Distribution and predictors of F-18-FDG uptake values of non-malignant cervical lymph nodes in pediatric patients.

BACKGROUND: F-18-flurodeoxyglucose (FDG) PET/CT is routinely used for staging, evaluation of response to treatment and follow-up of most pediatric malignancies. Cervical lymph nodes can be involved in some pediatric malignancies, but increased uptake in non-malignant cervical lymph nodes is not exceptional in this population. The aim of the present study is to identify predictors of the maximum uptake in non-malignant cervical lymph nodes in the pediatric population. METHODS: 191 FDG PET/CT studies of pediatric patients without malignant involvement of cervical lymph nodes were retrospectively reviewed. The maximal Standard Uptake Value in the hottest cervical lymph node (SUVmaxCLN), as well as demographic, technical and imaging variables were recorded. The predictive effect of those variables on SUVmaxCLN was estimated using linear regression models. RESULTS: Increased FDG activity in cervical nodes was observed in 136/191 studies (71%). The mean SUVmaxCLN was 2.2 ± 1.3. Ipsilateral palatine tonsil SUVmax, mean liver uptake, and treatment status were all statistically significant predictors of SUVmaxCLN. However, in multivariate regression analysis, only ipsilateral palatine tonsil SUVmax was found to be significant. In addition, SUVmaxCLN was greater than the mean liver uptake in 50% of all studies. This proportion was higher in younger children, reaching 77% of studies of children younger than six years. CONCLUSION: SUVmax in ipsilateral palatine tonsil is a strong predictor of the maximal uptake value of non-malignant cervical lymph nodes in children. The intensity of uptake in non-malignant cervical lymph nodes is frequently higher than liver uptake in children, and this tendency increases for younger patients. TRIAL WAS REGISTERED: In the internal hospital registry under TRN 0209-22-HMO on date 23.04.2022.

Impact of Single-Time-Point Estimates of 177Lu-PRRT Absorbed Doses on Patient Management: Validation of a Trained Multiple-Linear-Regression Model in 159 Patients and 477 Therapy Cycles.

Dosimetry after 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) enables estimation of radiation doses absorbed by normal organs and target lesions. This process is time-consuming and requires multiple posttreatment studies on several subsequent days. In a previous study, we described a newly developed multiple-linear-regression model to predict absorbed doses (ADs) from a single-time-point (STP) posttreatment study acquired 168 h after the first infusion and 24 h after the following ones, with similar results to the standard multiple-time-point (MTP) protocol. The present study aimed to validate this model in a large patient cohort and to assess whether STP dosimetry affects patient management decisions compared with our MTP protocol. Methods: Quantitative 177Lu-DOTATATE SPECT/CT post-PRRT data from 159 consecutive patients (172 therapies, 477 therapy cycles) were retrospectively analyzed. ADs obtained from an STP model were compared with those obtained using an MTP model. We evaluated the impact of the STP model on the decision on whether PRRT should be stopped because of an expected kidney AD exceeding the safety threshold. We hypothesized that patient management based on the STP model does not differ from that based on the MTP model in at least 90% of the cases. Results: There was no difference in management decisions between the MTP and STP models in 170 of 172 therapies (98.8%). A Fisher χ2 test for combined probabilities produced a composite P value of 0.0003. Mean cumulative AD relative differences between the STP and MTP models were 0.8% ± 8.0%, -7.7% ± 4.8%, 0.0% ± 11.4%, -2.8% ± 6.3%, and -2.1% ± 18.4% for kidneys, bone marrow, liver, spleen, and tumors, respectively (Pearson r = 0.99 for all), for patients who underwent 4 therapy cycles. Similar results were obtained with fewer therapy cycles. Conclusion: Estimated radiation ADs and patient management decisions were similar with the STP and MTP models. The STP model can simplify the dosimetry process while also reducing scanner and staff time and improving patient comfort.

Perceptual omission errors in positron emission tomography and computed tomography reporting.

