PARP-Targeted Radiotheranostics with Auger Electrons: An Updated Overview.

Auger electrons (AEs) represent an intriguing topic in the field of radionuclide therapy. They are emitted by several radionuclides commonly used in nuclear medicine (indium-111, iodine-123, iodine-125), allowing for highly localized energy deposition and thus exerting a radiotoxic effect on specific cellular and sub-cellular targets. However, due to their short range in matter, AEs have had limited use in therapeutic applications so far. In recent years, the synthesis of various radiopharmaceuticals capable of binding to the enzyme poly(ADP-ribose) polymerase 1 has reignited interest in this type of therapy, laying the groundwork for a theranostic approach based on radionuclides emitting AEs. The enzyme PARP-1 operates enzymatically in close proximity to DNA that represents the prime target of radionuclide therapies. Following this trend, several PARP-targeted radiopharmaceuticals for AE-based theranostics have been developed. We provide an updated overview of preclinical studies focused on the applications of this new theranostic approach in glioblastoma, breast, prostate and ovarian carcinoma, and pancreatic adenocarcinoma.

Prostate cancer: nuclear medicine imaging in the biochemical recurrence and in oligometastatic disease.

INTRODUCTION: The aim of this article was to offer a comprehensive non-systematic review of the literature about the use of Nuclear Medicine imaging exams for the evaluation of prostate cancer (PCa) in the recurrent setting, with a particular regard to positron emission tomography/computed tomography (PET/CT) imaging. EVIDENCE ACQUISITION: A comprehensive nonsystematic literature review was performed in March 2024. Literature search was updated until March 2024. The most relevant studies have been summarized, giving priority to registered clinical trials and multicenter collaborations. EVIDENCE SYNTHESIS: Restaging BCR with advanced Nuclear Medicine Imaging, such as prostate-specific membrane antigen-PET/CT could lead to stage migration and pave the way for additional management strategies, such as stereotactic ablative radiotherapy in patients with low-burden or oligometastatic disease, potentially delaying the need of systemic therapies. While OS benefits of targeting PET/CT positive disease are still lacking, data on progression- and metastasis-free-survival are emerging. Improvements in quality-of-life assessments are already evident. CONCLUSIONS: PCa is one of the most common malignancy in men. In the last 10 years PCa imaging has become significantly more accurate and is now essential for the definition of the extent of the disease in different phases of its natural history. This opened the road to novel management strategies, especially in the recurrent setting, in which the oligometastatic state is now being explored in several trials regarding the prognostic significance of metastasis directed therapies aimed at personalizing the treatment for every single patient.

New target therapies in prostate cancer: from radioligand therapy, to PARP-inhibitors and immunotherapy.

Prostate cancer (PCa) remains a significant global health challenge, particularly in its advanced stages. Despite progress in early detection and treatment, PCa is the second most common cancer diagnosis among men. This review aims to provide an overview of current therapeutic approaches and innovations in PCa management, focusing on the latest advancements and ongoing challenges. We conducted a narrative review of clinical trials and research studies, focusing on PARP inhibitors (PARPis), phosphoinositide 3 kinase-protein kinase B inhibitors, immunotherapy, and radioligand therapies (RLTs). Data was sourced from major clinical trial databases and peer-reviewed journals. Androgen deprivation therapy and androgen-receptor pathway inhibitors remain foundational in managing castration-sensitive and early-stage castration-resistant PCa (CRPC). PARPi's, such as olaparib and rucaparib, have emerged as vital treatments for metastatic CRPC with homologous recombination repair gene mutations, highlighting the importance of personalized medicine. Immune checkpoint inhibitors (ICIs) have shown clinical benefit limited to specific subgroups of PCa, demonstrating significant improvement in efficacy in patients with microsatellite instability/mismatch repair or cyclin-dependent kinase 12 alteration, highlighting the importance of focusing ongoing research on identifying and characterizing these subgroups to maximize the clinical benefits of ICIs. RLTs have shown effectiveness in treating mCRPC. Different alpha emitters (like [225Ac]PSMA) and beta emitters compounds (like [177Lu]PSMA) impact treatment differently due to their energy transfer characteristics. Clinical trials like VISION and TheraP have demonstrated positive outcomes with RLT, particularly [177Lu]PSMA-617, leading to FDA approval. Ongoing trials and future perspectives explore the potential of [225Ac]PSMA, aiming to improve outcomes for patients with mCRPC. The landscape of PCa treatment is evolving, with significant advancements in both established and novel therapies. The combination of hormonal therapies, chemotherapy, PARPis, immunotherapy, and RLTs, guided by genetic and molecular insights, opens new possibilities for personalized treatment.

