Progressive motor neuron syndromes with single CNS lesions and CSF oligoclonal bands: never forget solitary sclerosis!

We describe 3 cases of solitary sclerosis (SS), a rare condition characterized by a single inflammatory demyelinating lesion in the white matter of the brain or spinal cord. All patients had progressive limb motor impairment (patient 1, 66-year-old female: left spastic hemiparesis; patient 2, 39-year-old male: right spastic hemiparesis; patient 3, 42-year-old female: proximally predominant left upper limb weakness with amyotrophy and fasciculations). In all patients, MRI disclosed a single small T2-hyperintense demyelinating lesion: in the right anterior paramedian upper medulla, in the median-left paramedian anterior lower medulla, and in the left paramedian anterior cervical spinal cord at C4 level, respectively. In patients 1 and 2, transcranial magnetic stimulation (TMS) demonstrated altered motor evoked potentials (MEPs) and increased central motor conduction time (CMCT) in the affected limbs; in patient 3, needle EMG revealed chronic neurogenic changes in C5-C7 muscles of left upper limb. Patients 1 and 2 had normal brain 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET). CSF analysis demonstrated IgG oligoclonal bands in all patients. In patients 2 and 3, levels of neurofilament light chain (NFL) in CSF and serum, respectively, were within normal limits. The three cases were consistent with the diagnosis of SS. Notably, while the first two cases mimicked Mills' syndrome (the hemiparetic variant of primary lateral sclerosis, PLS), the third one was rather reminiscent of amyotrophic lateral sclerosis (ALS). This suggests including SS in the differential diagnosis not only of PLS, but also of ALS. We also report the first quantification of NFL levels in SS.

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.

Prevalence of interstitial pneumonia suggestive of COVID-19 at 18F-FDG PET/CT in oncological asymptomatic patients in a high prevalence country during pandemic period: a national multi-centric retrospective study.

PURPOSE: To assess the presence and pattern of incidental interstitial lung alterations suspicious of COVID-19 on fluorine-18-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) ([18F]FDG PET/CT) in asymptomatic oncological patients during the period of active COVID-19 in a country with high prevalence of the virus. METHODS: This is a multi-center retrospective observational study involving 59 Italian centers. We retrospectively reviewed the prevalence of interstitial pneumonia detected during the COVID period (between March 16 and 27, 2020) and compared to a pre-COVID period (January-February 2020) and a control time (in 2019). The diagnosis of interstitial pneumonia was done considering lung alterations of CT of PET. RESULTS: Overall, [18F]FDG PET/CT was performed on 4008 patients in the COVID period, 19,267 in the pre-COVID period, and 5513 in the control period. The rate of interstitial pneumonia suspicious for COVID-19 was significantly higher during the COVID period (7.1%) compared with that found in the pre-COVID (5.35%) and control periods (5.15%) (p < 0.001). Instead, no significant difference among pre-COVID and control periods was present. The prevalence of interstitial pneumonia detected at PET/CT was directly associated with geographic virus diffusion, with the higher rate in Northern Italy. Among 284 interstitial pneumonia detected during COVID period, 169 (59%) were FDG-avid (average SUVmax of 4.1). CONCLUSIONS: A significant increase of interstitial pneumonia incidentally detected with [18F]FDG PET/CT has been demonstrated during the COVID-19 pandemic. A majority of interstitial pneumonia were FDG-avid. Our results underlined the importance of paying attention to incidental CT findings of pneumonia detected at PET/CT, and these reports might help to recognize early COVID-19 cases guiding the subsequent management.

Plasma levels of extracellular vesicles and the risk of post-operative pulmonary embolism in patients with primary brain tumors: a prospective study.

