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Purpose: Rhabdomyosarcomas are a major cause of cancer death in children, described with MYCN amplification and, in the alveolar subtype, transcription driven by the PAX3-FOXO1 fusion protein. Our aim was to determine the prevalence of N-Myc protein expression and the potential therapeutic effects of reducing expression in rhabdomyosarcomas, including use of an antigene strategy that inhibits transcription.Experimental Design: Protein expression was assessed by immunohistochemistry. MYCN expression was reduced in representative cell lines by RNA interference and an antigene peptide nucleic acid (PNA) oligonucleotide conjugated to a nuclear localization signal peptide. Associated gene expression changes, cell viability, and apoptosis were analyzed in vitro. As a paradigm for antigene therapy, the effects of systemic treatment of mice with rhabdomyosarcoma cell line xenografts were determined.Results: High N-Myc levels were significantly associated with genomic amplification, presence of the PAX3/7-FOXO1 fusion genes, and proliferative capacity. Sustained reduction of N-Myc levels in all rhabdomyosarcoma cell lines that express the protein decreased cell proliferation and increased apoptosis. Positive feedback was shown to regulate PAX3-FOXO1 and N-Myc levels in the alveolar subtype that critically decrease PAX3-FOXO1 levels on reducing N-Myc. Pharmacologic systemic administration of the antigene PNA can eliminate alveolar rhabdomyosarcoma xenografts in mice, without relapse or toxicity.Conclusion: N-Myc, with its restricted expression in non-fetal tissues, is a therapeutic target to treat rhabdomyosarcomas, and blocking gene transcription using antigene oligonucleotide strategies has therapeutic potential in the treatment of cancer and other diseases that has not been previously realized in vivo. Clin Cancer Res; 18(3); 796–807. ©2011 AACR.

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Supplementary Tables 1 and 2. Supplementary Table 1 describes Summary of FDG PET/CT positivity criteria Supplementary Table 2 contains Univariate analysis of baseline and post-treatment variables adversely affecting progression-free survival and overall survival

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CCR Translation for This Article from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

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Purpose: To evaluate the role of 18F-FDG PET/CT in 282 symptomatic multiple myeloma patients treated up-front between 2002 and 2012.Experimental Design: All patients were studied by PET/CT at baseline, during posttreatment follow-up, and at the time of relapse. Their median duration of follow-up was 67 months.Results: Forty-two percent of the patients at diagnosis had >3 focal lesions, and in 50% SUVmax was >4.2; extramedullary disease was present in 5%. On multivariate analysis, ISS stage 3, SUVmax >4.2, and failure to achieve best complete response (CR) were the leading factors independently associated with shorter progression-free survival (PFS) and overall survival (OS). These 3 variables were used to construct a prognostic scoring system based on the number of risk factors. After treatment, PET/CT negativity (PET-neg) was observed in 70% of patients, whereas conventionally defined CR was achieved in 53%. Attainment of PET-neg favorably influenced PFS and OS. PET-neg was an independent predictor of prolonged PFS and OS for patients with conventionally defined CR. Sixty-three percent of patients experienced relapse or progression; in 12%, skeletal progression was exclusively detected by systematic PET/CT performed during follow-up. A multivariate analysis revealed that persistence of SUVmax >4.2 following first-line treatment was independently associated with exclusive PET/CT progression.Conclusions: PET/CT combined with ISS stage and achievement or not of CR on first-line therapy sorted patients into different prognostic groups. PET/CT led to a more careful evaluation of CR. Finally, in patients with persistent high glucose metabolism after first-line treatment, PET/CT can be recommended during follow-up, to screen for otherwise unidentifiable progression. Clin Cancer Res; 21(19); 4384–90. ©2015 AACR.

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Non-Hodgkin lymphomas represents a heterogeneous group of lymphoproliferative disorders characterized by different clinical courses, varying from indolent to highly aggressive.

FDG-PET/CT is a standardized imaging technique that has reached a great importance in the management of patients affected by Multiple Myeloma. It is proved, in fact, that it allows a deep evaluation of therapy efficacy and provides several prognostic indexes both at staging and after therapy. For this reason, it is now recognised as a gold standard for therapy assessment. Beside this, in reacent years FDG-PET/CT contribution to the understanding of Multiple Myeloma has progressively grown. Papers have been published analyzing the prognostic value of active disease volume measurement and standardization issues, the meaning of FDG positive paramedullary and extrameduallary disease, the prognostic impact of FDG positive minimal residual disease, the relation between focal lesions and clonal eterogenity of this disease and the comparison with whole body DWI-MR in terms of detection and therapy assessment. These newer aspects not of clinical impact yet, of FDG-PET/CT in Multiple Myeloma will be presented and discussed in this review.

