Publications by authors named "Giovanni Paganelli"

180 Publications

Flare phenomenon in prostate cancer: recent evidence on new drugs and next generation imaging.

Ther Adv Med Oncol 2021 24;13:1758835920987654. Epub 2021 Feb 24.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori "Dino Amadori" (IRST), IRCCS, Meldola, Emilia-Romagna, Italy.

Over the years, an increasing proportion of metastatic prostate cancer patients has been found to experience an initial bone flare phenomenon under both standard therapies (androgen deprivation therapy, chemotherapy, radiotherapy, abiraterone, enzalutamide) and novel agents (immunotherapy, bone-targeting radioisotopes). The underlying biological mechanisms of the flare phenomenon are still elusive and need further clarification, particularly in relation to different types of treatment and their treatment response assessment. Flare phenomenon is often underestimated and, in some cases, can negatively affect clinical outcome. In cases with suspected bone flare, the treatment should be continued for a minimum of 12 more weeks before further decisions about efficacy can be taken. Physicians and patients should be aware of this effect to avoid unwarranted anxiety and inadequate early discontinuation of treatment. This review aims at highlighting new evidence on flare phenomenon arising after the introduction of new drugs extending across the biochemical, radiographic and clinical spectrum of the disease.
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http://dx.doi.org/10.1177/1758835920987654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907710PMC
February 2021

Combined use of 177Lu-DOTATATE and metronomic capecitabine (Lu-X) in FDG-positive gastro-entero-pancreatic neuroendocrine tumors.

Eur J Nucl Med Mol Imaging 2021 Feb 18. Epub 2021 Feb 18.

Nuclear Medicine and Radiometabolic Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy.

Purpose: FDG-positive neuroendocrine tumors (NETs) have a poorer prognosis and exhibit shorter response duration to peptide receptor radionuclide therapy (PRRT). The aim of this prospective phase II study was to evaluate the efficacy and toxicity of PRRT with Lu-DOTATATE associated with metronomic capecitabine as a radiosensitizer agent in patients with advanced progressive FDG-positive gastro-entero-pancreatic (GEP) NETs.

Patients And Methods: Patients with advanced somatostatin receptor- and FDG-positive G1-G3 GEP-NETs (Ki67 < 55%) were treated with a cumulative activity of 27.5 GBq of Lu-DOTATATE divided in five cycles of 5.5 GBq each every 8 weeks. Capecitabine (1000-1500 mg daily) was administered orally in the inter-cycle period between Lu-DOTATATE treatments. Prior to commencing capecitabine, all patients were triaged with the dihydropyrimidine dehydrogenase (DPD) test. Only DPD-proficient individuals were enrolled. The primary objectives were disease control rate (DCR) and safety. Secondary aims included progression-free (PFS) and overall survival (OS). Treatment response was assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Toxicity was assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Results: From August 2015 to December 2016, 37 subjects were consecutively enrolled. A total of 25 (68%) were affected by pancreatic neuroendocrine tumors (P-NETs), and 12 (32%) had gastrointestinal neuroendocrine tumors (GI-NETs). By grading (WHO 2010 classification), 12 patients (32%) had G1 (Ki67 ≤ 2%), 22 (59%) had G2 (3% < Ki67 ≤ 20%), and 3 patients (9%) had G3 (Ki67 > 20%) NETs. Grade 3 (G3) or 4 (G4) hematological toxicity occurred in 16.2% of patients. Other G3-G4 adverse events were diarrhea in 5.4% of cases and asthenia in 5.4%. No renal toxicity was observed for the duration of follow-up. In 37 patients, 33 were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%) and stable disease (SD) in 18 patients (55%), with a DCR of 85%. The median follow-up was 38 months (range 4.6-51.1 months). The median PFS was 31.4 months (17.6-45.4), and mOS was not reached.

Conclusions: This study demonstrated that the combination of PRRT with Lu-DOTATATE and metronomic capecitabine is active and well tolerated in patients with aggressive FDG-positive G1-G3 GEP-NETs. These data constitute the basis for a randomized study of PPRT alone vs. PRRT plus metronomic capecitabine.
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http://dx.doi.org/10.1007/s00259-021-05236-zDOI Listing
February 2021

PET/CT in Multiple Myeloma: Beyond FDG.

Front Oncol 2020 25;10:622501. Epub 2021 Jan 25.

Hematology Unit, Istituto Scientifico Romagnolo per lo studio e la cura dei tumori (IRST) IRCCS, Meldola, Italy.

Recent advances in the diagnosis and treatment of multiple myeloma (MM) have highlighted the importance of imaging methods, not only in the localization and extent of the disease but also in prognostic stratification and assessment of response to therapy. In this context, PET/CT, combining both morphological and functional information, is particularly useful in this pathology. The tracer mostly used is 18F-FDG, a glucose analog, which provides extremely accurate information with a sensitivity ranging from 80 to 100%. However, this tracer has some limitations, mostly related to the physiological uptake of FDG in the bone marrow and brain, which reduce its effectiveness. For this reason, some studies in the literature have evaluated the effectiveness of other PET tracers, which provide information on protein metabolism or the synthesis of metabolic plasma membranes, such as choline and methionine, as well as innovative radiopharmaceuticals, directed against receptors expressed by cells of myeloma, including tracers directed to the chemokine receptor. This review analyzes the characteristics and accuracy of non-FDG tracers in the management of patients with multiple myeloma.
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http://dx.doi.org/10.3389/fonc.2020.622501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868556PMC
January 2021

Importance of PET with Ga-Labeled Somatostatin Analogs.

J Nucl Med 2020 12;61(Suppl 2):187S-188S

Nuclear Medicine Diagnostic Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

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http://dx.doi.org/10.2967/jnumed.120.254631DOI Listing
December 2020

Radiology imaging management in an Italian cancer center (IRST IRCCS) during the COVID-19 pandemic.

Insights Imaging 2020 Dec 3;11(1):129. Epub 2020 Dec 3.