BACKGROUND: Omission errors in medical imaging can lead to missed diagnosis and harm to patients. The subject has been studied in conventional imaging, but no data is available for functional imaging in general and for PET/CT in particular. In this work, we evaluated the frequency and characteristics of perceptual omission errors in the PET component of oncologic PET/CT imaging, and we analyzed the hazardous scenarios prone to such modality-specific errors. METHODS: Perceptual omission errors were collected in one tertiary center PET/CT clinic during routine PET/CT reporting over a 26-month period. The omissions were detected either in reporting follow-up PET/CT studies of the same patient or during multidisciplinary meetings. RESULTS: Significant omission errors were found in 1.2% of the 2100 reports included in the study. The most common omissions were bone metastases and focal colon uptake. We identified six PET-specific causative factors contributing to the occurrence of omissions, and we propose solutions to minimize their influence. CONCLUSIONS: The data presented here can help to promote the awareness of interpreting physicians to body areas that require higher attention and to implement reading strategies for improving the accuracy of PET/CT interpretation.

Case report: Robust response of metastatic clear cell sarcoma treated with cabozantinib and immunotherapy.

Clear Cell Sarcoma (CCS), also referred to as malignant melanoma of soft parts, is a rare and aggressive malignant tumor. It comprises 1% of all soft tissue sarcomas and is known to be radio- and chemotherapy resistant. CCS shares morphological and immunohistochemical features with malignant melanoma, including melanin biosynthesis and melanocytic markers. However, it is distinct for the presence of EWSR1-ATF1 translocation which activates MITF transcription factor. We report here of an aggressive case of CCS in a 9-year-old patient, which demonstrates the critical role of molecular analysis in the diagnosis and treatment of uncommon cancer variants in the era of personalized medicine. The EWSR1-ATF1 translocation induces pathological c-Met activation, and so, following unsuccessful CTLA4 and PD-1 blockade immunotherapy, the child received cabozantinib, a small molecule tyrosine kinase inhibitor, with the intent to block c-Met oncogenic effect. In parallel, active immunization, using hapten di-nitrophenyl modified autologous tumor cells was administered with monotherapy PD-1 inhibitor nivolumab. Under this "triplet" therapy, the patient attained an initial partial response and was progression-free for 2 years, in good performance status and resumed schooling. Based on our observation, cabozantinib can be used as an effective and potentially life-prolonging treatment in CCS. We suggest that priming the child's immune system using her autologous tumor and combating T cell exhaustion with PD-1 blockade may have synergized with the targeted therapy. Combining targeted and immunotherapy is a rapidly growing practice in solid tumors and provides a glimpse of hope in situations that previously lacked any treatment option.

[THE MAGIC OF IMMUNOTHERAPY - ANTI-PD1 TREATMENT IN ADENOCARCINOMA OF THE GASTROESOPHAGEAL JUNCTION].

INTRODUCTION: Adenocarcinomas of the gastroesophageal junction (GEJ) are tumors whose incidence rates increased significantly in recent years. These tumors have a poor prognosis, and are treated with a palliative approach when diagnosed in an advanced stage. Some tumors overexpress PDL-1 proteins which are partially responsible for the "immune escape" of tumor cells. However, this over-expression enables the use of an immunotherapeutic treatment approach. Immunotherapy using anti-PD1/PDL-1 shows promising results in patients with metastatic GEJ tumors. In the present case report, we describe a young patient who was diagnosed with a non-resectable GEJ adenocarcinoma and was found to have almost 100% positivity for PDL-1 in the tumor biopsy, using standard immunohistochemistry. The patient had rapid and complete response to the anti-PD1 antibody treatment with further development of immune mediated side effects.

Simple model for estimation of absorbed dose by organs and tumors after PRRT from a single SPECT/CT study.

