The Association between the Body Mass Index, Chronic Obstructive Pulmonary Disease and SUV of the Non-Tumorous Lung in the Pretreatment [18F]FDG-PET/CT of Patients with Lung Cancer.

Background: A debate persists on the prognostic value of the pre-therapeutic standardized uptake value (SUV) of non-tumorous lung tissue for the risk assessment of therapy-related pneumonitis, with most studies lacking significant correlation. However, the influence of patient comorbidities on the pre-therapeutic lung SUV has not yet been systematically evaluated. Thus, we aimed to elucidate the association between comorbidities, biological variables and lung SUVs in pre-therapeutic [18F]FDG-PET/CT. Methods: In this retrospective study, the pre-therapeutic SUV in [18F]FDG-PET/CT was measured in non-tumorous areas of both lobes of the lung. SUVMEAN, SUVMAX and SUV95 were compared to a multitude of patient characteristics and comorbidities with Spearman's correlation analysis, followed by a Bonferroni correction and multilinear regression. Results: In total, 240 patients with lung cancer were analyzed. An elevated BMI was significantly associated with increased SUVMAX (ß = 0.037, p < 0.001), SUVMEAN (ß = 0.017, p < 0.001) and SUV95 (ß = 0.028, p < 0.001). Patients with chronic obstructive pulmonary disease (COPD) showed a significantly decreased SUVMAX (ß = -0.156, p = 0.001), SUVMEAN (ß = -0.107, p < 0.001) and SUV95 (ß = -0.134, p < 0.001). Multiple other comorbidities did not show a significant correlation with the SUV of the non-tumorous lung. Conclusions: Failure to consider the influence of BMI and COPD on the pre-therapeutic SUV measurements may lead to an erroneous interpretation of the pre-therapeutic SUV and subsequent treatment decisions in patients with lung cancer.

High-Dose Rate Brachytherapy Combined with PD-1 Blockade as a Treatment for Metastatic Adrenocortical Carcinoma - A Single Center Case Series.

The response rate of advanced adrenocortical carcinoma (ACC) to standard chemotherapy with mitotane and etoposide/doxorubicin/cisplatin (EDP-M) is unsatisfactory, and benefit is frequently short lived. Immune checkpoint inhibitors (CPI) have been examined in patient's refractory to EDP-M, but objective response rates are only approximately 15%. High-dose rate brachytherapy (HDR-BT) is a catheter-based internal radiotherapy and expected to favorably combine with immunotherapies. Here we describe three cases of patients with advanced ACC who were treated with HDR-BT and the CPI pembrolizumab. None of the tumors were positive for established response markers to CPI. All patients were female, had progressed on EDP-M and received external beam radiation therapy for metastatic ACC. Pembrolizumab was initiated 7 or 23 months after brachytherapy in two cases and prior to brachytherapy in one case. Best response of lesions treated with brachytherapy was complete (n=2) or partial response (n=1) that was ongoing at last follow up after 23, 45 and 4 months, respectively. Considering all sites of tumor, response was complete and partial remission in the two patients with brachytherapy prior to pembrolizumab. The third patient developed progressive disease with severe Cushing's syndrome and died due to COVID-19. Immune-related adverse events of colitis (grade 3), gastroduodenitis (grade 3), pneumonitis (grade 2) and thyroiditis (grade 1) occurred in the two patients with systemic response. HDR-BT controlled metastases locally. Sequential combination with CPI therapy may enhance an abscopal antitumoral effect in non-irradiated metastases in ACC. Systematic studies are required to confirm this preliminary experience and to understand underlying mechanisms.

[Special diagnostics in pediatric urology-Ultrasound, VCUG, CT and MRI : Part 1: tips for the practice]. / Spezielle Diagnostik in der Kinderurologie ­ konventionelle und spezielle Sonographie, MCU, CT und MRT : Teil 1: Tipps für die Praxis.