Role of radiomic analysis of [18F]fluoromethylcholine PET/CT in predicting biochemical recurrence in a cohort of intermediate and high risk prostate cancer patients at initial staging.

AIM: To study the feasibility of radiomic analysis of baseline [18F]fluoromethylcholine positron emission tomography/computed tomography (PET/CT) for the prediction of biochemical recurrence (BCR) in a cohort of intermediate and high-risk prostate cancer (PCa) patients. MATERIAL AND METHODS: Seventy-four patients were prospectively collected. We analyzed three prostate gland (PG) segmentations (i.e., PGwhole: whole PG; PG41%: prostate having standardized uptake value - SUV > 0.41*SUVmax; PG2.5: prostate having SUV > 2.5) together with three SUV discretization steps (i.e., 0.2, 0.4, and 0.6). For each segmentation/discretization step, we trained a logistic regression model to predict BCR using radiomic and/or clinical features. RESULTS: The median baseline prostate-specific antigen was 11 ng/mL, the Gleason score was > 7 for 54% of patients, and the clinical stage was T1/T2 for 89% and T3 for 9% of patients. The baseline clinical model achieved an area under the receiver operating characteristic curve (AUC) of 0.73. Performances improved when clinical data were combined with radiomic features, in particular for PG2.5 and 0.4 discretization, for which the median test AUC was 0.78. CONCLUSION: Radiomics reinforces clinical parameters in predicting BCR in intermediate and high-risk PCa patients. These first data strongly encourage further investigations on the use of radiomic analysis to identify patients at risk of BCR. CLINICAL RELEVANCE STATEMENT: The application of AI combined with radiomic analysis of [18F]fluoromethylcholine PET/CT images has proven to be a promising tool to stratify patients with intermediate or high-risk PCa in order to predict biochemical recurrence and tailor the best treatment options. KEY POINTS: • Stratification of patients with intermediate and high-risk prostate cancer at risk of biochemical recurrence before initial treatment would help determine the optimal curative strategy. • Artificial intelligence combined with radiomic analysis of [18F]fluorocholine PET/CT images allows prediction of biochemical recurrence, especially when radiomic features are complemented with patients' clinical information (highest median AUC of 0.78). • Radiomics reinforces the information of conventional clinical parameters (i.e., Gleason score and initial prostate-specific antigen level) in predicting biochemical recurrence.

Detection rate of 18F-Choline positron emission tomography/computed tomography in patients with non-metastatic hormone sensitive and castrate resistant prostate cancer.

