Next-level precision medicine: why the theragnostic approach is the future.

Theragnostics represents one of the most innovative fields of precision medicine with a huge potential in the field of oncology in the next years. The use of a pair of selective radiopharmaceuticals for cellular receptors, used for diagnostic and therapeutic purposes (PRRT), finds applications in the Neuroendocrine tumors and metastatic Castration-Resistant prostate cancer (mCRPC) thanks, respectively, to somatostatin receptor agonists and PSMA-based peptides. Further evolutions of theragnostics will be possible to the radioimmunoconjugates used both in the diagnostic (Immuno-PET) and in the therapeutic fields (radioimmunotherapy). It is evident that in the "omics-era," theragnostics could become a necessary method, not only in order to improve our knowledge of tumor biology, but also, to find more and more targeted therapies in a multidisciplinary context and in a tailor-based approach.

Breast Imaging Physics in Mammography (Part II).

One of the most frequently detected neoplasms in women in Italy is breast cancer, for which high-sensitivity diagnostic techniques are essential for early diagnosis in order to minimize mortality rates. As addressed in Part I of this work, we have seen how conditions such as high glandular density or limitations related to mammographic sensitivity have driven the optimization of technology and the use of increasingly advanced and specific diagnostic methodologies. While the first part focused on analyzing the use of a mammography machine from a physical and dosimetric perspective, in this paper, we will examine other techniques commonly used in breast imaging: contrast-enhanced mammography, digital breast tomosynthesis, radio imaging, and include some notes on image processing. We will also explore the differences between these various techniques to provide a comprehensive overview of breast lesion detection techniques. We will examine the strengths and weaknesses of different diagnostic modalities and observe how, with the implementation of improvements over time, increasingly effective diagnoses can be achieved.

The Role of Imaging of Lymphatic System to Prevent Cancer Related Lymphedema.

Lymphedema is a progressive chronic condition affecting approximately 250 million people worldwide, a number that is currently underestimated. In Western countries, the most common form of lymphedema of the extremities is cancer-related and less radical surgical intervention is the main option to prevent it. Standardized protocols in the areas of diagnosis, staging and treatment are strongly required to address this issue. The aim of this study is to review the main diagnostic methods, comparing new emerging procedures to lymphoscintigraphy, considered as the golden standard to date. The roles of Magnetic Resonance Lymphangiography (MRL) or indocyanine green ICG lymphography are particularly reviewed in order to evaluate diagnostic accuracy, potential associations with lymphoscintigraphy, and future directions guided by AI protocols. The use of imaging to treat lymphedema has benefited from new techniques in the area of lymphatic vessels anatomy; these perspectives have become of value in many clinical scenarios to prevent cancer-related lymphedema.

Automated 3D Ultrasound as an Adjunct to Screening Mammography Programs in Dense Breast: Literature Review and Metanalysis.

Purpose: The purpose of this meta-analysis is to investigate the effectiveness of supplementing screening mammography with three-dimensional automated breast ultrasonography (3D ABUS) in improving breast cancer detection rates in asymptomatic women with dense breasts. Materials and Methods: We conducted a thorough review of scientific publications comparing 3D ABUS and mammography. Articles for inclusion were sourced from peer-reviewed journal databases, namely MEDLINE (PubMed) and Scopus, based on an initial screening of their titles and abstracts. To ensure a sufficient sample size for meaningful analysis, only studies evaluating a minimum of 20 patients were retained. Eligibility for evaluation was further limited to articles written in English. Additionally, selected studies were required to have participants aged 18 or above at the time of the study. We analyzed 25 studies published between 2000 and 2021, which included a total of 31,549 women with dense breasts. Among these women, 229 underwent mammography alone, while 347 underwent mammography in combination with 3D ABUS. The average age of the women was 50.86 years (±10 years standard deviation), with a range of 40-56 years. In our efforts to address and reduce bias, we applied a range of statistical analyses. These included assessing study variation through heterogeneity assessment, accounting for potential study variability using a random-effects model, exploring sources of bias via meta-regression analysis, and checking for publication bias through funnel plots and the Egger test. These methods ensured the reliability of our study findings. Results: According to the 25 studies included in this metanalysis, out of the total number of women, 27,495 were diagnosed with breast cancer. Of these, 211 were diagnosed through mammography alone, while an additional 329 women were diagnosed through the combination of full-field digital mammography (FFDSM) and 3D ABUS. This represents an increase of 51.5%. The rate of cancers detected per 1000 women screened was 23.25‱ (95% confidence interval [CI]: 21.20, 25.60; p < 0.001) with mammography alone. In contrast, the addition of 3D ABUS to mammography increased the number of tumors detected to 20.95‱ (95% confidence interval [CI]: 18.50, 23; p < 0.001) per 1000 women screened. Discussion: Even though variability in study results, lack of long-term outcomes, and selection bias may be present, this systematic review and meta-analysis confirms that supplementing mammography with 3D ABUS increases the accuracy of breast cancer detection in women with ACR3 to ACR4 breasts. Our findings suggest that the combination of mammography and 3D ABUS should be considered for screening women with dense breasts. Conclusions: Our research confirms that adding 3D automated breast ultrasound to mammography-only screening in patients with dense breasts (ACR3 and ACR4) significantly (p < 0.05) increases the cancer detection rate.