Radiology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

In Italy, the first case of the coronavirus disease 2019 (COVID-19) was officially reported on 20.02.2020. The disease has since rapidly evolved, causing a public health emergency throughout the country but especially in our region, one of the most widely affected areas. We reorganized the daily routine of our cancer center to reduce the risk of contagion. A temporary tensile structure was set up as an entry-point triage, and a COVID-19 route was created with a dedicated CT scanner. A pre-access telephonic triage was performed the day before a patient was scheduled to come in for an examination. At the time of writing (May 4), 4053 patients had been to our center since the emergency officially began (9.03.2020) and the COVID-19 route had been activated for only 9 paucisymptomatic outpatients and 7 symptomatic inpatients. We also re-evaluated patient radiology examination lists and rescheduled non-urgent tests in consensus with the referring oncologist. Out of a total of 1438 patients scheduled for radiological examinations, 456 were postponed for a total volume reduction of 29.1%. Nine asymptomatic patients with typical CT findings of COVID-19 were identified during routine CTs, but none were RT-PCR-positive for SARS-CoV-2. We guaranteed all urgent and semi-urgent examinations, including those to stage newly diagnosed cancers and to evaluate response to treatment, ensuring the continuation of the diagnostic and therapeutic pathway of our patients. The measures we took were instrumental in keeping the institute COVID-19-free. We also describe the planned measures to resume normal clinical practice at the center.
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http://dx.doi.org/10.1186/s13244-020-00935-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711054PMC
December 2020

Optimizing PSMA Radioligand Therapy for Patients with Metastatic Castration-Resistant Prostate Cancer. A Systematic Review and Meta-Analysis.

Int J Mol Sci 2020 Nov 28;21(23). Epub 2020 Nov 28.

Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori (IRST) IRCCS, 7014 Meldola, Italy.

The aim of the review was to evaluate patient and treatment characteristics for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with PSMA radioligand therapy (PRLT) associated with above-average outcome. The systematic review and meta-analysis followed recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). We searched for publications in PubMed, Embase, and ClinicalTrials.gov up to 31 September 2020. Thirty-six publications and four duplicates reported 2346 patients. Nearly two-thirds of the patients had bone metastases. Median overall survival (OS) was 16 months. Asymptomatic patients and patients with only lymph node metastases lived longer than symptomatic patients and patients with more extensive metastases. Patients treated with an intensified schedule of Lu PRLT lived longer than those treated with a conventional schedule. Half of the patients obtained a PSA decline ≥ 50% and these patients lived longer than those with less PSA decline. Approximately 10% of the patients developed hematologic toxicity with anemia grade 3 as the most severe adverse effect. Characteristics for patients, cancer, restaging, and PRLT predict above average overall survival following treatment with PRLT.
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http://dx.doi.org/10.3390/ijms21239054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730994PMC
November 2020

Ga-PSMA-11 PET/CT-Guided Stereotactic Body Radiation Therapy Retreatment in Prostate Cancer Patients with PSA Failure after Salvage Radiotherapy.

Biomedicines 2020 Nov 25;8(12). Epub 2020 Nov 25.

Department of Radiotherapy, Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

(1) Purpose: To investigate the role of Ga-PSMA-11 PET/CT in guiding retreatment stereotactic body radiation therapy (SBRT) in prostate cancer (PCa) patients in biochemical recurrence (BCR) after salvage radiotherapy (S-RT). (2) Methods: We retrospectively evaluated PCa patients previously treated with S-RT on the prostate bed and with proven serum prostate antigen (PSA) failure after S-RT. In all patients (pts), Ga-PSMA-11 PET/CT was positive in the prostate bed only and guided retreatment SBRT. All retreatments were performed by applying the same radiotherapy protocol (median dose of 18 Gy/3 fractions; IQR 18-21 Gy). The median follow-up was 27 months (range 4-35 months). (3) Results: 38 consecutive patients were considered in this analysis. The overall median PSA level before RT was 1.10 ng/mL (IQR 0.82-2.59). PSA decreased at 3 and 6 months after treatment, with a median value of 0.60 ng/mL (IQR 0.31-0.96; < 0.001) and 0.51 ng/mL (IQR 0.29-1.17; < 0.001), respectively. Overall, biochemical recurrence-free survival (b-RFS) was 15.0 months (95% CI 13-23). Grade-1 toxicity was reported in 31.6% of patients (12/38). (4) Conclusion: These results confirm that Ga-PSMA-11-PET/CT is able to identify the site of recurrence in patients who have failed S-RT, thus supporting the use of metastases-directed radiotherapy as a safe and effective treatment.
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http://dx.doi.org/10.3390/biomedicines8120536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761444PMC
November 2020

Targeted Alpha Therapy in mCRPC (Metastatic Castration-Resistant Prostate Cancer) Patients: Predictive Dosimetry and Toxicity Modeling of Ac-PSMA (Prostate-Specific Membrane Antigen).

Front Oncol 2020 5;10:531660. Epub 2020 Nov 5.

