Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate specific membrane antigen

PURPOSE: We performed an interim analysis of imaging data collected in 2 phase I radioimmunotherapy trials to determine the ability of monoclonal antibody (mAb) J591 directed to the extracellular domain of prostate specific membrane antigen (PSMA) to target sites of known metastatic prostate cancer accurately. MATERIALS AND METHODS: Patients with progressing hormone independent prostate cancer were entered in 2 phase I dose finding trials with radiolabeled mAb J591. J591 is the first mAb targeting the extracellular domain of PSMA as well as the first de-immunized (humanized) mAb to PSMA to be tested in humans. These trials were primarily designed to assess dose limiting toxicity, maximum tolerated dose, pharmacokinetics and organ dosimetry. Planar gamma camera imaging studies obtained on the first 53 patients were reviewed and compared to sites of metastatic prostate cancer visualized on conventional imaging studies including bone scan, computerized tomography and/or magnetic resonance imaging. In 1 trial 29 patients received 111indium-J591 for imaging followed by 90yttrium-J591 for therapy. In the parallel trial 24 patients were treated with 177lutetium-J591, an isotope that can be imaged directly. RESULTS: Of 53 patients reviewed 46 (87%) had evidence of metastatic disease on conventional scans. Overall, of the 43 evaluable patients J591 accurately targeted bone and/or soft tissue lesions in 42 (98%). J591 accurately targeted bone lesions in 32 of 34 (94%) and soft tissue lesions in 13 of 18 (72%) evaluable patients. CONCLUSIONS: Radiolabeled J591 accurately targets bone and soft tissue metastatic prostate cancer sites, and may be useful for targeting therapeutic and/or diagnostic imaging agents.     

Radioimmunotherapy of prostate cancer in human xenografts using monoclonal antibodies specific to prostate specific membrane antigen (PSMA): studies in nude mice

BACKGROUND: Prostate specific membrane antigen (PSMA), expressed by virtually all prostate cancers is an ideal target for targeted therapy of prostate cancer. Radiolabeled J591 monoclonal antibody (MAb) binds with high affinity to an extracellular epitope of PSMA and localizes specifically in PSMA positive LNCaP tumors in vivo. METHODS: Pre-clinical radioimmunotherapy (RIT) studies using (131)I-huJ591 and (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-huJ591 MAbs were studied in nude mice bearing LNCaP xenografts. RESULTS: A 15-90% reduction in mean tumor volume was observed after a single dose of (131)I-huJ591 (3.7-11.1 MBq) or (90)Y-DOTA-huJ591 (3.7-7.4 MBq). The median survival time increased 2-3 times relative to untreated controls. Multiple administrations of fractionated doses of (90)Y-DOTA-huJ591 were even more effective with minimal toxicity. Radiation dose to blood and tumor was higher with (90)Y than with (131)I. The maximum tolerated dose (MTD) is 5.55 MBq for (90)Y-DOTA-huJ591 and more than 11.1 MBq for (131)I-huJ591. For (90)Y-DOTA-huJ591 at MTD, dose to the tumor was 2,753 cGy. CONCLUSIONS: In nude mice bearing PSMA positive tumors, radiation dose to the tumor with (90)Y-DOTA-J591 is greater for large tumors than with (131)I-J591. The theoretical and practical considerations strongly suggest that (90)Y-DOTA-huJ591 may be a suitable radiopharmaceutical for the treatment of prostate cancer.     