The diagnostics and treatment of pediatric urology patients in the clinical routine can be extremely challenging. In comparison to adult patients, congenital diseases, more time consuming examinations and limited options in addition to the parents' expectations must be taken into account in the diagnostic work up. In this first of two parts we will delve into ultrasound diagnostics as the cornerstone in the diagnostic pathway of children with hydronephrosis ans take a closer look on contrast enhanced ultrasound (CEUS). Conventional voiding cystourethrography still plays a major role in the diagnostic pathway of vesicoureteric reflux and will be treated in this article. Computed tomography should only be considered in pediatric patients in rare cases, always taking radiation into critical account. Magnetic resonance imaging provides an excellent anatomical overview without exposing the child to unnecessary radiation. This article provides an overview on the diagnostic imaging studies in pediatric urology and brings tips for the diagnostic evaluation.

Validation of Convolutional Neural Networks for Fast Determination of Whole-Body Metabolic Tumor Burden in Pediatric Lymphoma.

18F-FDG PET/CT quantification of whole-body tumor burden in lymphoma is not routinely performed because of the lack of fast methods. Although the semiautomatic method is fast, it is not fast enough to quantify tumor burden in daily clinical practice. Our purpose was to evaluate the performance of convolutional neural network (CNN) software in localizing neoplastic lesions in whole-body 18F-FDG PET/CT images of pediatric lymphoma patients. Methods: The retrospective image dataset, derived from the data pool of the International Atomic Energy Agency (coordinated research project E12017), included 102 baseline staging 18F-FDG PET/CT studies of pediatric lymphoma patients (mean age, 11 y). The images were quantified to determine the whole-body tumor burden (whole-body metabolic tumor volume [wbMTV] and whole-body total lesion glycolysis [wbTLG]) using semiautomatic software and CNN-based software. Both were displayed as semiautomatic wbMTV and wbTLG and as CNN wbMTV and wbTLG. The intraclass correlation coefficient (ICC) was applied to evaluate concordance between the CNN-based software and the semiautomatic software. Results: Twenty-six patients were excluded from the analysis because the software was unable to perform calculations for them. In the remaining 76 patients, CNN and semiautomatic wbMTV tumor burden metrics correlated strongly (ICC, 0.993; 95% CI, 0.989 - 0.996; P < 0.0001), as did CNN and semiautomatic wbTLG (ICC, 0.999; 95% CI, 0.998-0.999; P < 0.0001). However, the time spent calculating these metrics was significantly (<0.0001) less by CNN (mean, 19 s; range, 11-50 s) than by the semiautomatic method (mean, 21.6 min; range, 3.2-62.1 min), especially in patients with advanced disease. Conclusion: Determining whole-body tumor burden in pediatric lymphoma patients using CNN is fast and feasible in clinical practice.

Predicitve Value of FDG Uptake in the Remaining Adrenal Gland Following Adrenalectomy for Adrenocortical Cancer.

Following initial surgery, patients with adrenocortical carcinoma (ACC) are commonly treated with the adrenolytic substance mitotane in an adjuvant or therapeutic setting. Treatment responses, however, are variable. The objective of the study was to investigate a possible correlation between FDG-PET activity of the remaining adrenal gland and therapeutic response of mitotane treatment. This is a retrospective study enrolling patients from two German centers with operated ACC and minimal information on PET-CT scanning. Eighty-two ACC patients after adrenalectomy were included (66 treated with mitotane and 16 without medical therapy). FDG uptake of the contralateral adrenal gland, liver and mediastinum was analyzed from a total of 291 PET/CT scans (median 4 scans per patient) and correlated with clinical annotations including overall and recurrence free survival. The majority of patients (81%) displayed a temporary increase in adrenal FDG uptake within the first 18 months following surgery, which was not associated with a morphological correlate for potential malignancy. This increase was mainly present in patients treated with mitotane (51/61, 84%) but less frequent in the control group (4/7, 57%). No direct correlation with mitotane plasma levels were evident. Patients following R0 resection with high adrenal uptake showed a tendency towards better clinical outcome without reaching a significance value (HR 1.41; CI 0.42-4.75; p=0.059). FDG update of the contralateral adrenal gland may not be misinterpreted as sign of malignancy but might be rather associated with a trend towards better clinical outcome.

18F-FDG PET/CT for Response Assessment in Pediatric Sebaceous Carcinoma of the Parotid Gland.