Nuclear Medicine Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Radioligand therapy is a type of internal radiotherapy combining a short-range radioisotope labeled to a carrier with a high affinity for a specific receptor expressed on tumor cells. Targeted alpha therapy (TAT) combines a high-linear energy transfer (LET) emitter (Ac) with a prostate-specific membrane antigen (PSMA) carrier, specifically binding tumor cells in patients with metastatic castration-resistant prostate cancer. Although the antitumor activity of Ac-PSMA is well-documented, this treatment is nowadays only used as salvage therapy because the high incidence of xerostomia limits the therapeutic window. Thus, methods to reduce salivary toxicity and models able to describe xerostomia incidence are needed. We recently studied the efficacy of salivary gland protectors administered in combination with Lu-PSMA therapy. Starting from these data, we performed a predictive dosimetric evaluation of Ac-PSMA to assess the impact of salivary gland protectors in TAT. Ac-PSMA predictive dosimetry was performed in 13 patients treated with Lu-PSMA. Sequential whole-body planar images were acquired 0.5-1, 16-24, 36-48, and 120 h post-injection. Lu time-activity curves were corrected for Ac physical decay and assumed in equilibrium for all daughters. The OLINDA/EXM spherical model was used for dose estimation of the parotid and submandibular glands. The dose for each daughter was calculated and summed for the total dose estimation. The biologically effective dose formalism was extended to high-LET emitters. For the total biologically effective dose formalism extended to high-LET emitters, including the contribution of all daughter isotopes, the brachytherapy formalism for a mixture of radionuclides was implemented. Equivalent doses in 2 Gy/fraction (EQD2) were then calculated and compared with the normal tissue complication probability model derived from external beam radiotherapy for grade ≥2 xerostomia induction. Median predictive doses were 0.86 Bd/MBq for parotid glands and 1.05 Bd/MBq for submandibular glands, with a 53% reduction compared with previously published data. The results show that the radiobiological model implemented is conservative, as it overestimates the complication rate with respect to the clinical data. Our data shows the possibility of reducing salivary gland uptake in TAT with the coadministration of organ protectors, but these results should be confirmed for TAT with Ac-PSMA by carrying out prospective trials with defined toxicity endpoints and dosimetry procedures.
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http://dx.doi.org/10.3389/fonc.2020.531660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674768PMC
November 2020

Plasma tumour DNA as an early indicator of treatment response in metastatic castration-resistant prostate cancer.

Br J Cancer 2020 09 16;123(6):982-987. Epub 2020 Jul 16.

University College London Cancer Institute, London, WC1E 6DD, UK.

Background: Plasma tumour DNA (ptDNA) levels on treatment are associated with response in a variety of cancers. However, the role of ptDNA in prostate cancer monitoring remains largely unexplored. Here we characterised on-treatment ptDNA dynamics and evaluated its potential for early assessment of therapy efficacy for metastatic castration-resistant prostate cancer (mCRPC).

Methods: Between 2011 and 2016, 114 sequential plasma samples from 43 mCRPC abiraterone-treated patients were collected. Targeted next-generation sequencing was performed to determine ptDNA fraction. ptDNA progressive disease was defined as a rise in the fraction compared to the pre-treatment.

Results: A ptDNA rise in the first on-treatment sample (interquartile range (IQR) 2.6-3.7 months) was significantly associated with increased risk of early radiographic or any prostate-specific antigen (PSA) rise (odds ratio (OR) = 15.8, 95% confidence interval (CI) 3.5-60.2, p = 0.0002 and OR = 6.0, 95% CI 1.6-20.0, p = 0.01, respectively). We also identified exemplar cases that had a rise in PSA or pseudoprogression secondary to bone flare but no rise in ptDNA. In an exploratory analysis, initial ptDNA change was found to associate with the duration of response to prior androgen deprivation therapy (p < 0.0001) but not to prior taxanes (p = 0.32).

Conclusions: We found that ptDNA assessment for therapy monitoring in mCRPC is feasible and provides data relevant to the clinical setting. Prospective evaluation of these findings is now merited.
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http://dx.doi.org/10.1038/s41416-020-0969-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492429PMC
September 2020

Lu-PRRT in advanced gastrointestinal neuroendocrine tumors: 10-year follow-up of the IRST phase II prospective study.

Eur J Nucl Med Mol Imaging 2021 Jan 29;48(1):152-160. Epub 2020 May 29.

Nuclear Medicine and Radiometabolic Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy.

Purpose: In March 2014, we reported the activity and safety of Lu-DOTA-octreotate peptide receptor radionuclide therapy (Lu-PRRT) at two different dosages (18.5 GBq and 27.5 GBq in 5 cycles) in patients with progressive metastatic gastrointestinal neuroendocrine tumors (GI-NETs). Disease control rate (DCR) and toxicity were addressed. Herein, we report the late toxicity, progression-free survival (PFS), and overall survival (OS) in the same cohort after a 10-year follow-up.

Methods: We conducted an open-label, disease-oriented prospective phase II trial. From March 2008 to June 2011, 43 patients received 3.7 GBq or 5.5 GBq of Lu-PRRT every 6 to 8 weeks, each cycle repeated 5 times. All patients showed Gallium-DOTA-peptide PET/Octreoscan® positivity (score 3-4 Rotterdam scale) in known lesions. Tumor burden was estimated radiologically. Time-to-event data (PFS and OS) were described using Kaplan-Meier curves and compared with the log-rank test.

Results: Forty-three patients (28 males and 15 females) were evaluable and were monitored for a median period of 118 months (range 12.6-139.6). Median PFS in patients receiving 18.5 GBq was 59.8 months (95% confidence interval [95% CI] 14.3-79.6), identical to that of patients treated with 27.5 GBq (59.8 months, 95% CI 23.4-82.0). Median OS was 71.0 months (95% CI 46.1-107.3) in the group who received 18.5 GBq and 97.6 months (95% CI 64.3-not reached) in the group treated with 27.5 GBq (P = 0.22). Patients with progression limited to lymph nodes showed significantly longer median PFS and OS than those with hepatic lesions (P = 0.02 for PFS and P = 0.04 for OS). Age over 65 years at the time of PRRT was also significant for OS. Of note, no late hematological or renal toxicity was observed in either group.

Conclusions: The long-term follow-up of the IRST phase II study shows that Lu-PRRT is a safe and effective therapy for patients with advanced GI-NET, the most important prognostic factor being tumor burden, hepatic lesions, and age. We believe that Lu-PRRT should be offered to patients with early-stage disease.
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http://dx.doi.org/10.1007/s00259-020-04873-0DOI Listing
January 2021

Dosimetry and safety of Lu PSMA-617 along with polyglutamate parotid gland protector: preliminary results in metastatic castration-resistant prostate cancer patients.

