff value used corresponded to a sensitivity of 95%, urine-derived exosomal PSMA could avoid unnecessary biopsies in 41.2% of cases and missed only 0.7% of csPCa cases. CONCLUSIONS: Urine-derived exosomal PSMA exhibits a good diagnostic yield for detecting PCa and csPCa. Findings of the present study provide the foothold for future studies on cancer management and research in this patient population.

Assuntos

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Despite of the capacity that several drugs have for specific inhibition of the androgen receptor (AR), in most cases, PCa progresses to an androgen-independent stage. In this context, the development of new targeted therapies for prostate cancer (PCa) has remained as a challenge. To overcome this issue, new tools, based on nucleic acids technology, have been developed. Aptamers are small oligonucleotides with a three-dimensional structure capable of interacting with practically any desired target, even large targets such as mammalian cells or viruses. Recently, aptamers have been studied for treatment and detection of many diseases including cancer. In PCa, numerous works have reported their use in the development of new approaches in diagnostics and treatment strategies. Aptamers have been joined with drugs or other specific molecules such as silencing RNAs (aptamer-siRNA chimeras) to specifically reduce the expression of oncogenes in PCa cells. Even though these studies have shown good results in the early stages, more research is still needed to demonstrate the clinical value of aptamers in PCa. The aim of this review was to compile the existing scientific literature regarding the use of aptamers in PCa in both diagnosis and treatment studies. Since Prostate-Specific Membrane Antigen (PSMA) aptamers are the most studied type of aptamers in this field, special emphasis was given to these aptamers.

Assuntos

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Prostate-specific membrane antigen (PSMA) is expressed in a variety of cancer cells, while the fibroblast activation protein (FAP) is expressed in the microenvironment of tumors. Previously, we reported the ability of iPSMA and iFAP ligands to specifically target PSMA and FAP proteins, as well as the preparation of stable 177Lu2O3 nanoparticles (<100 nm) functionalized with target-specific peptides. This research aimed to evaluate the dosimetry and therapeutic response of Lu2O3-iPSMA and Lu2O3-iFAP nanoparticles activated by neutron irradiation to demonstrate their potential for theranostic applications in nuclear medicine. The biokinetic behavior, radiation absorbed dose, and metabolic activity ([18F]FDG/micro-PET, SUV) in preclinical tumor tissues (athymic mice), following treatment with 177Lu2O3-iPSMA, 177Lu2O3-iFAP or 177Lu2O3 nanoparticles, were assessed. One patient with multiple colorectal liver metastases (PSMA-positive) received 177Lu2O3-iPSMA under a "compassionate use" protocol. Results indicated no significant difference (p < 0.05) between 177Lu2O3-iPSMA and 177Lu2O3-iFAP, regarding tumor radiation absorbed doses (105 ± 14 Gy, 99 ± 12 Gy and 58 ± 7 Gy for 177Lu2O3-iPSMA, 177Lu2O3-iFAP, and 177Lu2O3, respectively) and tumor metabolic activity (SUV of 0.421 ± 0.092, 0.375 ± 0.104 and 1.821 ± 0.891 for 177Lu2O3-iPSMA, 177Lu2O3-iFAP, and 177Lu2O3, respectively) in mice after treatment, which correlated with the observed therapeutic response. 177Lu2O3-iPSMA and 177Lu2O3-iFAP significantly inhibited tumor progression, due to the prolonged tumor retention and a combination of 177Lu radiotherapy and iPSMA or iFAP molecular recognition. There were negligible uptake values in non-target tissues and no evidence of liver and renal toxicity. The doses received by the patient's liver metastases (42−210 Gy) demonstrated the potential of 177Lu2O3-iPSMA for treating colorectal liver metastases.

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PSMA expression occurs in epithelial cells in both normal and hyperplastic prostates. In adenocarcinoma, it is present in greater intensity, especially in the more aggressive ones. This made it possible to develop diagnostic tools with greater specificity for detecting prostate cancer metastases like the 68Ga-PSMA PET/CT. Several benign neoplasms with increased marker uptake have been described in the literature. Such false-positives are usually associated with soft tissue injuries, abnormal vascular proliferation, neurogenic injuries, thymomas and adenomas. In the present work we present a case report that exemplifies the above.

