Improved detection rates and treatment planning of head and neck cancer using dual-layer spectral CT.

PURPOSE: The aim of this study was to evaluate the advantages of dual-layer spectral CT (DLSCT) in detection and staging of head and neck cancer (HNC) as well as the imaging of tumour margins and infiltration depth compared to conventional contrast enhanced CT (CECT). MATERIALS AND METHODS: Thirty-nine patients with a proven diagnosis of HNC were examined with a DLSCT scanner and retrospectively analysed. An age-matched healthy control group of the same size was used. Images were acquired in the venous phase. Virtual monoenergetic 40keV-equivalent (MonoE40) images were compared to CECT-images. Diagnostic confidence for tumour identification and margin detection was rated independently by four experienced observers. The steepness of the Hounsfield unit (HU)-increase at the tumour margin was analysed. External carotid artery branch image reconstructions were performed and their contrast compared to conventional arterial phase imaging. Means were compared using a Student's t-test. ANOVA was used for multiple comparisons. RESULTS: MonoE40 images were superior to CECT-images in tumour detection and margin delineation. MonoE40 showed significantly higher attenuation differences between tumour and healthy tissue compared to CECT-images (p < 0.001). The HU-increase at the boundary of the tumour was significantly steeper in MonoE40 images compared to CECT-images (p < 0.001). Iodine uptake in the tumour was significantly higher compared to healthy tissue (p < 0.001). MonoE40 compared to conventional images allowed visualisation of external carotid artery branches from the venous phase in a higher number of cases (87% vs. 67%). CONCLUSION: DLSCT enables improved detection of primary and recurrent head and neck cancer and quantification of tumour iodine uptake. Improved contrast of MonoE40 compared to conventional reconstructions enables higher diagnostic confidence concerning tumour margin detection and vessel identification. KEY POINTS: • Sensitivity concerning tumour detection are higher using dual-layer spectral-CT than conventional CT. • Lesion to background contrast in DLSCT is significantly higher than in CECT. • DLSCT provides sufficient contrast for evaluation of external carotid artery branches.

CXCR4 Is a Potential Target for Diagnostic PET/CT Imaging in Barrett's Dysplasia and Esophageal Adenocarcinoma.

Purpose: Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma.Experimental Design: Here we utilized an IL1ß transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis.Results: IL1ß overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1ß mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4+) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4+ columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in ex vivo fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer.Conclusion: In conclusion, the recruitment of CXCR4+ immune cells and expansion of CXCR4+ epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. Clin Cancer Res; 24(5); 1048-61. ©2017 AACR.

Response assessment with the CXCR4-directed positron emission tomography tracer [68Ga]Pentixafor in a patient with extranodal marginal zone lymphoma of the orbital cavities.

CXCR4 belongs to the family of chemokine receptors. Together with its sole known ligand CXCL12 (SDF-1alpha), it has a pivotal role during organogenesis and for homing of hematopoietic stem cells. CXCR4 is overexpressed in various malignancies, and this is often associated with poor prognosis. Therefore, molecular imaging of CXCR4 bears a great potential for diagnostics and selecting patients for CXCR4-directed therapies. The CXCR4-directed positron emission tomography (PET) tracer [68Ga]Pentixafor has been shown to visualize CXCR4 expression in various malignancies in vivo. Whereas this tracer has limitations compared to 18F-Fluorodeoxyglucose ([18F]FDG) in diagnostic PET imaging in peripheral tumour lesions, it might add valuable information in routine diagnostics and response assessment of tumours in close proximity to the central nervous system (CNS) and malignancies within this organ. As a proof-of-concept, we performed [68Ga]Pentixafor PET imaging in a patient with extranodal marginal zone lymphoma (MZL) of the orbital cavities at diagnosis and for post-therapy response assessment. Compared to routinely conducted [18F]FDG PET, the lymphoma lesions determined by magnetic resonance imaging (MRI) showed high tracer accumulation at diagnosis, which decreased upon treatment. We therefore propose that imaging of CXCR4 with [68Ga]Pentixafor is a potential diagnostic tool for tumours close to or within the CNS and suggest this being studied in clinical trials.

Active Brown Fat During 18F-FDG PET/CT Imaging Defines a Patient Group with Characteristic Traits and an Increased Probability of Brown Fat Redetection.