Eur J Nucl Med Mol Imaging 2020 12 20;47(13):3008-3017. Epub 2020 May 20.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Purpose: Radioligand therapy (RLT) with Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate cancer (mCRPC). The present study was designed to define the safety and initial response to a minimal effective injected activity/cycle of Lu-PSMA-617 in mCRPC patients. New protective agents for salivary glands and kidney were co-administered and dosimetry was carried out.

Patients And Methods: A prospective single-arm, open label phase II study on mCRPC was activated at our institute in April 2017. Patients with histologically confirmed advanced mCRPC previously treated with standard life-prolonging agents were enrolled. Folic polyglutamate tablets were orally administered as parotid gland protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake before the injection of 3.7-5.5 GBq of Lu-PSMA-617 repeated four times at interval of 8 weeks. The adsorbed dose calculation was performed with MIRD formalism (OLINDA/EXM software). The Bryant and Day design was used to estimate the sample size taking account of both activity and toxicity.

Results: Forty-three eligible patients were evaluated for toxicity and initial response. Dosimetry was carried out in 13 patients. Two (4.8%) patients had G3 and 8 (19.5%) had G2 hematological toxicity. Only 3 (6.9%) patients had mild G1 salivary gland toxicity and 8 (19.5%) had G1 renal toxicity. A decrease of ≥ 30% in prostate-specific antigen (PSA) was achieved after the first cycle in 17 (40.5%) patients, of whom 13 had a PSA decline of >50% after the second cycle. The median adsorbed doses were 0.65 mGy/MBq (range 0.33-2.63) for parotid glands, 0.42 mGy/MBq (0.14-0.81) for kidneys, 0.036 mGy/MBq (0.023-0.067) for red marrow, and 0.038 mGy/MBq (0.018-0.135) for the whole body.

Conclusion: In advanced, heavily pre-treated mCRPC patients, 3.7 GBq/cycle of Lu-PSMA-617 was safe and produced early biochemical and imaging responses at PSMA whole-body scan post injection. Dosimetry of salivary glands suggests that the co-administration of polyglutamate tablets may reduce salivary gland uptake.

Clinical Trial Registration: EU Clinical Trials Register No.: 2016-002732-32; NCT03454750. Collection and assembly of data: April 2017 and February 2019.
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http://dx.doi.org/10.1007/s00259-020-04856-1DOI Listing
December 2020

A Whole Body Dosimetry Protocol for Peptide-Receptor Radionuclide Therapy (PRRT): 2D Planar Image and Hybrid 2D+3D SPECT/CT Image Methods.

J Vis Exp 2020 04 24(158). Epub 2020 Apr 24.

Medical Physics Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Peptide-receptor-radionuclide-therapy (PPRT) is a targeted therapy that combines a short-range energy radionuclide with a substrate with high specificity for cancer cell receptors. After injection, the radiotracer is distributed throughout the entire body, with a higher uptake in tissues where targeted receptors are overexpressed. The use of beta/gamma radionuclide emitters enables therapy imaging (beta-emission) and post-therapy imaging (gamma-emission) to be performed at the same time. Post-treatment sequential images permit absorbed dose calculation based on local uptake and wash-in/wash-out kinetics. We implemented a hybrid method that combines information derived from both 2D and 3D images. Serial whole-body images and blood samples are acquired to estimate the absorbed dose to different organs at risk and to lesions disseminated throughout the body. A single 3D-SPECT/CT image, limited to the abdominal region, overcomes projection overlap on planar images of different structures such as the intestines and kidneys. The hybrid 2D+3D-SPECT/CT method combines the effective half-life information derived from 2D planar images with the local uptake distribution derived from 3D images. We implemented this methodology to estimate the absorbed dose for patients undergoing PRRT with Lu-PSMA-617. The methodology could, however, be implemented with other beta-gamma radiotracers. To date, 10 patients have been enrolled into the dosimetry study with Lu-PSMA-617 combined with drug protectors for kidneys and salivary glands (mannitol and glutamate tablets, respectively). The median ratio between kidney uptake at 24 h evaluated on planar images and 3D-SPECT/CT is 0.45 (range:0.32-1.23). The comparison between hybrid and full 3D approach has been tested on one patient, resulting in a 1.6% underestimation with respect to full 3D (2D: 0.829 mGy/MBq, hybrid: 0.315 mGy/MBq, 3D: 0.320 mGy/MBq). Treatment safety has been confirmed, with a mean absorbed dose of 0.73 mGy/MBq (range:0.26-1.07) for kidneys, 0.56 mGy/MBq (0.33-2.63) for the parotid glands and 0.63 mGy/MBq (0.23-1.20) for submandibular glands, values in accordance with previously published data.
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http://dx.doi.org/10.3791/60477DOI Listing
April 2020

Author Correction: A new microdispersed albumin derivative potentially useful for radio-guided surgery of occult breast cancer lesions.

Sci Rep 2020 Mar 10;10(1):4633. Epub 2020 Mar 10.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRST-IRCCS, Meldola. via P. Maroncelli 40, Meldola, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-60471-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064564PMC
March 2020

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with Lu-Dotatate: an analysis of the NETTER-1 study.

Eur J Nucl Med Mol Imaging 2020 09 2;47(10):2372-2382. Epub 2020 Mar 2.

Department of Nuclear Medicine, Cyclotron Rotterdam BV, Erasmus University Medical Center, Rotterdam, Netherlands.

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with Lu-Dotatate.

Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression.

Results: Significantly prolonged median PFS occurred with Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden.

Conclusions: Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.
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http://dx.doi.org/10.1007/s00259-020-04709-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396396PMC
September 2020

PRRT neuroendocrine tumor response monitored using circulating transcript analysis: the NETest.

Eur J Nucl Med Mol Imaging 2020 04 14;47(4):895-906. Epub 2019 Dec 14.

LuGenIum Consortium, Milan, Rotterdam, London, Bad Berka, 54 Portland Place, London, W1B1DY, UK.

