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Simple Summary Prostate cancer (PCa) relapse occurs in up to 50% of patients after radical treatment. Once PCa recurrence is detected, a precise identification of the number and sites of recurrence is necessary to tailor the treatment on the patient’s needs. Positron emission tomography (PET) plays a pivotal role in this clinical setting and new radiotracers have been developed to improve its performance. While 68Ga-PSMA is a well-established radiotracer for PCa recurrence detection, 68Ga-DOTA-RM2 is a recently proposed tracer that targets the gastrin-releasing peptide receptors that are overexpressed in prostate cancer. In this work, the performance of 68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI in identifying recurrent disease were compared on the same cohort, using the same study protocol, as this is the only way to assess whether one outperforms the other and therefore should be preferred in clinical practice. Furthermore, the association between PET findings and clinical and histopathological characteristics was investigated to find potential biomarkers. Abstract The aim of the present study is to investigate and compare the performances of 68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI in identifying recurrent prostate cancer (PCa) after primary treatment and to explore the association of dual-tracer PET findings with clinical and histopathological characteristics. Thirty-five patients with biochemical relapse (BCR) of PCa underwent 68Ga PSMA PET/MRI for restaging purpose, with 31/35 also undergoing 68Ga-DOTA-RM2 PET/MRI scan within 16 days (mean: 3 days, range: 2–16 days). Qualitative and quantitative image analysis has been performed by comparing 68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI findings both on a patient and lesion basis. Clinical and instrumental follow-up was used to validate PET findings. Fisher’s exact test and Mann-Whitney U test were used to investigate the association between dual-tracer PET findings, clinical and histopathological data. p-value significance was defined below the 0.05 level. Patients’ mean age was 70 years (range: 49–84) and mean PSA at time of PET/MR scans was 1.88 ng/mL (range: 0.21–14.4). A higher detection rate was observed for 68Ga-PSMA PET/MRI, with more lesions being detected compared to 68Ga-DOTA-RM2 PET/MRI (26/35 patients, 95 lesions vs. 15/31 patients, 41 lesions; p = 0.016 and 0.002). 68Ga-PSMA and 68Ga-DOTA-RM2 PET/MRI findings were discordant in 11/31 patients; among these, 10 were 68Ga-PSMA positive (9/10 confirmed as true positive and 1/10 as false positive by follow-up examination). Patients with higher levels of PSA and shorter PSA doubling time (DT) presented more lesions on 68Ga-PSMA PET/MRI (p = 0.006 and 0.044), while no association was found between PET findings and Gleason score. 68Ga-PSMA has a higher detection rate than 68Ga-DOTA-RM2 in detecting PCa recurrence. The number of 68Ga-PSMA PET positive lesions is associated with higher levels of PSA and shorter PSA DT, thus representing potential prognostic factors.

The aim of the present study is to investigate the synergic role of 68Ga-PSMA PET/MRI and 68Ga-DOTA-RM2 PET/MRI in prostate cancer (PCa) staging. We present pilot data on twenty-two patients with biopsy-proven PCa that underwent 68Ga-PSMA PET/MRI for staging purposes, with 19/22 also undergoing 68Gaa-DOTA-RM2 PET/MRI. TNM classification based on image findings was performed and quantitative imaging parameters were collected for each scan. Furthermore, twelve patients underwent radical prostatectomy with the availability of histological data that were used as the gold standard to validate intraprostatic findings. A DICE score between regions of interest manually segmented on the primary tumour on 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and on T2 MRI was computed. All imaging modalities detected the primary PCa in 18/19 patients, with 68Ga-DOTA-RM2 PET not detecting any lesion in 1/19 patients. In the remaining patients, 68Ga-PSMA and MRI were concordant. Seven patients presented seminal vesicles involvement on MRI, with two of these being also detected by 68Ga-PSMA, and 68Ga-DOTA-RM2 PET being negative. Regarding extraprostatic disease, 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and MRI resulted positive in seven, four and five patients at lymph-nodal level, respectively, and at a bone level in three, zero and one patients, respectively. These preliminary results suggest the potential complementary role of 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and MRI in PCa characterization during the staging phase.