Breast Imaging Physics in Mammography (Part I).

Breast cancer is the most frequently diagnosed neoplasm in women in Italy. There are several risk factors, but thanks to screening and increased awareness, most breast cancers are diagnosed at an early stage when surgical treatment can most often be conservative and the adopted therapy is more effective. Regular screening is essential but advanced technology is needed to achieve quality diagnoses. Mammography is the gold standard for early detection of breast cancer. It is a specialized technique for detecting breast cancer and, thus, distinguishing normal tissue from cancerous breast tissue. Mammography techniques are based on physical principles: through the proper use of X-rays, the structures of different tissues can be observed. This first part of the paper attempts to explain the physical principles used in mammography. In particular, we will see how a mammogram is composed and what physical principles are used to obtain diagnostic images.

Role of Nuclear Sentinel Lymph Node Mapping Compared to New Alternative Imaging Methods.

With the emergence of sentinel node technology, many patients can be staged histopathologically using lymphatic mapping and selective lymphadenectomy. Structural imaging by using US, CT and MR permits precise measurement of lymph node volume, which is strongly associated with neoplastic involvement. Sentinel lymph node detection has been an ideal field of application for nuclear medicine because anatomical data fails to represent the close connections between the lymphatic system and regional lymph nodes, or, more specifically, to identify the first draining lymph node. Hybrid imaging has demonstrated higher accuracy than standard imaging in SLN visualization on images, but it did not change in terms of surgical detection. New alternatives without ionizing radiations are emerging now from "non-radiological" fields, such as ophthalmology and dermatology, where fluorescence or opto-acoustic imaging, for example, are widely used. In this paper, we will analyze the advantages and limits of the main innovative methods in sentinel lymph node detection, including innovations in lymphoscintigraphy techniques that persist as the gold standard to date.

Radiomics in Breast Imaging: Future Development.

Breast cancer is the most common and most commonly diagnosed non-skin cancer in women. There are several risk factors related to habits and heredity, and screening is essential to reduce the incidence of mortality. Thanks to screening and increased awareness among women, most breast cancers are diagnosed at an early stage, increasing the chances of cure and survival. Regular screening is essential. Mammography is currently the gold standard for breast cancer diagnosis. In mammography, we can encounter problems with the sensitivity of the instrument; in fact, in the case of a high density of glands, the ability to detect small masses is reduced. In fact, in some cases, the lesion may not be particularly evident, it may be hidden, and it is possible to incur false negatives as partial details that may escape the radiologist's eye. The problem is, therefore, substantial, and it makes sense to look for techniques that can increase the quality of diagnosis. In recent years, innovative techniques based on artificial intelligence have been used in this regard, which are able to see where the human eye cannot reach. In this paper, we can see the application of radiomics in mammography.

Unespected dectection of unruptured brain arteriovenous malformation with 18F-DOPA PET/MR.