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Splenic hemangiosarcoma (HSA) is a malignant tumor of endothelial cells that affects middle-aged and elderly dogs and is characterized by the formation of new blood vessels, commonly associated with necrotic and hemorrhagic areas. Despite its importance in veterinary medicine, few studies have identified markers with prognostic value for canine HSA. Thus, this study aimed to associate the clinicopathological findings (prostate-specific membrane antigen [PSMA], Claudin-5, and Ki67 gene and protein expression) with overall survival in HSA-affected patients. Fifty-three formalin-fixed and paraffin-embedded canine splenic HSA samples, previously diagnosed by histopathological examination, were used in this study. Claudin-5, PSMA, and Ki67 protein expression levels were evaluated by immunohistochemistry, and gene expression was evaluated by quantitative polymerase chain reaction. Claudin-5 protein overexpression was observed in patients with metastasis (p = 0.0078) and with stage III tumors compared to those with stage I and II tumors (p = 0.0451). In patients treated with surgery alone, low PSMA gene and protein expression (p = 0.05 and p = 0.0355, respectively) were associated with longer survival time. Longer survival time was observed in patients with a low Ki67 index (p = 0.0488). Our results indicate that Claudin-5 protein expression is associated with metastatic status, and PSMA gene and protein expression, and Ki67 index are associated with survival time.

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PURPOSE: To evaluate the performance of [68Ga]Ga-PSMA-11 PET/CT in the diagnosis of recurrent prostate cancer (PC) after prostatectomy in a large multicentre cohort. METHODS: The centres, which contributed to this study, were the departments of nuclear medicine of Heidelberg (Germany), Technical University of Munich (Germany) and Albert Einstein Hospital of São Paulo (Brazil). A total of 2533 patients who were scanned with [68Ga]Ga-PSMA-11 PET/CT at 1 h p.i. due to recurrent PC after prostatectomy were included in this retrospective analysis. Exclusion criteria were as follows: patients with untreated primary tumour, previous chemotherapy or Xofigo®; those previously treated with exclusively external beam radiation therapy or HIFU; those referred for PSMA-therapy; and those treated with ADT (including first- and second-generation ADT) within the last 6 months. Potential influences of different factors such as PSA level, PSA doubling-time (PSADT), PSA velocity (PSAVel), Gleason Score (GSC, including the separate analysis of 7a and 7b), age and amount of injected tracer were evaluated in a multivariable analysis. RESULTS: The rate of pathologic PET/CT-scans was 43% for PSA ≤ 0.2 ng/ml, 58% for PSA > 0.2 to ≤ 0.5, 72% for PSA > 0.5 to ≤ 1.0 and increased to a maximum of 93% for PSA > 10 ng/ml. A pathological PET/CT was significantly (p = 0.001) associated with PSA level and higher GSC. Amount of injected tracer, age, PSADT and PSAVel were not associated with a higher probability of a pathological scan. CONCLUSION: [68Ga]Ga-PSMA-11 PET/CT at 1 h p.i. confirmed its high performance in the largest patient cohort yet analysed. Tumour detection showed a clear association with higher PSA and higher GSC. No association was found between a pathological [68Ga]Ga-PSMA-11 PET/CT and age, amount of injected tracer, PSADT or PSAVel.

Assuntos

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Positron emission tomography/computed tomography (PET/CT) using 68Ga-labeled prostate-specific membrane antigen (68Ga-PSMA) became an important tool in the prostate cancer (PC) diagnosis. Despite its high sensitivity and specificity, this method may produce false-positive findings, as indicated by previous studies. This case report aims to warn nuclear medicine physicians, oncologists, and urologists about the possibility of false-positive findings using this imaging modality, especially in patients who have already been diagnosed with other malignancies. A 69-year-old man, previously treated for an extrapleural solitary fibrous tumor (ESFT), underwent staging tests after a new diagnosis of high-risk PC. 68Ga-PSMA PET/CT imaging revealed an abnormal uptake in the prostate and in the right humerus. A biopsy was performed, and the pathology showed a lesion consisting of an ESFT metastasis. Diagnostic issues related to 68Ga-PSMA PET/CT imaging should be disseminated to help physicians make appropriate treatment choices for each patient and avoid unnecessary procedures.

