Supervised machine learning enables non-invasive lesion characterization in primary prostate cancer with [68Ga]Ga-PSMA-11 PET/MRI.

PURPOSE: Risk classification of primary prostate cancer in clinical routine is mainly based on prostate-specific antigen (PSA) levels, Gleason scores from biopsy samples, and tumor-nodes-metastasis (TNM) staging. This study aimed to investigate the diagnostic performance of positron emission tomography/magnetic resonance imaging (PET/MRI) in vivo models for predicting low-vs-high lesion risk (LH) as well as biochemical recurrence (BCR) and overall patient risk (OPR) with machine learning. METHODS: Fifty-two patients who underwent multi-parametric dual-tracer [18F]FMC and [68Ga]Ga-PSMA-11 PET/MRI as well as radical prostatectomy between 2014 and 2015 were included as part of a single-center pilot to a randomized prospective trial (NCT02659527). Radiomics in combination with ensemble machine learning was applied including the [68Ga]Ga-PSMA-11 PET, the apparent diffusion coefficient, and the transverse relaxation time-weighted MRI scans of each patient to establish a low-vs-high risk lesion prediction model (MLH). Furthermore, MBCR and MOPR predictive model schemes were built by combining MLH, PSA, and clinical stage values of patients. Performance evaluation of the established models was performed with 1000-fold Monte Carlo (MC) cross-validation. Results were additionally compared to conventional [68Ga]Ga-PSMA-11 standardized uptake value (SUV) analyses. RESULTS: The area under the receiver operator characteristic curve (AUC) of the MLH model (0.86) was higher than the AUC of the [68Ga]Ga-PSMA-11 SUVmax analysis (0.80). MC cross-validation revealed 89% and 91% accuracies with 0.90 and 0.94 AUCs for the MBCR and MOPR models respectively, while standard routine analysis based on PSA, biopsy Gleason score, and TNM staging resulted in 69% and 70% accuracies to predict BCR and OPR respectively. CONCLUSION: Our results demonstrate the potential to enhance risk classification in primary prostate cancer patients built on PET/MRI radiomics and machine learning without biopsy sampling.

Sex-differences in [68Ga]Ga-DOTANOC biodistribution.

INTRODUCTION: Still little is known about factors, influencing the organ uptake of somatostatin receptor (SSTR)-targeting radiopharmaceuticals. The aim of this study was to assess the influence of gender on [68Ga]Ga-DOTANOC uptake. Further on, we assessed other factors such as diabetes, proton pump inhibitors (PPIs) and oral antidiabetics (OADs). METHODS: In 118 studies of patients with a [68Ga]Ga-DOTANOC PET/CT (m = 60, f = 58; mean age: 61 ±â€¯15 yrs) SUVmax and SUVmean of the stomach, liver, spleen, kidneys, adrenal glands, and pancreas were assessed. Patients with history of splenectomy and significant tumor burden were excluded. Additionally, clinical information (gender, diabetes, age, pre-medications such as PPIs, OADs and somatostatin analogues (SSAs), were collected. RESULTS: [68Ga]Ga-DOTANOC uptake proved to be significantly lower in female patients compared to males for the SUVmax of the stomach (7.1, 9.1; P = 0.04), liver (8.3, 9.4; P = 0.0007), adrenal glands (15.9, 19.9; P = 0.05) kidneys (20.3, 18.9; P = 0.05) and the SUVmean of the pancreatic tail (2.9, 3.2; P = 0.03) and the kidneys (11.8, 10.6, P = 0.004). Additionally, patients with diabetes and below the age of 50 yrs. showed significantly higher SUVmax and SUVmean values of the stomach (diabetes: 9.1, 7.8; P = 0.01 and 6.0, 5.3; P = 0.004; age: 6.3, 8.3; P = 0.01 and 4.4, 5.5; P = 0.03). In contrast, intake of PPIs only affected the SUVmean of the liver (11.0, 9.0; P = 0.005), whereas OADs caused higher SUVmax values in the stomach (10.0, 7.8; P = 0.02), spleen (42.5, 32.6; P = 0.0005) adrenal glands (25.0, 16.9; P = 0.0003) and also higher SUVmean in the spleen (26.1, 21.4; P = 0.002) and adrenal glands (14.8, 12.4; P = 0.02). CONCLUSION: Factors such as gender, diabetes and age influence [68Ga]Ga-DOTANOC uptake, whereas ongoing medications such as PPIs and OADs exerted less influence.

68Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy - diagnostic performance and impact on therapeutic decision-making.

OBJECTIVE: To evaluate the diagnostic performance of [68Ga]Ga-PSMAHBED-CC conjugate 11 positron emission tomography (PSMA-PET) in the early detection of metastases in patients with biochemical recurrence (BCR) after radical prostatectomy (RP) for clinically non-metastatic prostate cancer, to compare it to CT/MRI alone and to assess its impact on further therapeutic decisions. MATERIAL AND METHODS: We retrospectively assessed 117 consecutive hormone-naïve BCR patients who had 68Ga-PSMA 11 PET/CT (n = 46) or PET/MRI (n = 71) between May 2014 and January 2017. BCR was defined as two PSA rises above 0.2 ng/ml. Two dedicated uro-oncological imaging experts (radiology/nuclear medicine) reviewed separately all images. All results were presented in a blinded sequential fashion to a multidisciplinary tumorboard in order to assess the influence of PSMA-PET imaging on decision-making. RESULTS: The median time from RP to BCR was 36 months (IQR 16-72). Overall, 69 (59%) patients received postoperative radiotherapy. Median PSA level at the time of imaging was 1.04 ng/ml (IQR 0.58-1.87). PSMA-positive lesions were detected in 100 (85.5%) patients. Detection rates were 65% for a PSA value of 0.2 to <0.5 ng/ml, 85.7% for 0.5 to <1, 85.7% for 1 to <2 and 100% for ≥2. PSMA-positive lesions could be confirmed by either histology (16%), PSA decrease in metastasis-directed radiotherapy (45%) or additional information in diffusion-weighted imaging when PET/MRI was performed (18%) in 79% of patients. PSMA-PET detected lesions in 67 patients (57.3%) who had no suspicious correlates according to the RECIST 1.1 criteria on MRI or CT. PSMA-PET changed therapeutic decisions in 74.6% of these 67 patients (p < 0.001), with 86% of them being considered for metastases-directed therapies. CONCLUSIONS: We confirm the high performance of PSMA-PET imaging for the detection of disease recurrence sites in patients with BCR after RP, even at relatively low PSA levels. Moreover, it adds significant information to standard CT/MRI, changing treatment strategies in a significant number of patients.

Hematopoiesis is prognostic for toxicity and survival of 223Radium treatment in patients with metastatic castration-resistant prostate cancer.

OBJECTIVE: We evaluated the impact of pre-therapeutic hematopoiesis on survival, hematotoxicity (HT) and number of 223Radium (223Ra) treatments in patients with metastatic castration-resistant prostate cancer. SUBJECTS AND METHOD: Hemoglobin-levels (Hb), the number of platelets (Plts), leukocytes (Leuk), and survival data were collected in 56 patients treated with 223Ra. Pre-therapeutic hematopoiesis as well as adverse events during and after therapy were scored (grade 0-4) according to the CTCAE recommendations. The association of pre-therapeutic hematopoiesis, survival, HT and numbers of 223Ra cycles was analyzed. RESULTS: Median survival in all patients was 69.9 weeks; 77% of patients had pre-existing impaired Hb (1.7% grade 3, 12.5% grade 2, 62.5% grade 1). 8/56 (14.3%) had impaired Plt (grade 1) Maximum toxicity (Tox) grades of patients during treatment were grade 4 (Hb 1.7%; Plt 1.7%), grade 3 (Hb 14.3%; Plt 7.1%; Leu 7.1%), grade 2 (Hb 33.9%; Plt 7.1%; Leu 23.2%), grade 1 (Hb 46.4%; Plt 17.9%; Leu 23.2%) and grade 0 (Hb 5.4%; Plt 66.1%; Leu 44.6%). Interestingly, patients with thrombocytopenia had a significantly shorter survival compared to those with normal Plt levels (21 weeks vs not reached; P<0.003). As expected patients with pre-therapeutic low Hb-level (<10g/dL) had a significantly shorter survival compared to those with Hb-level >10g/dL (28 weeks vs not reached, P<0.004), whereas survival of patients with mildly impaired Hb (>10 but <13.5g/dL) did not differ from patients with normal levels of Hb (X vs. Y, P=...). Also patients with impaired Hb also developed significantly more grade 3 and 4 HT (Hb <10g/dL: 42.9 vs 14.3%, P<0.001; Plt <150G/mL: 25.0% vs 6.3%; P=0.002) and received significantly fewer treatment cycles (Hb<10g/dL: 5.1 vs 5.8, P<0.04; Plt <150G/mL: 3.4 vs 5.6; P<0.001). Neither extent of bone metastases nor previous chemotherapy were associated with survival, number of 223Ra cycles and HT. CONCLUSION: Patients with metastatic castration-resistant prostate cancer and impaired hematopoiesis, in particular thrombocytopenia and anemia, before 223Ra therapy suffer from significantly more high-grade HT, shorter survival and receive significantly fewer 223Ra treatments. Therefore, Hb-levels and platelet counts are essential parameters for adequate patient selection for 223Ra therapy.