Unruptured brain arteriovenous malformations (AVM) have a heterogeneous clinical presentation, mainly related to the presence of intracerebral hemorrhage. We report the diagnosis of AVM in a patient with Parkinson's disease (PD), who undergone positron emission tomography/magnetic resonance imaging (PET/MRI) molecular brain imaging with fluorine-18-dihydroxyphenylalanine (18F-DOPA). This case suggests that AVM may be occasionally recognized in molecular imaging studies using positron-emitting amino acids. Magnetic resonance imaging with susceptibility-weighted imaging (SWI) sequences and 3D time of flight (TOF) reconstruction may contribute to manage patients with AVM.

Tailored Molecular Imaging of Pheochromocytoma and Paraganglioma: Which Tracer and When.

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neoplasms that fall within the category of neuroendocrine tumors. In the last decade, their diagnostic algorithm has been modified to include the evaluation of molecular pathways, genotype, and biochemical phenotype, in order to correctly interpret anatomical and functional imaging results and tailor the best therapeutic choices to patients. More specifically, the identification of germline mutations has led to a three-way cluster classification: pseudo-hypoxic cluster, cluster of kinase receptor signaling and protein translation pathways, and cluster of Wnt-altered pathway. In this context, functional imaging gained a crucial role in the management of these patients in agreement with the ever-growing concept of personalized medicine. In this paper, we provide an overview of three specific molecular pathways targeted by positron-emitting tracers to image PCCs and PGLs: catecholamine metabolism, somatostatin receptors, and glucose uptake. Finally, we recommend different flow charts for use in the selection of tracers for specific clinical scenarios, based on sporadic/inherited tumor and known/unknown mutation status.

Second-Generation 3D Automated Breast Ultrasonography (Prone ABUS) for Dense Breast Cancer Screening Integrated to Mammography: Effectiveness, Performance and Detection Rates.

In our study, we added a three-dimensional automated breast ultrasound (3D ABUS) to mammography to evaluate the performance and cancer detection rate of mammography alone or with the addition of 3D prone ABUS in women with dense breasts. Our prospective observational study was based on the screening of 1165 asymptomatic women with dense breasts who selected independent of risk factors. The results evaluated include the cancers detected between June 2017 and February 2019, and all surveys were subjected to a double reading. Mammography detected four cancers, while mammography combined with a prone Sofia system (3D ABUS) doubled the detection rate, with eight instances of cancer being found. The diagnostic yield difference was 3.4 per 1000. Mammography alone was subjected to a recall rate of 14.5 for 1000 women, while mammography combined with 3D prone ABUS resulted in a recall rate of 26.6 per 1000 women. We also observed an additional 12.1 recalls per 1000 women screened. Integrating full-field digital mammography (FFDM) with 3D prone ABUS in women with high breast density increases and improves breast cancer detection rates in a significant manner, including small and invasive cancers, and it has a tolerable impact on recall rate. Moreover, 3D prone ABUS performance results are comparable with the performance results of the supine 3D ABUS system.

FDG-CT/PET false positive case in hip prosthesis: a clue to avoid error.

A 62 years old woman 6 months after left total hip prosthesis referred to our institution for persistent pain and warm, stiff, and swollen joint. 18F-FDG CT/PET Images showed an intense focal uptake corresponding to the external margin of inter-trochanteric region of prosthesis and inside the stem inferiorly, but common decision was to reconstruct PET images without attenuation correction and now showed a complete and unexpected disappearance of focal and pathological FDG uptake. This case shows the potential propagation of CT artifacts into PET emission data close to metal implants and should be taken in account together to SUV values.

The Role of Molecular Imaging in a Muscle-Invasive Bladder Cancer Patient: A Narrative Review in the Era of Multimodality Treatment.

Diagnostic imaging in bladder cancer plays an important role since it is needed from pretreatment staging to follow-up, but a morphological evaluation performed with both CT and MRI showed low sensitivities and specificities in detecting pathologic lymph nodes, due to the occurrence of false positive results. Implementation of functional information provided by PET/CT could be a determinant in the management of patients with muscle-invasive bladder cancer. A focus on the role of 18F-FDG PET/CT and alternative tracers in patients with muscle-invasive bladder cancer is provided in this analysis in order to outline its potential applications in staging settings and response evaluation after neoadjuvant chemotherapy.