BACKGROUND: Following each cycle of peptide receptor radionuclide therapy (PRRT), absorbed doses by tumors and normal organs are typically calculated from three quantitative single-photon emission computed tomography (SPECT)/computed tomography (CT) studies acquired at t1 = 24 h, t2 = 96 h, t3 = 168 h after the first cycle of treatment and from a single study at t1 after the subsequent cycles. In the present study, we have assessed the feasibility of a single SPECT/CT study after each PRRT cycle using a trained multiple linear regression (MLR) model for absorbed dose calculation and have evaluated its impact on patient management. Quantitative [177Lu]-DOTA-TATE SPECT/CT data after PRRT of seventy-two consecutive metastatic neuroendocrine tumors patients were retrospectively evaluated. A set of 40 consecutive studies was used to train the MLR model. The two independent variables of the model included the time of imaging after administration of the treatment and the radiopharmaceutical activity concentration in a given  organ/tumor. The dependent variable was the dose absorbed by the organ/tumor obtained with the standard protocol. For bone marrow dosimetry, the independent variables included the time of imaging, and the blood and remainder of the body activity concentration. The model was evaluated in 32 consecutive patients. Absorbed doses were assessed for kidneys, bone marrow, liver, spleen and tumor sites. RESULTS: There was no difference in management decisions, whether PRRT can be safely continued or not because unsafe absorbed dose to risk organs between the standard and the MLR model-based protocol using a single SPECT/CT study performed at t3 = 168 h after the first cycle and at t1 = 24 h after the subsequent cycles. Cumulative absorbed doses were obtained with mean relative differences of - 0.5% ± 5.4%, 1.6% ± 15.1%, - 6.2% ± 7.3%, - 5.5% ± 5.8% and 2.9% ± 12.7% for kidneys, bone marrow, liver, spleen and tumors, respectively (Pearson's r correlation coefficient 0.99, 0.91, 0.99, 0.99 and 0.97, respectively). CONCLUSION: Dosimetry calculations using a MLR model with a single SPECT/CT study are in good agreement with the standard protocol, while avoiding the use of dosimetry software and enabling improved patient comfort and reduced scanner and staff time.

[RADIONUCLIDE THERAPY OF NEUROENDOCRINE TUMORS - IMPROVEMENTS IN THE PROTOCOL FOR MEASUREMENT OF PATIENT RADIATION EXPOSURE].

AIMS: The aim of this study was to evaluate the predictive power of the absorbed dose to kidneys after the first course of treatment with [177Lu]-DOTA-TATE on the cumulative kidney absorbed dose after 3 or 4 cycles of treatment. BACKGROUND: Peptide receptor radionuclide therapy (PRRT) with [177Lu]-DOTA-TATE is an effective treatment for somatostatin receptor positive neuroendocrine tumors (NETs). Post-treatment scans (PTS) are required after each cycle of treatment for personalized radiation dosimetry in order to calculate the dose to organs and tumors and to ensure a cumulative absorbed dose to kidneys under a safety threshold of 25 Gy. METHODS: A total of 187 patients who completed treatment and underwent PTS for dosimetry calculation were included in this retrospective study. The correlation between the cumulative absorbed dose to the kidneys after completion of treatment and the absorbed dose after the first cycle(s) was studied. Multilinear regression analysis was performed to predict the cumulative absorbed dose by the kidneys in the subsequent cycles. An algorithm for the follow-up of the kidney absorbed dose is proposed. RESULTS: When the absorbed dose to kidneys after the first cycle of treatment is below 5.6 Gy, four cycles of treatment can be safely administered with a cumulative dose less than 25 Gy (p < 0.1). For the remaining patients, the cumulative dose absorbed after 3 or 4 cycles of treatment can be predicted after the second cycle of treatment. This protocol enabled early decisions on the number of treatment cycles and reduced the number of post-treatment SPECT/CT studies for dosimetry in 34% of patients, as well as hospitalization time for 56% of the treatment cycles. CONCLUSIONS: Assessment of the kidney absorbed dose after PRRT can be simplified with the algorithm presented in this study. This approach enabled early decisions on the number of therapy cycles in 75% of patients. DISCUSSION: The validity of these results is limited to the protocol of dosimetry calculation used in our institution. Implementation in other centers may require standardization of the acquisition parameters and the dosimetry protocol.

Can a penalized-likelihood estimation algorithm be used to reduce the injected dose or the acquisition time in 68Ga-DOTATATE PET/CT studies?