Purpose: The aim of the present study is to investigate the synergic role of 68Ga-PSMA PET/MRI and 68Ga-DOTA-RM2 PET/MRI in PCa staging. Methods: Fifteen patients with biopsy-proven PCa underwent both 68Ga-PSMA PET/MRI and 68Ga-DOTA-RM2 PET/MRI within one month. TNM classification based on image findings was performed and semi-quantitative PET and quantitative MRI parameters were collected for each scan. Finally, DICE score between regions of interest manually segmented on the primary tumor on 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and on T2 MRI was computed. Results: All imaging modalities detected the primary PCa in 15 patients, with slight differences regarding the multifocality of intra-prostatic findings. Two patients presented seminal vesicles involvement on MRI, one of these was also detected by 68Ga-PSMA, with no uptake on 68Ga-DOTA-RM2 images. Regarding extra prostatic disease, 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and MRI resulted positive in 6, 2 and 4 patients at lymph-nodal level, respectively, and at bone level in 2, 0 and 1 patients, respectively, with 68Ga-PSMA PET detecting more lesions compared to 68Ga-DOTA-RM2 PET. The different findings detected by 68Ga-PSMA PET and 68Ga-DOTA-RM2 PET might reflect the complementary role of these radiotracers, as they detected different foci of intraprostatic disease, seminal vesicle invasion, lymph nodal and bone involvement. Conclusion: These preliminary results suggest a synergic role of 68Ga-PSMA PET, 68Ga-DOTA-RM2 PET and mpMRI in PCa characterization during the staging phase. (EudraCT: 2018-001034-18)

Simple Summary PET/MRI is a relatively new, hybrid imaging tool that allows practitioners to obtain both a local and systemic staging in breast cancer patients in a single exam. To date, the available evidence is not sufficient to determine the role of PET/MRI in breast cancer management. The aims of this paper are to provide an overview of the current literature on PET/MRI in breast cancer, and to illustrate two ongoing trials aimed at defining the eventual role of PET/MRI in axillary staging in two different settings: patients with early breast cancer and patients with positive axillary nodes that are candidates for primary systemic therapy. In both cases, findings from PET/MRI will be compared with the final pathology and could be helpful to better tailor axillary surgery in the future. Abstract Axillary surgery in breast cancer (BC) is no longer a therapeutic procedure but has become a purely staging procedure. The progressive improvement in imaging techniques has paved the way to the hypothesis that prognostic information on nodal status deriving from surgery could be obtained with an accurate diagnostic exam. Positron emission tomography/magnetic resonance imaging (PET/MRI) is a relatively new imaging tool and its role in breast cancer patients is still under investigation. We reviewed the available literature on PET/MRI in BC patients. This overview showed that PET/MRI yields a high diagnostic performance for the primary tumor and distant lesions of liver, brain and bone. In particular, the results of PET/MRI in staging the axilla are promising. This provided the rationale for two prospective comparative trials between axillary surgery and PET/MRI that could lead to a further de-escalation of surgical treatment of BC. • SNB vs. PET/MRI 1 trial compares PET/MRI and axillary surgery in staging the axilla of BC patients undergoing primary systemic therapy (PST). • SNB vs. PET/MRI 2 trial compares PET/MRI and sentinel node biopsy (SNB) in staging the axilla of early BC patients who are candidates for upfront surgery. Finally, these ongoing studies will help clarify the role of PET/MRI in BC and establish whether it represents a useful diagnostic tool that could guide, or ideally replace, axillary surgery in the future.

Specific targeting of radioactive agents to tumor cells has been a major goal of the in vivo use of monoclonal antibodies (MoAb) for diagnostic and therapeutic purposes. However, only a relatively small amount of the injected dose of MoAbs is bound by the tumor, while MoAb conjugated to radioisotope keep circulating in the blood stream and in normal tissue. Indeed, a relatively low tumor to non-tumor ratio is one of the major drawbacks of the use of antibodies for tumor radioimaging. The avidin-biotin system is widely used for in vitro applications, in immunohistochemistry, for the stepwise construction of macromolecular complexes onto specific target molecules in order to make them detectable by chemical or physical methods. The affinity of avidin for biotin is extremely high. The combined use of biotin and avidin and MoAb not only enhances the effect of MoAb at the binding site but also allows one to separate the delivery of the MoAb and the radioactive label.