Safety of Radioembolization with (90)Yttrium Resin Microspheres Depending on Coiling or No-Coiling of Aberrant/High-Risk Vessels.

PURPOSE: To evaluate the safety of radioembolization (RE) with (90)Yttrium ((90)Y) resin microspheres depending on coiling or no-coiling of aberrant/high-risk vessels. MATERIALS AND METHODS: Early and late toxicity after 566 RE procedures were analyzed retrospectively in accordance with the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE v3.0). For optimal safety, aberrant vessels were either coil embolized (n = 240/566, coiling group) or a more peripheral position of the catheter tip was chosen to treat right or left liver lobes (n = 326/566, no-coiling group). RESULTS: Clinically relevant late toxicities (≥ Grade 3) were observed in 1% of our overall cohort. The no-coiling group had significantly less "any" (P = 0.0001) or "clinically relevant" (P = 0.0003) early toxicity. There was no significant difference (P > 0.05) in delayed toxicity in the coiling versus the no-coiling group. No RE-induced liver disease was noted after all 566 procedures. CONCLUSION: RE with (90)Y resin microspheres is a safe and effective treatment option. Performing RE without coil embolization of aberrant vessels prior to treatment could be an alternative for experienced centers.

Radioembolization with Yttrium-90 microspheres (SIRT) in pancreatic cancer patients with liver metastases: efficacy, safety and prognostic factors.

OBJECTIVE: To analyze the clinical efficacy of (90)Y radioembolization in liver metastases from pancreatic cancer, to describe treatment toxicities and to identify biomarkers as predictors of outcome. METHODS: Data from 19 pancreatic cancer patients (9 females/10 males) who had received (90)Y radioembolization for metastatic liver disease between 06/2004 and 01/2011 were analyzed retrospectively. RESULTS: The median age at (90)Y radioembolization was 63 years (range 43-77). In 16 patients, previous palliative gemcitabine-based chemotherapy was given for metastatic disease. Objective response in the liver after (90)Y radioembolization was 47%. Median local progression-free survival in the liver was 3.4 months (range 0.9-45.0). Median overall survival (OS) was 9.0 months (range 0.9-53.0) and 1-year survival was 24%. Cox regression models for baseline biomarkers at (90)Y radioembolization revealed correlations of increased carbohydrate antigen 19-9 (p = 0.02) and C-reactive protein (p = 0.03) with shorter OS. Short-term adverse events (nausea, vomiting, fatigue, fever and abdominal pain) did not exceed grade 3. As long-term adverse events, liver abscesses, gastroduodenal ulceration, cholestasis and cholangitis, ascites and spleen infarction were observed. CONCLUSION: (90)Y radioembolization is able to induce an encouraging local response rate of liver metastases of pancreatic cancer patients. Most short-term toxicities are manageable; however, patients should be followed up carefully for severe long-term toxicities.

Radioembolization as locoregional therapy of hepatic metastases in uveal melanoma patients.

PURPOSE: To retrospectively evaluate the overall survival, safety, and efficacy of metastatic uveal melanoma patients after radioembolization as salvage therapy. MATERIALS AND METHODS: Thirteen patients were treated with radioembolization of branches of the hepatic artery with resin-based yttrium-90 ((90)Y)-labelled microspheres. Twelve patients underwent a single application, and 1 patient underwent 4 interventions. Dosages from 644 to 2,450 MBq (mean activity 1,780) were applied. Treatment response was evaluated by way of liver magnetic resonance imaging and computed tomography (CT) as well as whole-body fluorodeoxyglucose positron emission tomography (PET)/CT with evaluation of percentage changes in SUV(max) before and at 2-3 months after therapy. Kaplan-Meier analysis was calculated to determine overall survival. RESULTS: Partial remission (PR) was observed in 8 (62 %), stable disease (SD) in 2 (15 %), and progressive disease (PD) in 3 (23 %) patients under terms of standard criteria and PR in 3 (23 %), SD in 3 (23 %), and PD in 7 (54 %) patients according to PET criteria. Neither RECIST nor PET criteria showed a significant difference in predicting overall survival (P = 0.12 and 0.11, respectively). Median survival time after radioembolization was 7 months. No acute toxicity with in-hospital morbidity was observed. One patient developed hepatomegaly, and 1 patient developed gastric ulceration. Throughout follow-up, progression of extrahepatic metastases was observed. CONCLUSION: Radioembolization may be a promising therapy in uveal melanoma patients with predominant hepatic metastases. At first follow-up, we observed PR or SD in 77 % patients under terms of standard criteria with an acceptable toxicity profile.