A 16-year-old male patient underwent 18F-FDG PET/CT staging after multiple surgical resections and radiotherapy of an uncommon metastatic pediatric sebaceous carcinoma of the parotid gland. Initial PET/CT imaging exhibited a recurrent paravertebral metastasis (C4) as well as a metabolically active tumor tissue at the primary site. Follow-up PET/CT after radiotherapy of the cervical spine (C4) and four cycles of chemotherapy with cisplatin and palbociclib revealed complete functional remission in the cervical spine and partial remission at the primary site. This case illustrates the 18F-FDG-uptake behavior and the disease course of a very rare malignant epithelial tumor of the salivary glands.

What and how should we measure in paediatric oncology FDG-PET/CT? Comparison of commonly used SUV metrics for differentiation between paediatric tumours.

BACKGROUND: In clinical routine, SUVmax and SUVpeak are most often used to determine the glucose metabolism in tumours by 18F-FDG PET/CT. Both metrics can be further normalised to SUVs in reference regions resulting in a SUV ratio (SUVratio). The aim of the study was to directly compare several widely used SUVs/SUVratios with regard to differentiation between common tumours in paediatric patients; a special focus was put on characteristics of reference region SUVs. METHODS: The final study population consisted of 61 children and adolescents with diagnoses of non-Hodgkin lymphoma (NHL, n = 25), Hodgkin lymphoma (HL, n = 14), and sarcoma (n = 22). SUV metrics included SUVmax and SUVpeak as well as both parameters normalised to liver and mediastinal blood pool, respectively, yielding the SUVratios SUVmax/liver, SUVmax/mediastinum, SUVpeak/liver, and SUVpeak/mediastinum. RESULTS: The metrics SUVmax, SUVpeak, SUVmax/liver, and SUVpeak/liver all proved to be sensitive for tumour differentiation (p ≤ 0.008); in contrast, SUVmax/mediastinum and SUVpeak/mediastinum revealed to be non-sensitive approaches. Correlation analyses showed inverse associations between reference region SUVs and SUVratios (p < 0.05). Multiple regression analyses demonstrated significant effects of factors as bodyweight and uptake time on reference region SUVs (p < 0.01), and thus indirectly on the corresponding SUVratios. CONCLUSIONS: In the paediatric population, the ability to differentiate between common tumours remarkably varies between SUV metrics. When using SUVratios, the choice of reference region is crucial. Factors potentially influencing reference region SUVs (and thus SUVratios) should be taken into account in order to avoid erroneous conclusions. When not possible, SUVmax and SUVpeak represent less complex, more robust alternatives.

Is True Whole-Body 18F-FDG PET/CT Required in Pediatric Lymphoma? An IAEA Multicenter Prospective Study.

Guidelines recommend true whole-body 18F-FDG PET/CT scans from vertex to toes in pediatric lymphoma patients, although this suggestion has not been validated in large clinical trials. The objective of the study was to evaluate the incidence and clinical impact of lesions outside the "eyes to thighs" regular field of view (R-FOV) in 18F-FDG PET/CT staging (sPET) and interim (iPET) scans in pediatric lymphoma patients. Methods: True whole-body sPET and iPET scans were prospectively obtained in pediatric lymphoma patients (11 worldwide centers). Expert panel central review of sPET and iPET scans were evaluated for lymphoma lesions outside the R-FOV and clinical relevance of these findings. Results: A total of 610 scans were obtained in 305 patients. The sPET scans did not show lesions outside the R-FOV in 91.8% of the patients, whereas in 8.2% patients the sPET scans demonstrated lesions also outside the R-FOV (soft tissue, bone, bone marrow, and skin); however, the presence of these lesions did not change the clinical stage of any patient and did not affect treatment decision. Among the 305 iPET scans, there were no new positive 18F-FDG-avid lesions outside the R-FOV, when compared with their paired sPET scans. A single lesion outside the R-FOV on iPET occurred in 1 patient (0.3%), with the primary lesion diagnosed in the femur on sPET that persisted on iPET. Conclusion: The identification of additional lesions outside the R-FOV (eyes to thighs) using 18F-FDG PET/CT has no impact in the definition of the clinical stage of disease and minimal impact in the treatment definition of patients with pediatric lymphoma. As so, R-FOV for both sPET and iPET scans could be performed.