This atlas is intended to enable nuclear medicine practitioners who routinely read PET/CT scans to recognize the most common CT abnormalities. Reading PET/CT scans can sometimes be challenging. It is not infrequent, in fact, to encounter abnormal findings in CT images (not related to the neoplastic disease under evaluation) that are functionally silent and therefore difficult to interpret for nuclear medicine practitioners. Frequently, these findings are clinically relevant and should be reported, interpreted and compared to previous scans. This may also have an impact on patient management, since expensive tests like PET/CT are expected to provide the highest level of diagnostic information. Generally, CT images associated with a PET scan are acquired in a low-dose modality, and therefore prove to be sub-optimal for CT image interpretation. Sometimes a comparison with a full-resolution and contrast-enhanced CT atlas may be difficult. Low-dose CT slices are thicker than diagnostic CT and offer less anatomical detail, which can affect accuracy in terms of recognizing both anatomical structures and pathological findings.

PURPOSE 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is currently the standard technique to define minimal residual disease (MRD) status outside the bone marrow (BM) in patients with multiple myeloma (MM). This study aimed to define criteria for PET complete metabolic response after therapy, jointly analyzing a subgroup of newly diagnosed transplantation-eligible patients with MM enrolled in two independent European randomized phase III trials (IFM/DFCI2009 and EMN02/HO95). PATIENTS AND METHODS Two hundred twenty-eight patients were observed for a median of 62.9 months. By study design, PET/CT scans were performed at baseline and before starting maintenance (premaintenance [PM]). The five-point Deauville scale (DS) was applied to describe BM (BM score [BMS]) and focal lesion (FL; FL score [FS]) uptake and tested a posteriori in uni- and multivariable analyses for their impact on clinical outcomes. RESULTS At baseline, 78% of patients had FLs (11% extramedullary), 80% with an FS ≥ 4. All patients had BM diffuse uptake (35.5% with BMS ≥ 4). At PM, 31% of patients had visually detectable FLs (2% extramedullary), 24% and 67.7% of them with an FS of 3 and ≥ 4, respectively. At PM, 98% of patients retained residual BM diffuse uptake, which was significantly lower than at baseline (mainly between BMS 2 and 3, BMS was ≥ 4 in only 8.7% of patients). By both uni- and multivariable analysis, FS and BMS < 4 were associated with prolonged progression-free survival (PFS) and overall survival (OS) at PM (OS: hazard ratio [HR], 0.6 and 0.47, respectively; PFS: HR, 0.36 and 0.24, respectively) CONCLUSION FL and BM FDG uptake lower than the liver background after therapy was an independent predictor for improved PFS and OS and can be proposed as the standardized criterion of PET complete metabolic response, confirming the value of the DS for patients with MM.

Sarcoma represents less than 2% of adult malignancies and about 15% to 20% of malignancies in children and adolescents/young adults. This neoplasm accounts for more than 80 different clinico-pathological entities with different clinical behavior; osteosarcoma and ewing sarcoma are the most frequent primary bone tumors. Because of the general poor prognosis, it is important to find out as many prognostic factors as possible to choose the best therapeutical approach and to correctly schedule the follow-up examinations. Third level imaging such as MRI and PET/CT are of utmost importance in the evaluation of sarcoma patients. The spine and bones in general are optimal sites to be evaluated with FDG PET/CT since the physiological background is low. The standardized uptake value (SUV max, a semiquantitave parameter) is used as a surrogate for proliferative cell rate, and the spatial heterogeneity of FDG distribution within the primary mass as a surrogate for malignancy. In several studies SUVmax was a predictive value for overall survival and progression-free survival. Whole-body MRI is a well-established technique for systemic, radiation-free evaluation, which is mostly applied in the oncological field. WB-MRI provides a combination of anatomical and functional sequences and is useful specifically in the evaluation of disease in organs with relatively high background activity such as the brain, liver, kidney, and spinal canal. These technologies provide accurate staging (also useful to drive the biopsy towards the most active foci in large heterogeneous masses), therapy assessment, relapse detection of local recurrence and distance metastasis but also prognostic indexes, in the context of whole body diagnostic procedures. This paper will provide an overview of the role and added value of PET/CT and WB-MRI in bone sarcomas particular focus on osteosarcoma. We also analyzed the role of the PET/CT and MRI for target delineation of radiation therapy and we and we will do an analysis of future prospects as new tracer non FDG.