[Importance of PET/CT for imaging of colorectal cancer]. / Stellenwert der PET/CT zur Bildgebung des kolorektalen Karzinoms.

CLINICAL/METHODICAL ISSUE: Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) has emerged as a very useful imaging modality in the management of colorectal carcinoma. Data from the literature regarding the role of PET/CT in the initial diagnosis, staging, radiotherapy planning, response monitoring and surveillance of colorectal carcinoma is presented. Future directions and economic aspects are discussed. STANDARD RADIOLOGICAL METHODS: Computed tomography (CT), magnetic resonance imaging (MRI) and FDG-PET for colorectal cancer and endorectal ultrasound for rectal cancer. METHODICAL INNOVATIONS: Combined FDG-PET/CT. PERFORMANCE: While other imaging modalities allow superior visualization of the extent and invasion depth of the primary tumor, PET/CT is most sensitive for the detection of distant metastases of colorectal cancer. ACHIEVEMENTS: We recommend a targeted use of PET/CT in cases of unclear M staging, prior to metastasectomy and in suspected cases of residual or recurrent colorectal carcinoma with equivocal conventional imaging. The role of PET/CT in radiotherapy planning and response monitoring needs to be determined. Currently there is no evidence to support the routine use of PET/CT for colorectal screening, staging or surveillance. PRACTICAL RECOMMENDATIONS: To optimally exploit the synergy between morphologic and functional information, FDG-PET should generally be performed as an integrated FDG-PET/CT with a contrast-enhanced CT component in colorectal carcinoma.

[Gastroenteropancreatic neuroendocrine tumors: diagnosis and therapy in nuclear medicine]. / Neuroendokrine Tumoren des gastroenteropankreatischen Systems: Nuklearmedizinische Diagnostik und Therapie.

The over expression of somatostatin receptors (SSTR) in neuroendocrine tumors (NET) enables diagnosis and targeted therapy using radio-labelled somatostatin analogues. PET with (68)Ga-DOTATATE or (68)Ga-DOTATOC, both with a high affinity to the SSTR subtype 2, enables diagnosis of NET with a very high sensitivity and has a significant influence on the therapeutic management of patients with NET. In particular, therapy with (177)Lu-DOTATATE, which offers a considerably lower nephrotoxicity as compared to (90)Y-DOTATOC, has only few side effects and is usually well tolerated. Up to 46% of patients suffering from GEP-NET show a response to this therapy, which is able to mitigate tumour-related symptoms and significantly improve quality of life.

Combined anatomical and functional imaging using coronary CT angiography and myocardial perfusion SPECT in symptomatic adults with abnormal origin of a coronary artery.

There has been a lack of standardized workup guidelines for patients with congenital abnormal origin of a coronary artery from the opposite sinus (ACAOS). We aimed to evaluate the use of cardiac hybrid imaging using multi-detector row CT (MDCT) for coronary CT angiography (Coronary CTA) and stress-rest myocardial perfusion SPECT (MPS) for comprehensive diagnosis of symptomatic adult patients with ACAOS. Seventeen symptomatic patients (12 men; 54 ± 13 years) presenting with ACAOS underwent coronary CTA and MPS. Imaging data were analyzed by conventional means, and with additional use of 3D image fusion to allocate stress induced perfusion defects (PD) to their supplying coronary arteries. An anomalous RCA arose from the left anterior sinus in eight patients, an abnormal origin from the right sinus was detected in nine patients (5 left coronary arteries, LCA and 4 LCx). Five of the 17 patients (29%) demonstrated a reversible PD in MPS. There was no correlation between the anatomical variants of ACAOS and the presence of myocardial ischemia. Image fusion enabled the allocation of reversible PD to the anomalous vessel in three patients (two cases in the RCA and the other in the LCA territory); PD in two patients were allocated to the territory of artery giving rise to the anomalies, rather than the anomalies themselves. In a small cohort of adult symptomatic patients with ACAOS anomaly there was no relation found between the specific anatomical variant and the appearance of stress induced myocardial ischemia using cardiac hybrid imaging.