Anti-tumor effects of toxins targeted to the prostate specific membrane antigen

BACKGROUND: There is presently no effective therapy for relapsing, metastatic, androgen-independent prostate cancer. Immunotherapy with monoclonal antibody-vehicled toxins (Immunotoxins, ITs) may be a promising novel treatment option for the management of prostate cancer in these cases. METHODS: Three anti-prostate specific membrane antigen (anti-PSMA) monoclonals (J591, PEQ226.5, and PM2P079.1) were cross-linked to ricin A-chain (RTA; native or recombinant), and their cytotoxic effects were investigated in monolayer and three-dimensional (3-D) cell cultures of prostate carcinoma cells (LNCaP). RESULTS: The various Immunotoxins showed effects in the nanomolar range (IC(50s) of 1.6-99 ng/ml) against PSMA+ cells (IC(50) being the concentration inhibiting 50% cell proliferation or protein synthesis). PSMA(-) cell lines were 62- to 277-fold less sensitive to anti-PSMA ITs, evidencing an appreciable therapeutic window. Treatment with J591-smpt-nRTA (0.35-31.7ng/ml) resulted in complete eradication of 3-D tumor micromasses or in 1.46- to 0.35-log reduction of target cells number, depending on the dose. CONCLUSION: Anti-PSMA ITs appear to be promising for use in the eradication of small prostate tumor cell aggregates present in tissues and in the bone marrow.     

Prostate‐specific membrane antigen for the surgical oncologist: interpreting expression beyond the prostate

The use of prostate‐specific membrane antigen (PSMA) radiotracer in positron emission tomography (PET) has been successfully incorporated into the clinical management of prostate cancer. However, PSMA tracer uptake is not limited to prostate cancer tissue. We reviewed studies exploring PSMA expression beyond the prostate gland using techniques of ⁶⁸Ga‐PSMA PET imaging and immunohistochemistry. PSMA expression has been associated with a variety of solid tumours, and the vasculature associated with neoplastic disease, suggesting that this trans‐membrane glycoprotein may be involved in the neovascularisation process in malignancy. These studies demonstrate the need for more research into the potential utility for ⁶⁸Ga‐PSMA PET imaging in patients with non‐prostatic cancers.     

Fluorodeoxyglucose positron emission tomography studies in the diagnosis and staging of clinically advanced prostate cancer

OBJECTIVE: To determine the value of 18F-fluoro-2-deoxyglucose (FDG) positron-emission tomography (PET) studies in evaluating patients with advanced prostate cancer. PATIENTS AND METHODS: FDG-PET scans were taken in 30 patients with advanced prostate cancer 1 h after an injection with 555 MBq of FDG. Patients were scanned from the base of the skull to the inguinal region (including the pelvis). They were also assessed by computed tomography (CT) of the abdomen and pelvis, and bone scintigraphy, to evaluate them for metastases. RESULTS: Thirteen patients had locally extensive prostate cancer and 17 had metastatic disease. Twenty of the 30 patients were positive for radioisotope uptake in the prostate or extraprostatically. The patients with PET-detected prostate cancer were untreated (seven), treated hormonally while they had rising PSA levels (eight), or treated hormonally with a detectable but stable PSA (five). The remaining 10 patients were negative for FDG uptake in the prostate or any metastatic sites; these 10 patients were receiving hormone therapy, with undetectable PSA levels. CONCLUSION: FDG-PET imaging is not a useful test in evaluating advanced prostate cancer in patients being treated and who have an undetectable PSA level. Staging of advanced prostate cancer may be enhanced by FDG-PET imaging in patients who are untreated, who have had an incomplete response to therapy, or who have a rising PSA level despite treatment.     

Laparoscopic radioisotope-guided sentinel lymph node dissection in staging of prostate cancer

OBJECTIVES: To present our experience in laparoscopic sentinel lymph node (SLN) dissection in staging of clinically localized prostate cancer. METHODS: From November 2001 to January 2005 laparoscopic SLN dissection was performed in 140 patients with clinically localized prostate cancer preceding radical prostatectomy. Mean preoperative prostate-specific antigen (PSA) level was 8.26 ng/ml (SD 9.46). At 24 h before surgery, 2 ml 99mTc-labeled human albumin (2 ml/200 MBq) colloid was injected into the prostate gland under transrectal ultrasound guidance. Prostatic SLNs were detected by preoperative planar scintigraphy and intraoperative scanning with a specially designed laparoscopic gamma probe. The detected nodes were dissected and evaluated on frozen section. In case of positive frozen section extended lymph node dissection was performed. RESULTS: SLN was identified on both or one pelvic sidewall in 96 (68.1%) and 36 (25.7%) of the patients, respectively. SLNs were undetectable in 8 (5.7%) cases. In 48.2% (135 of 280) of the pelvic sidewalls, SLNs were exclusively outside the obturator fossa. Final histopathologic examination revealed SLN metastases in 19 (13.5%) patients; 71.4% (20 of 28) of the detected metastases were outside the current standard of lymph node dissection limited to the obturator fossa. Mean tumor size was 2.3 mm (SD 1.7). CONCLUSIONS: Our data confirm the reliability of laparoscopic SLN dissection in staging of prostate cancer. Significant numbers of detected metastases were outside of the routinely sampled obturator fossa. Small metastasis size makes them undetectable by currently available preoperative imaging modalities.     