Purpose: Peptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is usually efficient subsequent to treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy; NETest monitors disease. We prospectively evaluated: (1) NETest as a surrogate biomarker for RECIST; (2) the correlation of NETest levels with PPQ prediction.

Methods: Three independent Lu-PRRT-treated GEP-NET and lung cohorts (Meldola, Italy: n = 72; Bad-Berka, Germany: n = 44; Rotterdam, Netherlands: n = 41). Treatment response: RECIST1.1 (responder (stable, partial, and complete response) vs non-responder). Blood sampling: pre-PRRT, before each cycle and follow-up (2-12 months). PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable < 40; progressive > 40). CgA (ELISA) as comparator. Samples de-identified, measurement and analyses blinded. Kaplan-Meier survival and standard statistics.

Results: One hundred twenty-two of the 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly (p < 0.0001) decreased in RECIST "responders" (- 47 ± 3%); in "non-responders," it remained increased (+ 79 ± 19%) (p < 0.0005). NETest monitoring accuracy was 98% (119/122). Follow-up levels > 40 (progressive) vs stable (< 40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04 (95%CI, 0.02-0.07). PPQ response prediction was accurate in 118 (97%) with a 99% accurate positive and 93% accurate negative prediction. NETest significantly (p < 0.0001) decreased in PPQ-predicted responders (- 46 ± 3%) and remained elevated or increased in PPQ-predicted non-responders (+ 75 ± 19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06 (95%CI, 0.03-0.12). CgA did not reflect PRRT treatment: in RECIST responders decrease in 38% and in non-responders 56% (p = NS).

Conclusions: PPQ predicts PRRT response in 97%. NETest accurately monitors PRRT response and is an effective surrogate marker of PRRT radiological response. NETest decrease identified responders and correlated (> 97%) with the pretreatment PPQ response predictor. CgA was non-informative.
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http://dx.doi.org/10.1007/s00259-019-04601-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515632PMC
April 2020

SUV as a Reliable Alternative to SUV for Determining Renal Uptake in [Ga] PSMA PET/CT.

Mol Imaging Biol 2020 08;22(4):1070-1077

Medical Physics Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Purpose: Widely used in clinical practice, the maximum standardized uptake value (SUV) is a statistical index highly prone to physical and biological variations, which can lead to unpredictable errors. This study has a methodological aim: to identify a more robust SUV-based index representing the tracer accumulation. In particular, the new metric was tested to confirm the potential of mannitol to reduce renal uptake Ga-68 prostate-specific membrane antigen ([Ga]PSMA).

Procedures: To this aim, our previously published work, proving the efficacy of mannitol, was considered as a background study. Renal SUV was calculated in nine patients undergoing [Ga]PSMA positron emission tomography (PET)/X-ray computed tomography (CT) at baseline (b-PET/CT) and at follow-up after intravenous infusion of 500 ml of 10 % mannitol (m-PET/CT). SUV values of kidney volumes were extracted by a new 3D segmentation method. A new parameter, the median computed on the upper 10% of the SUV distribution (SUV), was introduced to better characterize the tracer accumulation. A comparison between SUV and SUV was also performed. Kruskal-Wallis test was used to assess the statistical significance of the differences in SUV between b-PET/CT and m-PET/CT.

Results: SUV not only confirmed the efficacy of mannitol as demonstrated in the previous study but improved the separability of b-PET/CT and m-PET/CT examinations, overturning SUV findings in two cases. The outcomes of the Kruskal-Wallis test computed for each kidney proved that differences between b-PET/CT and m-PET/CT SUV values were significant (p value < 0.001).

Conclusions: Our findings indicate that SUV is a more robust index to assess high uptake level, representing a reliable alternative to SUV. Independently from the segmentation method, the superiority of SUV and its easy computation could make its clinical impact decisive. The results obtained with SUV, more representative of tracer uptake than those with SUV suggest, in our opinion, that mannitol infusion could be used to reduce the adsorbed dose to the kidneys during [Ga]PSMA PET/CT and Lu-177 or Ac-225 therapy. Our future goal will be confirming this effect in a larger cohort of patients, also verifying the role of SUV in the evaluation of tumor response to therapy.
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http://dx.doi.org/10.1007/s11307-019-01451-1DOI Listing
August 2020

Clinical evidence of abscopal effect in cutaneous squamous cell carcinoma treated with diffusing alpha emitters radiation therapy: a case report.

J Contemp Brachytherapy 2019 Oct 30;11(5):449-457. Epub 2019 Oct 30.

Skin Cancer Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy.

Purpose: Alpha particle treatments could enhance the probability of an immune response, which can lead to abscopal effects (AE). We report a case of a patient affected by multiple cutaneous squamous cell carcinoma (cSCC). After the treatment with diffusing alpha emitters radiation therapy (DaRT) of one lesion, an AE was observed on at least two distant ones.

Material And Methods: We investigated a case of a 65-year-old female patient with multiple synchronous lesions of the skin of lower limbs confirmed by a biopsy. Patient was enrolled in a clinical trial N.CTP-SCC-00 (NCT03015883), with the objective to assess effectiveness of DaRT technique. DaRT is based on the insertion of locally Ra-loaded seeds in a clinical target volume (CTV). Treatment plan with positron emission tomography/computed tomography (PET/CT) was used to entirely cover the CTV. Follow-up and biopsy evaluations were employed to outline the patient outcome.

Results: We performed seeds implantation according to the Paris system. At 28 day, an evident lesion shrinkage with a persistent minimal area of hyperkeratosis was noted. 76 days after implantation, a complete remission of the treated lesion was observed and an evident reduction of the area with two more distant lesion, which could be associated to an immune-mediated response. One year after the treatment, a complete remission of treated lesion was observed as well as spontaneous regression of untreated distant ones.