BACKGROUND: To assess the detection rate of 18F-choline PET/CT in non-metastatic hormone-sensitive prostate cancer (hsPCa) and non-metastatic castrate resistant prostate cancer (CRPCa), based on the criteria proposed in the phase III SPARTAN trial and with high Gleason Score (GS). METHODS: Between October 2008 and September 2019, data from a retrospective multicenter study (N.=4 centers), involving patients undergoing 18F-choline PET/CT scans for a biochemical recurrence of PCa, were collected. The following inclusion criteria were used: 1) histologically proven PCa; 2) a non-metastatic disease in accordance with conventional imaging findings; 3) a PSA doubling time (PSAdt) <10 months; 4) a GS>8; and 5) no pelvic node>2 cm. The group of hsPCa and CRPCa patients, were compared by using a non-parametric statistical analysis. Moreover, a logistic regression analysis and ROC curves were used. RESULTS: One hundred forty patients were included. Of these, 82 patients were affected by hsPCa, and 58 had a CRPCa. Overall, 18F-Choline PET/CT was positive in 99/140 (70.7%). It was positive in 55/82 (67.1%) hsPCa patients and in 44/58 (75.9%) CRPCa subjects, respectively. The site of recurrence at 18F-Choline PET/CT were: 16 (27.6%) and 20 (24.4%) in prostatic bed, 25 (43.1%) and 24 (29.3%) in loco-regional lymph nodes and in 27 (46.6%) and 28 (34.1%) in distant organs, respectively for CRPCa and hsPCa patients. The optimal cut-off values for PSA at the time of PET/CT for the prediction or recurrence were 0.5 vs. 2.5 ng/mL for all site of recurrence (AUC: 0.70 vs. 0.72), 0.48 vs. 3.4 ng/mL for prostatic bed (AUC: 0.60 vs. 0.59), 0.5 vs. 1.5 for loco-regional lymph nodes (AUC: 0.62 vs. 0.57) and 2.2 vs. 2.8 ng/mL for distant metastasis (AUC: 0.74 vs. 0.71), respectively in CRPCa and hsPCa (all P=NS). Sensitivities and specificities of 18F-Choline PET/CT for the identification of recurrence disease in all patient population, in hsPCa and CRPCa were 83.7% and 87.5%, 78.9% and 88.9%, 91.4% and 85.7%, respectively. CONCLUSIONS: The rate of positive 18F-Choline PET/CT is similar in patients with a hsPCa and CRPCa, in case of low PSAdt and high GS. Therefore, non-metastatic PCa patients should be assessed by molecular imaging, in order to adapt the most appropriate therapeutic approach.

Radionuclide Delivery Strategies in Tumor Treatment: A Systematic Review.

The aim of this review was to assess recent progress in targeted radionuclide tumor therapy, focusing on the best delivery strategies. A literature search was conducted in PubMed, Web of Science, and Scopus using the terms "radionuclides", "liposomes", "avidin-biotin interaction", "theranostic", and "molecular docking". The 10 year filter was applied, except for the avidin-biotin interaction. Data were retrieved from both preclinical and clinical settings. Three targeting strategies were considered: pretargeting, liposomes, and ligands. Pretargeting can be achieved by exploiting the avidin-biotin interaction. This strategy seems very promising, although it has been investigated mainly in resectable tumors. Radiolabeled liposomes have attracted new interest as probes to identify the most suitable patients for treatment with liposomal formulations of common chemotherapeutics. The use of ligands for the delivery of radiotherapeutics to a specific target is still the most appealing strategy for treating tumors. The most appropriate ligand can be identified by virtually simulating its interaction with the receptor. All strategies showed great potential for use in targeted radionuclide therapy, but they also have numerous drawbacks. The most promising option is probably the one based on the use of new ligands.

Head-to-Head Comparison between Peptide-Based Radiopharmaceutical for PET and SPECT in the Evaluation of Neuroendocrine Tumors: A Systematic Review.