Primary brain tumors are associated with an increased risk of pulmonary embolism (PE), particularly in the early post-operative period. The pathophysiological mechanisms of PE are poorly understood. This study aims to describe prospectively extracellular vesicles (EVs) levels and investigate whether or not their variations allow to identify patients at increased risk of post-operative PE. Consecutive meningioma or glioma patients candidate to tumor resection were included in the study if a pulmonary perfusion scan (Q-scan) performed before surgery ruled out PE. EVs derived from platelets (CD41+) or endothelial cells (CD144+), tissue factor-bearing EVs (CD142+) and their procoagulant subtype (annexin V+) were analyzed by flow cytometry before surgery (T0), within 24 h (T1), two (T2) and seven days (T7) after surgery. Q-scan was repeated at T2. Ninety-three patients with meningioma, 59 with glioma and 76 healthy controls were included in the study. CD142+ and annexin V+/CD142+ EVs were increased at T0 in meningioma and glioma patients compared to healthy controls. Twenty-nine meningioma (32%) and 16 glioma patients (27%) developed PE at T2. EVs levels were similar in meningioma patients with or without PE, whereas annexin V+ and annexin V+/CD142+ EVs were significantly higher at T1 and T2 in glioma patients with PE than in those without. Procoagulant EVs, particularly annexin V+/CD142+, increase after surgery and are more prevalent in glioma patients who developed PE after surgery than in those who did not.

Risk of post-operative venous thromboembolism in patients with meningioma.

The surgical resection of meningiomas can be complicated by venous thromboembolism (VTE) in the post-operative period, but the exact incidence of this event is not known. Aim of this study was to assess the occurrence of VTE in patients operated for meningioma who underwent a post-operative clinical and objective screening for VTE. Patients undergoing meningioma resection between 2000 and 2010 who accepted to be investigated for VTE in the post-operative period were included in the study. The screening included daily clinical assessment, pulmonary perfusion scintigraphy (Q-SCAN) on day 2 and venous compression ultrasonography (CUS) of the lower limbs within day 7. The univariate and multivariate statistical analysis of risk factors for VTE included sex, age, presence of comorbidities, pre- and post-operative Karnofsky Performance scale (KPS), post-operative neurological worsening and post-operative walking ability. Two-hundred and seventy-five patients were included in the study. VTE was diagnosed in 82 patients (29.8%). Univariate analysis revealed that age ≥ 65 years, cardiovascular comorbidities, pre- and post-operative KPS < 80/100, post-operative neurological worsening and impaired post-operative walking ability were significantly associated with VTE. Multivariate analysis confirmed only age ≥ 65 years (p = 0.011) and post-operative KPS < 80/100 (p = 0.002) as independent risk factors for VTE. Patients operated for meningioma have a 30% risk of VTE. Age ≥ 65 years and post-operative KPS < 80 were independent risk factors for VTE.

Analysis of NSCLC tumour heterogeneity, proliferative and 18F-FDG PET indices reveals Ki67 prognostic role in adenocarcinomas.

AIMS: The role of tumour metabolic and proliferative indices in predicting non-small-cell lung cancer (NSCLC) patients' prognosis is unclear. We correlated fluorine 18 ((18) F)-fluorodeoxyglucose (FDG)-positron emission tomography (PET) value and Ki67 index to patients' survival, taking into account tumour heterogeneity, disease characteristics and genetic aberrations. METHODS AND RESULTS: A series of 383 NSCLCs was arranged into tissue microarrays and Ki67 staining was analysed by immunohistochemistry. The maximum standardized uptake (SUV(MAX) ) value detected by (18) F-FDG-PET analysis was calculated over a region of interest. Large-cell and squamous cell carcinomas had higher proliferative and metabolic activities than adenocarcinomas, and the two measures were correlated significantly. The hot-spot Ki67 value was correlated with patients' survival and the cut-off to discriminate patients in the survival risk groups was 20%. Ki67 hot-spot values were greater in anaplastic lymphoma kinase (ALK) rearranged tumours. Adenocarcinomas showed the highest intratumour heterogeneity in proliferative activity and the hot-spot Ki67 value predicted only the prognosis of patients in this group. Although tumour metabolic activity was not associated with patients' prognosis, a SUV(MAX) > 2 was related to nodal metastases, tumour size and grade. CONCLUSIONS: Our results highlight how tumour heterogeneity influences evaluation of prognostic biomarkers. Our data support Ki67 evaluation to estimate NSCLC patients' prognosis, particularly for adenocarcinoma.

Does FDG PET-Based Radiomics Have an Added Value for Prediction of Overall Survival in Non-Small Cell Lung Cancer?