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BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a malignant renal neoplasm with a peculiar propensity to propagate as a contiguous tumor extension via the renal vein and inferior vena cava, occasionally reaching the right atrium. This intravascular tumor extension, often referred to as a tumor thrombus, represents the active growing front of the cancer. Prostate specific membrane antigen (PSMA), a glycoprotein that is extensively used in prostate cancer diagnostics, is a useful vascular marker for a variety of solid tumors. It is expressed in renal carcinomas. The aim of the current investigation was to analyse and compare the expression of PSMA at the growing front of the vena cava tumor extension with that found in the primary renal lesion. METHODS: Immunohistochemical (IHC) analysis of PSMA and CD34 was performed on archived paraffin embedded vena cava tumour thrombus tissue and matching renal tumours. These specimens were collected from radical nephrectomies of 10 patients with vena cava invasive (pT3b) ccRCC in a large tertiary hospital in Australia. Quantitative and qualitative morphometric analysis of PSMA IHC expression was performed with Aperio ImageScope morphometry using intensity and positive pixel counts of CD34 and PSMA from the IVC tumour slides and the corresponding renal tumour mass. RESULTS: PSMA and CD34 immunostaining were noted in the neovasculature of IVC tumour and renal tumour tissue. There was a higher PSMA/CD34 positive pixel count ratio noted in IVC tumour tissue when compared to renal tumour tissue. PSMA showed consistently increased expression in vena cava tumour, in comparison with the renal tumour mass. CONCLUSIONS: Intravascular venous tumour extension expresses PSMA more intensely compared to intrarenal tumour tissue neovasculature. Our data suggest a possible mechanism for PSMA in neoangiogenesis and local progression of ccRCC and therefore its usefulness as a biomarker of neoangiogenesis for future diagnostic and therapeutic advancements.

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Positron emission tomography/computed tomography (PET/CT) using 68Ga-labeled prostate-specific membrane antigen (68Ga-PSMA) has become an important tool in restaging patients with prostate cancer (PCa). Despite its high sensitivity and specificity, this method may produce false-positive findings, as indicated by previous studies. This case report aims to warn nuclear medicine physicians, oncologists, and urologists about the possibility of false-positive findings using this imaging modality, especially when the detected site is unusual for bone metastasis. A 68-year-old man with PCa underwent restaging tests after presenting with increased prostate-specific antigen. 68Ga-PSMA PET/CT imaging revealed abnormal uptake in the left humeral head, which anatomically corresponded to the intramedullary and cortical sclerotic area. A biopsy was performed, and the pathology showed a lesion consisting of hard bone tissue with a small focal spot of fibrous dysplasia. Diagnostic issues related to 68Ga-PSMA PET/CT imaging should be disseminated to help physicians make appropriate treatment choices for each patient.

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BACKGROUND: To investigate the efficacy and toxicity of 68Ga-PSMA-HBED-CC (68Ga-PSMA) PET-CT-guided RT in the treatment of oligometastatic prostate cancer retrospectively. METHODS: A total of 23 prostate cancer patients with biochemical relapse, of which 13 were castration sensitive (CS) and 10 castration resistant (CR), were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤3 metastases detected by 68Ga PSMA PET-CT. Androgen deprivation therapy was continued in CR patients. RESULTS: A total of 38 metastases were treated. The involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), paraaortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.1 ng/mL (range 0.1-29.0 ng/mL). A median dose of 43.5 Gy (range 30-64 Gy) was delivered by IMRT-IGRT in 12-27 fractions. At a median follow-up of 7 months (range 2-17 months), 19 patients (83%) were in remission. Four patients (17%) developed distant recurrences. The actuarial 1-year LC, PFS and OS rates were 100, 51 (95% CI 8-83%) and 100%. Univariate analysis demonstrated a statistically significantly better PFS in CS patients as compared to CR patients (1-year PFS 67 vs. 0%, p < 0.01). One patient experienced grade 2 acute gastrointestinal toxicity. Grade 3 or more toxicity events were not observed. CONCLUSIONS: By providing optimal LC, low toxicity and a promising PFS in CS patients, the current retrospective study illustrated that 68Ga PSMA PET-CT-guided RT may be an attractive treatment strategy in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited.

