Patterns of relapse and long-term outcome in patients treated with a curative intent for advanced Hodgkin lymphoma.

BACKGROUND: Consolidation radiotherapy for advanced Hodgkin lymphoma (AHL) is controversial. Precise knowledge of the most likely relapse location is crucial for radiotherapy planning. We performed detailed patterns of relapse analyses and evaluated if initial bulky disease, initial 18F-fluoro-deoxy-glucose (FDG)-avidity and/or a residual mass on computed tomography (CT)-scan after chemotherapy are sites with a high risk of relapse. This information could provide guidance for optimal use of radiotherapy in AHL. MATERIAL AND METHODS: We included 133 patients treated with curatively intended chemotherapy for AHL. 23 patients received consolidation radiotherapy. For relapsed patients, imaging from diagnosis, response evaluation, relapse, and any radiotherapy planning, were retrieved and co-registered to determine the exact site(s) of relapse relative to initial site(s), residual mass(es) and to any irradiated volumes. Size and FDG-avidity of initial sites with later relapse, and residual CT-abnormalities after chemotherapy in these sites were registered. Survival analyses were done using the Kaplan-Meier method. RESULTS: Nine (6.8%) patients relapsed, eight in initially involved sites. One relapse was in an initially irradiated site (as well as other sites). Initial bulky disease, high initial FDG-uptake, and/or residual masses on CT-scan after chemotherapy did not predict sites with a high risk of relapse. Overall survival was 79.6% (95% CI, 72.7-86.5%) and 70.6% (95% CI, 62.4-78.8%) at 5 and 10 years, respectively. Time to progression analysis showed 91.8% (95% CI, 86.9-96.7%) and 90.7% (95% CI, 85.4-96.0%) without progression at 5 and 10 years, respectively. CONCLUSION: Current treatment strategies for AHL provide excellent disease control. Neither initial bulk, high initial FDG-uptake, nor a residual CT-abnormality post-chemotherapy seem to indicate sites with a high risk of relapse.

Baseline FDG PET/CT in free breathing versus deep inspiration breath-hold for pediatric patients with mediastinal lymphoma.

INTRODUCTION: The prospective TEDDI protocol investigates the feasibility of radiotherapy delivery in deep inspiration breath-hold (DIBH) for pediatric patients. To secure optimal radiotherapy planning, a diagnostic baseline FDG PET/CT in free breathing (FB) and DIBH was acquired. The anatomical changes in the mediastinum and the effect on PET metrics between the two breathing conditions were assessed for pediatric patients with mediastinal lymphoma. MATERIAL AND METHODS: Ten patients aged 5-17 were included and had a PET/CT in FB and DIBH. Metabolic active lymphoma volumes were manually delineated with a visually based segmentation method and the PET metrics were extracted. The anatomical lymphoma, lung and heart volumes were delineated on CT. RESULTS: The lung volume increased while the heart was displaced caudally and separated from the lymphoma in DIBH compared to FB. Both the anatomical and the metabolically active lymphoma volumes appeared different regarding shape and configuration in the two breathing conditions. The image quality of the DIBH PET was equal to the FB PET regarding interpretation and delineation of lymphoma lesions. All PET metrics increased on the DIBH PET compared to the FB PET with the highest increase observed for the maximum standardized uptake value (33%, range 7-56%). CONCLUSION: Diminished respiratory motion together with anatomical changes within the lymphoma increased all PET metrics in DIBH compared to FB. The anatomical changes observed in DIBH compared to FB are expected to reduce radiation doses to the heart and lungs in pediatric patients with mediastinal lymphoma referred for radiotherapy delivery in DIBH and, thereby, reduce their risk of late effects. TRIAL REGISTRATION: The Danish Ethical Committee (H-16035870, approved November 24th 2016), the Danish Data Protection Agency (2012-58-0004, approved 1 January 2017). Registered retrospectively at clinicaltrials.gov (NCT03315546, 20 October 2017).

Unexplained fever in children-Benefits and challenges of FDG-PET/CT.