PurposeHormonal assessment (HA) and contrast-enhanced CT (ceCT) show insufficient sensitivity and specificity when staging unilateral adrenal lesions (ALs). We aimed at: 1) developing an imaging-based, i.e. ceCT and FDG-PET, diagnostic score able to discriminate adrenal tumors entailing adrenalectomy from those who need clinical monitoring, and 2) identifying a diagnostic flow-chart that allows clinicians to avoid unneeded diagnostic procedures and to address patients to the optimal management.MethodsRetrospective single-center study assessing patients with unilateral AL and the following inclusion criteria: a) a four-phase ceCT; b) FDG-PET within one month of the ceCT; c) histopathology or a clinical follow-up of at least 24 months. Firstly, multivariate logistic regression analysis was employed to identify the predictors of adrenal tumors to treat surgically (AL-to-treat) and regression-based coefficients were used to develop a diagnostic score. Secondly, using cut-offs of predictor variables, a diagnostic flow-chart was defined.ResultsForty-eight patients were enrolled (mean age 61 years), of whom 21/48 (44%) had AL-to-treat. The remaining 27/48 (56%) presented with AL to follow-up only (i.e. benign). Maximum and minimum lesion diameter, Hounsfield units (HU) before contrast media injection and HU at the delayed phase (HUdelayed), relative and absolute washout, AL SUVmax, AL SUVmean, ratio SUVmax AL/SUVmax liver (adrenal-liver ratio) were associated with the presence of AL-to-treat (all pConclusionWe developed a two-parameter imaging-based score that may be applied to predict adrenal tumors requiring adrenalectomy. Furthermore, a diagnostic flow-chart to stratify patients on the basis of the optimal management was proposed, thus guiding undefined unilateral adrenal lesions to FDG-PET imaging.

The aim of this guideline is to provide standards for the recommendation, performance, interpretation, and reporting of [18F]Fluciclovine PET/CT for prostate cancer imaging. These recommendations will help to improve accuracy, precision, and repeatability of [18F]Fluciclovine PET/CT for prostate cancer essentially needed for implementation of this modality in science and routine clinical practice.

Fluorodeoxyglucose-PET/CT is a valuable tool for the work-up of patients with newly diagnosed and relapsed/refractory multiple myeloma, because it assesses bone damage with high sensitivity and specificity and detects extramedullary sites of proliferating clonal plasma cells (extramedullary diseases). PET/CT provides valuable prognostic data at diagnosis and at restaging during the course of the disease. Consistencies between independent studies confirm the negative prognostic value of extramedullary disease and greater than 3 focal lesions, whereas the role of standardized uptake value is more conflicting. Standardization of the technique is ongoing.

Soft tissue sarcomas (STS) are highly fluorine-18-fluorodeoxyglucose (F-FDG)-avid tumours. PET seems to be effective for the assessment of the extent of disease. However, the use of PET to stratify STS into different risk histotypes still remains controversial. Our aim was to evaluate F-FDG uptake in different STS types and to assess the prognostic value of the maximum standardized uptake value (SUVmax).We reviewed 50 adult patients with primary high-grade STS of the extremities with a preoperative PET. Overall survival and local recurrence were analysed.The mean SUVmax was 12.9 (range: 2.2-33.4). All cases of myxoid liposarcoma and all cases of synovial sarcoma had SUVmax of less than 10.3. A better overall survival and local recurrence were observed in patients with SUVmax of less than 10.3 (P=0.005 and 0.046, respectively).SUVmax seems to be specific among different STS histotypes. PET does not seem to be useful in myxoid liposarcoma as well as synovial sarcoma as these tumours seem to have a low uptake of glucose. SUVmax might also be included as a prognostic factor.