BACKGROUND: Image quality and quantitative accuracy of positron emission tomography (PET) depend on several factors such as uptake time, scanner characteristics and image reconstruction methods. Ordered subset expectation maximization (OSEM) is considered the gold standard for image reconstruction. Penalized-likelihood estimation (PL) algorithms have been recently developed for PET reconstruction to improve quantitation accuracy while maintaining or even improving image quality. In PL algorithms, a regularization parameter ß controls the penalization of relative differences between neighboring pixels and determines image characteristics. In the present study, we aim to compare the performance of Q.Clear (PL algorithm, GE Healthcare) and OSEM (3 iterations, 8 subsets, 6-mm post-processing filter) for 68Ga-DOTATATE (68Ga-DOTA) PET studies, both visually and quantitatively. Thirty consecutive whole-body 68Ga-DOTA studies were included. The data were acquired in list mode and were reconstructed using 3D OSEM and Q.Clear with various values of ß and various acquisition times per bed position (bp), thus generating images with reduced injected dose (1.5 min/bp: ß = 300-1100; 1.0 min/bp: ß = 600-1400 and 0.5 min/bp: ß = 800-2200). An additional analysis adding ß values up to 1500, 1700 and 3000 for 1.5, 1.0 and 0.5 min/bp, respectively, was performed for a random sample of 8 studies. Evaluation was performed using a phantom and clinical data. Two experienced nuclear medicine physicians blinded to the variables assessed the image quality visually. RESULTS: Clinical images reconstructed with Q.Clear, set at 1.5, 1.0 and 0.5 min/bp using ß = 1100, 1300 and 3000, respectively, resulted in images with noise equivalence to 3D OSEM (1.5 min/bp) with a mean increase in SUVmax of 14%, 13% and 4%, an increase in SNR of 30%, 24% and 10%, and an increase in SBR of 13%, 13% and 2%. Visual assessment yielded similar results for ß values of 1100-1400 and 1300-1600 for 1.5 and 1.0 min/bp, respectively, although for 0.5 min/bp there was no significant improvement compared to OSEM. CONCLUSION: 68Ga-DOTA reconstructions with Q.Clear, 1.5 and 1.0 min/bp, resulted in increased tumor SUVmax and in improved SNR and SBR at a similar level of noise compared to 3D OSEM. Q.Clear with ß = 1300-1600 enables one-third reduction of acquisition time or injected dose, with similar image quality compared to 3D OSEM.

Posttreatment FDG-Avid Splenic Lesions in DLBCL and HD: Clinical and Radiographic Characteristics for Risk Assessment.

Residual end of treatment (EOT) FDG-avid lesions are often due to infectious or inflammatory process and not due to refractory lymphoma. Nonetheless, such lesions prompt diagnostic and therapeutic interventions. We evaluate clinical and radiological characteristics of patients with EOT FDG-avid splenic lesions. Comparing metabolic volume (MV) ratio between EOT to interim, showed a marked difference between false positive and true positive lesions (0.5 vs 3.6, P = 0.02). EOT SUVmax was also significantly different between the groups (7 vs. 19, P = 0.02). We suggest EOT/interim-MV ratio as a tool to identify patients at low risk of refractory disease allowing non-invasive surveillance.

Dosimetry after peptide receptor radionuclide therapy: impact of reduced number of post-treatment studies on absorbed dose calculation and on patient management.

BACKGROUND: After each cycle of [177Lu]-DOTA-TATE peptide receptor radionuclide therapy (PRRT) dosimetry is performed to enable precise calculation of the radiation-absorbed dose to tumors and normal organs. Absorbed doses are routinely calculated from three quantitative single-photon emission computed tomography (SPECT) studies corrected by computed tomography (CT) acquired at t1 = 24 h, t2 = 96 h, and t3 = 168 h after the first cycle of treatment. After following cycles, a single SPECT/CT study is performed. The aim of the present study is to assess the feasibility of a "two time point" quantitative SPECT/CT protocol after the first PRRT cycle and its impact on patient management. Quantitative SPECT/CT data of 25 consecutive patients with metastatic neuroendocrine tumors after PRRT were retrospectively analyzed. Radiation-absorbed doses calculated using the standard protocol with three SPECT/CT studies acquired at (t1, t2, t3) were compared to those obtained from three different "two time point" protocols with SPECT/CT studies performed at (t1, t2), (t1, t3), or (t2, t3). RESULTS: The best agreement for the cumulative doses absorbed by the kidneys, bone marrow, liver, spleen, and tumors with the conventional protocol was obtained with the (t1, t3) protocol with mean relative differences of - 1.0% ± 2.4%, 0.4% ± 3.1%, - 0.9% ± 4.0%, - 0.8% ± 1.1%, and - 0.5% ± 2.0%, respectively, and correlation coefficients of r = 0.99 for all. In all patients, there was no difference in the management decision of whether or not to stop PRRT because of unsafe absorbed dose to risk organs using either the standard protocol or the (t1, t3) protocol. CONCLUSION: These preliminary results demonstrate that dosimetry calculations using two quantitative SPECT/CT studies acquired at 24 and 168 h after the first PRRT cycle are feasible and are in good agreement with the standard imaging protocol with no change in patient management decisions, while enabling improved patient comfort and reduced scanner and staff time.