MRI of the skeleton in prostate cancer staging

OBJECTIVE: To explore the value of MRI in the detection of bone metastases in newly diagnosed prostate cancer. MATERIAL AND METHODS: MRI examinations of the axial skeleton in 76 patients with newly diagnosed prostate cancer were reviewed, and the relation of these findings to the serum level of prostate specific antigen (PSA) was examined. RESULTS: MRI indicated bone metastases in 26/76 patients (34%) in the entire study group, in 4/24 (17%) with serum PSA <20 ng/ml and in 22/52 (42%) with serum PSA >20 ng/ml. CONCLUSIONS: These results suggest that MRI is a more sensitive indicator of suspected bone metastases than bone scintigraphy in the low range of serum PSA, but less sensitive in the high range. Further studies of MRI and bone scintigraphy in parallel in patients with serum PSA <20 ng/ml are needed to elucidate their relative value in the staging of patients with prostate cancer.     

Preoperative Localization of Parathyroid Adenomas Using 99mTc-MIBI Scintigraphy in Patients with Hyperparathyroidism

Background Technetium (Tc) 99m methoxyisobutyl isonitrile (_99mTc-MIBI) has recently been introduced for parathyroid imaging, as well as for myocardial imaging. We studied the usefulness of _99mTc-MIBI scintigraphy for preoperative localization of abnormal parathyroid glands.
Methods The usefulness of _99mTc-MIBI scintigraphy for detection of hyperfunctional parathyroid lesions was evaluated in 5 patients with primary hyperparathyroidism. The results of localizing the abnormal glands by using _99mTc-MIBI were compared with those obtained by using thallium (Tl) 201-technetium (Tc) 99m (_2ulTI-_99mTc) subtraction scintigraphy, computed tomography, and ultrasonography.
Results The delayed (2 hours) imaging of _99mTc-MIBI scintigraphy was highly useful for accurate localization of the abnormal parathyroid lesions. The diseased glands were detected in all cases where _99mTc-MIBI scintigraphy was used, and using _99mTc-MIBI scintigraphy provided more information than did computed tomography, ultrasonography, or ₂₀₁Tl-_99mTc subtraction scintigraphy. Conclusion: This method is simple and essential for detecting hyperfunctioning parathyroid glands, especially those with small or ectopic lesions. This technique should be widely applied as a localizing diagnostic method for hyperparathyroidism.     