Purpose: To evaluate the role of F-18-Fluorothymidine (FLT) PET/CT in lymphoma patients with suspected recurrent or residual disease. Methods: Adult lymphoma patients presenting with positive or equivocal F-18-FDG PET/CT at end-treatment or follow-up were prospectively addressed to an additional F-18-FLT-PET/CT. SUV max and tumour-to-background ratios (TBRs) were recorded for the most avid lesion. Biopsy or, when not available, clinical or imaging assessment were employed as standard of reference. Results: Overall 52 patients were recruited. Histology was available in 20/52 patients (38%), proliferation-index (Ki-67) in 14/20. Disease was excluded in 13/52 patients (25%) (one reactive follicular hyperplasia, five reactive-inflammatory tissues, four reactive nodes, two nodal sarcoid-like and one non-specific peri-caecal finding). FDG and FLT scans were concordant in disease restaging in 34/52 patients (65%), whereas in 18/52 cases (35%) relevant discrepancies were recorded. SUV max and TBR were significantly higher in the disease versus the disease-free group, with both tracers (p = 0.0231 and 0.0219 for FDG; p = 0.0008 and 0.0016 for FLT). FLT-SUVmax demonstrated slightly better performance in discriminating benign from malignant lesions (ROC-AUC: 0.8116 and 0.7949 for FLT-SUV max and TBR; 0.7120 and 0.7140 for FDG). Optimal FLT-SUV max cut-offs were searched: three would lead to 95% sensitivity, 81% accuracy, and 39% specificity, whereas seven led to 100%, 41%, and 56% respectively. No statistically significant correlation was observed between the two FLT indices and Ki-67. Conclusions: According to our results in a clinical setting of recurrent or residual lymphoma, FLT is not significantly superior to FDG and it is unlikely that it will be employed independently. FLT may be restricted to a few specific cases, as complementary to standard FDG imaging, to confirm a diagnosis or to define a better target to biopsy. However, due to FLT suboptimal performance, many findings would remain inconclusive, requiring further diagnostic procedures and reducing the effectiveness of performing an additional FLT scan.

The finding of an indeterminate adrenal mass at radiological investigations is a challenge for physicians. Complex diagnostic work-up, periodic follow-up, or surgical intervention are therefore needed to rule out malignant lesions. Tertiary care hospitals are provided with F-18-fludeoxyglucose (F-18-FDG) positron emission tomography (PET) and F-18-dihydroxyphenylalanine (F-18-DOPA) PET, which aid in the characterization of indeterminate adrenal masses. Nevertheless, the histopathological examination may be required to exclude malignancy or rare etiologies. A 54-year-old woman presented to our clinic 6 months after a cerebral hemorrhage. She was hypertensive and had recently discovered a left adrenal mass of 15 mm during an abdominal ultrasound. Contrast-enhanced CT, following adrenal protocol, revealed a 14-mm adrenal mass without characteristics suggestive of an adrenal adenoma. Tumor markers were negative. Functional tests excluded hormone hypersecretion. An F-18-DOPA PET was negative. An F-18-FDG PET showed mild uptake of both the adrenal glands, with a more circumscribed pattern in the left one (maximum standardized uptake value 5 4). As the clinical diagnosis was still indeterminate, we performed laparoscopic left adrenalectomy. The histopathological examination described a sclerosing angiomatoid nodular transformation (SANT) of the adrenal gland, a benign lesion already described as a rare occurrence only in the spleen. IgG4 levels were reduced. In conclusion, this is a report of a SANT of the adrenal gland, a novel entity that should be taken into consideration in the differential diagnosis of indeterminate adrenal masses at CT scan. Copyright (C) 2019 Endocrine Society

Simple Summary Visceral involvement in prostate cancer (PCa) represents a negative prognostic factor. Liver metastases typically occur in systemic, late-stage, castration-resistant prostate cancer (CRPC). The diagnostic performance of [68Ga]Ga-PSMA-11-PET for visceral metastases of CRPC patients has never been systematically assessed. Our aim was to evaluate the diagnostic performance of PSMA-PET compared to conventional imaging, i.e., CT or MRI, or liver biopsy in the detection of liver metastases in CRPC patients. The secondary aim was to assess the ability of radiomics to predict the presence of liver metastases. Regarding liver metastases assessment in CRPC patients, [68Ga]-PSMA-11-PET demonstrated moderate sensitivity while high specificity, positive predictive value, and reproducibility compared to conventional imaging and liver biopsy. However, nuclear medicine physicians should carefully assess the liver parenchyma on PET images, especially in patients at higher risk for liver metastases and with high PSA values. Moreover, radiomic features may aid in recognizing higher-risk patients to develop them. Background: To evaluate the diagnostic performance of PSMA-PET compared to conventional imaging/liver biopsy in the detection of liver metastases in CRPC patients. Moreover, we evaluated a PSMA-PET/CT-based radiomic model able to identify liver metastases. Methods: Multicenter retrospective study enrolling patients with the following inclusion criteria: (a) proven CRPC patients, (b) PSMA-PET and conventional imaging/liver biopsy performed in a 6 months timeframe, (c) no therapy changes between PSMA-PET and conventional imaging/liver biopsy. PSMA-PET sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for liver metastases were calculated. After the extraction of radiomic features, a prediction model for liver metastases identification was developed. Results: Sixty CRPC patients were enrolled. Within 6 months before or after PSMA-PET, conventional imaging and liver biopsy identified 24/60 (40%) patients with liver metastases. PSMA-PET sensitivity, specificity, PPV, NPV, and accuracy for liver metastases were 0.58, 0.92, 0.82, 0.77, and 0.78, respectively. Either number of liver metastases and the maximum lesion diameter were significantly associated with the presence of a positive PSMA-PET (p < 0.05). On multivariate regression analysis, the radiomic feature-based model combining sphericity, and the moment of inverse difference (Idm), had an AUC of 0.807 (95% CI:0.686-0.920). Conclusion: For liver metastases assessment, [68Ga]Ga-PSMA-11-PET demonstrated moderate sensitivity while high specificity, PPV, and inter-reader agreement compared to conventional imaging/liver biopsy in CRPC patients.