Guidelines on nuclear medicine imaging in neuroblastoma.

Nuclear medicine has a central role in the diagnosis, staging, response assessment and long-term follow-up of neuroblastoma, the most common solid extracranial tumour in children. These EANM guidelines include updated information on 123I-mIBG, the most common study in nuclear medicine for the evaluation of neuroblastoma, and on PET/CT imaging with 18F-FDG, 18F-DOPA and 68Ga-DOTA peptides. These PET/CT studies are increasingly employed in clinical practice. Indications, advantages and limitations are presented along with recommendations on study protocols, interpretation of findings and reporting results.

Neuroblastoma: MIBG Imaging and New Tracers.

Neuroblastoma is an embryonic tumor of the peripheral sympathetic nervous system, and is metastatic or otherwise high risk for relapse in nearly 50% of cases, with a long-term survival of <40%. Therefore, exact staging with radiological and nuclear medicine imaging methods is crucial for finding the adequate therapeutic choice. The tumor cells express the norepinephrine transporter, which makes metaiodobenzylguanidine (MIBG), an analogue of norepinephrine, an ideal tumor-specific agent for imaging. On the contrary, MIBG imaging has several disadvantages such as limited spatial resolution, limited sensitivity in small lesions, need for two or even more acquisition sessions, and a delay between the start of the examination and result. Most of these limitations can be overcome with positron emission tomography (PET) using different radiotracers. Furthermore, for operative or biopsy planning, a combination with morphological imaging methods is indispensable. This article would discuss the therapeutic strategy for primary and follow-up diagnosis in neuroblastoma using MIBG scintigraphy and different new PET tracers as well as multimodality imaging.

Combined Scintigraphy and Tumor Marker Analysis Predicts Unfavorable Histopathology of Neuroblastic Tumors with High Accuracy.

OBJECTIVES: Our aim was to improve the prediction of unfavorable histopathology (UH) in neuroblastic tumors through combined imaging and biochemical parameters. METHODS: 123I-MIBG SPECT and MRI was performed before surgical resection or biopsy in 47 consecutive pediatric patients with neuroblastic tumor. Semi-quantitative tumor-to-liver count-rate ratio (TLCRR), MRI tumor size and margins, urine catecholamine and NSE blood levels of neuron specific enolase (NSE) were recorded. Accuracy of single and combined variables for prediction of UH was tested by ROC analysis with Bonferroni correction. RESULTS: 34 of 47 patients had UH based on the International Neuroblastoma Pathology Classification (INPC). TLCRR and serum NSE both predicted UH with moderate accuracy. Optimal cut-off for TLCRR was 2.0, resulting in 68% sensitivity and 100% specificity (AUC-ROC 0.86, p < 0.001). Optimal cut-off for NSE was 25.8 ng/ml, resulting in 74% sensitivity and 85% specificity (AUC-ROC 0.81, p = 0.001). Combination of TLCRR/NSE criteria reduced false negative findings from 11/9 to only five, with improved sensitivity and specificity of 85% (AUC-ROC 0.85, p < 0.001). CONCLUSION: Strong 123I-MIBG uptake and high serum level of NSE were each predictive of UH. Combined analysis of both parameters improved the prediction of UH in patients with neuroblastic tumor. MRI parameters and urine catecholamine levels did not predict UH.

Successful Combination of Sequential Gene Therapy and Rescue Allo-HSCT in Two Children with X-CGD - Importance of Timing.