[Hepatic metastases in CUP (cancer of unknown primary) and painful amaurosis]. / Hepatische Filiae bei CUP ("cancer of unknown primary") und schmerzhafter Amaurose.

A 63-year-old woman presented with a 9-month history of painful amaurosis of the left eye caused by hemophthalmos. She was already undergoing chemotherapy for histopathologically proven liver metastases caused by an assumed melanoma. The location of the primary tumor was unknown. Whole-body FDG-PET/CT staging identified a lesion with characteristically malignant uptake in the region of the left eye as the primary tumor. After enucleation, a primary uveal melanoma was verified that expressed the serological marker melanoma inhibitory activity (MIA). FDG-PET/CT was able to successfully align hepatic metastases due to CUP with local ophthalmologic diagnostic findings and led to a correct diagnosis.

[Quantification of immunohistochemical expression of somatostatin receptors in neuroendocrine tumors using 68Ga-DOTATATE PET/CT]. / Quantifizierung der Somatostatinrezeptorexpression neuroendokriner Tumoren mit der (68)Ga-DOTATATE-PET/CT.

PURPOSE: The immunohistochemical expression of somatostatin receptor (SSTR) subtype 2 was compared to quantitative (68)Ga-DOTATATE PET in neuroendocrine tumors (NET). MATERIAL AND METHODS: In 27 patients suffering from metastatic NET the expression of somatostatin receptors (SSTR, score 0-3) and the Ki-67 index were assessed. The immunohistochemical findings were compared with the (68)Ga-DOTATATE PET uptake in these tumors using the SUV(max) (standardized uptake value). Both values were compared with the Ki-67 proliferation index. RESULTS: The SUV(max) in NET without SSTR expression was significantly lower compared to those with SSTR expression (p <0.05), even though 3 out of 5 NETs with a score of 0 showed a high uptake of (68)Ga-DOTATATE. The SUV(max) correlated significantly (r=0.40, p <0.05) with the score of immunohistochemical SSTR expression (negative, score 0, moderate, score 1 and high, scores 2 and 3). The Ki-67 index correlated inversely with the SSTR expression score (r=-0.42, p <0.05), but not significantly with the SUV(max) (r=-0.33, p=0.11). CONCLUSION: (68)Ga-DOTATATE uptake was moderately correlated with the results of immunohistochemical SSTR analyses. However, SSTR negative NET may show high uptake of (68)Ga-DOTATATE.

Localization of spin labels in oat leaf protoplasts.

An assay based on light-mediated oxidation was used to determine whether specific spin labels were partitioned throughout the protoplast or retained in the plasmalemma of Avena sativa L. cv. Garry and Park. Many classes of spin label were tested, including phospholipids, fatty acid, fatty acid methyl ester, maleimide, iodoacetamide, short chain hydrocarbon, androstane, 2,2,6,6-tetramethyl-4-aminopiperidinooxyl (TEMPAMINE) and 2,2,6,6-tetramethylpiperidinooxyl (TEMPO). All except the phosphotidylcholine spin label were found to partition throughout the cell. The phosphotidylcholine spin label may have been selectively retained in the plasmalemma.

Interaction of nitroxide spin labels with chloroplasts.

Chloroplasts isolated from oats eliminated the electron spin resonance (ESR) signals from spin labels in white light and partially restored them in far-red light. Only the white light-mediated reaction was blocked by 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU). In contrast, oat (Avena sativa L. cv. Garry and Park) leaf mesophyll protoplasts oxidized the spin labels in both white and far-red light, with and without DCMU. Light had no obvious effect on spin label motion within chloroplast membranes. The results suggest that, in isolated chloroplasts, nitroxide spin labels may be reduced by photosystem I within the thylakoid bilayer resulting in loss of the ESR signals. The reduced forms may be reoxidized by an element of the photosynthetic electron transport chain which operates between the DCMU block and the photosystem I reaction center. In addition, a light-mediated destruction of the spin labels occurs in both chloroplasts and protoplasts. The reduced form of the nitroxide (i.e. the hydroxylamine) may be resistant to this destruction.