Objectives: Radiomics and machine learning are innovative approaches to improve the clinical management of NSCLC. However, there is less information about the additive value of FDG PET-based radiomics compared with clinical and imaging variables. Methods: This retrospective study included 320 NSCLC patients who underwent PET/CT with FDG at initial staging. VOIs were placed on primary tumors only. We included a total of 94 variables, including 87 textural features extracted from PET studies, SUVmax, MTV, TLG, TNM stage, histology, age, and gender. We used the least absolute shrinkage and selection operator (LASSO) regression to select variables with the highest predictive value. Although several radiomics variables are available, the added value of these predictors compared with clinical and imaging variables is still under evaluation. Three hundred and twenty NSCLC patients were included in this retrospective study and underwent 18F-FDG PET/CT at initial staging. In this study, we evaluated 94 variables, including 87 textural features, SUVmax, MTV, TLG, TNM stage, histology, age, and gender. Image-based predictors were extracted from a volume of interest (VOI) positioned on the primary tumor. The least absolute shrinkage and selection operator (LASSO) Cox regression was used to reduce the number of variables and select only those with the highest predictive value. The predictive model implemented with the variables selected using the LASSO analysis was compared with a reference model using only a tumor stage and SUVmax. Results: NGTDM coarseness, SUVmax, and TNM stage survived the LASSO analysis and were used for the radiomic model. The AUCs obtained from the reference and radiomic models were 80.82 (95%CI, 69.01-92.63) and 81.02 (95%CI, 69.07-92.97), respectively (p = 0.98). The median OS in the reference model was 17.0 months in high-risk patients (95%CI, 11-21) and 113 months in low-risk patients (HR 7.47, p < 0.001). In the radiomic model, the median OS was 16.5 months (95%CI, 11-20) and 113 months in high- and low-risk groups, respectively (HR 9.64, p < 0.001). Conclusions: Our results indicate that a radiomic model composed using the tumor stage, SUVmax, and a selected radiomic feature (NGTDM_Coarseness) predicts survival in NSCLC patients similarly to a reference model composed only by the tumor stage and SUVmax. Replication of these preliminary results is necessary.

Duodenojejunal inflammation causing chronic vomiting in adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disease with a broad spectrum of clinical manifestations including fever, skin rash, arthralgia and neutrophilic leucocytosis. Small bowel inflammation in AOSD has been reported in association with Crohn's disease, coeliac disease and chronic intestinal pseudo-obstruction. We have here reported the first-time case of AOSD with small bowel involvement, presenting with chronic vomiting. Fluorodeoxyglucose total-body positron emission tomography/CT showed high uptake of the duodenum and first jejunal loop. Faecal calprotectin increased. Duodenal histology revealed neutrophilic infiltrate among duodenal enterocytes and severe chronic lymphoplasmacellular infiltrate of the lamina propria. Vomiting disappeared when duodenojejunal inflammation was controlled by immunomodulatory treatments for AOSD, suggesting a possible causal relation between duodenojejunal inflammation and the symptom.

Brain 18 F-FET in a Case of Acute Myeloid Leukemia.

ABSTRACT: A 58-year-old woman, with a history of acute myeloid leukemia in complete response, was referred to the emergency department of our hospital for loss of consciousness. A brain MRI showed an intracranial mass suggestive for either primary brain tumor or brain metastasis. 18 F-FET PET/CT revealed increased uptake of the lesion. Metastasis from acute myeloid leukemia was diagnosed after brain biopsy. Whole-body 18 F-FDG PET/CT did not demonstrate other abnormal foci of 18 F-FDG accumulation, whereas brain lesion had an uptake slightly below the adjacent brain.

Diagnostic Accuracy of PET with 18F-Fluciclovine ([18F]FACBC) in Detecting High-Grade Gliomas: A Systematic Review and Meta-Analysis.

BACKGROUND: 18F-Fluciclovine ([18F]FACBC) has been recently proposed as a synthetic radiolabeled amino acid for positron emission tomography (PET) imaging in patients with brain neoplasms. Our aim is to evaluate the diagnostic performance of [18F]FACBC PET in high-grade glioma (HGG) patients, taking into account the literature data. METHODS: A comprehensive literature search was performed. We included original articles evaluating [18F]FACBC PET in the detection of HGG before therapy and for the suspicion of tumor recurrence. Pooled sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), and diagnostic odds ratios (DOR), including 95% confidence intervals (95% CI), were measured. Statistical heterogeneity and publication bias were also assessed. RESULTS: ten studies were included in the review and eight in the meta-analysis (113 patients). Regarding the identification of HGG, the sensitivity of [18F]FACBC PET ranged between 85.7% and 100%, with a pooled estimate of 92.9% (95% CI: 84.4-96.9%), while the specificity ranged from 50% to 100%, with a pooled estimate of 70.7% (95% CI: 47.5-86.5%). The pooled LR+, LR-, and DOR of [18F]FACBC PET were 2.5, 0.14, and 37, respectively. No significant statistical heterogeneity or publication bias were found. CONCLUSIONS: evidence-based data demonstrate the good diagnostic accuracy of [18F]FACBC PET for HGG detection. Due to the still limited data, further studies are warranted to confirm the promising role of [18F]FACBC PET in this context.