We report on a series of sequential events leading to long-term survival and cure of pediatric X-linked chronic granulomatous disease (X-CGD) patients after gamma-retroviral gene therapy (GT) and rescue HSCT. Due to therapyrefractory life-threatening infections requiring hematopoietic stem cell transplantation (HSCT) but absence of HLAidentical donors, we treated 2 boys with X-CGD by GT. Following GT both children completely resolved invasive Aspergillus nidulans infections. However, one child developed dual insertional activation of ecotropic viral integration site 1 (EVI1) and signal transducer and activator of transcription 3 (STAT3) genes, leading to myelodysplastic syndrome (MDS) with monosomy 7. Despite resistance to mismatched allo-HSCT with standard myeloablative conditioning, secondary intensified rescue allo-HSCT resulted in 100 % donor chimerism and disappearance of MDS. The other child did not develop MDS despite expansion of a clone with a single insertion in the myelodysplasia syndrome 1 (MDS1) gene and was cured by early standard allo-HSCT. The slowly developing dominance of clones harboring integrations in MDS1-EVI1 may guide clinical intervention strategies, i.e. early rescue allo-HSCT, prior to malignant transformation. GT was essential for both children to survive and to clear therapy-refractory infections, and future GT with safer lentiviral self-inactivated (SIN) vectors may offer a therapeutic alternative for X-CGD patients suffering from life-threatening infections and lacking HLA-identical HSC donors.

High ¹²³I-MIBG uptake in neuroblastic tumours indicates unfavourable histopathology.

PURPOSE: Scintigraphy using (123)I-metaiodobenzylguanidine ((123)I-MIBG) is widely used for the detection of neuroblastic tumours. The aim of this study was to identify a possible correlation between the uptake intensity on (123)I-MIBG SPECT and histopathology of neuroblastic tumours. METHODS: (123)I-MIBG SPECT examinations were performed in 55 paediatric patients with neuroblastic tumour and compared to histopathology after surgical resection or biopsy at a mean of 2 weeks after SPECT. For each lesion International Neuroblastoma Pathology Classification System (INPC) stage, mitosis karyorrhexis index (MKI), location and a semiquantitative tumour-to-liver count-rate ratio (TLCRR) were determined. Also, the presence or absence of MYCN amplification, p1 deletion, urine catecholamine and neuron-specific enolase blood levels at the time of scanning were recorded. RESULTS: In the 55 patients, 61 lesions were evaluated with (123)I-MIBG SPECT and corresponding histopathological findings were reviewed (11 ganglioneuroma, 11 ganglioneuroblastoma and 39 neuroblastoma). TLCRR was significantly higher in the neuroblastoma group (mean TLCRR 2.7) than in the ganglioneuroblastoma group (mean TLCRR 1.0) and ganglioneuroma group (mean TLCRR 0.7) at the time of primary diagnosis (p < 0.001) and at follow-up (p = 0.039). Intense (123)I-MIBG uptake was found in tumour tissue with a high mitotic activity (MKI-high or MKI-intermediate) after treatment. Four ganglioneuromas (36 %), three ganglioneuroblastomas (27 %) and six neuroblastomas (15 %) were (123)I-MIBG-negative. CONCLUSION: In paediatric patients with peripheral neuroblastic tumours, strong (123)I-MIBG uptake indicates unfavourable histopathology. High uptake was seen in neuroblastomas and in tumours with a high mitotic activity.

The diagnostic value of 18F-FDG PET and MRI in paediatric histiocytosis.

PURPOSE: To analyse the diagnostic value of (18)F-FDG PET and MRI for the evaluation of active lesions in paediatric Langerhans cell histiocytosis. METHODS: We compared 21 (18)F-FDG PET scans with 21 MRI scans (mean time interval 17 days) in 15 patients (11 male, 4 female, age range 4 months to 19 years) with biopsy-proven histiocytosis. Primary criteria for the lesion-based analysis were signs of vital histiocyte infiltrates (bone marrow oedema and contrast enhancement for MRI; SUV greater than the mean SUV of the right liver lobe for PET). PET and MR images were analysed separately and side-by-side. The results were validated by biopsy or follow-up scans after more than 6 months. RESULTS: Of 53 lesions evaluated, 13 were confirmed by histology and 40 on follow-up investigations. The sensitivity and specificity of PET were 67 % and 76 % and of MRI were 81 % and 47 %, respectively. MRI showed seven false-positive bone lesions after successful chemotherapy. PET showed five false-negative small bone lesions, one false-negative lesion of the skull and three false-negative findings for intracerebral involvement. PET showed one false-positive lesion in the lymphoid tissue of the head and neck region and two false-positive bone lesions after treatment. Combined PET/MR analysis decreased the number of false-negative findings on primary staging, whereas no advantage over PET alone was seen in terms of false-positive or false-negative results on follow-up. CONCLUSION: Our retrospective analysis suggests a pivotal role of (18)F-FDG PET in lesion follow-up due to a lower number of false-positive findings after chemotherapy. MRI showed a higher sensitivity and is indispensable for primary staging, evaluation of brain involvement and biopsy planning. Combined MRI/PET analysis improved sensitivity by decreasing the false-negative rate during primary staging indicating a future role of simultaneous whole-body PET/MRI for primary investigation of paediatric histiocytosis.

