Annals of Nuclear Medicine (v.32, #8)

CXCR4-directed theranostics in oncology and inflammation by Malte Kircher; Peter Herhaus; Margret Schottelius; Andreas K. Buck; Rudolf A. Werner; Hans-Jürgen Wester; Ulrich Keller; Constantin Lapa (503-511).
Given its prominent role in inflammation and cancer biology, the C-X-C motif chemokine receptor 4 (CXCR4) has gained a lot of attention in the recent years. This review gives a short overview of the physiology and pathology of chemokines and chemokine receptors and then focuses on the current experience of targeting CXCR4, using radiolabeled receptor ligands suitable for positron emission tomography (PET) imaging, in both hematologic and solid malignancy as well as in inflammatory conditions. Additionally, CXCR4-directed endoradiotherapy (ERT) as a new treatment option is discussed.
Keywords: Chemokine; Cancer; Theranostics; Pentixafor; Pentixather

Molecular imaging reporting and data systems (MI-RADS): a generalizable framework for targeted radiotracers with theranostic implications by Rudolf A. Werner; Ralph A. Bundschuh; Lena Bundschuh; Mehrbod S. Javadi; Takahiro Higuchi; Alexander Weich; Sara Sheikhbahaei; Kenneth J. Pienta; Andreas K. Buck; Martin G. Pomper; Michael A. Gorin; Constantin Lapa; Steven P. Rowe (512-522).
Both prostate-specific membrane antigen (PSMA)- and somatostatin receptor (SSTR)-targeted positron emission tomography (PET)-based imaging agents for prostate carcinoma and neuroendocrine tumors, respectively, are seeing rapidly expanding use. In addition to diagnostic applications, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy. While interpreting PSMA- or SSTR-targeted PET/computed tomography (CT) scans, the reader has to be aware of certain pitfalls. Adding to the complexity of the interpretation of those imaging agents, both normal biodistribution, and also false-positive and -negative findings differ between PSMA- and SSTR-targeted PET radiotracers. Herein summarized under the umbrella term molecular imaging reporting and data systems (MI-RADS), two novel RADS classifications for PSMA- and SSTR-targeted PET imaging are described (PSMA- and SSTR-RADS). Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e., if the reader is familiar with one system, the other system can readily be applied, as well. In the present review, we will discuss the most common pitfalls on PSMA- and SSTR-targeted PET/CT, briefly introduce PSMA- and SSTR-RADS, and define a potential future role of the umbrella framework MI-RADS compared to other classification systems.
Keywords: Prostate cancer; Neuroendocrine tumor; Prostate-specific membrane antigen (PSMA); Somatostatin receptor (SSTR); Positron emission tomography; Theranostics; Standardization; RADS; Reporting and data systems

Reproducibility of standardized uptake values of same-day randomized 68Ga-PSMA-11 PET/CT and PET/MR scans in recurrent prostate cancer patients by Anna Ringheim; Guilherme de Carvalho Campos Neto; Karine Minaif Martins; Taise Vitor; Marcelo Livorsi da Cunha; Ronaldo Hueb Baroni (523-531).
Positron emission tomography in association with magnetic resonance imaging (PET/MR) and 68Ga-PSMA-11 has shown superior detection in recurrent prostate cancer patients as compared to PET/computed tomography (PET/CT). There are, however, several technological differences between PET/CT and PET/MR systems which affect the PET image quality. The objective of this study was to assess the reproducibility of PET/CT and PET/MR SUV’s in recurrent prostate cancer patients. We randomized the patients regarding the order of the PET/CT and PET/MR scans to reduce the influence of tracer uptake as a function of time.Thirty patients, all with biochemical recurrence after radical prostatectomy, underwent whole-body PET/CT and PET/MR scans after intravenous injection of a single dose of 68Ga-PSMA-11. Fifteen patients underwent PET/CT first and 15 patients underwent PET/MR first. Volumes of interest on tumor lesions were outlined and maximum standardized uptake value (SUVmax) corrected for lean body mass was calculated. Correlation and agreement between scans were assessed by generalized linear mixed-effects models and Bland–Altman analysis. The association between SUV, patient characteristics and imaging parameters was assessed.Eighteen of the 30 evaluated patients had at least one positive lesion, giving an overall detection rate of 60%. In total, there were 34 visible lesions: 5 local recurrences, 22 lymph node metastases and 7 bone metastases. One group acquired PET/CT and PET/MR at median time points of 63.0 and 159.0 min, while the other group acquired PET/MR and PET/CT at median time points of 92.0 and 149.0 min. SUVmax between scans was linearly correlated, described by the equation Y(PET/CT SUVmax) = 0.75 + 1.00 × (PET/MR SUVmax), on average 20% higher on PET/CT than on PET/MR. SUV associated significantly only with type of lesion, scan time post-injection and acquisition time per bed position.SUVmax from PET/CT and PET/MR are linearly correlated, on average 20% higher on PET/CT than on PET/MR and should, therefore, not be used interchangeably in patient follow-up.
Keywords: 68Ga-PSMA-11; PET/CT; PET/MR; Recurrent prostate cancer; SUVmax; Mixed-model