Relevance of Volumetric Parameters Applied to [68Ga]Ga-DOTATOC PET/CT in NET Patients Treated with PRRT.

BACKGROUND: this study aims to explore the prognostic and predictive role of volumetric parameters on [68Ga]Ga-DOTATOC PET/CT in neuroendocrine tumors (NET) patients treated with peptide receptor radionuclide therapy (PRRT). METHODS: We retrospectively evaluated 39 NET patients (21 male, 18 female; mean age 60.7 y) within the FENET-2016 trial (CTiD:NCT04790708). PRRT was proposed with [177Lu]Lu-DOTATOC alone or combined with [90Y]Y-DOTATOC. [68Ga]Ga-DOTATOC PET/CT was performed at baseline and 3 months after PRRT. For each PET/CT, we calculated SUVmax, SUVmean, somatostatin receptor expressing tumor volume (SRETV), and total lesion somatostatin receptor expression (TLSRE), as well as their percentage of changes (Δ), both for liver (_L) and for total tumor burden (_WB). Early clinical response (3 months after PRRT) and PFS were evaluated according to RECIST 1.1 and institutional NET board. RESULTS: Early clinical response identified 9 partial response (PR), 25 stable disease (SD), and 5 progressive disease (PD). Post-SRETV_WB and ΔSRETV_WB were progressively increased among response groups (p = 0.02 and p = 0.03, respectively). Likewise, median post-SRETV_L was significantly higher in PD patients (p = 0.03). SUVmax and TLSRE did not correlate with early clinical response. Median PFS was 31 months. Patients with ΔSRETV_WB lower than -4.17% as well as those with post-SRETV_WB lower than 34.8 cm3 showed a longer PFS (p = 0.006 and p = 0.06, respectively). Finally, multivariate analysis identified ΔSRETV_WB as an independent predictor for PFS. CONCLUSIONS: our results could strengthen the importance of evaluating the burden of disease on [68Ga]Ga-DOTATOC PET/CT in NET patients treated with PRRT.

Comparison of MRI vs. [18F]FDG PET/CT for Treatment Response Evaluation of Primary Breast Cancer after Neoadjuvant Chemotherapy: Literature Review and Future Perspectives.

The purpose of this systematic review was to investigate the diagnostic accuracy of [18F]FDG PET/CT and breast MRI for primary breast cancer (BC) response assessment after neoadjuvant chemotherapy (NAC) and to evaluate future perspectives in this setting. We performed a critical review using three bibliographic databases (i.e., PubMed, Scopus, and Web of Science) for articles published up to the 6 June 2023, starting from 2012. The Quality Assessment of Diagnosis Accuracy Study (QUADAS-2) tool was adopted to evaluate the risk of bias. A total of 76 studies were identified and screened, while 14 articles were included in our systematic review after a full-text assessment. The total number of patients included was 842. Eight out of fourteen studies (57.1%) were prospective, while all except one study were conducted in a single center. In the majority of the included studies (71.4%), 3.0 Tesla (T) MRI scans were adopted. Three out of fourteen studies (21.4%) used both 1.5 and 3.0 T MRI and only two used 1.5 T. [18F]FDG was the radiotracer used in every study included. All patients accepted surgical treatment after NAC and each study used pathological complete response (pCR) as the reference standard. Some of the studies have demonstrated the superiority of [18F]FDG PET/CT, while others proved that MRI was superior to PET/CT. Recent studies indicate that PET/CT has a better specificity, while MRI has a superior sensitivity for assessing pCR in BC patients after NAC. The complementary value of the combined use of these modalities represents probably the most important tool to improve diagnostic performance in this setting. Overall, larger prospective studies, possibly randomized, are needed, hopefully evaluating PET/MR and allowing for new tools, such as radiomic parameters, to find a proper place in the setting of BC patients undergoing NAC.