Nuclear medicine and multimodality imaging of pediatric neuroblastoma.

Neuroblastoma is an embryonic tumor of the peripheral sympathetic nervous system and is metastatic or high risk for relapse in nearly 50% of cases. Therefore, exact staging with radiological and nuclear medicine imaging methods is crucial for defining the adequate therapeutic choice. Tumor cells express the norepinephrine transporter, which makes metaiodobenzylguanidine (MIBG), an analogue of norepinephrine, an ideal tumor specific agent for imaging. MIBG imaging has several disadvantages, such as limited spatial resolution, limited sensitivity in small lesions and the need for two or even more acquisition sessions. Most of these limitations can be overcome with positron emission tomography (PET) using [F-18]2-fluoro-2-deoxyglucose [FDG]. Furthermore, new tracers, such as fluorodopa or somatostatin receptor agonists, have been tested for imaging neuroblastoma recently. However, MIBG scintigraphy and PET alone are not sufficient for operative or biopsy planning. In this regard, a combination with morphological imaging is indispensable. This article will discuss strategies for primary and follow-up diagnosis in neuroblastoma using different nuclear medicine and radiological imaging methods as well as multimodality imaging.

Diagnostic value of combined ¹8F-FDG PET/MRI for staging and restaging in paediatric oncology.

PURPOSE: The present study compares the diagnostic value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and MRI to combined/registered (18)F-FDG PET/MRI for staging and restaging in paediatric oncology. METHODS: Over 8 years and 2 months, 270 (18)F-FDG PET and 270 MRI examinations (mean interval 5 days) were performed in 132 patients with proven (n = 117) or suspected (n = 15) malignant disease: solid tumours (n = 64), systemic malignancy (n = 53) and benign disease (n = 15). A total of 259 suspected tumour lesions were analysed retrospectively during primary diagnosis and 554 lesions during follow-up. Image analysis was performed separately on each modality, followed by analysis of combined and registered (18)F-FDG PET/MRI imaging. RESULTS: A total of 813 lesions were evaluated and confirmed by histopathology (n = 158) and/or imaging follow-up (n = 655) after 6 months. In the separate analysis of (18)F-FDG PET and MRI, sensitivity was 86 %/94 % and specificity 85 %/38 %. Combined/registered (18)F-FDG PET/MRI led to a sensitivity of 97 %/97 % and specificity of 81 %/82 %. False-positive results ((18)F-FDG PET n = 69, MRI n = 281, combined (18)F-FDG PET/MRI n = 85, registered (18)F-FDG PET/MRI n = 80) were due to physiological uptake or post-therapeutic changes. False-negative results ((18)F-FDG PET n = 50, MRI n = 20, combined (18)F-FDG PET/MRI n = 11, registered (18)F-FDG PET/MRI n = 11) were based on low uptake or minimal morphological changes. Examination-based evaluation during follow-up showed a sensitivity/specificity of 91 %/81 % for (18)F-FDG PET, 93 %/30 % for MRI and 96 %/72 % for combined (18)F-FDG PET/MRI. CONCLUSION: For the detection of single tumour lesions, registered (18)F-FDG PET/MRI proved to be the methodology of choice for adequate tumour staging. In the examination-based evaluation, MRI alone performed better than (18)F-FDG PET and combined/registered imaging during primary diagnosis. At follow-up, however, the examination-based evaluation demonstrated a superiority of (18)F-FDG PET alone.