Periprosthetic capsules are a common reaction of the body to silicone or polyurethane breast implants. The aim of this study was to evaluate similarities and differences in the histological features of periprosthetic capsules surrounding silicone implants and polyurethane foam-coated implants and to correlate those features with the age of the implants. Tissues were studied from 41 periprosthetic capsules surrounding textured prostheses and from 20 capsules surrounding polyurethane foam-coated implants. For each sample we evaluated synovial metaplasia, density of collagen fibers or fibrosis, orientation of collagen fibers, and foreign body reaction (granulomatous reaction). Synovial metaplasia was seen in the capsular tissue from both types of implant, but more so from capsules surrounding polyurethane implants more than 5 years old. The density and orientation of the collagen fibers and the foreign body reaction were very similar for the two types of implant.

The diagnosis of recurrent ovarian carcinoma is usually determined at surgical re-exploration since the main non-invasive diagnostic tests have low accuracy. It would be desirable to have a high accuracy non-invasive diagnostic procedure. With this aim, we have assessed the utility of three-step immunoscintigraphy. Thirty patients were intravenously injected with biotinylated monoclonal antibodies MOv18 and B72.3, followed by avidin–streptavidin injection and finally by111In-biotin. Tumour recurrences were imaged 2 h post radioactivity injection. All patients underwent surgical re-exploration 3–4 days after immunoscintigraphy; the presence of tumour in the area of immunoscintigraphic uptake was evaluated in the biopsied material. Twenty-one patients studied were true-positive, five were true-negative, four were false-positive and none was false-negative. The diagnostic accuracy, positive predictive value and negative predictive value were 87%, 84% and 100% respectively. If these findings are confirmed in a larger number of patients, we expect immunoscintigraphy to be introduced as a cost-effective procedure in the follow-up of patients who have received surgery for ovarian carcinoma, since it promises to reliably identify patients who do not require surgical re-exploration, and guide biopsies when they are indicated. © 2000 Cancer Research Campaign

The in vivo post-targeting of tumor by means of anti-carcinoembryonic-antigen (CEA) monoclonal antibodies (MAbs) and the avidin-biotin three-step system was tested by immunoscintigraphy and radioimmunoguided surgery (RIGS) in six patients with primary or recurrent rectal cancer. The patients were preoperatively injected with 1 mg of FO23C5 (anti-CEA) and/or B72.3 anti-tumor-associated glycoprotein (TAG-72) biotinylated MAb; after 24 hours, 1 mg of avidin was administered, and, after a further 24 hours, biotin labeled to Indium-111 (In111) was injected. Preoperative imaging was obtained by means of a gamma camera, and a portable gamma-detecting probe (Neoprobe 1000) was intraoperatively used to count tumor and surrounding normal tissue. Eight tumor sites were localized in the six patients. Four lesions were identified preoperatively and six intraoperatively with a mean tumor-to-normal-tissue (T/NT) ratio of 1:8. This method allowed preoperative scintigraphy and intraoperative radioimmunodetection to be performed with a single radioactive compound injection of biotin labeled to In111 within few days before surgery.