Conclusions: In this study, we reported evidences of an AE in cSCC stimulated by radiation and possibly mediated by immune system. In the next DaRT treatments, our intent is to monitor T-lymphocytes variations in peripheral blood in order to demonstrate indirect activation of the immune system mediated by radiation also in patients with solitary lesions, in which, by definition, an AE cannot be observed.
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http://dx.doi.org/10.5114/jcb.2019.88138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854861PMC
October 2019

CAR-T cell therapy: a potential new strategy against prostate cancer.

J Immunother Cancer 2019 10 16;7(1):258. Epub 2019 Oct 16.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy.

Prostate cancer (PCa) is one of the main causes of cancer-related death in men. In the present immunotherapy era, several immunotherapeutic agents have been evaluated in PCa with poor results, possibly due to its low mutational burden. The recent development of chimeric antigen receptor (CAR)-T cell therapy redirected against cancer-specific antigens would seem to provide the means for bypassing immune tolerance mechanisms. CAR-T cell therapy has proven effective in eradicating hematologic malignancies and the challenge now is to obtain the same degree of in solid tumors, including PCa. In this study we review the principles that have guided the engineering of CAR-T cells and the specific prostatic antigens identified as possible targets for immunological and non-immunological therapies. We also provide a state-of-the-art overview of CAR-T cell therapy in PCa, defining the key obstacles to its development and underlining the mechanisms used to overcome these barriers. At present, although there are still many unanswered questions regarding CAR-T cell therapy, there is no doubt that it has the potential to become an important treatment option for urological malignancies.
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http://dx.doi.org/10.1186/s40425-019-0741-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794851PMC
October 2019

Texture analysis in 177Lu SPECT phantom images: Statistical assessment of uniformity requirements using texture features.

PLoS One 2019 31;14(7):e0218814. Epub 2019 Jul 31.

Nuclear Medicine Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forli-Cesena, Italy.

The purpose of this study was to apply texture analysis (TA) to evaluate the uniformity of SPECT images reconstructed with the 3D Ordered Subsets Expectation Maximization (3D-OSEM) algorithm. For this purpose, a cylindrical homogeneous phantom filled with 177Lu was used and a total of 24 spherical volumes of interest (VOIs) were considered inside the phantom. The location of the VOIs was chosen in order to define two different configurations, i.e. gravity and radial configuration. The former configuration was used to investigate the uniformity of distribution of 177Lu inside the phantom, while the latter configuration was used to investigate the lack of uniformity from center towards edge of the images. For each VOI, the trend of different texture features considered as a function of 3D-OSEM updates was investigated in order to evaluate the influence of reconstruction parameters. TA was performed using CGITA software. The equality of the average texture feature trends in both spatial configurations was assumed as the null hypothesis and was tested by functional analysis of variance (fANOVA). With regard to the gravity configuration, no texture feature rejected the null hypothesis when the number of subsets increased. For the radial configuration, the statistical analysis revealed that, depending on the 3D-OSEM parameters used, a few texture features were capable of detecting the non-uniformity of 177Lu distribution inside the phantom moving from the center of the image towards its edge. Finally, cross-correlation coefficients were calculated to better identify the features that could play an important role in assessing quality assurance procedures performed on SPECT systems.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218814PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668785PMC
February 2020

Early use of abiraterone and radium-223 in metastatic prostate cancer.

Lancet Oncol 2019 05;20(5):e228

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.

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http://dx.doi.org/10.1016/S1470-2045(19)30226-8DOI Listing
May 2019

A new microdispersed albumin derivative potentially useful for radio-guided surgery of occult breast cancer lesions.

Sci Rep 2019 04 4;9(1):5623. Epub 2019 Apr 4.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRST-IRCCS, Meldola. via P. Maroncelli 40, Meldola, Italy.

This paper describes a new nuclear imaging agent, 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid of human albumin (HAC), potentially suitable for application in the Radio-guided Occult Lesion Localization (ROLL) of non-palpable mammalian cancerous lesions, as a tool to overtake the short radio-signal half-life of the technetium-99m based radiopharmaceutical currently used. This conjugate is a microsized powder aggregate, water-insoluble between pH 3 and 8.5, obtained by conjugating the protein with the macrocyclic chelating agent DOTA through a one-pot reaction in aqueous medium. The product has been fully characterized and is stable to the thermal conditions adopted for labeling; after radiolabeling with longer half-life radionuclides such as Lu or In, it has shown radiochemical purity (RCP) >90% and resulted stable when stored in saline or plasma for 6 days at 37 °C. A μPET/CT study, performed in vivo on adult female rats, showed that the radioactivity of HAC labeled with Cu remained located in the mammary glands for at least 40 h, without diffusion or drainage in healthy tissues or in the lymphatic circulation. This new imaging agent might make the ROLL procedure more accessible, safe and flexible, promoting a significant time and cost reduction of this intervention. Moreover, HAC might also be used in other radio-guided surgical procedures in oncology.
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http://dx.doi.org/10.1038/s41598-019-42014-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449347PMC
April 2019

Dosimetry of Lu-PSMA-617 after Mannitol Infusion and Glutamate Tablet Administration: Preliminary Results of EUDRACT/RSO 2016-002732-32 IRST Protocol.

Molecules 2019 Feb 11;24(3). Epub 2019 Feb 11.