AIM: To explore [fluorine-18]-fluoro-2-deoxy-d-glucose positron-emission-tomography/computed tomography (18 FDG-PET/CT) in patients where standard investigations were non-diagnostic. METHODS: We reviewed medical records of previously healthy children who had 18 FDG-PET/CT performed at Copenhagen University Hospital in 2015-2020 due to unexplained fever. RESULTS: Thirty-five of 819 paediatric 18 FDG-PET/CT were performed due to unexplained fever. The final diagnoses were malignancy (11%), infections (23%), inflammatory diseases (43%) and miscellaneous (26%). 18 FDG-PET/CT was diagnostic in six cases with Takayasu's arteritis, tuberculosis, Langerhans cell histiocytosis and Ewing sarcoma. Sixteen cases had focal 18 FDG-uptake, but 18 FDG-PET/CT could only differentiate malignancy, infection and inflammation in three cases. In six cases with inflammatory diseases and no focal signs, PET/CT was normal except increased non-specific 18 FDG-uptake in bone marrow and spleen in five cases. One case was false positive (suspicion of appendicitis) and two false negative (leukaemia and inflammatory disease). CONCLUSION: 18 FDG-PET/CT was diagnostic, or contributed to the diagnosis, in several children with unexplained fever referred to a tertiary centre. Challenges comprised (i) only increased non-specific 18 FDG-uptake in bone marrow and spleen in half of cases with inflammatory diseases, (ii) no differentiation between complicated infections, malignancy and inflammation in most cases with focal processes and (iii) a small risk of false positive and false negative results.

FDG-PET/CT identified distant metastases and synchronous cancer in squamous cell carcinoma of the head and neck: the impact of smoking and P16-s.

PURPOSE: Whole-body FDG-PET-CT is widely used at diagnosis of squamous cell carcinoma of the head and neck (SCCHN) but may identify suspicious lesions outside the neck that require investigation. This study evaluated the impact of smoking and P16-status on the incidence of malignant disease outside the head and neck region in newly diagnosed patients with SCCHN. METHODS: All PET-positive foci outside the head-neck area were registered in 1069 patients planned for postoperative or curative intent radiotherapy with whole-body FDG-PET/CT from 2006 to 2012. All patient files were retrospectively investigated and clinical parameters, tobacco use, HPV (P16)-status and subsequent malignant disease registered. RESULTS: Malignancy outside the neck was diagnosed in 9% of smokers, 2% of never-smokers, and 5% of patients with P16-positive oropharyngeal squamous cell carcinoma (OPSCC). Clinically suspicious PET-positive foci outside the head-neck were malignant in 55% of smokers, 34% of never-smokers, and in 38% of P16-pos OPSCC. All but two patients with cancer occurring outside the head and neck region were smokers. CONCLUSION: Malignancy outside the neck at diagnosis was more frequent in smokers compared to non-smokers or P16-pos OPSCC. A high proportion of clinically suspicious PET-positive foci were non-malignant.

Relapse localization in Danish pediatric patients with Hodgkin lymphoma.

BACKGROUND: Pediatric Hodgkin lymphoma (pHL) is highly curable. However, a minority experience relapse and are subjected to toxic salvage regimens. Investigating the patterns of relapse could help to select the patients and/or the involved sites that would benefit from consolidating radiotherapy. MATERIAL AND METHODS: The Danish Childhood Cancer Registry was used to identify children <18 years with relapsed pHL from 1990-2018. The lymphoma volumes involved at diagnosis and at relapse were contoured on the patients' original scans. Rigid image co-registration was used to merge the scans enabling a visual assessment of the anatomical relapse localization relative to the initially involved lymph nodes, and if irradiated, to the radiotherapy field. RESULTS: From 185 patients with pHL, 24 patients with relapse were available for analysis. All patients received combination chemotherapy and seven had consolidating radiotherapy. Relapses exclusively in initially involved sites occurred in 14 patients. Relapses exclusively in new sites were rare and only observed in three irradiated patients. Seven patients relapsed in both initially involved and new sites. The median time to relapse was 6 months (range 2-59 months), however, in-field relapses in irradiated patients occurred later (54 months, range 10-59 months). Neither risk group, initial bulky disease, early response, or metabolic activity seemed to be associated with the site of a later relapse. CONCLUSION: The number of relapses were small, and conclusions regarding the selection of patients for radiotherapy could not be drawn. Relapse exclusively in initially involved sites were the most common, most often in the exact same initially involved lymph nodes. Hence, modern involved site radiotherapy, focusing on the initially involved lymphoma volume and minimizing the radiation doses to normal tissues, should be applied when consolidating radiotherapy is used in patients with pHL.