The use of a cocktail of monoclonal antibodies in intraoperative radioimmunodetection of colorectal tumour has been evaluated in 14 patients. Eight patients had primary and six recurrent colorectal cancer. Three different monoclonal antibodies were used included B72.3, recognizing TAG72 antigen, FO23C3 and FO23C5 directed against two epitopes of CEA. The antibodies were labeled with 125I. During surgery the radioactive emission of tumour and normal tissue was evaluated by a gamma detecting probe. Ten patients showed positive intraoperative results and in particular 6 (75%) of the 8 patients with primary tumour and 4 (67%) of the 6 patients with recurrence, with a mean tumour to normal tissue ratio of 2.2. Intraoperative radioimmunodetection was instrumental in modifying the therapeutic approach in two patients with recurrent cancer but in none of the patients with a primary presentation. Immunohistochemical analysis, to evaluate TAG72 and CEA antigen expression, was performed in 13 cases. CEA antigen was expressed in 8/13 cases and TAG72 in 5/13. Thus the sensitivity was 38.5% and 61.5% with B72.3 and anti-CEA monoclonal antibodies respectively, while in combination the sensitivity was 71.4%. The use of a cocktail of different antibodies improved the sensitivity of intraoperative radioimmunodetection of colorectal tumours, when compared with a single antibody injection. This approach might improve the clinical use of radioimmunodetection.

Few data are available on the visualization of somatostatin receptors in vivo in patients with thyrotropin (TSH)-secreting adenoma. We studied five patients with TSH-secreting adenomas using single-photon emission tomography (SPET) after administration of indium-111 pentetreotide. The intensity of 111In-pentetreotide uptake by the tumours was correlated with the degree of TSH suppression after a single administration of 100 microg octreotide s. c. Five patients (three women and two men) aged 27-46 years were investigated. Except for one patient with acromegaly, all had pure TSH-secreting tumours. One patient was previously untreated, while two had received octreotide, one antithyroid drugs, and one radioiodine. In all patients SPET demonstrated increased uptake of 111In-pentetreotide by the pituitary adenoma. The target to non-target ratio (T/nT) of 111In-pentetreotide uptake was higher than 10 in three patients. Administration of 100 microg octreotide s. c. caused a significant reduction in TSH levels from 4.8+/-1.4 mU/l to a nadir of 3.1+/-1.1 mU/l after 6 h (P

A method was set up for single-photon emission tomographic (SPET) quantification of radioactivity concentration in small anatomical structures. The method is based on the theoretical model proposed by Kessler et al. (J. Comput Assist Tomogr 1984; 8: 514–522) describing the effects of spatial resolution (partial volume effect and spillover) on the quantification of radioactivity concentration in small spherical objects. The model was validated here in SPET, by phantom experimental measurements, in relation to object size and source/background contrast. Good agreement was found between model-predicted and SPET-measured radioactivity concentration ratios in hot spots in hot background experiments. Accuracy of the method was assessed for comparison of model-corrected and true radioactivity concentration ratios and was found to be within 8.5% over the full range of object size (9.4–36.5 mm). The good agreement found indicates that the model can be used to correct for partial volume effect and spillover in specific clinical situations, when the anatomical structure under study can be approximated by a sphere of known size (e.g. neuroreceptor and tumour studies). The method was applied to a representative SPET monoclonal antibody patient study for the quantification of radioactivity concentration in ocular melanoma.

The detection of chromogranins (Cg) by immunohistochemistry and serology represents a new in vitro diagnostic tool for endocrine tumours. We have recently reported on the feasibility of targeting chromogranin A (CgA) for in vivo detection of pituitary adenomas by immunoscintigraphy (ISG). The scintigraphic procedure, based on an anti-CgA monoclonal antibody and on the avidin-biotin three-step method (Cg-3S-ISG), was evaluated on a group of 29 consecutive patients with known or suspected endocrine tumours other than pituitary adenomas, i.e. medullary thyroid carcinoma, carcinoid, insulinoma and parathormone- or ACTH-producing tumours. Primary tumours (10) and recurrences (16) were visualised in 26 patients, whereas conventional imaging techniques (planar radiography, computerised tomography, magnetic resonance imaging and ultrasonography) failed to detect the tumour sites in ten of the same (Cg-3S-ISG-positive) patients. Therefore, these preliminary results indicate that Cg-3S-ISG, the first immunological method able to detect endocrine tumours in vivo, has a higher diagnostic accuracy than conventional imaging techniques (93.1% compared with 65.5%).