MRI in Pregnancy and Precision Medicine: A Review from Literature.

Magnetic resonance imaging (MRI) offers excellent spatial and contrast resolution for evaluating a wide variety of pathologies, without exposing patients to ionizing radiations. Additionally, MRI offers reproducible diagnostic imaging results that are not operator-dependent, a major advantage over ultrasound. MRI is commonly used in pregnant women to evaluate, most frequently, acute abdominal and pelvic pain or placental abnormalities, as well as neurological or fetal abnormalities, infections, or neoplasms. However, to date, our knowledge about MRI safety during pregnancy, especially about the administration of gadolinium-based contrast agents, which are able to cross the placental barrier, is still limited, raising concerns about possible negative effects on both the mother and the health of the fetus. Contrast agents that are unable to cross the placenta in a way that is safe for the fetus are desirable. In recent years, some preclinical studies, carried out in rodent models, have evaluated the role of long circulating liposomal nanoparticle-based blood-pool gadolinium contrast agents that do not penetrate the placental barrier due to their size and therefore do not expose the fetus to the contrast agent during pregnancy, preserving it from any hypothetical risks. Hence, we performed a literature review focusing on contrast and non-contrast MRI use during pregnancy.

PET/CT in thyroid cancer - the importance of BRAF mutations.

Thyroid cancer (TC) represents less than 1% of all newly diagnosed malignancies. In some selected cases, with a high clinical suspicion for disease but negative I-131 scan, positron emission tomography/computed tomography (PET) with F-18-Fluorodeoxyglucose (FDG) could be helpful in the detection of disease and the definition of its extent. FDG PET/CT, better if performed after TSH stimulation analogously to patient preparation done for radioiodine scintigraphy, could be useful mainly in the detection of metastatic and recurrent disease since the uptake and diagnostic sensitivity of FDG are increased by TSH stimulation. Recently, the role of oncogenic mutations in the tumorigenesis of TCs has become clearer. Among such mutations, BRAFV600E represents the most common genetic alteration. Mutated BRAF may define a more aggressive papillary carcinoma with poorer prognosis and therefore its analysis has been extensively studied as a rule-in test for thyroid carcinoma. In this paper, we try to outline the possible role of FDG PET/CT in the management of patients with TC and positive BRAF mutations and the impact that it could have on their therapeutic algorithm, in terms of thyroidectomy and radioactive iodine (RAI) therapy.

99mTc-EDDA/HYNIC-TOC is a New Opportunity in Neuroendocrine Tumors of the Lung (and in other Malignant and Benign Pulmonary Diseases).

Neuroendocrine tumors (NETs) consist of a relatively rare spectrum of malignancies that can arise from neuroendocrine cells; lung NETs (L-NETs) represent about 25% of primary lung neoplasm and 10% of all carcinoid tumors. Diagnostic algorithm usually takes into consideration chest Xray, contrast-enhanced CT and MRI. Nuclear medicine plays a crucial role in the detection and correct assessment of neoplastic functional status as it provides in vivo metabolic data related to the overexpression of Somatostatin Receptors (SSTRs) and also predicting response to peptide receptor radionuclide therapy (PRRT). 111In-Pentreotide (Octreoscan®) is commercially available for imaging of neuroendocrine tumors, their metastases and the management of patients with NETs. More recently, 99mTc-EDDA/HYNIC-TOC(Tektrotyd®) was introduced into the market and its use has been approved for imaging of patients with L-NETs and other SSTR-positive tumors. 99mTc-EDDA/HYNIC-TOC could also represent a good alternative to 68Ga-DOTA-peptides (DOTA-TOC, DOTA-NOC, DOTATATE) in hospitals or centers where PET/CT or 68Ge/68Ga generators are not available. When compared to 111In-Pentetreotide, Tektrotyd® showed slightly higher sensitivity, in the presence of higher imaging quality and lower radiation exposure for patients. Interesting perspectives depending on the kinetic analysis allowed by Tektrotyd® may be obtained in differential diagnosis of non-small cells lung cancer (NSCLC) versus small cells lung cancer (SCLC) and NETs. An interesting perspective could be also associated with a surgery radio-guided by Tektrotyd® in operable lung tumors, including either NETs and NSCLC.