In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen

Limited options for the treatment of prostate cancer have spurred the search for new therapies. One innovative approach is the use of targeted alpha therapy (TAT) to inhibit cancer growth, using an alpha particle emitting radioisotope such as (213)Bi. Because of its short range and high linear energy transfer (LET), alpha-particles may be particularly effective in the treatment of cancer, especially in inhibiting the development of metastatic tumors from micro-metastases. Prostate-specific membrane antigen (PSMA) is expressed in prostate cancer cells and the neovasculature of a wide variety of malignant neoplasms including lung, colon, breast and others, but not in normal vascular endothelium. The expression is further increased in higher-grade cancers, metastatic disease and hormone-refractory prostate cancer (PCA). J591 is one of several monoclonal antibodies (mabs) to the extracellular domain of PSMA. Chelation of J591 mab with (213)Bi forms the alpha-radioimmunoconjugate (AIC). The objective of this preclinical study was to design an injectable AIC to treat human prostate tumors growing subcutaneously in mice. The anti-proliferative effects of AIC against prostate cancer were tested in vitro using the MTS assay and in vivo with the nude mice model. Apoptosis was documented using terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridinetriphosphate [dUTP] nick end-labeling (TUNEL) assay, while proliferative index was assessed using the Ki-67 marker. We show that a very high density of PSMA is expressed in an androgen-dependent human PCA cell line (LNCaP-LN3) and in tumor xenografts from nude mice. We also demonstrate that the AIC extensively inhibits the growth of LN3 cells in vitro in a concentration-dependent fashion, causing the cells to undergo apoptosis. Our in vivo studies showed that a local AIC injection of 50 microCi at 2 days post-cell inoculation gave complete inhibition of tumor growth, whereas results for a non-specific AIC were similar to those for untreated mice. Further, after 1 and 3 weeks post-tumor appearance, a single (100 microCi/100 microl) intra-lesional injection of AIC can inhibit the growth of LN3 tumor xenografts (volume<100 mm(3)) in nude mice. Tumors treated with AIC decreased in volume from a mean 46+/-14 mm(3) in the first week or 71+/-15 mm(3) in the third week to non-palpable, while in control mice treated with a non-specific AIC using the same dose, tumor volume increased from 42 to 590 mm(3). There were no observed side effects of the treatment. Because of its in vitro cytotoxicity and these anti-proliferative properties in vivo, the (213)Bi-J591 conjugate has considerable potential as a new therapeutic agent for the treatment of prostate cancer.     

Correlation between BMD and bone scintigraphy in patients with prostate cancer

OBJECTIVE: Bone metastasis is a major cause of morbidity in prostatic cancer. Therefore, detecting and monitoring bone lesions are crucial for treatment of prostatic carcinoma. We aimed to evaluate total body bone mineral density and regional bone mineral density in patients with prostate cancer with and without metastases, and to compare them with bone scintigraphy. METHODS: Fifty-four patients with prostatic carcinoma and 20 healthy subjects were investigated with bone scintigraphy and dual-energy X-ray absorptiometry. The bone scintigraphic findings were classified as normal (score 0: n = 22), abnormal but not typical for metastases (score 1: n = 18), and typical pattern of metastases (score 2: n = 14). RESULTS: The patients with bone metastases prostate cancer had significantly higher total bone mineral density and regional bone mineral density of trunk and pelvis than healthy controls and prostate cancer patients without bone metastases. There was a significant positive correlation between bone scan score and total bone mineral density and regional bone mineral density of trunk and pelvis (r = 0.328, P < 0.05, r = 0.60, P < 0.001, r = 0.480, P < 0.001, respectively). CONCLUSION: Our results show that patients of prostate cancer with bone metastases have increased bone mineral density (BMD) in the pelvis and trunk, possibly because of a predominance of osteoblastic over osteolytic metastases demonstrated by Tc-99m MDP bone scan.     

Sinnvolle bildgebende Diagnostik des lokal fortgeschrittenen Prostatakarzinoms

Prostate cancer is one of the principal medical problems facing the male population in developed countries with an increasing need for sophisticated imaging techniques and risk-adapted treatment options. This article presents an overview of the current imaging procedures in the diagnosis of locally advanced prostate cancer. Apart from conventional gray-scale transrectal ultrasound (TRUS) as the most frequently used primary imaging modality we describe computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). CT and MRI not only allow assessment of prostate anatomy but also a specific evaluation of the pelvic region. Color-coded and contrast-enhanced ultrasound, real-time elastography, dynamic contrast enhancement in MR imaging, diffusion imaging, and MR spectroscopy may lead to a clinically relevant improvement in the diagnosis of prostate cancer. While bone scintigraphy with (99m)Tc-bisphosphonates is still the method of choice in the evaluation of bone metastasis, whole-body MRI and PET using (18)F-NaF, (18)F-FDG, (11)C-choline, (11)C-acetate, and (18)F-choline as tracers achieve higher sensitivities.     