Prognostic role of pretreatment 18F-FDG PET/CT in primary brain lymphoma by Domenico Albano; Mattia Bertoli; Marco Battistotti; Carlo Rodella; Massimo Statuto; Raffaele Giubbini; Francesco Bertagna (532-541).
Primary brain lymphoma is an aggressive extranodal non-Hodgkin lymphoma with poor prognosis. Many possible prognostic factors are investigated with controversial results, but possible prognostic role of 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) features remains unclear. Our aim was to study the metabolic behavior of brain lymphoma at 18F-FDG PET/CT and the prognostic impact of qualitative and semiquantitative PET/CT parameters.Between 2006 and 2018, 52 patients (26 females and 26 males; mean age: 61 years) with histologically confirmed diagnosis of brain lymphoma who underwent 18F-FDG PET/CT for staging before any treatment were included. PET images were qualitatively and semiquantitatively analyzed by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The Kaplan–Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS) times. Cox regression models were performed to determinate the relation between qualitative and semiquantitative PET/CT features and OS and PFS.Thirty-nine patients had positive 18F-FDG PET/CT showing 18F-FDG uptake (mean SUVbw of 18.2; SUVlbm of 13.9; SUVbsa of 5; MTV of 14.8; TLG of 153) at the corresponding cerebral lesion; the remaining 13 were not 18F-FDG avid. Relapse or progression of disease occurred in 22 patients with an average time of 9.7 months; death occurred in 18 patients with an average of 7.9 months. There was no difference in PFS and OS between baseline PET/CT positive and negative groups or considering SUVbw, SUVlbm, and SUVbsa. PFS and OS was significantly shorter in patients with MTV ≥ 9.8 cm3 (p = 0.037 and p = 0.022, respectively) and TLG ≥ 94 (p = 0.045 and p = 0.0430, respectively).18F-FDG avidity was noted in 75% of cases. Only metabolic tumor parameters (MTV and TLG) were independently correlated with PFS and OS.
Keywords: Brain lymphoma; 18F-FDG PET/CT; Prognosis; MTV; TLG

To determine the association of 68 Ga-PSMA-I&T PET/CT SUV parameters with survival outcome in advanced prostate cancer patients.A total of 148 consecutive patients mean age: 69.3 ± 7.8 years with advanced prostate cancer who underwent 68 Ga-PSMA-I&T PET/CT were included in this retrospective study. Data on previous treatments, serum PSA levels (ng/mL), 68 Ga-PSMA-I&T PET/CT findings metastases as well as survival data were recorded.Multivariate regression analysis revealed that Level 1 LN SUV/Liver SUV ratios > 2.17 (OR 4.262; 95% CI 1.104–16.453, p = 0.035), bone SUV > 10.7(OR 23.650; 95% CI 4.056–137.888, p < 0.001), bone SUV/spleen SUV ratio > 1.842 (OR 25.324; 95% CI 4.204–152.552, p < 0.001), highest SUVmax/liver SUV ratio > 2.32 (OR 19.309; 95% CI 1.730–209.552, p = 0.016) and highest SUVmax/spleen SUV ratio > 1.842 (OR 22.354; 95% CI 2.637–189.493, p = 0.004) were significant in the determination of increased mortality risk in advanced prostate cancer patients.Our findings, for the first time in literature, provided evidence on potential utility of tracer uptake (SUV) cut-off values on 68 Ga-PSMA PET/CT in identification of the survival outcome of patients with metastatic disease and thereby in assisting in the selection of individualized therapeutic strategies tailored to the expected prognosis.
Keywords: Prostate cancer; 68 Ga-PSMA-I&T PET/CT; Metastasis; Lymph node; Bone; SUV

Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: report of the NRG Oncology RTOG 0517 trial by Michael J. Seider; Stephanie L. Pugh; Corey Langer; Gwen Wyatt; William Demas; Afshin Rashtian; Cathy L. Clausen; Jerome David Derdel; Sean F. Cleary; Christopher A. Peters; Ashok Ramalingam; James E. Clarkson; Michael Tomblyn; Rachel A. Rabinovitch; Lisa A. Kachnic; Lawrence B. Berk (553-560).
Skeletal-related events (SREs), common sequelae of metastatic cancer, are reduced by bisphosphonates. In this study, it was postulated that radiopharmaceuticals, added to bisphosphonates, could further decrease the incidence of SREs.NRG Oncology RTOG 0517 randomized patients with breast, lung, and prostate cancer and blastic bone metastases to either zoledronic acid (ZA) alone or ZA plus radiopharmaceuticals (Sr-89 or Sm-153). The primary endpoint was time to development of SREs. Secondary objectives included quality of life (QOL), pain control, overall survival (OS), and toxicity.261 patients (median age 68; 62% male; 55% prostate, 35% breast, 10% lung) were accrued between July 2006 and February 2011. The study closed early due to a lower than expected rate of SREs. 52 (42%) patients in the ZA arm and 49 (40%) in the radiopharmaceutical arm experienced an SRE. Median time free of SREs was 29.9 and 27.4 months, respectively (p = 0.84). Median OS in the ZA arm and radiopharmaceutical arms was 32.1 and 26.9 months, respectively (p = 0.37). Cox proportional hazards regression model showed that primary disease site (lung) and number of bone metastases (> 2) had a negative impact on OS (p < 0.0001, p = 0.01, respectively). The addition of radiopharmaceuticals to ZA led to a significant reduction in pain at 1 month based on BPI worst score (p = 0.02). No other group differences were noted for QOL or toxicity.The addition of radiopharmaceuticals to bisphosphonates did not alter time to SREs or OS for patients with breast, lung, prostate cancers and blastic bone metastases, although it was associated with significant pain reduction at 1 month.This protocol (RTOG 0517) is registered with ClinicalTrials.gov (NCT00365105), and may be viewed online at http://www.clinicaltrials.gov/ct2/show/NCT00365105?term=RTOG+0517&rank=1.

Detectability of residual invasive bladder cancer in delayed 18F-FDG PET imaging with oral hydration using 500 mL of water and voiding-refilling by Akira Higashiyama; Tsuyoshi Komori; Hiroshi Juri; Yuki Inada; Haruhito Azuma; Yoshifumi Narumi (561-567).
2-Fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET) imaging is not considered useful for assessing bladder cancer due to the physiological uptake of 18F-FDG in the bladder. Despite reports of the detection of bladder cancer by washing out 18F-FDG from the bladder, such methods are invasive and impractical in the routine practice. The purpose of this study was to evaluate prospectively the utility of oral hydration with 500 mL of water and voiding-refilling, a minimally invasive method that we introduced to enable detection of residual invasive bladder cancer on delayed 18F-FDG PET imaging.From January 2015 to December 2017, 267 consecutive patients with bladder cancer underwent 18F-FDG PET/computed tomography scans. Among these patients, 25 (19 men and 6 women; mean age, 72.0 ± 11.3 years) were newly diagnosed as having muscle-invasive bladder cancer by transurethral resection of bladder tumor and T3b or T4 by magnetic resonance imaging (MRI). All patients were orally hydrated with only 500 mL of water and were then instructed to void frequently for 60 min before early 18F-FDG PET imaging. After the scans, they were instructed to hold their urine for 60 min. Then, delayed imaging was performed. Two radiologists evaluated the early and delayed 18F-FDG PET images to determine whether residual invasive bladder cancer could be detected. The maximum standardized uptake values (SUVmax) of the bladder urine and residual tumor site were also measured on early and delayed images. The maximum diameter of the primary bladder tumor was measured on MRI.The sensitivity for detecting residual invasive bladder cancer on early and delayed imaging were 24.0 and 92.0%, respectively (P < 0.001). The SUVmax of the bladder urine on the early and delayed imaging were 34.7 ± 29.7 and 16.0 ± 10.7 (mean ± SD), respectively. The SUVmax of the residual tumor site on the early and delayed imaging were range 15.65–30.83 and 10.06–45.70, respectively.Delayed 18F-FDG PET imaging with oral hydration using only 500 mL of water and voiding-refilling is useful for detecting residual invasive bladder cancer.
Keywords: Invasive bladder cancer; 18F-FDG PET; Delayed image; Oral hydration