Nuclear Medicine Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

Radio-ligand therapy (RLT) withLu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate-cancer (mCRPC). A prospective phase-II study (EUDRACT/RSO,2016-002732-32) on mCRPC is ongoing at IRST (Meldola, Italy). A total of 9 patients (median age: 68 y, range: 53⁻85) were enrolled for dosimetry evaluation of parotid glands (PGs), kidneys, red marrow (RM) and whole body (WB). Folic polyglutamate tablets were orally administered as PGs protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake. The whole body planar image (WBI) and blood samples were acquired at different times post infusion (1 h, 16⁻24 h, 36⁻48 h and 120 h). Dose calculation was performed with MIRD formalism (OLINDA/EXM software). The median effective half-life was 33.0 h (range: 25.6⁻60.7) for PGs, 31.4 h (12.2⁻80.6) for kidneys, 8.2 h (2.5⁻14.7) for RM and 40.1 h (31.6⁻79.7) for WB. The median doses were 0.48 mGy/MBq (range: 0.33⁻2.63) for PGs, 0.70 mGy/MBq (0.26⁻1.07) for kidneys, 0.044 mGy/MBq (0.023⁻0.067) for RM and 0.04 mGy/MBq (0.02⁻0.11) for WB. A comparison with previously published dosimetric data was performed and a significant difference was found for PGs while no significant difference was observed for the kidneys. For PGs, the possibility of reducing uptake by administering glutamate tablets during RLT seems feasible while further research is warranted for a more focused evaluation of the reduction in kidney uptake.
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http://dx.doi.org/10.3390/molecules24030621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385027PMC
February 2019

Interim analysis of the REASSURE (Radium-223 alpha Emitter Agent in non-intervention Safety Study in mCRPC popUlation for long-teRm Evaluation) study: patient characteristics and safety according to prior use of chemotherapy in routine clinical practice.

Eur J Nucl Med Mol Imaging 2019 May 12;46(5):1102-1110. Epub 2019 Jan 12.

Royal Marsden Hospital, London, UK.

Purpose: REASSURE is a global, prospective, non-interventional study to assess long-term safety of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Here we report an interim analysis of patients according to previous use of chemotherapy.

Methods: Radium-223 was administered in routine clinical practice. Interim safety analysis was planned after enrolment of the first 600 patients. Patient characteristics and safety data by previous administration of chemotherapy (docetaxel and/or cabazitaxel) were investigated.

Results: This interim analysis included 583 patients. Median duration of observation was 7 months (range, 0-20). Nineteen patients treated with concomitant chemotherapy were excluded, 564 (97%) were eligible for exploratory analysis according to prior use of chemotherapy; 190 (34%) had previously received and completed chemotherapy, and 374 (66%) had not. In the prior versus no prior chemotherapy group, a higher proportion of patients had an Eastern Cooperative Oncology Group performance status of ≥2 (22% vs 11%) and > 20 metastatic lesions (26% vs 15%), median alkaline phosphatase (162.0 vs 115.0 U/L) and prostate-specific antigen (132.0 vs 40.2 ng/mL) levels were higher, and a lower proportion completed 6 radium-223 injections (45% vs 63%). Drug-related treatment-emergent adverse events (TEAEs) occurred in 63 and 48%, and haematological drug-related TEAEs in 21 and 9% of patients who had or had not previously received chemotherapy. Four drug-related deaths were reported, all in the prior chemotherapy group.

Conclusions: The short-term safety profile of radium-223 in routine clinical practice was comparable to other clinical studies, irrespective of prior chemotherapy use. Haematological TEAEs occurred more frequently in the prior chemotherapy group, presumably due to decreased bone marrow function as a consequence of more advanced disease and prior exposure to cytotoxic therapy. Patients who had not previously received chemotherapy appeared to have a lower burden of disease at baseline, and a lower proportion discontinued radium-223 treatment.
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http://dx.doi.org/10.1007/s00259-019-4261-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451709PMC
May 2019

Ga-PSMA-PET: added value and future applications in comparison to the current use of choline-PET and mpMRI in the workup of prostate cancer.

Radiol Med 2018 Dec 16;123(12):952-965. Epub 2018 Aug 16.

Nuclear Medicine Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Positron emission tomography (PET) has been commonly and successfully used, in combination with computed tomography (CT) and more recently magnetic resonance (MRI), in the workup of intermediate or high-risk prostate cancer (PCa). Nowadays, new specific receptor targeted PET tracers in prostate cancer imaging have been introduced; one of the most used is Ga-PSMA, that evaluates the expression of prostate-specific membrane antigen (PSMA). This tracer has been rapidly taken into account for its better sensitivity and specificity compared to lipid metabolism tracers, such as C/F labelled fluorocholine. Besides, in the era of theranostics, this tracer is having a useful application not only for imaging but also for therapeutic purposes. The aim of this review article is, in the first part, to give an overview of the main indications and future development of Ga-PSMA imaging, using PET/CT or PET/MRI, according to the clinical course of the disease and in view of the current use of multiparametric MRI (mpMRI) and choline PET in the management of PCa. In the second part, a brief overview of the promising F-labelled PSMA tracers and the current use of PSMA radionuclide therapy will be provided.
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http://dx.doi.org/10.1007/s11547-018-0929-9DOI Listing
December 2018

Ga-PSMA PET/CT in patients with recurrent prostate cancer after radical treatment: prospective results in 314 patients.

Eur J Nucl Med Mol Imaging 2018 11 19;45(12):2035-2044. Epub 2018 Jun 19.

Nuclear Medicine Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy.

Purpose: We studied the usefulness of Ga-prostate-specific membrane antigen (PSMA) PET/CT for detecting relapse in a prospective series of patients with biochemical recurrence (BCR) of prostate cancer (PCa) after radical treatment.

Methods: Patients with BCR of PCa after radical surgery and/or radiotherapy with or without androgen-deprivation therapy were included in the study. Ga-PSMA PET/CT scans performed from the top of the head to the mid-thigh 60 min after intravenous injection of 150 ± 50 MBq of Ga-PSMA were interpreted by two nuclear medicine physicians. The results were correlated with prostate-specific antigen (PSA) levels at the time of the scan (PSApet), PSA doubling time, Gleason score, tumour stage, postsurgery tumour residue, time from primary therapy to BCR, and patient age. When available, Ga-PSMA PET/CT scans were compared with negative F-choline PET/CT scans routinely performed up to 1 month previously.