To evaluate the use of pretargeted immunoscintigraphy (ISG) in the diagnosis and follow-up of patients with medullary thyroid carcinoma (MTC), we studied 25 patients with histologically proven disease; ISG was repeated after surgery in two patients. The antibody, either an anticarcinoembryonic antigen (CEA) or an antichromogranin A (CgA) biotinylated monoclonal antibody (MAb) or a cocktail of the two biotinylated MAbs was first injected. After 24 h, avidin was administrated i.v., followed by 111In-labelled biotin 24 h later. Fifty-two lesions were visualised. Six primary tumours, diagnosed by increased calcitonin levels, were all correctly diagnosed; 47 recurrences, also suspected by blood tumour markers, were detected and confirmed by cytology or histology. In one case, single photon emission tomography allowed the detection of small lymph nodes with a diameter of 4-7 mm. These lesions, not judged neoplastic by ultrasound, were confirmed to be neoplastic by fine needle aspiration. Pretargeted ISG correctly localises primary tumours and recurrences in MTC patients, when the only marker of relapse is serum elevation of calcitonin. With this three-step pretargeting method, cocktails of potentially useful MAbs can be used, avoiding false-negative studies that may occur when CEA or CgA are not expressed. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

The imaging of cerebral gliomas with radiolabelled monoclonal antibodies (MoAbs) has been previously reported. However, previous studies have been hampered by the drawback of a low tumour to non-tumour ratio. In order to overcome this problem we have developed a three-step pre-targeting method using the avidin-biotin system. The rationale of this technique consists in vivo labelling of biotinylated MoAbs targeted onto tumour deposits, when most of the unbound antibodies have been cleared from the bloodstream as avidin-bound complexes. The anti-tenascin MoAb BC2, specific for the majority of gliomas, was biotinylated and 1 mg was administered i.v. in 20 patients with histologically documented cerebral lesions. After 24–36 h, 5 mg avidin was injected i.v. followed 24 h later by a third i.v. injection of 0.2 mg PnAO-biotin labelled with 15–20 tnCi technetium-99m. No evidence of toxicity was observed. Whole-body biodistribution was measured at 20 min, 3 h and 5 h post-injection. [99mTc]PnAO-bio-tin had a fast blood clearance and was primarily excreted through the biliary system. A dedicated single-photon emission tomography system was used to acquire brain tomographic images 1–2 h after the administration of [99mTc]PnAO-biotin. Tumours were detected in 15/18 glioma patients with a tumour to non-tumour ratio of up 14:1. This three-step method, based on the sequential administration of anti-tenascin MoAb BC2, avidin and [99mTc]PnAO-biotin, can support computed tomography or magnetic resonance imaging for the diagnosis and follow-up of patients with glioma. Further studies are required to evaluate the potential of this technique for therapeutic application.

PURPOSE: Radiolabeled monoclonal antibodies (MAbs) have been reported to allow tumor intraoperative detection by means of a gamma-detecting probe. The technology is called the Radioimmunoguided Surgery (RIGS ® ) system. The main inconveniences of the method are 1) the long interval needed for clearance of unattached MAbs from the patient's body, between the injection of the MAb and surgery, and 2) the low sensitivity of current MAbs used in detecting small tumors. We describe a new method to overcome these inconveniences using biotinylated MAbs and avidin in order to obtain a rapid blood clearance of the radiolabeled MAbs both anticarcinoembryonic antigen and antitumor-associated glycoprotein-72 MAbs. METHODS: Twenty patients with primary and recurrent colorectal cancer have been enrolled in the study; 125 I-biotinylated MAbs FO23C5 (anticarcinoembryonic antigen) and B72.3 (antitumor-associated glycoprotein-72) followed by cold avidin were injected in 13 patients and 7 patients, respectively. RESULTS: A decrease of 94±3 perceNt of circulating radioactivity was Achieved in 3 to 5 days. PatientS underwent surgery approximAtely seven days after MAb injections rather than afder four weeks. Tumors were localized in 14/20 (70 pErcent) Patients (true positive), 2 (10 percent) were false Negative, and 4 (20 percent) were true negative. The overall sensitivity level in early-stage primary cancers was 37 percent when related to the presencE of disease and 75 percent when related to antigenic exprescion. The sensitivity for moRe advanced cancer and for recurRences was 10 percent. MoreOver, the in vivo tumor dargeting of biotinylated MAb was demonstrated in frozen tumor section by direct streptoavidin-peroxidasE staining. CONCLUSIONS: The avidin-biotin system may enhance applicability and effectiveness of radioimMunoguided surgery (RIGS ® ).