Brown adipose tissue (BAT) provides a means of nonshivering thermogenesis. In humans, active BAT can be visualized by 18F-FDG uptake as detected by PET combined with CT. The retrospective analysis of clinical scans is a valuable source to identify anthropometric parameters that influence BAT mass and activity and thus the potential efficacy of envisioned drugs targeting this tissue to treat metabolic disease. Methods: We analyzed 2,854 18F-FDG PET/CT scans from 1,644 patients and identified 98 scans from 81 patients with active BAT. We quantified the volume of active BAT depots (mean values in mL ± SD: total BAT, 162 ± 183 [n = 98]; cervical, 40 ± 37 [n = 53]; supraclavicular, 66 ± 68 [n = 71]; paravertebral, 51 ± 53 [n = 69]; mediastinal, 43 ± 40 [n = 51]; subphrenic, 21 ± 21 [n = 29]). Because only active BAT is detectable by 18F-FDG uptake, these numbers underestimate the total amount of BAT. Considering only 32 scans of the highest activity as categorized by a visual scoring strategy, we determined a mean total BAT volume of 308 ± 208 mL. In 30 BAT-positive patients with 3 or more repeated scans, we calculated a much higher mean probability to redetect active BAT (52% ± 25%) as compared with the overall prevalence of 4.9%. We calculated a BAT activity index (BFI) based on volume and intensity of individual BAT depots. Results: We detected higher total BFI in younger patients (P = 0.009), whereas sex, body mass index, height, mass, outdoor temperature, and blood parameters did not affect total or depot-specific BAT activity. Surprisingly, renal creatinine clearance as estimated from mass, age, and plasma creatinine was a significant predictor of BFI on the total (P = 0.005) as well as on the level of several individual depots. In summary, we detected a high amount of more than 300 mL of BAT tissue. Conclusion: BAT-positive patients represent a group with a higher than usual probability to activate BAT during a scan. Estimated renal creatinine clearance correlated with the extent of activated BAT in a given scan. These data imply an efficacy of drugs targeting BAT to treat metabolic disease that is at the same time higher and subject to a larger individual variation than previously assumed.

Targeted positron emission tomography imaging of CXCR4 expression in patients with acute myeloid leukemia.

Acute myeloid leukemia originates from leukemia-initiating cells that reside in the protective bone marrow niche. CXCR4/CXCL12 interaction is crucially involved in recruitment and retention of leukemia-initiating cells within this niche. Various drugs targeting this pathway have entered clinical trials. To evaluate CXCR4 imaging in acute myeloid leukemia, we first tested CXCR4 expression in patient-derived primary blasts. Flow cytometry revealed that high blast counts in patients with acute myeloid leukemia correlate with high CXCR4 expression. The wide range of CXCR4 surface expression in patients was reflected in cell lines of acute myeloid leukemia. Next, we evaluated the CXCR4-specific peptide Pentixafor by positron emission tomography imaging in mice harboring CXCR4 positive and CXCR4 negative leukemia xenografts, and in 10 patients with active disease. [(68)Ga]Pentixafor-positron emission tomography showed specific measurable disease in murine CXCR4 positive xenografts, but not when CXCR4 was knocked out with CRISPR/Cas9 gene editing. Five of 10 patients showed tracer uptake correlating well with leukemia infiltration assessed by magnetic resonance imaging. The mean maximal standard uptake value was significantly higher in visually CXCR4 positive patients compared to CXCR4 negative patients. In summary, in vivo molecular CXCR4 imaging by means of positron emission tomography is feasible in acute myeloid leukemia. These data provide a framework for future diagnostic and theranostic approaches targeting the CXCR4/CXCL12-defined leukemia-initiating cell niche.

First Experience with Chemokine Receptor CXCR4-Targeted PET Imaging of Patients with Solid Cancers.

UNLABELLED: CXCR4 is a chemokine receptor that is overexpressed in various human cancers and is involved in tumor metastasis. The aim of this proof-of-concept study was to evaluate a novel CXCR4-targeted PET probe in patients with solid cancers with reported in vitro evidence of CXCR4 overexpression and to estimate its potential diagnostic value. METHODS: Twenty-one patients with histologically proven pancreatic cancer, laryngeal cancer, non-small cell lung cancer, prostate cancer, melanoma, breast cancer, hepatocellular carcinoma, glioblastoma, sarcoma, or cancer of unknown primary underwent PET imaging using the novel CXCR4 nuclear probe (68)Ga-pentixafor. The SUVmax of the liver, spleen, and bone marrow was measured to determine physiologic tracer distribution. For evaluation of tracer accumulation in solid cancers, SUVmax and tumor-to-background (T/B) ratios were determined in a total of 43 malignant lesions, including 8 primary tumors, 3 locally recurrent tumors, and 32 metastases. When available, the SUVmax of malignant lesions was compared with the corresponding SUVmax measured in routine (18)F-FDG PET. RESULTS: Moderate tracer accumulation was detectable in the liver, bone marrow, and spleen, with a mean SUVmax of 3.1, 3.7, and 5.6, respectively. By visual interpretation criteria, 9 of 11 primary and locally recurrent tumors were detectable, exhibiting a mean SUVmax of 4.7 (range, 2.1-10.9) and a mean T/B ratio of 2.9. Twenty of 32 evaluated metastases were visually detectable (mean SUVmax, 4.5 [range, 3.2-13.8]; mean T/B ratio, 2.8). The highest signal was detected in a patient with non-small cell lung cancer (SUVmax, 10.9; T/B ratio, 8.4) and a patient with cancer of unknown primary (SUVmax, 13.8; T/B ratio, 8.1). Compared with (18)F-FDG PET, which was additionally performed in 10 patients, (68)Ga-pentixafor PET had a lower SUVmax in all measured malignant lesions. CONCLUSION: On the basis of these first observations in a small and heterogeneous patient cohort, the in vitro CXCR4 expression profile of solid cancers and metastases described in the previous literature does not seem to sufficiently depict the in vivo distribution revealed by CXCR4-targeted PET. Moreover, the detectability of solid cancers seems to be generally lower for (68)Ga-pentixafor than for (18)F-FDG PET.

Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging.

Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [(68)Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [(68)Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [(68)Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [(68)Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/CXCL12 ligand interaction in the pathogenesis and treatment of cancer, cardiovascular diseases and autoimmune and inflammatory disorders.

In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma.

CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination and poor prognosis. We evaluated the novel CXCR4 probe [(68)Ga]Pentixafor for in vivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [(68)Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [(68)Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [(18)F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34(+) flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [(68)Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases.

Effect of antiresorptive drugs on bony turnover in the jaw: denosumab compared with bisphosphonates.

Osteonecrosis of the jaw as a result of treatment with receptor activators of nuclear factor kappa-B ligand (RANKL) inhibitors (denosumab) is a new type of bony necrosis, the exact pathogenesis of which is unknown. Our aim was to find out whether the turnover of bone in the jaw is increased after denosumab has been given compared with other skeletal sites, and if that turnover might have a role in denosumab-related osteonecrosis of the jaw (DRONJ). Bone scintigraphic images of 45 female patients with breast cancer and bone metastases were analysed retrospectively, and divided into 3 groups: those given denosumab, those given a bisphosphonate, and a control group (n=15 in each). All patients had bone scintigraphy before treatment (T0) and during the course of treatment after 12 (T1) and 24 (T2) months. The data were analysed quantitatively using 6 preset bony regions of interest. There was similar turnover of bone in the mandible compared with other skeletal sites (such as the femur), while the maxilla showed significantly higher turnover. None of the bony regions investigated showed any significant changes after the bisphosphonate had been given. There was a tendency to increase bone turnover in those patients taking denosumab. The bone turnover of the jawbone is not overtly changed either by a bisphosphonate or denosumab, so it seems unlikely that oversuppression of bony turnover in the jawbones plays an important part either in the pathogenesis of DRONJ or in the bisphosphonate-related osteonecrosis of the jaw (BRONJ).

Is bone turnover of jawbone and its possible over suppression by bisphosphonates of etiologic importance in pathogenesis of bisphosphonate-related osteonecrosis?

PURPOSE: The pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is not completely understood. The most popular hypothesis has suggested that the bone turnover (BT) in the jawbone is greater than that in other sites and that this turnover will be overly suppressed by bisphosphonates. Using bone scintigraphy, a simple tool for the quantitative evaluation of bone metabolism and blood flow, the goals of the present study were to determine whether the rate of bone remodeling is greater in the jaw and whether the bone BT in the jaw is differentially altered after bisphosphonate intake compared with that in other skeletal sites. MATERIALS AND METHODS: The bone scintigraphies of 90 female patients with breast cancer were retrospectively analyzed (n = 45 with bisphosphonate intake; n = 45 without bisphosphonate intake [control group]). All patients in the study group had undergone bone scintigraphy before therapy and during the treatment (course after 12 and 24 months). The data were quantitatively analyzed using 6 predetermined regions of interest. RESULTS: The bone BT of the mandible was similar to that of the femur and significantly reduced compared with that of the maxilla (P < .01). None of the investigated bone regions (including the mandible and maxilla) were significantly altered after bisphosphonate administration (P > .05). CONCLUSIONS: The finding that the mandible had significantly lower bone BT than that of the maxilla and that two thirds of BRONJ cases occur in the mandible were inconsistent with the investigated hypothesis. Furthermore, the bone BT in the jawbone was not overly suppressed by bisphosphonates. Thus, it is unlikely that over suppression of bone BT is the exclusive causation playing a role in the pathomechanism of BRONJ.