Results: From November 2015 to October 2017, 314 PCa patients with BCR were evaluated. Their median age was 70 years (range 44-92 years) and their median PSApet was 0.83 ng/ml (range 0.003-80.0 ng/ml). Ga-PSMA PET/CT was positive (one or more suspected PCa lesions detected) in 197 patients (62.7%). Lesions limited to the pelvis, i.e. the prostate/prostate bed and/or pelvic lymph nodes (LNs), were detected in 117 patients (59.4%). At least one distant lesion (LNs, bone, other organs, separately or combined with local lesions) was detected in 80 patients (40.6%). PSApet was higher in PET-positive than in PET-negative patients (P < 0.0001). Of 88 patients negative on choline PET/CT scans, 59 (67%) were positive on Ga-PSMA PET/CT.

Conclusion: We confirmed the value of Ga-PSMA PET/CT in restaging PCa patients with BCR, highlighting its superior performance and safety compared with choline PET/CT. Higher PSApet was associated with a higher relapse detection rate.
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http://dx.doi.org/10.1007/s00259-018-4067-3DOI Listing
November 2018

[Lu]-PSMA-617 for targeted prostate cancer treatment: a magic bullet?

Lancet Oncol 2018 06 8;19(6):725-726. Epub 2018 May 8.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Istituto di Ricovero e Cura a Carattere Scientifico (IRST) IRCCS, 47014 Meldola, Italy.

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http://dx.doi.org/10.1016/S1470-2045(18)30268-7DOI Listing
June 2018

PSMA expression: a potential ally for the pathologist in prostate cancer diagnosis.

Sci Rep 2018 03 9;8(1):4254. Epub 2018 Mar 9.

Nuclear Medicine Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Prostate cancer (PCa) patients are risk-stratified on the basis of clinical stage and PSA level at diagnosis and the Gleason Score (GS) in prostate biopsy. However, these parameters are not completely accurate in discriminating between high- and low-risk disease, creating a need for a reliable marker to determine aggressiveness. Prostate-specific membrane antigen (PSMA) appears to fulfill this need. We analyzed 79 prostate biopsies and 28 prostatectomies to assess whether PSMA expression detected by immunohistochemistry is related to GS. PSMA expression was correlated with GS in both sample types (biopsies, P < 0.0001 and prostatectomy samples, P = 0.007). We observed lower PSMA expression in Gleason pattern 3 than Gleason pattern 4, suggesting that this biomarker could be useful to distinguish between these entities (p < 0.0001). The best cut-off value of 45% immunopositivity was determined by receiver operating characteristic (ROC) curve analysis. In Gleason pattern 3 vs. Gleason pattern 4 and 5, PSMA sensitivity was 84.1% (95% CI 76.5%-91.7%) and specificity was 95.2% (95% CI 90.6%-99.8%), with an area under the curve of 93.1 (95% CI 88.8-97.4). Our results suggest that PSMA represents a potential ally for the pathologist in the diagnostic work-up of PCa to overcome long-standing morphological classification limits.
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http://dx.doi.org/10.1038/s41598-018-22594-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844862PMC
March 2018

PRRT genomic signature in blood for prediction of Lu-octreotate efficacy.

Eur J Nucl Med Mol Imaging 2018 07 26;45(7):1155-1169. Epub 2018 Feb 26.

LuGenIum Consortium, Milan, Rotterdam, London, Bad Berka, 54 Portland Place, London, W1B1DY, UK.

Background: Peptide receptor radionuclide therapy (PRRT) utilizes somatostatin receptor (SSR) overexpression on neuroendocrine tumors (NET) to deliver targeted radiotherapy. Intensity of uptake at imaging is considered related to efficacy but has low sensitivity. A pretreatment strategy to determine individual PRRT response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ) which stratifies PRRT "responders" from "non-responders". This study clinically validates the utility of the PPQ in NETs.

Methods: The development and validation of the PPQ was undertaken in three independent Lu-PRRT treated cohorts. Specificity was tested in two separate somatostatin analog-treated cohorts. Prognostic value of the marker was defined in a cohort of untreated patients. The developmental cohort included lung and gastroenteropancreatic [GEP] NETs (n = 72) from IRST Meldola, Italy. The majority were GEP (71%) and low grade (86% G1-G2). Prospective validation cohorts were from Zentralklinik Bad Berka, Germany (n = 44), and Erasmus Medical Center, Rotterdam, Netherlands (n = 42). Each cohort included predominantly well differentiated, low grade (86-95%) lung and GEP-NETs. The non-PRRT comparator cohorts included SSA cohort I, n = 28 (100% low grade, 100% GEP-NET); SSA cohort II, n = 51 (98% low grade; 76% GEP-NET); and an untreated cohort, n = 44 (64% low grade; 91% GEP-NET). Baseline evaluations included clinical information (disease status, grade, SSR) and biomarker (CgA). NET blood gene transcripts (n = 8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model. This provided a binary output: "predicted responder" (PPQ+); "predicted non-responder" (PPQ-). Treatment response was evaluated using RECIST criteria [Responder (stable, partial and complete response) vs Non-Responder)]. Sample measurement and analyses were blinded to study outcome. Statistical evaluation included Kaplan-Meier survival and standard test evaluation analyses.

Results: In the developmental cohort, 56% responded to PRRT. The PPQ predicted 100% of responders and 84% of non-responders (accuracy: 93%). In the two validation cohorts (response: 64-79%), the PPQ was 95% accurate (Bad Berka: PPQ + =97%, PPQ- = 93%; Rotterdam: PPQ + =94%, PPQ- = 100%). Overall, the median PFS was not reached in PPQ+ vs PPQ- (10-14 months; HR: 18-77, p < 0.0001). In the comparator cohorts, the predictor (PPQ) was 47-50% accurate for SSA-treatment and 50% as a prognostic. No differences in PFS were respectively noted (PPQ+: 10-12 months vs. PPQ-: 9-15 months).

Conclusion: The PPQ derived from circulating NET specific genes and tumor grade prior to the initiation of therapy is a highly specific predictor of the efficacy of PRRT with an accuracy of 95%.
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http://dx.doi.org/10.1007/s00259-018-3967-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716527PMC
July 2018