We compared head-to-head the most used radiolabeled peptides for single photon computed emission tomography (SPECT) and positron emission tomography (PET) imaging of neuroendocrine tumors (NETs). A comprehensive literature search was performed in PubMed, Web of Science, and Scopus databases. The following words, coupled two by two, were used: 68Ga-DOTATOC; 68Ga-DOTATATE; 68Ga-DOTANOC; 99mTc-EDDA/HYNIC-TOC; 64Cu-DOTATATE; and 111In-DTPA-octreotide. Moreover, a second-step search strategy was adopted by using the following combined terms: "Somatostatin receptor imaging,"; "Somatostatin receptor imaging" and "Functional,"; "Somatostatin receptor imaging" and "SPECT,"; and "Somatostatin receptor imaging" and "PET". Eligible criteria were: (1) original articles focusing on the clinical application of the radiopharmaceutical agents in NETs; (2) original articles in the English language; (3) comparative studies (head-to-head comparative or matched-paired studies). Editorials, letters to the editor, reviews, pictorial essays, clinical cases, or opinions were excluded. A total of 1077 articles were found in the three electronic databases. The full texts of 104 articles were assessed for eligibility. Nineteen articles were finally included. Most articles focused on the comparison between 111In-DTPA-Octreotide and 68Ga-DOTATOC/TATE. Few papers compared 64Cu-DOTATATE and 68Ga-DOTATOC/TATE, or SPECT tracers. The rates of true positivity were 63.7%, 58.5%, 78.4% and 82.4%, respectively, for 111In-DTPA-Octreotide, 99mTc-EDDA/HYNIC-TOC, 68Ga-DOTATATE/TOC and 64Cu-DOTATATE. In conclusion, as highly expected, PET tracers are more suitable for the in vivo identification of NETs. Indeed, in comparative studies, they demonstrated a higher true positive rate than SPECT agents.

Tumor Immune-Infiltrate Landscape After Chemo-Radiotherapy in a Case Series of Patients with Non-small Cell Lung Cancer: Pretreatment Predictors and Correlation With Outcome.

INTRODUCTION: Data on tumor immune-milieu after chemo-radiation (CT-RT) are scarce. Noninvasive tools are needed to improve the treatment of non-small cell lung cancer (NSCLC), especially in the locally advanced (LA) setting. METHODS: We collected a series of superior-sulcus (SS)- patients with NSCLC referred to our Institute (2015-2019), eligible for a preoperative CT-RT. We characterized tumor-infiltrating immune cells (TIICs), determined PD-L1-TPS and the residual viable tumor cells (RVTC). Radiological and metabolic responses were reviewed. We calculated pre-surgery neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). RESULTS: Eight patients were included. Radiological responses were 6 disease stabilities (SD) and 2 partial responses (PR). Metabolic responses were 4 SD and 4 PR. CD68+-TIICs were correlated with metabolic response and lower RVTC. CD68+-TIICs were associated with higher PLR. Higher PLR values seemed linked with lower RVTC. CONCLUSIONS: These preliminary results could be useful for consolidation treatment selection for patients with LA-NSCLC without evaluable baseline PD-L1 and higher PLR values.

PET-Derived Radiomics and Artificial Intelligence in Breast Cancer: A Systematic Review.

Breast cancer (BC) is a heterogeneous malignancy that still represents the second cause of cancer-related death among women worldwide. Due to the heterogeneity of BC, the correct identification of valuable biomarkers able to predict tumor biology and the best treatment approaches are still far from clear. Although molecular imaging with positron emission tomography/computed tomography (PET/CT) has improved the characterization of BC, these methods are not free from drawbacks. In recent years, radiomics and artificial intelligence (AI) have been playing an important role in the detection of several features normally unseen by the human eye in medical images. The present review provides a summary of the current status of radiomics and AI in different clinical settings of BC. A systematic search of PubMed, Web of Science and Scopus was conducted, including all articles published in English that explored radiomics and AI analyses of PET/CT images in BC. Several studies have demonstrated the potential role of such new features for the staging and prognosis as well as the assessment of biological characteristics. Radiomics and AI features appear to be promising in different clinical settings of BC, although larger prospective trials are needed to confirm and to standardize this evidence.

PET/MRI in prostate cancer: a systematic review and meta-analysis.