Positron Emission Tomography-Derived Radiomics and Artificial Intelligence in Multiple Myeloma: State-of-the-Art.

Multiple myeloma (MM) is a heterogeneous neoplasm accounting for the second most prevalent hematologic disorder. The identification of noninvasive, valuable biomarkers is of utmost importance for the best patient treatment selection, especially in heterogeneous diseases like MM. Despite molecular imaging with positron emission tomography (PET) has achieved a primary role in the characterization of MM, it is not free from shortcomings. In recent years, radiomics and artificial intelligence (AI), which includes machine learning (ML) and deep learning (DL) algorithms, have played an important role in mining additional information from medical images beyond human eyes' resolving power. Our review provides a summary of the current status of radiomics and AI in different clinical contexts of MM. A systematic search of PubMed, Web of Science, and Scopus was conducted, including all the articles published in English that explored radiomics and AI analyses of PET/CT images in MM. The initial results have highlighted the potential role of such new features in order to improve the clinical stratification of MM patients, as well as to increase their clinical benefits. However, more studies are warranted before these approaches can be implemented in clinical routines.

Banks of the Superior Temporal Sulcus in Alzheimer's Disease: A Pilot Quantitative Susceptibility Mapping Study.

BACKGROUND: Brain iron homeostasis is disrupted in neurodegeneration and areas of iron overload partially overlap with regions of amyloid and tau burden in Alzheimer's disease (AD). Previous studies demonstrated alterations in brain iron accumulation in AD using quantitative susceptibility mapping (QSM). OBJECTIVE: Here, we investigate brain alterations of QSM values in AD and non-AD patients as compared to healthy controls (HC) in the superior temporal sulcus and its banks (BANKSSTS), one of the top AD-affected regions. METHODS: Thirty-four patients who underwent brain MRI including a multi-echo gradient-echo sequence were subdivided into AD (n = 19) and non-AD (n = 15) groups according to their clinical profile, CSF (Aß42/40) and/or amyloid-PET status. Ten HC were also included. QSM values were extracted from left and right BANKSSTS and compared among groups. Correlation and binomial regression analyses between QSM values and CSF-AD biomarkers were conducted. RESULTS: QSM in left BANKSSTS was significantly different among groups (p = 0.003, H = 11.40), being higher in AD. QSM values in left BANKSSTS were correlated with Aß42 (rho -0.55, p = 0.005), Aß42/40 (rho -0.66, p < 0.001), pTau (rho 0.63, p < 0.001), tTau (rho 0.56, p = 0.005), tTau/Aß42 (rho 0.68, p < 0.001) and pTau/Aß42 (rho 0.71, p < 0.001). No correlations between QSM values and amyloid-PET SUVR in the left BANKSSTS were found. QSM values in left BANKSSTS showed good accuracy in discriminating AD (AUC = 0.80, CI95 % [0.66-0.93]). Higher QSM values were independent predictors of Aß42 (B = 0.63, p = 0.032), Aß42/40 (B = 0.81, p = 0.028), pTau (B = 0.96, p = 0.046), tTau (B = 0.55, p = 0.027), and tTau/Aß42 (B = 1.13, p = 0.042) positivity. CONCLUSION: Our preliminary data support the potential role of increased QSM values in the left BANKSSTS as an auxiliary imaging biomarker in AD diagnosis.

The Role of Molecular Imaging in Patients with Brain Metastases: A Literature Review.

Over the last several years, molecular imaging has gained a primary role in the evaluation of patients with brain metastases (BM). Therefore, the "Response Assessment in Neuro-Oncology" (RANO) group recommends amino acid radiotracers for the assessment of BM. Our review summarizes the current use of positron emission tomography (PET) radiotracers in patients with BM, ranging from present to future perspectives with new PET radiotracers, including the role of radiomics and potential theranostics approaches. A comprehensive search of PubMed results was conducted. All studies published in English up to and including December 2022 were reviewed. Current evidence confirms the important role of amino acid PET radiotracers for the delineation of BM extension, for the assessment of response to therapy, and particularly for the differentiation between tumor progression and radionecrosis. The newer radiotracers explore non-invasively different biological tumor processes, although more consistent findings in larger clinical trials are necessary to confirm preliminary results. Our review illustrates the role of molecular imaging in patients with BM. Along with magnetic resonance imaging (MRI), the gold standard for diagnosis of BM, PET is a useful complementary technique for processes that otherwise cannot be obtained from anatomical MRI alone.