The Molecular Effects of Ionizing Radiations on Brain Cells: Radiation Necrosis vs. Tumor Recurrence.

The central nervous system (CNS) is generally resistant to the effects of radiation, but higher doses, such as those related to radiation therapy, can cause both acute and long-term brain damage. The most important results is a decline in cognitive function that follows, in most cases, cerebral radionecrosis. The essence of radio-induced brain damage is multifactorial, being linked to total administered dose, dose per fraction, tumor volume, duration of irradiation and dependent on complex interactions between multiple brain cell types. Cognitive impairment has been described following brain radiotherapy, but the mechanisms leading to this adverse event remain mostly unknown. In the event of a brain tumor, on follow-up radiological imaging often cannot clearly distinguish between recurrence and necrosis, while, especially in patients that underwent radiation therapy (RT) post-surgery, positron emission tomography (PET) functional imaging, is able to differentiate tumors from reactive phenomena. More recently, efforts have been done to combine both morphological and functional data in a single exam and acquisition thanks to the co-registration of PET/MRI. The future of PET imaging to differentiate between radionecrosis and tumor recurrence could be represented by a third-generation PET tracer already used to reveal the spatial extent of brain inflammation. The aim of the following review is to analyze the effect of ionizing radiations on CNS with specific regard to effect of radiotherapy, focusing the attention on the mechanism underling the radionecrosis and the brain damage, and show the role of nuclear medicine techniques to distinguish necrosis from recurrence and to early detect of cognitive decline after treatment.

Gamma Emitters in Pancreatic Endocrine Tumors Imaging in the PET Era: Is there a Clinical Space for 99mTc-peptides?

BACKGROUND: Pancreatic Neuroendocrine Tumors (PNETs) are rare neoplasms, sporadic or familial, even being part of a syndrome. Their diagnosis is based on symptoms, hormonal disorders or may be fortuitous. The role of Nuclear Medicine is important, mainly because of the possibility of a theranostic strategy. This approach is allowed by the availability of biochemical agents, which may be labeled with radionuclides suitable for diagnostic or therapeutic purposes, showing almost identical pharmacokinetics. The major role for radiopharmaceuticals is connected with radiolabeled Somatostatin Analogues (SSA), since somatostatin receptors are highly expressed on some of the neoplastic cell types. DISCUSSION: Nowadays, in the category of radiolabeled SSA, although 111In-pentetreotide, firstly commercially proposed, is still used, the best choice for diagnosis is related to the so called DOTAPET radiotracers labeled with 68-Gallium (Ga), such as 68Ga-DOTATATE, 68Ga-DOTANOC, and 68Ga-DOTATOC. More recently, labeling with 64-Copper (Cu) (64Cu-DOTATATE) has also been proposed. In this review, we discuss the clinical interest of a SAA (Tektrotyd©) radiolabeled with 99mTc, a gamma emitter with better characteristics, with respect to 111Indium, radiolabeling Octreoscan ©. By comparing both pharmacokinetics and pharmacodynamics of Octreoscan©, Tektrotyd© and PET DOTA-peptides, on the basis of literature data and of our own experience, we tried to highlight these topics to stimulate further studies, individuating actual clinical indications for all of these radiotracers. CONCLUSION: In our opinion, Tektrotyd© could already find its applicative dimension in the daily practice of NETs, either pancreatic or not, at least in centers without a PET/CT or a 68Ga generator. Because of wider availability, a lower cost, and a longer decay, compared with respect to peptides labeled with 68Ga, it could be also proposed, in a theranostic context, for a dosimetry evaluation of patients undergoing Peptide Receptor Radionuclide Therapy (PRRT), and for non-oncologic indications of radiolabelled SSA. In this direction, and for a more rigorous cost/effective evaluation, more precisely individuating its clinical role, further studies are needed.

Physiopathological Premises to Nuclear Medicine Imaging of Pancreatic Neuroendocrine Tumours.