Toward PET/MRI as one-stop shop for radiotherapy planning in cervical cancer patients.

BACKGROUND: Radiotherapy (RT) planning for cervical cancer patients entails the acquisition of both Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Further, molecular imaging by Positron Emission Tomography (PET) could contribute to target volume delineation as well as treatment response monitoring. The objective of this study was to investigate the feasibility of a PET/MRI-only RT planning workflow of patients with cervical cancer. This includes attenuation correction (AC) of MRI hardware and dedicated positioning equipment as well as evaluating MRI-derived synthetic CT (sCT) of the pelvic region for positioning verification and dose calculation to enable a PET/MRI-only setup. MATERIAL AND METHODS: 16 patients underwent PET/MRI using a dedicated RT setup after the routine CT (or PET/CT), including eight pilot patients and eight cervical cancer patients who were subsequently referred for RT. Data from 18 patients with gynecological cancer were added for training a deep convolutional neural network to generate sCT from Dixon MRI. The mean absolute difference between the dose distributions calculated on sCT and a reference CT was measured in the RT target volume and organs at risk. PET AC by sCT and a reference CT were compared in the tumor volume. RESULTS: All patients completed the examination. sCT was inferred for each patient in less than 5 s. The dosimetric analysis of the sCT-based dose planning showed a mean absolute error (MAE) of 0.17 ± 0.12 Gy inside the planning target volumes (PTV). PET images reconstructed with sCT and CT had no significant difference in quantification for all patients. CONCLUSIONS: These results suggest that multiparametric PET/MRI can be successfully integrated as a one-stop-shop in the RT workflow of patients with cervical cancer.

Premature Termination of a Randomized Controlled Trial on Image-Guided Stereotactic Body Radiotherapy of Metastatic Spinal Cord Compression.

LESSONS LEARNED: It is possible to plan and treat some patients with stereotactic body radiotherapy (SBRT) in a timely fashion in an acute setting. Advanced and, in some indications, already implemented technologies such as SBRT are difficult to test in a randomized trial. BACKGROUND: Stereotactic body radiotherapy (SBRT) in metastatic spinal cord compression (MSCC) could be an alternative to decompressive surgery followed by fractionated radiotherapy. METHODS: In a randomized, single-institution, noninferiority trial, patients with MSCC were assigned to stereotactic body radiotherapy of 16 Gy in 1 fraction or decompression surgery followed by fractionated radiotherapy of 30 Gy in 10 fractions. Primary endpoint was ability to walk by EQ5D-5L questionnaire. Based on power calculations, 130 patients had to be included to be 89% sure that a 15% difference between the treatment arm and the experimental arm could be detected. RESULTS: Ten patients were accrued in 23 months, with six patients allocated to surgery and four patients to stereotactic body radiotherapy. The trial was closed prematurely because of poor accrual. One patient undergoing surgery and one patient undergoing stereotactic body radiotherapy were unable to walk at 6 weeks. Two patients were not evaluable at 6 weeks. CONCLUSION: A randomized, phase II, clinical trial comparing surgery followed by fractionated radiotherapy or image-guided SBRT of MSCC was initiated. SBRT was shown to be feasible, with three out of four patients retaining walking function. The trial was determined futile as a result of low accrual.

FDG-PET/CT in the surveillance of head and neck cancer following radiotherapy.

PURPOSE: To examine the time-dependent diagnostic performance of FDG-PET/CT in the follow-up of head and neck cancer (HNC) and to assess the prognostic value of PET-negative and PET-inconclusive findings. MATERIAL AND METHODS: 279 HNC patients primarily treated with radiotherapy from 2006 to 2012 were included. The follow-up PET/CT scans were categorized as benign, malignant or inconclusive by a radiologist and a nuclear physician. The reference standard was histology or verification by progression on imaging. The outcome measures were positive (PPV) and negative predictive value (NPV), and the PET/CT scans were grouped according to time since treatment and compared. An analysis of the diagnostic accuracy was performed with the inconclusive results categorized as both benign and malignant to create ranges for the diagnostic performance. RESULTS: The proportion of inconclusive results declined from 26 to 8.4% and 0% after 0-3, 3-6 and 12-24 months post-treatment. The ranges for diagnostic performance after 0-3, 3-6, 6-12, 12-24 months and overall post-treatment were: PPV 27.3-50, 48.4-58.3, 71.4-100, 100 and 50.5-65.7 and NPV 75.0-84.6, 95.1-96.8, 92.9-100, 100 and 94.8-96.7. Time to recurrence was not statistically different after a PET-negative or a PET-inconclusive result. CONCLUSION: The diagnostic accuracy of a surveillance PET/CT scan after HNC improves with time since treatment, and is very reliable after 1 year. However, the NPV is already high 3 months post-treatment supporting the use of PET/CT for early evaluation of head and neck cancer patients.