Highly favourable outcomes with peptide receptor radionuclide therapy (PRRT) for metastatic rectal neuroendocrine neoplasia (NEN).

PURPOSE: Rectal neuroendocrine neoplasia (NEN) is more common than other NEN origins, but is less commonly metastatic. However, when present, distant disease carries a particularly poor prognosis. Evidence guiding optimal treatment of such patients is lacking. We assessed PRRT outcomes in patients with somatostatin receptor (SSTR) positive metastatic rectal NEN from two referral centres. METHODS: Patients treated with PRRT were retrospectively reviewed. Morphologic (RECIST 1.1), SSTR imaging responses and toxicity were assessed 3 months post-PRRT. Kaplan-Meier estimate was used to determine progression-free survival (PFS) and overall survival (OS) from start of PRRT. RESULTS: Twenty-seven consecutive patients (M = 20, age 31-81 years) were reviewed. The majority (70%) had ENETs grade 2 disease (19 patients), three had Grade 3, one Grade 1, and four not documented. Overall, 63% (10/16 patients with available FDG PET/CT) had FDG avid disease. Twenty-six patients were treated for disease progression. Most had 177Lu-DOTA-octreotate with median cumulative activity of 30 GBq, median four cycles. 14 patients had radiosensitising chemotherapy (5FU or capecitabine). At 3 months post-PRRT, CT disease control rate (DCR) was 96%: partial response was observed in 70% (19/27) and stable disease in 26%. All but one had partial SSTR imaging response. The median PFS was 29 months. Ten patients died, with median overall survival 81 months with a median follow-up of 67 months. Seventeen patients had further treatments after initial PRRT (10 had further cycles of PRRT). Three patients had grade 3 lymphopenia, without significant renal toxicity, MDS or leukaemia. CONCLUSION: Our results indicate high efficacy and morphologic responses with minimal toxicity and very encouraging survival from PRRT in patients with metastatic rectal NEN despite the adverse prognostic features of this cohort. Further prospective PRRT trials are warranted in this subgroup.

Predictive power of the post-treatment scans after the initial or first two courses of [177Lu]-DOTA-TATE.

BACKGROUND: The aim of this study was to evaluate the predictive power of the absorbed dose to kidneys after the first course of treatment with [177Lu]-DOTA-TATE for neuroendocrine tumors (NETs) on the cumulative kidney absorbed dose after 3 or 4 cycles of treatment. Post-treatment scans (PTS) are acquired after each cycle of peptide receptor radionuclide therapy (PRRT) with [177Lu]-DOTA-TATE for personalized radiation dosimetry in order to ensure a cumulative absorbed dose to kidneys under a safety threshold of 25 Gy. One hundred eighty-seven patients who completed treatment with [177Lu]-DOTA-TATE and underwent PTS for dosimetry calculation were included in this retrospective study. The correlation between the cumulative absorbed dose to kidneys after the completion of treatment and the absorbed dose after the first cycle(s) was studied. Multilinear regression analysis was done to predict the cumulative absorbed dose to the kidneys of the subsequent cycles, and an algorithm for the follow up of kidney absorbed dose is proposed. RESULTS: Patients whose absorbed dose to kidneys after the first cycle of treatment is below 5.6 Gy can receive four cycles of treatment with a cumulative dose less than 25 Gy (p < 0.1). For the other patients, the cumulative absorbed dose after 3 or 4 cycles of treatment can be predicted after the second cycle of treatment to allow for an early decision regarding the number of cycles that may be given. CONCLUSIONS: The follow up of kidney absorbed dose after PRRT can be simplified with the algorithm presented in this study, reducing by one-third the number of post-treatment scans and reducing hospitalization time for more than half of the treatment cycles.