International audience; Purpose: Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is included in the International Myeloma Working Group (IMWG) imaging guidelines for the work-up at diagnosis and the follow-up of multiple myeloma (MM) notably because it is a reliable tool as a predictor of prognosis. Nevertheless, none of the published studies focusing on the prognostic value of PET-derived features at baseline consider tumor heterogeneity, which could be of high importance in MM. The aim of this study was to evaluate the prognostic value of baseline PET-derived features in transplant-eligible newly diagnosed (TEND) MM patients enrolled in two prospective independent European randomized phase III trials using an innovative statistical random survival forest (RSF) approach.Methods: Imaging ancillary studies of IFM/DFCI2009 and EMN02/HO95 trials formed part of the present analysis (IMAJEM and EMN02/HO95, respectively). Among all patients initially enrolled in these studies, those with a positive baseline FDG-PET/CT imaging and focal bone lesions (FLs) and/or extramedullary disease (EMD) were included in the present analysis. A total of 17 image features (visual and quantitative, reflecting whole imaging characteristics) and 5 clinical/histopathological parameters were collected. The statistical analysis was conducted using two RSF approaches (train/validation + test and additional nested cross-validation) to predict progression-free survival (PFS).Results: One hundred thirty-nine patients were considered for this study. The final model based on the first RSF (train/validation + test) approach selected 3 features (treatment arm, hemoglobin, and SUVmaxBone Marrow (BM)) among the 22 involved initially, and two risk groups of patients (good and poor prognosis) could be defined with a mean hazard ratio of 4.3 ± 1.5 and a mean log-rank p value of 0.01 ± 0.01. The additional RSF (nested cross-validation) analysis highlighted the robustness of the proposed model across different splits of the dataset. Indeed, the first features selected using the train/validation + test approach remained the first ones over the folds with the nested approach.Conclusion: We proposed a new prognosis model for TEND MM patients at diagnosis based on two RSF approaches.Trial registration: IMAJEM: NCT01309334 and EMN02/HO95: NCT01134484.

The primary aim of the study was to evaluate the role of [18F]Fluciclovine PET/CT in the characterization of intra-prostatic lesions in high-risk primary PCa patients eligible for radical prostatectomy, in comparison with conventional [11C]Choline PET/CT and validated by prostatectomy pathologic examination. Secondary aims were to determine the performance of PET semi-quantitative parameters (SUVmax, target-to-background ratios [TBRs], using abdominal aorta, bone marrow and liver as backgrounds) for malignant lesion detection (and best cut-off values) and to search predictive factors of malignancy. A six sextants prostate template was created and used by PET readers and pathologists for data comparison and validation. PET visual and semi-quantitative analyses were performed: for instance, patient-based, blinded to histopathology, subsequently lesion-based, un-blinded, according to the pathology reference template. Among 19 patients included (mean age 63 years, 89% high and 11% very-high-risk, mean PSA 9.15 ng/mL), 45 malignant and 31 benign lesions were found and 19 healthy areas were selected (n = 95). For both tracers, the location of the “blinded” prostate SUVmax matched with the lobe of the lesion with the highest pGS in 17/19 cases (89%). There was direct correlation between [18F]Fluciclovine uptake values and pISUP. Overall, lesion-based (n = 95), the performance of PET semiquantitative parameters, with either [18F]Fluciclovine or [11C]Choline, in detecting either malignant/ISUP2-5/ISUP4-5 PCa lesions, was moderate and similar (AUCs ≥ 0.70) but still inadequate (AUCs ≤ 0.81) as a standalone staging procedure. A [18F]Fluciclovine TBR-L3 ≥ 1.5 would depict a clinical significant lesion with a sensitivity and specificity of 85% and 68% respectively, whereas a SUVmax cut-off value of 4 would be able to identify a ISUP 4-5 lesion in all cases (sensitivity 100%), although with low specificity (52%). TBRs (especially with threshold significantly higher than aorta and slightly higher than bone marrow), may be complementary to implement malignancy targeting.