Interobserver delineation uncertainty in involved-node radiation therapy (INRT) for early-stage Hodgkin lymphoma: on behalf of the Radiotherapy Committee of the EORTC lymphoma group.

BACKGROUND AND PURPOSE: In early-stage classical Hodgkin lymphoma (HL) the target volume nowadays consists of the volume of the originally involved nodes. Delineation of this volume on a post-chemotherapy CT-scan is challenging. We report on the interobserver variability in target volume definition and its impact on resulting treatment plans. MATERIALS AND METHODS: Two representative cases were selected (1: male, stage IB, localization: left axilla; 2: female, stage IIB, localizations: mediastinum and bilateral neck). Eight experienced observers individually defined the clinical target volume (CTV) using involved-node radiotherapy (INRT) as defined by the EORTC-GELA guidelines for the H10 trial. A consensus contour was generated and the standard deviation computed. We investigated the overlap between observer and consensus contour [Sørensen-Dice coefficient (DSC)] and the magnitude of gross deviations between the surfaces of the observer and consensus contour (Hausdorff distance). 3D-conformal (3D-CRT) and intensity-modulated radiotherapy (IMRT) plans were calculated for each contour in order to investigate the impact of interobserver variability on each treatment modality. Similar target coverage was enforced for all plans. RESULTS: The median CTV was 120 cm3 (IQR: 95-173 cm3) for Case 1, and 255 cm3 (IQR: 183-293 cm3) for Case 2. DSC values were generally high (>0.7), and Hausdorff distances were about 30 mm. The SDs between all observer contours, providing an estimate of the systematic error associated with delineation uncertainty, ranged from 1.9 to 3.8 mm (median: 3.2 mm). Variations in mean dose resulting from different observer contours were small and were not higher in IMRT plans than in 3D-CRT plans. CONCLUSIONS: We observed considerable differences in target volume delineation, but the systematic delineation uncertainty of around 3 mm is comparable to that reported in other tumour sites. This report is a first step towards calculating an evidence-based planning target volume margin for INRT in HL.

Survival outcomes in patients with cervical cancer after inclusion of PET/CT in staging procedures.

PURPOSE: In cancer of the uterine cervix, lymph node metastases are associated with a poor prognosis. Even so, the International Federation of Gynecology and Obstetrics (FIGO) does not take into account diagnostic results of methods such as PET/CT, since these are not readily available everywhere. As undetected lymph node metastases can lead to undertreatment, any difference in the underlying prevalence of false-negative scans between CT and PET/CT may be reflected in treatment outcomes. This study investigated survival outcomes in node-negative patients before and after the introduction of PET/CT. METHODS: This was a single-institution retrospective analysis of 301 patients with a histopathological diagnosis of cervical cancer. The patients were receiving chemoradiotherapy with curative intent according to the standard protocol of the department for patients without lymph node metastases as assessed by pretreatment CT or PET/CT. Patients were stratified into two groups: PET/CT and non-PET/CT. Patient characteristics and treatment outcomes were acquired from the treatment database. RESULTS: Significant differences of 23 % (95 % CI 17 - 29 %), 19 % (95 % CI 13 - 25 %) and 12 % (95 % CI 6 - 18 %) in 5-year overall, disease-free and disease-specific survival, respectively, were observed between the two patient groups. The difference remained significant in univariate and multivariate analyses of overall survival (hazard ratio 0.61, 95 % CI 0.42 - 0.89; p = 0.010), including age, FIGO stage, performance status, BMI, and histopathology. CONCLUSION: Inclusion of PET/CT in the preradiotherapy diagnostic protocol may lead to nodal stage migration not reflected in the FIGO stage. It was found to be a significant covariate, and could lead to selection bias that needs to be taken into account when designing and reporting on clinical trials.

Positron emission tomography/computed tomography for optimized colon cancer staging and follow up.