Preoperative technetium Tc 99m sestamibi SPECT imaging in the management of primary hyperparathyroidism in patients with concomitant multinodular goiter

HYPOTHESIS: Preoperative parathyroid and thyroid imaging using technetium Tc 99m sestamibi scintigraphy-single-photon emission computed tomography (Tc 99m MIBI SPECT) and technetium Tc 99m sodium pertechnetate, respectively, in patients with parathyroid adenomas and concomitant multinodular goiters enables the selection of those suitable for minimally invasive radio-guided surgery. DESIGN: One hundred thirty patients with primary hyperparathyroidism were treated surgically during a 30-month period. Forty-one of these 130 patients had an associated multinodular goiter. All patients underwent planar and SPECT parathyroid scintigraphy using Tc 99m MIBI, and thyroid scintigraphy with technetium Tc 99m pertechnetate 2 to 5 days before surgery. On the morning of surgery each patient was reinjected with Tc 99m MIBI for intraoperative localization and validation. Minimally invasive radio-guided parathyroidectomy was performed using a handheld gamma-detection device with a thyroid probe. Removed glands were submitted for histopathologic examination for comparison with the scintigraphic results. Quantitative analysis of parathyroid activity was performed. RESULTS: Minimally invasive, radioguided parathyroidectomy was successfully performed in 21 (51%) of 41 patients who had a concomitant multinodular goiter. The remaining 20 patients underwent standard neck exploratory surgery because of associated thyroid disease; 5 of them had malignant thyroid disease. Among the 41 patients planar scintigraphy correctly identified 28 adenomas (68%). Single-photon emission computed tomographic imaging identified an additional 11 adenomas for a sensitivity of 95% and a specificity of 100%. Moreover, SPECT imaging correctly identified malignant thyroid nodules in 4 of 5 patients. Technetium Tc 99m MIBI retention was noted in only 25 adenomas (61%) while the remaining adenomas demonstrated a rapid washout. The average uptake ratio of parathyroid counts to maximum thyroid activity was significantly correlated with parathyroid hormone levels before surgery (P = .04). CONCLUSIONS: Our data encourage the use of preoperative SPECT imaging of parathyroid adenomas in patients who have multinodular goiters to select those suitable for minimally invasive radioguided surgery. This technique also offers important information regarding thyroid nodules that are suspicious for malignancy. The intraoperative gamma-probe technique enables the surgeon to focus his or her search, provides instant feedback regarding the progress of the operation, reduces surgical trauma and complications, and yields better cosmetic results. Patients with higher presurgical parathyroid hormone levels may especially benefit from radioguided surgery.     

Primary lymph-node staging with 68Ga-PSMA PET in high-risk prostate cancer: pathologic correlation with extended pelvic lymphadenectomy specimens

Aim of the studyThis study aims to assess the diagnostic efficacy of Gallium-68-prostate-specific membrane antigen positron emission tomography (PET)/computed tomography (CT) (68Ga PSMA PET-CT) in primary nodal staging of high-risk prostate cancer (PCa) when compared to pathologic findings of extended pelvic lymph-node dissection (eLND).Materials and methodsThe records of high-risk PCa patients who were preoperatively staged through 68Ga PSMA PET-CT and who underwent robot-assisted radical prostatectomy with eLND either alone or as part of multimodal definitive therapy between August 2016 and November 2019 were retrospectively reviewed. Surgeons were not blinded to the results of the 68Ga PSMA PET-CT scan. Pathologic uptake was defined as any anomalous uptake which was not better explained by another cause and was suggestive of PCa. The reference standard for this study was the pathologic confirmation using a node-based analysis. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for 68Ga PSMA PET-CT were calculated in a per-patient analysis using IBM SPSS Statistics version 25.ResultsSeventeen patients met the selection criteria. Mean age was 63 years (range 44–77) and mean and median preoperative serum prostate specific antigen was 19.25 and 9 ng/ml (range 6–131), respectively. The most common pathologic Gleason score was 8 (52.9% of cases). Seven patients (41%) had positive surgical margins and were submitted to adjuvant radiotherapy. Mean number of per patient removed lymph-nodes was 13 (±2.19). 68Ga PSMA PET-CT showed findings compatible with lymph node metastases in 4/17 patients and with locally-confined disease in 13/17 patients. Following pathologic confirmation, the per-patient sensibility of the 68Ga PSMA PET-CT was calculated at 75% (1 false negative) and the specificity at 92.3% (1 false positive) for detection of lymph node metastasis on primary staging of high-risk PCa patients. Positive and negative predictive value were 75% and 92.3%, respectively; accuracy of the test was calculated at 88.2%. All patients were submitted to 68Ga PSMA PET-CT re-evaluation 6 months after surgery and tested negative for local, nodal, or distant recurrence of disease.Conclusions68Ga PSMA PET-CT appears to have a high negative predictive value for local lymph node metastases in high-risk primary PCa when compared to pathologic findings of eLND. Its role in the primary nodal staging of high-risk PCa patients worths further evaluation.     