AIM: In recent years, the clinical availability of scanners for integrated positron emission tomography (PET) and magnetic resonance imaging (MRI) has enabled the practical potential of multimodal, combined metabolic-receptor, anatomical, and functional imaging to be explored. The present systematic review and meta-analysis summarize the diagnostic information provided by PET/MRI in patients with prostate cancer (PCa). MATERIALS AND METHODS: A literature search was conducted in three different databases. The terms used were "choline" or "prostate-specific membrane antigen - PSMA" AND "prostate cancer" or "prostate" AND "PET/MRI" or "PET MRI" or "PET-MRI" or "positron emission tomography/magnetic resonance imaging." All relevant records identified were combined, and the full texts were retrieved. Reports were excluded if (1) they did not consider hybrid PET/MRI; or (2) the sample size was < 10 patients; or (3) the raw data were not enough to enable the completion of a 2 × 2 contingency table. RESULTS: Fifty articles were eligible for systematic review, and 23 for meta-analysis. The pooled data concerned 2104 patients. Initial disease staging was the main indication for PET/MRI in 24 studies. Radiolabeled PSMA was the tracer most frequently used. In primary tumors, the pooled sensitivity for the patient-based analysis was 94.9%. At restaging, the pooled detection rate was 80.9% and was higher for radiolabeled PSMA than for choline (81.8% and 77.3%, respectively). CONCLUSIONS: PET/MRI proved highly sensitive in detecting primary PCa, with a high detection rate for recurrent disease, particularly when radiolabeled PSMA was used.

An international expert opinion statement on the utility of PET/MR for imaging of skeletal metastases.

BACKGROUND: MR is an important imaging modality for evaluating musculoskeletal malignancies owing to its high soft tissue contrast and its ability to acquire multiparametric information. PET provides quantitative molecular and physiologic information and is a critical tool in the diagnosis and staging of several malignancies. PET/MR, which can take advantage of its constituent modalities, is uniquely suited for evaluating skeletal metastases. We reviewed the current evidence of PET/MR in assessing for skeletal metastases and provided recommendations for its use. METHODS: We searched for the peer reviewed literature related to the usage of PET/MR in the settings of osseous metastases. In addition, expert opinions, practices, and protocols of major research institutions performing research on PET/MR of skeletal metastases were considered. RESULTS: Peer-reviewed published literature was included. Nuclear medicine and radiology experts, including those from 13 major PET/MR centers, shared the gained expertise on PET/MR use for evaluating skeletal metastases and contributed to a consensus expert opinion statement. [18F]-FDG and non [18F]-FDG PET/MR may provide key advantages over PET/CT in the evaluation for osseous metastases in several primary malignancies. CONCLUSION: PET/MR should be considered for staging of malignancies where there is a high likelihood of osseous metastatic disease based on the characteristics of the primary malignancy, hight clinical suspicious and in case, where the presence of osseous metastases will have an impact on patient management. Appropriate choice of tumor-specific radiopharmaceuticals, as well as stringent adherence to PET and MR protocols, should be employed.

Challenges in theragnostics.

Precision medicine (or personalized medicine) is an intriguing, and still involving part of modern medicine. Theragnostics is a combination of therapies and diagnostics targeting pathophysiological processes at molecular level using radiopharmaceuticals. It is a valuable resource in efforts to implement precision medicine in clinical practice, but the theragnostic era poses an abundance of challenges. The aim of the present paper study was to analyze some of these challenges in the field of theragnostics, irrespective of their clinical applications. Three experts in this field discussed the balance between the demand, the costs of theragnostics, the need of appropriate infrastructures, and the opportunities for new developments in this area.

Copper, PET/CT and prostate cancer: a systematic review of the literature.

Copper is an essential element that plays an important role in both cancer development and growth. Indeed, high levels of copper have been found in prostate cancer (PCa), and this finding have paved the way for the use of this element as a target for positron emission tomography (PET) imaging. Copper64 (64Cu) can be used alone, as 64CuCl2, and also as a precursor for the in-vitro radio-labelling of specific carriers for PET imaging in PCa, (e.g. associated to prostate-specific membrane antigen: PSMA). The use of 64Cu-PSMA can yield late acquisitions in which PET images are characterized by a higher target-to-background ratio. At the same time, the shorter positron range of 64Cu provides high spatial resolution, which leads to better detection of small lesions. In this context, the aim of this review was to systematically review studies evaluating the identification of PCa in humans by means of 64CuCl2 and other PET tracers radio-labelled with 64Cu.

Molecular Imaging of Pulmonary Inflammation and Infection.