OBJECTIVES: Optimal management of colon cancer (CC) requires detailed assessment of extent of disease. This study prospectively investigates the diagnostic accuracy of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (PET/CT) for staging and detection of recurrence in primary CC. MATERIAL AND METHODS: PET/CT for preoperative staging was performed in 66 prospectively included patients with primary CC. Diagnostic accuracy for PET/CT and CT was analyzed. In addition to routine follow up, 42 stages I-III CC patients had postoperative PET/CT examinations every 6 months for 2 years. Serological levels of tissue inhibitor of metalloproteinase-1 (TIMP-1), carcinoembryonic antigen, and liberated domain I of urokinase plasminogen activator receptor were analyzed. RESULTS: Accuracy for tumor, nodal, and metastases staging by PET/CT were 82% (95% confidence interval [CI]: 70; 91), 66% (CI: 51; 78), and 89% (CI: 79; 96); for CT the accuracy was 77% (CI: 64; 87), 60% (CI: 46; 73), and 69% (CI: 57; 80). Cumulative relapse incidences for stages I-III CC at 6, 12, 18, and 24 months were 7.1% (CI: 0; 15); 14.3% (CI: 4; 25); 19% (CI: 7; 31), and 21.4% (CI: 9; 34). PET/CT diagnosed all relapses detected during the first 2 years. High preoperative TIMP-1 levels were associated with significant hazards toward risk of recurrence and shorter overall survival. CONCLUSIONS: This study indicates PET/CT as a valuable tool for staging and follow up in CC. TIMP-1 provided prognostic information potentially useful in selection of patients for intensive follow up.

SUVmax of 18FDG PET/CT as a predictor of high-risk endometrial cancer patients.

OBJECTIVE: To evaluate SUVmax in the assessment of endometrial cancer preoperatively with particular focus on myometrial invasion (MI), cervical invasion (CI), FIGO stage, risk-stratification and lymph node metastases (LNM). METHODS: A total of 268 women with endometrial cancer or atypical endometrial hyperplasia underwent FDG PET/CT imaging before surgical treatment. SUVmax of the primary tumour was compared with histological prognostic factors. RESULTS: SUVmax was significantly higher in patients with high FIGO stages (p<0.0001), deep MI (p=0.002), CI (p=0.04), LNM (p=0.04) and high risk tumours (p=0.003). Linear regression found that SUVmax was dependent of MI (p=0.001, 95% CI 2.863-11.098), CI (p=0.001, 95% CI 2.896-11.499), risk (p=0.004, 95% CI 0.077-0.397), LNM (p=0.04, 95% CI 0.011-0.482) and FIGO stage (p<0.0001, 95% CI 0.158-0.473). CONCLUSIONS: Preoperative PET/CT scanning and SUVmax measurements of the primary tumour may provide additional clinical and prognostic information about MI, CI, LNM and high risk disease in patients with endometrial cancer and allow for individualization of patient care. However, the sensitivity and specificity of the SUVmax in staging endometrial cancer is not high enough to reliably replace surgical staging.

MRI, PET/CT and ultrasound in the preoperative staging of endometrial cancer - a multicenter prospective comparative study.

OBJECTIVES: The aim of this prospective multicenter study was to evaluate and compare the diagnostic performance of PET/CT, MRI and transvaginal two-dimensional ultrasound (2DUS) in the preoperative assessment of endometrial cancer (EC). METHODS: 318 consecutive women with EC were included when referred to three Danish tertiary gynecological centers for surgical treatment. Preoperatively they were PET/CT-, MRI-, and 2DUS scanned. The imaging results were compared to the final pathological findings. This study was approved by the National Committee on Health Research Ethics. RESULTS: For predicting myometrial invasion, we found sensitivity, specificity, PPV, NPV, and accuracy for PET/CT to be 93%, 49%, 41%, 95% and 61%, for MRI to be 87%, 57%, 44%, 92%, and 66% and for 2DUS to be 71%, 72%, 51%, 86% and 72%. For predicting cervical invasion, the values were 43%, 94%, 69%, 85% and 83%, respectively, for PET/CT, 33%, 95%, 60%, 85%, and 82%, respectively, for MRI, and 29%, 92%, 48%, 82% and 78% for 2DUS. Finally, for lymph node metastases, the values were 74%, 93%, 59%, 96%, and 91% for PET/CT and 59%, 93%, 40%, 97% and 90% for MRI. When comparing the diagnostic performance we found PET/CT, MRI and 2DUS to be comparable in predicting myometrial invasion. For cervical invasion and lymph node metastases, however, PET/CT was the best. CONCLUSIONS: None of the modalities can yet replace surgical staging. However, they all contributed to important knowledge and were, furthermore, able to upstage low-risk patients who would not have been recommended lymph node resection based on histology and grade alone.