Long-term outcome of thyroid abnormalities in patients with severe Covid-19.

Objective: We have previously observed thyroid dysfunction, i.e. atypical thyroiditis (painless thyrotoxicosis associated with non-thyroidal illness syndrome), in patients with severe acute respiratory syndrome coronavirus 2 disease (Covid-19). This study aimed to analyse the evolution of thyroid dysfunction over time. Methods: One hundred eighty-three consecutive patients hospitalised for severe Covid-19 without known thyroid history were studied at hospital admission (baseline). Survivors were offered 12-month longitudinal follow-up including assessment of thyroid function, autoantibodies and ultrasound scan (US). Patients showing US focal hypoechoic areas suggestive of thyroiditis (focal hypoechogenicity) also underwent thyroid 99mTc or 123I uptake scan. Results: At baseline, after excluding from TSH analysis, 63 out of 183 (34%) Covid-19 patients commenced on steroids before hospitalisation, and 12 (10%) showed atypical thyroiditis. Follow-up of 75 patients showed normalisation of thyroid function and inflammatory markers and no increased prevalence of detectable thyroid autoantibodies. Baseline US (available in 65 patients) showed focal hypoechogenicity in 28% of patients, of whom 82% had reduced thyroid 99mTc/123I uptake. The presence of focal hypoechogenicity was associated with baseline low TSH (P = 0.034), high free-thyroxine (FT4) (P = 0.018) and high interleukin-6 (IL6) (P = 0.016). Focal hypoechogenicity persisted after 6 and 12 months in 87% and 50% patients, respectively, but reduced in size. After 9 months, thyroid 99mTc/123I uptake partially recovered from baseline (+28%) but was still reduced in 67% patients. Conclusions: Severe Covid-19 induces mild transient thyroid dysfunction correlating with disease severity. Focal hypoechogenicity, associated with baseline high FT4, IL6 and low TSH, does not seem to be related to thyroid autoimmunity and may persist after 1 year although decreasing in size. Long-term consequences seem unlikely.

PSMA PET/CT in Castration-Resistant Prostate Cancer: Myth or Reality?

BACKGROUND: prostate-specific membrane antigen (PSMA) ligand PET has been recently incorporated into international guidelines for several different indications in prostate cancer (PCa) patients. However, there are still some open questions regarding the role of PSMA ligand PET in castration-resistant prostate cancer (CRPC). The aim of this work is to assess the clinical value of PSMA ligand PET/CT in patients with CRPC. RESULTS: PSMA ligand PET has demonstrated higher detection rates in comparison to conventional imaging and allows for a significant reduction in the number of M0 CRPC patients. However, its real impact on patients' prognosis is still an open question. Moreover, in CRPC patients, PSMA ligand PET presents some sensitivity and specificity limitations. Due to its heterogeneity, CRPC may present a mosaic of neoplastic clones, some of which could be PSMA-/FDG+, or vice versa. Likewise, unspecific bone uptake (UBU) and second primary neoplasms (SNPs) overexpressing PSMA in the neoangiogenic vessels represent potential specificity issues. Integrated multi-tracer imaging (PSMA ligand and [18F]FDG PET) together with a multidisciplinary discussion could allow for reaching the most accurate evaluation of each patient from a precision medicine point of view.

Lutathera® Orphans: State of the Art and Future Application of Radioligand Therapy with 177Lu-DOTATATE.

Lutathera® is the first EMA- and FDA-approved radiopharmaceutical for radioligand therapy (RLT). Currently, on the legacy of the NETTER1 trial, only adult patients with progressive unresectable somatostatin receptor (SSTR) positive gastroenteropancreatic (GEP) neuroendocrine neoplasms (NET) can be treated with Lutathera®. Conversely, patients with SSTR-positive disease arising from outside the gastroenteric region do not currently have access to Lutathera® treatment despite several papers in the literature reporting the effectiveness and safety of RLT in these settings. Moreover, patients with well-differentiated G3 GEP-NET are also still "Lutathera orphans", and retreatment with RLT in patients with disease relapse is currently not approved. The aim of this critical review is to summarize current literature evidence assessing the role of Lutathera® outside the approved indications. Moreover, ongoing clinical trials evaluating new possible applications of Lutathera® will be considered and discussed to provide an updated picture of future investigations.