Reducing the number of CTs performed to monitor personalized dosimetry during peptide receptor radionuclide therapy (PRRT).

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) with [177Lu]-DOTA-TATE is an effective treatment of neuroendocrine tumors (NETs). After each cycle of treatment, patient dosimetry evaluates the radiation dose to the risk organs, kidneys, and bone marrow, the most radiosensitive tissues. Absorbed doses are calculated from the radioactivity in the blood and from single photon emission computed tomography (SPECT) images corrected by computed tomography (CT) acquired after each course of treatment. The aim of this work is to assess whether the dosimetry along all treatment cycles can be calculated using a single CT. We hypothesize that the absorbed doses to the risk organs calculated with a single CT will be accurate enough to correctly manage the patients, i.e., whether or not to continue PRRT. Twenty-four patients diagnosed with metastatic NETs undergoing PRRT with [177Lu]-DOTA-TATE were retrospectively included in this study. We compared radiation doses to the kidneys and bone marrow using two protocols. In the "classical" one, dosimetry is calculated based on a SPECT and a CT after each treatment cycle. In the new protocol, dosimetry is calculated based on a SPECT study after each cycle but with the first acquired CT for all cycles. RESULTS: The decision whether or not to stop PRRT because of unsafe absorbed dose to the risk organs would have been the same had the classical or the new protocol been used. The agreement between the cumulative doses to the kidneys and bone marrow obtained from the two protocols was excellent with Pearson's correlation coefficients r = 0.95 and r = 0.99 (P < 0.0001) and mean relative differences of 5.30 ± 6.20% and 0.48 ± 4.88%, respectively. CONCLUSIONS: Dosimetry calculations for a given patient can be done using a single CT registered to serial SPECTs. This new protocol reduces the need for a hybrid camera in the follow-up of patients receiving [177Lu]-DOTA-TATE.

Elliptical Fourier descriptors for contours in three dimensions: a new tool for morphometrical analysis in biology.

Elliptical Fourier descriptor analysis is a method for the morphometric study of curves. It has been used in the two-dimensional plane for closed contours, but rarely for lines in the three-dimensional space. The method consists of an expansion of a contour as a sum of ellipses. In this article, we study three-dimensional contours, i.e. lines embedded in the three-dimensional space. We compute for the first time the relations between the Fourier coefficients and its geometric parameters. We then use these relations for normalization and reorientation of three-dimensional contours. Such an algorithm can be used to perform inter-individual comparisons between contours, regardless of differences in viewpoint or global size. Human and small animal illustrative examples using biomedical X-ray CT imaging data of open bone structures demonstrate the interest and potential of the method for morphological analysis.

Toward an artificial cell based on gene expression in vesicles.

We present a new experimental approach to build an artificial cell using the translation machinery of a cell-free expression system as the hardware and a DNA synthetic genome as the software. This approach, inspired by the self-replicating automata of von Neumann, uses cytoplasmic extracts, encapsulated in phospholipid vesicles, to assemble custom-made genetic circuits to develop the functions of a minimal cell. Although this approach can find applications, especially in biotechnology, the primary goal is to understand how a DNA algorithm can be designed to build an operating system that has some of the properties of life. We provide insights on this cell-free approach as well as new results to transform step by step a long-lived vesicle bioreactor into an artificial cell. We show how the green fluorescent protein can be anchored to the membrane and we give indications of a possible insertion mechanism of integral membrane proteins. With vesicles composed of different phospholipids, the fusion protein alpha-hemolysin-eGFP can be expressed to reveal patterns on the membrane. The specific degradation complex ClpXP from E. coli is introduced to create a sink for the synthesized proteins. Perspectives and subsequent limitations of this approach are discussed.