PET/MRI in cancer patients: first experiences and vision from Copenhagen.

Combined PET/MRI systems are now commercially available and are expected to change the medical imaging field by providing combined anato-metabolic image information. We believe this will be of particular relevance in imaging of cancer patients. At the Department of Clinical Physiology, Nuclear Medicine & PET at Rigshospitalet in Copenhagen we installed an integrated PET/MRI in December 2011. Here, we describe our first clinical PET/MR cases and discuss some of the areas within oncology where we envision promising future application of integrated PET/MR imaging in clinical routine. Cases described include brain tumors, pediatric oncology as well as lung, abdominal and pelvic cancer. In general the cases show that PET/MRI performs well in all these types of cancer when compared to PET/CT. However, future large-scale clinical studies are needed to establish when to use PET/MRI. We envision that PET/MRI in oncology will prove to become a valuable addition to PET/CT in diagnosing, tailoring and monitoring cancer therapy in selected patient populations.

Positron emission tomography/computed tomography predictors of overall survival in stage IIIC/IV ovarian cancer.

OBJECTIVE: To evaluate the role of 2-deoxy-2-(F)fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) for selecting patients with extensive ovarian cancer (OC) for neoadjuvant chemotherapy by evaluating predictors of overall survival in patients with stage IIIC/IV OC. MATERIALS AND METHODS: From September 1, 2004, to November 20, 2011, 514 consecutive patients with a pelvic tumor underwent preoperative PET/CT; 179 patients had stage IIIC/IV OC. Patients' characteristics were collected from 153 patients with stage IIIC/IV OC who underwent primary surgery. In 152 patients with stage IIIC/IV OC, clinical predictors and PET/CT predictors of survival were evaluated. RESULTS: Median age was 64 years (range, 38-88 years); 87% (113) of the 153 patients had a performance status of less than 2; 55% (84) of the 153 patients had PET/CT stage III, and 45% (69) of the 153 patients had PET/CT stage IV. Using univariate analysis, incomplete debulking (P = 0.0001), pleural exudates (P = 0.001), postmenopausal state (P = 0.01), WHO performance status greater than 2 (P = 0.01), PET/CT stage IV (P = 0.01), and large bowel mesentery implants (P = 0.02) were statistically significant prognostic variables. Using multivariate Cox regression analysis, incomplete debulking was the only statistically significant independent prognostic variable (P = 0.0001). Median overall survival was significantly longer in the 53 patients with no residual tumor than in the 99 patients with residual tumor (33.3 vs 25.5 months; P = 0.0001) CONCLUSION: Suggested PET/CT criteria for referral of patients with advanced OC to neoadjuvant chemotherapy are PET/CT stage IV, pleural exudates, and PET-positive large bowel mesentery implants. Evaluation of selection criteria for neoadjuvant chemotherapy should be promoted in prospective clinical trials, with survival as the primary end point.

RootPainter3D: Interactive-machine-learning enables rapid and accurate contouring for radiotherapy.

PURPOSE: Organ-at-risk contouring is still a bottleneck in radiotherapy, with many deep learning methods falling short of promised results when evaluated on clinical data. We investigate the accuracy and time-savings resulting from the use of an interactive-machine-learning method for an organ-at-risk contouring task. METHODS: We implement an open-source interactive-machine-learning software application that facilitates corrective-annotation for deep-learning generated contours on X-ray CT images. A trained-physician contoured 933 hearts using our software by delineating the first image, starting model training, and then correcting the model predictions for all subsequent images. These corrections were added into the training data, which was used for continuously training the assisting model. From the 933 hearts, the same physician also contoured the first 10 and last 10 in Eclipse (Varian) to enable comparison in terms of accuracy and duration. RESULTS: We find strong agreement with manual delineations, with a dice score of 0.95. The annotations created using corrective-annotation also take less time to create as more images are annotated, resulting in substantial time savings compared to manual methods. After 923 images had been delineated, hearts took 2 min and 2 s to delineate on average, which includes time to evaluate the initial model prediction and assign the needed corrections, compared to 7 min and 1 s when delineating manually. CONCLUSIONS: Our experiment demonstrates that interactive-machine-learning with corrective-annotation provides a fast and accessible way for non computer-scientists to train deep-learning models to segment their own structures of interest as part of routine clinical workflows.