For various pituitary adenomas, it has been demonstrated that somatostatin receptor can be present. Pilot studies have shown that radio-indium labeled pentetreotide allows very good scintigraphic localization of somatostatin receptor-bearing cell masses. Recently, the presence of CgA in pituitary adenomas has also been demonstrated. MAb A11, raised against CgA, has been successfully used with a three-step ISG for the diagnosis of neuroendocrine tumors. Therefore the combined use of three-step ISG with MAb A11 and radiolabeled somatostatin can be useful in the diagnosis of pituitary adenomas. Twelve patients, 5 secreting (group A) and 7 nonsecreting (group B) pituitary adenomas, were enrolled in the study. All patients underwent three-step ISG, and, 2 wk later, scintigraphy with 111In-labeled pentetreotide (Octreoscan). Three-step ISG consisted of i.v. injection of 1 mg of biotinylated MAb A11 (first step), followed by 10 mg of avidin (second step) and [99mTc]PnAO-biotin (third step). Tomographic imaging were acquired for three-step ISG and Octreoscan at 2 and 4 h after radiotracer injection, respectively. The results are the following: 2 patients of group A (secreting tumors) had a positive three-step ISG, whereas all the patients but one of the same group had a positive pentetreotide study; all the patients of group B (nonsecreting tumors) had a positive three-step ISG and 4 had a positive pentetreotide scintigraphy. These data suggest the utility of the combined use of these techniques for a better diagnosis of pituitary adenomas.

This article reports the experience acquired through the use of ultrasonography applied to the study of the mammary gland affected by augmentation of reduction mammaplasty. Thirty-eight patients who had undergone either augmentation or reduction mammaplasty were submitted to ultrasonographic examination. Such a technique, besides being easy to perform, noninvasive, specific, and well accepted by the patients, showed to be remarkably interesting. It offered a wide display of the mammary parenchyma, showing its possible alterations, and supplying useful information on any possible postoperative implant ruptures, cicatricial reactions, seromas, and any other possible alterations that occurred.

A new method for intraperitoneal tumour targetting in ovarian cancer using biotinylated monoclonal antibodies (MoAb) and radioactive streptavidin is described. Fifteen patients with histologically documented ovarian carcinoma were injected intraperitoneally with 2 mg of biotinylated MoAb MOv18, followed 3-5 days later by 100-150 micrograms of indium-111 streptavidin, at the specific activity of 280-370 MBq/mg in 500 ml of normal saline. No toxicity was observed. Tumours were imaged from 2 to 48 h after radioactivity injection by recording both planar and single photon emission tomography (SPET) data. All patients underwent surgery 1-8 days later (mean 3 days) after scanning. The resected tumour and normal tissue radioactivity were measured. On the day of surgery, the tumour to normal tissue ratio was 9:1 (range 3:1-30:1) and 45:1 (range 12:1-120:1) for intra- and extraperitoneal samples, respectively. The mean tumor to blood ratio was 14:1 (range 4:1-30:1). The injected dose (i.d.) per gram of tumour was 0.112 (range 0.01-0.3) for recurrences and 0.05 for primary tumour (range 0.005-0.2). Over 24-48 h 14% i.d. (range 8-18% i.d.) was found in the urine, 14% i.d. (range 6-29% i.d.) in the blood and 63% i.d. (range 56-70% i.d.) was still in the peritoneal cavity. These preliminary clinical data suggest that this two-step strategy may be superior to the conventional approach (radiolabelled antibodies) for intraperitoneal radioimmunolocalization and radioimmunotherapy of ovarian cancer.