Large cell neuroendocrine carcinoma of the lung with atypical evolution and a remarkable response to lutetium Lu 177 dotatate by Roberto A. Escala Cornejo; Paloma García-Talavera; Miguel Navarro Martin; Berta Pérez López; María García Muñoz; Ma. Pilar Tamayo Alonso; Juan J. Cruz Hernández (568-572).
Large cell neuroendocrine carcinoma of the lung (LCNEC) is a high-grade, poorly differentiated tumor that typically does not express somatostatin receptors. Thus, it does not benefit from treatment with somatostatin analogs and peptide receptor radionuclide therapy (PRRT). The current study objective was to demonstrate that treatment with PRRT may be a valid option in neuroendocrine carcinomas with high expression of somatostatin receptors. This is a case report of a 58-year-old man who was diagnosed with LCNEC and received chemotherapy treatment with little benefit. Extensive hepatic and bone metastasis was detected on 111In-pentetreotide scintigraphy following high uptake of the radionuclide by the tumors. The patient benefitted from neuroendocrine treatment initially and from lutetium Lu 177 dotatate subsequently. A significant clinical and radiological response was observed, along with an improvement in quality of life. The use of PRRT is a valid alternative to chemotherapy in patients with LCNEC involving the expression of somatostin receptors.

Diagnosing polymyalgia rheumatica on 18F-FDG PET/CT: typical uptake patterns by Shunsuke Yuge; Koya Nakatani; Kumiko Yoshino; Takashi Koyama (573-577).
The diagnosis of polymyalgia rheumatica (PMR) is often challenging, since similar clinical features and laboratory findings can be observed in several inflammatory conditions. PMR involves affected sites in a specific manner, and 18F-FDG PET/CT has the advantage for assessing the disease activity of each site. The purpose of this study was to identify the patterns of 18F-FDG uptake that suggest the diagnosis of PMR.We studied 60 patients who had undergone 18F-FDG PET/CT scans for workup of suspected PMR, arthritis, enthesitis, or myopathy. Final diagnoses were made by board-certified rheumatologists. The incidence of significant 18F-FDG uptake, higher than mediastinal blood pool, of the following sites were compared among PMR patients and patients with other diseases: wrists, elbows, shoulders, sternoclavicular joints, acromioclavicular joints, spinous processes, ischial tuberosities, and greater trochanters. For the spinous processes, the incidence of “Y”-shaped uptake along the interspinous bursae was also evaluated.A definitive diagnosis of PMR was given to 16 of 60 patients. The incidence of significant 18F-FDG uptake in the definitive PMR group was 6% for wrists and for elbows, 88% for glenohumeral and sternoclavicular joints, 25% for acromioclavicular joints, 81% for spinous processes, 69% for ischial tuberosities, and 81% for greater trochanters. Patients with PMR showed a significantly higher incidence of “Y”-shaped uptake along the interspinous bursae than the other patients (38 vs. 9%) (P = 0.016). 18F-FDG uptake distribution patterns and morphology can contribute to the diagnosis of PMR. Significant 18F-FDG uptake in the sternoclavicular joints is one of the characteristic findings in patients with PMR as well as the uptake in the shoulders, ischial tuberosities, and greater trochanters. “Y”-shaped spinous process uptake may be one of the specific findings for PMR.
Keywords: Polymyalgia rheumatica; 18F-FDG PET/CT; Spinous processes; Interspinous bursa; Sternoclavicular joints