Prospective Phase II Trial of Prognostication by 68Ga-NOTA-AE105 uPAR PET in Patients with Neuroendocrine Neoplasms: Implications for uPAR-Targeted Therapy.

The clinical course for patients with neuroendocrine neoplasms (NENs) ranges from indolent to highly aggressive. Noninvasive tools to improve prognostication and guide decisions on treatment are warranted. Expression of urokinase plasminogen activator receptor (uPAR) is present in many cancer types and associated with a poor outcome. Therefore, using an in-house-developed uPAR PET tracer [68Ga]Ga-NOTA-Asp-Cha-Phe-D-Ser-D-Arg-Tyr-Leu-Trp-Ser-OH (68Ga-NOTA-AE105), we aimed to assess uPAR expression in NENs. We hypothesized that uPAR expression was detectable in a significant proportion of patients and associated with a poorer outcome. In addition, as uPAR-targeted radionuclide therapy has previously proven effective in preclinical models, the study would also indicate the potential for uPAR-targeted radionuclide therapy in NEN patients. Methods: In a prospective clinical phase II trial, we included 116 patients with NENs of all grades, of whom 96 subsequently had uPAR PET/CT performed with evaluable lesions. PET/CT was performed 20 min after injection of approximately 200 MBq of 68Ga-NOTA-AE105. uPAR target-to-liver ratio was used to define lesions as uPAR-positive when lesion SUVmax-to-liver SUVmean ratio was at least 2. Patients were followed for at least 1 y to assess progression-free and overall survival. Results: Most patients had small intestinal NENs (n = 61) and metastatic disease (n = 86). uPAR-positive lesions were seen in 68% (n = 65) of all patients and in 75% (n = 18) of patients with high-grade (grade 3) NENs. During follow-up (median, 28 mo), 59 patients (62%) experienced progressive disease and 28 patients (30%) died. High uPAR expression, defined as a uPAR target-to-liver ratio above median, had a hazard ratio of 1.87 (95% CI, 1.11-3.17) and 2.64 (95% CI, 1.19-5.88) for progression-free and overall survival, respectively (P < 0.05 for both). Conclusion: When 68Ga-NOTA-AE105 PET was used to image uPAR in patients with NENs, uPAR-positive lesions were seen in most patients, notably in patients with both low-grade and high-grade NENs. Furthermore, uPAR expression was associated with a worse prognosis. We suggest that uPAR PET is relevant for risk stratification and that uPAR may be a promising target for therapy in patients with NENs.

First-in-Human Study of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET for Integrin αvß3 Imaging in Patients with Breast Cancer and Neuroendocrine Neoplasms: Safety, Dosimetry and Tumor Imaging Ability.

Arginine-Glycine-Aspartate (RGD)-recognizing cell surface integrins are involved in tumor growth, invasiveness/metastases, and angiogenesis, and are therefore an attractive treatment target in cancers. The subtype integrin αvß3 is upregulated on endothelial cells during angiogenesis and on tumor cells. In vivo assessment of integrin αvß3 is possible with positron emission tomography (PET). Preclinical data on radiochemical properties, tumor uptake and radiation exposure identified [68Ga]Ga-NODAGA-E[c(RGDyK)]2 as a promising candidate for clinical translation. In this first-in-human phase I study, we evaluate [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET in patients with neuroendocrine neoplasms (NEN) and breast cancer (BC). The aim was to investigate safety, biodistribution and dosimetry as well as tracer uptake in tumor lesions. A total of 10 patients (5 breast cancer, 5 neuroendocrine neoplasm) received a single intravenous dose of approximately 200 MBq [68Ga]Ga-NODAGA-E[c(RGDyK)]2. Biodistribution profile and dosimetry were assessed by whole-body PET/CT performed at 10 min, 1 h and 2 h after injection. Safety assessment with vital parameters, electrocardiograms and blood tests were performed before and after injection. In vivo stability of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 was determined by analysis of blood and urine. PET images were analyzed for tracer uptake in tumors and background organs. No adverse events or pharmacologic effects were observed in the 10 patients. [68Ga]Ga-NODAGA-E[c(RGDyK)]2 exhibited good in vivo stability and fast clearance, primarily by renal excretion. The effective dose was 0.022 mSv/MBq, equaling a radiation exposure of 4.4 mSv at an injected activity of 200 MBq. The tracer demonstrated stable tumor retention and good image contrast. In conclusion, this first-in-human phase I trial demonstrated safe use of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 for integrin αvß3 imaging in cancer patients, low radiation exposure and favorable uptake in tumors. Further studies are warranted to establish whether [68Ga]Ga-NODAGA-E[c(RGDyK)]2 may become a tool for early identification of patients eligible for treatments targeting integrin αvß3 and for risk stratification of patients.