The prostate-specific membrane antigen: Lessons and current clinical implications from 20 years of research

ObjectiveDespite 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 materialsA 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.ResultsSixty 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.ConclusionsTwenty 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.     

1alpha,25-Dihydroxyvitamin D3 down-regulates expression of prostate specific membrane antigen in prostate cancer cells

BACKGROUND: Prostate specific membrane antigen (PSMA) expression correlates with prostate cancer grade and is increased in hormone-refractory prostate cancer. The increased expression of PSMA following androgen deprivation therapy may be a consequence of the down-regulation of PSMA expression by androgen. Moreover, 1alpha,25-dihydroxyvitamin D3 (1,25-VD) has been shown to suppress prostate cancer progression as well as cell motility and invasion. Since PSMA is positively correlated with both of these characteristics, we hypothesized that 1,25-VD would regulate PSMA expression. METHODS: LNCaP prostate cancer cells were treated with 1,25-VD, followed by analysis of cell surface PSMA expression. The PSMA enhancer, located within the third intron of the PSMA gene, was cloned into a reporter vector and regulation by 1,25-VD was investigated. The role of the androgen receptor (AR) in 1,25-VD mediated suppression of PSMA expression was examined using Casodex and AR specific siRNA. RESULTS: Surface expression of PSMA was significantly decreased in a dose-dependent manner by 10 nM 1,25-VD or greater. Regulation by 1,25-VD occurred at the level of the PSMA enhancer. Over-expression of the vitamin D receptor (VDR) also decreased expression of PSMA. Additionally, suppression of AR translation using siRNA technology blocked the suppressive effect of 1,25-VD on PSMA expression, however inhibition of PSMA expression by 1,25-VD occurred in the absence of androgens. CONCLUSIONS: Suppression of PSMA by 1,25-VD occurs at the level of the PSMA enhancer and is elevated by over-expression of the VDR. This regulation involves the AR, but is not dependent on the presence of androgens.     

A new generation of monoclonal and recombinant antibodies against cell-adherent prostate specific membrane antigen for diagnostic and therapeutic targeting of prostate cancer

BACKGROUND: Prostate-specific membrane antigen (PSMA) is an excellent candidate for targeting prostate cancer by virtue of its restricted expression on prostatic epithelial cells and its upregulation on prostatic carcinoma cells. PSMA is expressed on the cell surface displaying a specific three-dimensional structure. Therefore, only antibodies with a high cell binding activity will have an important impact on antibody-based imaging and therapy. METHODS: Monoclonal antibodies (mAbs) and single chain antibody fragments (scFvs) were prepared from spleen cells of mice that had been immunized either with purified PSMA or a cell lysate of prostate cancer LNCaP cells containing native PSMA. mAbs and scFvs were screened for reactivity with purified PSMA and binding to PSMA-expressing LNCaP cells. RESULTS: From mice immunized with purified PSMA, we obtained three mAbs (K7, K12, D20) and four scFvs (G0, G1, G2, G4), which were highly reactive with the isolated antigen, but showed weak or no reaction with viable LNCaP cells. From mice immunized with unpurified LNCaP lysate, we obtained three mAbs (3/E7, 3/F11, 3/A12), and one scFv (A5), which were reactive with purified PSMA, also showing a strong and specific binding to viable LNCaP cells and PSMA-transfected cells. CONCLUSIONS: Our results suggest that only the mAbs and scFvs, that were elicited with unpurified LNCaP lysate and not with purified PSMA will be useful agents for diagnostic imaging and therapeutic applications of prostate cancer.     