Assuntos

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OBJECTIVE: Despite a multitude of detection and treatment advances in the past 2 decades, prostate cancer remains the second leading cause of deaths due to cancer among men in the United States. Technological evolution and expanding knowledge of tumor biomarkers have invigorated exploration in prostate cancer therapeutics. Prostate-specific membrane antigen (PSMA) was one of the first prostate cancer biomarkers successfully cloned. Since then, it has been characterized as the prototypical cell-surface marker for prostate cancer and has been the subject of intense clinical inquiry. In this article, we review the relevant research in PSMA on the 20th anniversary of its cloning. METHODS AND MATERIALS: A PubMed search using the keywords "prostate-specific membrane antigen" or "glutamate carboxypeptidase II" provided 1019 results. An additional 3 abstracts were included from scientific meetings. Articles were vetted by title and abstract with emphasis placed on those with clinically relevant findings. RESULTS: Sixty articles were selected for inclusion. PSMA was discovered and cloned in 1993. Its structure and function were further delineated in the ensuing decade. Consensus sites of expression in normal physiology are prostate, kidney, nervous system, and small intestine. PSMA has been implicated in the neovasculature of several tumors including urothelial and renal cell carcinomas. In prostate cancer, expression of PSMA is directly related to the Gleason grade. PSMA has been tested both in imaging and therapeutics in a number of prostate cancer clinical trials. Several recent approaches to target PSMA include the use of small molecule inhibitors, PSMA-based immunotherapy, RNA aptamer conjugates, and PSMA-targeted prodrug therapy. Future study of PSMA in prostate cancer might focus on its intracellular functions and possible role in tumor neurogenesis. CONCLUSIONS: Twenty years from its discovery, PSMA represents a viable biomarker and treatment target in prostate cancer. Research to delineate its precise role in prostate carcinogenesis and within the therapeutic armamentarium for patients with prostate cancer remains encouraging.

Assuntos

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Reports remain insufficient on whether and how prostate-specific membrane antigen (PSMA) can influence in vivo osseous metastasis of prostate cancer (PCa). In the present study, the authors induced stable expression of PSMA in mouse PCa cell line RM-1. In vivo osseous metastasis was induced in 37 6-week-old female C57BL/6 mice weighing 22.45 ± 0.456 g. RM-1 cells were actively injected into the femoral bone cavity, leading to bilateral dissymmetry of bone density in the femoral bone. Tumor cells were also detected in bone tissue by pathological examination. The impact on bone density was demonstrated by the significant difference between animals injected with RM-PSMA cells (0.0738 ± 0.0185 g/cm²) and animals injected with RM-empty plasmid cells (0.0895 ± 0.0241 g/cm²). The lytic bone lesion of the RM-PSMA group (68.4%) was higher than that of the control group (27.8%). Immunohistochemistry showed that the expression of both vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) was distinctly higher in the RM-PSMA group than in the control group, while ELISA and Western blot assay indicated that VEGF and MMP-9 were higher in the RM-PSMA group compared to the control group (in vitro). Thus, the present study proposed and then confirmed for the first time that PSMA can promote in vivo osseous metastasis of PCa by increasing sclerotic destruction of PCa cells. Further analyses also suggested that PSMA functions positively on the invasive ability of RM-1 by increasing the expression of MMP-9 and VEGF by osseous metastases in vivo.

Assuntos