Multi-parametric PET/MRI for enhanced tumor characterization of patients with cervical cancer.

AIM: The concept of personalized medicine has brought increased awareness to the importance of inter- and intra-tumor heterogeneity for cancer treatment. The aim of this study was to explore simultaneous multi-parametric PET/MRI prior to chemoradiotherapy for cervical cancer for characterization of tumors and tumor heterogeneity. METHODS: Ten patients with histologically proven primary cervical cancer were examined with multi-parametric 68Ga-NODAGA-E[c(RGDyK)]2-PET/MRI for radiation treatment planning after diagnostic 18F-FDG-PET/CT. Standardized uptake values (SUV) of RGD and FDG, diffusion weighted MRI and the derived apparent diffusion coefficient (ADC), and pharmacokinetic maps obtained from dynamic contrast-enhanced MRI with the Tofts model (iAUC60, Ktrans, ve, and kep) were included in the analysis. The spatial relation between functional imaging parameters in tumors was examined by a correlation analysis and joint histograms at the voxel level. The ability of multi-parametric imaging to identify tumor tissue classes was explored using an unsupervised 3D Gaussian mixture model-based cluster analysis. RESULTS: Functional MRI and PET of cervical cancers appeared heterogeneous both between patients and spatially within the tumors, and the relations between parameters varied strongly within the patient cohort. The strongest spatial correlation was observed between FDG uptake and ADC (median r = - 0.7). There was moderate voxel-wise correlation between RGD and FDG uptake, and weak correlations between all other modalities. Distinct relations between the ADC and RGD uptake as well as the ADC and FDG uptake were apparent in joint histograms. A cluster analysis using the combination of ADC, FDG and RGD uptake suggested tissue classes which could potentially relate to tumor sub-volumes. CONCLUSION: A multi-parametric PET/MRI examination of patients with cervical cancer integrated with treatment planning and including estimation of angiogenesis and glucose metabolism as well as MRI diffusion and perfusion parameters is feasible. A combined analysis of functional imaging parameters indicates a potential of multi-parametric PET/MRI to contribute to a better characterization of tumor heterogeneity than the modalities alone. However, the study is based on small patient numbers and further studies are needed prior to the future design of individually adapted treatment approaches based on multi-parametric functional imaging.

18F-FDG PET/CT as a diagnostic tool in patients with extracervical carcinoma of unknown primary site: a literature review.

BACKGROUND: Carcinoma of unknown primary (CUP) represents a heterogeneous group of metastatic malignancies for which no primary tumor site can be identified after extensive diagnostic workup. Failure to identify the primary site may negatively influence patient management. The aim of this review was to evaluate (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) as a diagnostic tool in patients with extracervical CUP. MATERIALS AND METHODS: A comprehensive literature search was performed and four publications were identified (involving 152 patients) evaluating (18)F-FDG PET/CT in CUP patients with extracervical metastases. All studies were retrospective and heterogeneous in inclusion criteria, study design, and diagnostic workup prior to (18)F-FDG PET/CT. RESULTS: (18)F-FDG PET/CT detected the primary tumor in 39.5% of patients with extracervical CUP. The lung was the most commonly detected primary tumor site (∼50%). The pooled estimates of sensitivity, specificity, and accuracy of (18)F-FDG PET/CT in the detection of the primary tumor site were 87%, 88%, and 87.5%, respectively. CONCLUSIONS: The present review of currently available data indicates that (18)F-FDG PET/CT might contribute to the identification of the primary tumor site in extracervical CUP. However, prospective studies with more uniform inclusion criteria are required to evaluate the exact value of this diagnostic tool.