Infectious and inflammatory pulmonary diseases are a leading cause of morbidity and mortality worldwide. Although infrequently used in this setting, molecular imaging may significantly contribute to their diagnosis using techniques like single photon emission tomography (SPET), positron emission tomography (PET) with computed tomography (CT) or magnetic resonance imaging (MRI) with the support of specific or unspecific radiopharmaceutical agents. 18F-Fluorodeoxyglucose (18F-FDG), mostly applied in oncological imaging, can also detect cells actively involved in infectious and inflammatory conditions, even if with a low specificity. SPET with nonspecific (e.g., 67Gallium-citrate (67Ga citrate)) and specific tracers (e.g., white blood cells radiolabeled with 111Indium-oxine (111In) or 99mTechnetium (99mTc)) showed interesting results for many inflammatory lung diseases. However, 67Ga citrate is unfavorable by a radioprotection point of view while radiolabeled white blood cells scan implies complex laboratory settings and labeling procedures. Radiolabeled antibiotics (e.g., ciprofloxacin) have been recently tested, although they seem to be quite unspecific and cause antibiotic resistance. New radiolabeled agents like antimicrobic peptides, binding to bacterial cell membranes, seem very promising. Thus, the aim of this narrative review is to provide a comprehensive overview about techniques, including PET/MRI, and tracers that can guide the clinicians in the appropriate diagnostic pathway of infectious and inflammatory pulmonary diseases.

The future of choline PET in the era of prostate specific membrane antigen.

Radiolabeled choline was the first radiopharmaceutical agent employed in prostate cancer patients. It has been considered a metabolic agent able to detect the presence of prostate cancer cell, both in the initial phase of the disease and in the restaging setting. Three agents are now available in clinical practice: one radiolabeled with 11C (called 11C-Choline) and two with 18F (either as 18F-methylcholine or 18F-ethylcholine). During the years, different studies have been performed with 11C -Choline and 18F-Choline demonstrating their performance for the detection of prostate cancer, in different settings of the disease. However, recently, new radiopharmaceutical agents for prostate cancer have been developed, gaining an important role for the diagnosis of prostate cancer, particularly in the restaging setting. The present review has been conceived in order to discuss the current role of radiolabeled choline PET/CT in the era of new agents for prostate cancer, in particular in the era of radiolabeled PSMA.

The effects of androgen deprivation therapy on the 18F-Chcoline uptake in prostate cancer patients undergoing neoadjuvant treatment.

BACKGROUND: The aim of the present study was to evaluate how neoadjuvant androgen deprivation therapy (ADT) can impact 18F-choline uptake in primary prostate cancer (PC) and its metastases before radical prostatectomy (RP) or radiation therapy (RT). METHODS: We retrospectively reviewed images of 79 PC patients undergoing 18F-choline PET/CT before RP or RT. Based on concomitant administration of neoadjuvant ADT at the time of 18F-choline PET/CT, patients were subdivided into naïve group (Group 1) and neoadjuvant ADT group (Group 2). PET/CT results, SUVmax and metabolic tumor volume (MTV) for each site were re-assessed by two nuclear medicine physicians with more than 5 years of experience. A chi-square and a U-Mann Whitney test were used to compare the two groups. RESULTS: Sixty-two patients were included in Group 1, while 17 in Group 2. PET/CT was positive in all patients, in particular: 54 had a significant uptake in prostate alone, 12 in prostate plus lymph nodes (LN), 4 in prostate plus LN and bone, 3 in prostate plus bone and 6 in prostate plus other organs (such as lung or thyroid). PET/CT was more frequently positive in a different site, outside the prostate, in Group 1 as compared to Group 2 (P<0.001). Conversely, median SUVmax and MTV in the prostate resulted significantly lower in Group 2 than in Group 1 (5.34 vs. 7.72 and 3.66 vs. 6.86 cm3, respectively; both P<0.05). CONCLUSIONS: PET/CT could have an important role in prostate cancer staging before primary treatment; however, before imaging, hormonal therapy status should be carefully evaluated.