18F-PSMA-1007 PET/CT uptake in multiple angiolipomas caused by PSMA expression in capillaries: a case report

Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein that was originally cloned in the membrane of prostate gland epithelial cells. It has been confirmed to be highly expressed in prostate cancer cells, and in some non-prostatic tissues, including the brain and some benign lesions. PSMA-based imaging has been extensively used for the assessment of prostate carcinoma. The high uptake of PSMA imaging in these non-prostate cancer lesions may lead to some misdiagnosis. It is of important clinical significance to explore the possible causes of high PSMA uptake in these lesions. Here, we present a case of a 77-year-old man with prostate carcinoma who underwent a whole-body ¹⁸F-PSMA-1007 positron emission tomography/computed tomography (PET/CT) scan for staging. The results of the scan showed intense tracer uptake in both the prostatic bed and in multiple subcutaneous lesions. The subcutaneous lesions were later found to be angiolipomas by histopathological examination. Immunohistochemistry demonstrated strong positive cytoplasmic PSMA staining in lesional prostate cancer cells in prostate carcinoma, and mild-to-moderate positive cytoplasmic capillary PSMA staining in angiolipoma fatty density nodules. Our case report therefore demonstrated that ¹⁸F-PSMA-1007 PET/CT uptake in multiple angiolipomas was caused by PSMA expression in capillaries, and further knowledge of PSMA expression in benign lesions may be critical to minimize false-positive findings with ¹⁸F-PSMA-1007 PET/CT imaging.     

Evaluation of prostate cancer patients receiving multiple staging tests, including ProstaScint scintiscans

BACKGROUND: Multiple serum tests were performed on archival samples from patients who participated in trials to assess the ProstaScint scan staging ability. Traditional statistical analysis as well as artificial neural network (ANN) analysis were employed to evaluate individual patients and the group as a whole. The results were evaluated so that each factor was tested for prognostic value. METHODS: Data obtained from serum tests, bone scans, and ProstaScint scans were evaluated by traditional statistical methods and ANN to determine the individual value in clinical staging of prostate cancer. RESULTS: Two hundred seventy-five patients (180 postprostatectomy, 95 intact prostate) with prostate cancer (14 with distant metastases) were available for analysis. Data available included: clinical state (remission or progression), most recent clinical TNM stage, bone scan, and ProstaScint scan. Serum was tested for prostate-specific membrane antigen(PSMA), prostate-specific antigen(PSA), free PSA (fPSA), and complexed PSA (cPSA). Additional calculations included percent free PSA, and percent complexed PSA. Spearman individual statistical assessment for traditional group evaluation revealed no significant factors for T-stage. The free PSA and complex PSA had a significant association with node (N)-status. The distant metastases (M) stage correlated well with the bone scan and clinical stage. ANN analysis revealed no significant T-stage factors. N-stage factors showed a 95% sensitivity and 49% specificity. These factors included the presence or absence of a prostate, PSA serum levels, bone scan, and ProstaScint scans as major associated indicators. ANN analysis of the important variables for M-stage included ProstaScint scan score, and PSA levels (total, percent complexed, percent free, and fPSA). These factors were associated with a 95% sensitivity and 15% specificity level. CONCLUSIONS: Two hundred seventy-five patients receiving treatment for prostate cancer were evaluated by ANN and traditional statistical analysis for factors related to stage of disease. ANN revealed that PSA levels, determined by a variety of ways, ProstaScint scan, and bone scan, were significant variables that had prognostic value in determining the likelihood of nodal disease, or distant disease in prostate cancer patients.