BACKGROUND: Pancreatic Neuroendocrine Tumors (P-NETs) are a challenge in terms of both diagnosis and therapy; morphological studies need to be frequently implemented with nonstandard techniques such as Endoscopic Ultrasounds, Dynamic CT, and functional Magnetic Resonance. DISCUSSION: The role of nuclear medicine, being scarcely sensitive F-18 Fluorodeoxyglucose, is mainly based on the over-expression of Somatostatin Receptors (SSTR) on neuroendocrine tumor cells surface. Therefore, SSTR can be used as a target for both diagnosis, using radiotracers labeled with gamma or positron emitters, and therapy. SSTRs subtypes are capable of homo and heterodimerization in specific combinations that alter both the response to ligand activation and receptor internalization. CONCLUSION: Although agonists usually provide efficient internalization, also somatostatin antagonists (SS-ANTs) could be used for imaging and therapy. Peptide Receptor Radionuclide Therapy (PRRT) represents the most successful option for targeted therapy. The theranostic model based on SSTR does not work in insulinoma, in which different radiotracers such as F-18 FluoroDOPA or tracers for the glucagon-like peptide-1 receptor have to be preferred.

Microvascular Invasion in HCC: The Molecular Imaging Perspective.

Hepatocellular carcinoma represents the most frequent primary liver tumor; curative options are only surgical resection and liver transplantation. From 1996, Milan Criteria are applied in consideration of patients with cirrhosis and hepatocellular for liver transplantation; nonetheless, more recently, Milan Criteria have been criticized because they appear over conservative. Apart from number and size of lesions and biomarker levels, which already have been associated with poorer prognosis, overall survival and recurrence rates after transplantation are affected also by the presence of vascular invasion. Microvascular invasion suggests a poor prognosis but it is often hard to detect before transplant. Diagnostic imaging and tumor markers may play an important role and become the main tools to define microvascular invasion. In particular, a possible role could be found for computed tomography, magnetic resonance imaging, and positron emission tomography. In this paper, we analyze the possible role of positron emission tomography as a preoperative imaging biomarker capable of predicting microvascular invasion in patients with hepatocellular carcinoma and thus selecting optimal candidates for liver transplantation.

Nuclear Medicine in Prostate Cancer: A New Era for Radiotracers.

Natural history of prostate cancer (PCa) is extremely variable, as it ranges from indolent and slow growing tumors to highly aggressive histotypes. Genetic background and environmental factors co-operate to the genesis and clinical manifestation of the tumor and include among the others race, family, specific gene variants (i.e., BRCA1 and BRCA2 mutations), acute and chronic inflammation, infections, diet and drugs. In this scenario, remaining actual the clinical interest of bone scan (BS) in detecting skeletal metastases, an important role in diagnostic imaging may be also carried out by, positron emission tomography/computed tomography (PET/CT) and PET/magnetic resonance imaging (PET/MRI), which combine morphological information provided by CT and MRI with functional and metabolic data provided by PET acquisitions. With respect to PET radiotracers, being ancillary the usefulness of F-18 fluoro-deoxyglucose and not yet demonstrated the cost-effectiveness of F-18 Fluoride respect to BS, the main role is now played by choline derivatives, in particular by 11C-choline and 18F-fluorocholine. More recently, a greater interest for both diagnostic and therapeutic purposes has been associated with radiotracers directed to prostate-specific membrane antigen (PSMA), a transmembrane protein expressed on the cell surface, which showed high selective expression in PCa, metastatic lymph nodes and bone metastases. Several PSMA-targeted PET tracers have been developed many of which showing promising results for accurate diagnosis and staging of primary PCa and re-staging after biochemical recurrence, even in case of low prostate specific antigen values. In particular, the most widely used PSMA ligand for PET imaging is a 68Ga-labelled PSMA inhibitor, 68Ga-PSMA-HBED-CC (68Ga-PSMA-11). 99mTc-HYNIC-Glu-Urea-A for single photon emission computed tomography, and 177Lu-PSMA-617 for radioligand therapy has also been applied in humans, with interesting preliminary results related to a possible theranostic approach. A potential role of PSMA radioligands in radio-guided surgery has also been proposed.