Does regular zoledronic acid change the bone turnover of the jaw in men with metastatic prostate cancer: a possible clue to the pathogenesis of bisphosphonate related osteonecrosis of the jaw?

PURPOSE: To find out whether the most popular pathogenesis hypothesis of the bisphosphonate (BP) related osteonecrosis of the jaw (BRONJ) is comprehensible: (1) is there a higher bone remodeling in the jaw compared with other skeletal sites? (2) Is the bone turnover (BT) of the jaw overly altered after BP intake? (3) Are there gender- or entity-specific differences in BT before and after BP intake? METHODS: Bone scintigraphies of 42 patients with prostate cancer were retrospectively analyzed (n = 21 with BP intake; n = 21 no BP). All patients received bone scintigraphy prior to the therapy and in the course of the treatment (after 12 and 24 months). Data were quantitatively analyzed using six predetermined regions of interest and compared with a breast cancer cohort. RESULTS: The mandible revealed a similar BT as the femur and a significant lower BT compared with the maxilla. All investigated bone regions showed no significant changes under BP administration. Inter-gender differences revealed significantly lower BT values for the prostate cancer compared with the female breast cancer cohort, changes over the course of time could not be found. CONCLUSIONS: The finding that the mandible revealed a significant lower BT than the maxilla and the fact that 2/3 of the BRONJ cases occur in the mandible are inconsistent with the investigated hypothesis. Furthermore, the BT in the jawbone is not overly suppressed by BP. Thus, it seems implausible that a high BT and its over-suppression play the key role in the pathomechanism of BRONJ.

Long-term follow-up after endoscopic stent therapy for benign biliary strictures.

BACKGROUND AND AIMS: Endoscopic therapy holds an important role in the management of benign biliary strictures. This study compares the long-term outcome of stenting therapy depending on the underlying cause of the stricture. METHODS: In a retrospective cohort study, 228 patients with benign biliary strictures were identified using an endoscopic database, hospital charts, and cholangiograms between January 1992 and December 2008. Long-term follow-up was evaluated with cholangiograms, transabdominal ultrasound, laboratory parameters, and physical examination. The median follow-up period was 44.7 months. RESULTS: Endoscopic management showed best long-term results in patients with stone-associated biliary stricture. In this subgroup, endoscopic therapy could be successfully completed in 92% (71/77) of the patients. Patients with postoperative biliary stricture had good outcome in 83% (53/64) of cases. Idiopathic strictures presented a successful outcome in 58% (15/26). Biliary strictures caused by chronic pancreatitis had a significantly poorer outcome compared with strictures of other origin. Therapeutic success of endoscopic therapy could only be observed in 31% of patients (19/61). CONCLUSIONS: Long-term outcome of endoscopic therapy for benign strictures was significantly dependent on the underlying cause of the stricture. In particular, patients with biliary strictures due to chronic pancreatitis benefit least from endoscopic therapy, whereas patients with stone-associated strictures had the highest therapeutic success rate.

Long-term outcome of endoscopic and/or percutaneous transhepatic therapy in patients with biliary stricture after orthotopic liver transplantation.

BACKGROUND: Biliary strictures are a serious complication after liver transplantation. Endoscopic and percutaneous transhepatic procedures have gained an increasing potential for the management of this problem. OBJECTIVE: Long-term follow-up of endoscopic and/or percutaneous transhepatic therapy of biliary strictures after liver transplantation was evaluated. PATIENTS AND METHODS: Between January 1996 and December 2007, 47 patients with biliary stricture after liver transplantation were identified by analysing the endoscopic database, hospital charts and cholangiograms. Long-term follow-up was evaluated using cholangiograms, transabdominal ultrasound, laboratory parameters and physical examination. RESULTS: The type of biliary stricture after liver transplantation was subdivided into anastomotic stricture (n = 29), non-anastomotic stricture (n = 14) and bilioenterostomy stricture (n = 4). Of the patients, 38/47 were treated by endoscopic procedures (ERCP), and 9/47 patients were treated by percutaneous transhepatic procedures (PTBD). In 2 of 47 patients combined approaches (rendezvous technique) were performed. Overall, 23/29 patients in the anastomotic group, 12/14 patients in the non-anastomotic group, and 3/4 patients in the bilioenterostomy group had successfully completed endoscopic and/or percutaneous transhepatic therapy. Biliary drainage could be respectively terminated after median 9 (1-83), 11 (1-89) and 10 (4-14) months. CONCLUSIONS: Endoscopic as well as percutaneous transhepatic approaches in combination or as monotherapy are effective in the management of anastomotic and non-anastomotic strictures after liver transplantation.