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  • Prostate-Specific Membrane Antigen–Guided Surgery
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Tobias Maurer; Markus Graefen; Henk van der Poel; Freddie Hamdy; Alberto Briganti; Matthias Eiber; Hans-Jürgen Wester; Fijs W.B. van Leeuwen

    Since its introduction to the diagnostic pathway for prostate cancer management, prostate-specific membrane antigen (PSMA)–ligand PET has demonstrated great potential. PSMA-ligand imaging is increasingly influencing therapeutic decision making, although its impact on patient outcomes still needs to be defined. One relatively new application, enabled through chemical and engineering efforts, is PSMA-guided surgery. This review highlights the potential of PSMA-guided surgery and discusses its implications in lymph node dissection in primary and recurrent prostate cancer.

    更新日期:2020-01-02
  • Trending: Radioactive and Fluorescent Bimodal/Hybrid Tracers as Multiplexing Solutions for Surgical Guidance
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Fijs W.B. van Leeuwen; Margret Schottelius; Oscar R. Brouwer; Sergi Vidal-Sicart; Samuel Achilefu; Joachim Klode; Hans-Jurgen Wester; Tessa Buckle

    By contributing to noninvasive molecular imaging and radioguided surgery, nuclear medicine has been instrumental in the realization of precision medicine. During the last decade, it has also become apparent that nuclear medicine (e.g., in the form of bimodal/hybrid tracers) can help to empower fluorescence-guided surgery. More specifically, when using hybrid tracers, lesions can be noninvasively identified and localized with a high sensitivity and precision (guided by the radioisotope) and ultimately resected under real-time optical guidance (fluorescent dye). This topical review discusses early clinical successes, preclinical directions, and key aspects that could have an impact on the future of this field.

    更新日期:2020-01-02
  • Multiparametric 18F-FDG PET/MRI of the Breast: Are There Differences in Imaging Biomarkers of Contralateral Healthy Tissue Between Patients With and Without Breast Cancer?
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Doris Leithner; Thomas H. Helbich; Blanca Bernard-Davila; Maria Adele Marino; Daly Avendano; Danny F. Martinez; Maxine S. Jochelson; Panagiotis Kapetas; Pascal A.T. Baltzer; Alexander Haug; Marcus Hacker; Yasemin Tanyildizi; Elizabeth A. Morris; Katja Pinker

    The rationale was to assess whether there are differences in multiparametric 18F-FDG PET/MRI biomarkers of contralateral healthy breast tissue in patients with benign and malignant breast tumors. Methods: In this institutional review board–approved prospective single-institution study, 141 women with imaging abnormalities on mammography or sonography (BI-RADS 4/5) underwent combined 18F-FDG PET/MRI of the breast at 3T with dynamic contrast-enhanced MRI, diffusion-weighted imaging, and the radiotracer 18F-FDG. In all patients, the following imaging biomarkers were recorded for the contralateral (tumor-free) breast: breast parenchymal uptake (BPU) (from 18F-FDG PET), mean apparent diffusion coefficient (from diffusion-weighted imaging), background parenchymal enhancement (BPE), and amount of fibroglandular tissue (FGT) (from MRI). Appropriate statistical tests were used to assess differences in 18F-FDG PET/MRI biomarkers between patients with benign and malignant lesions. Results: There were 100 malignant and 41 benign lesions. BPE was minimal in 61 patients, mild in 56, moderate in 19, and marked in 5. BPE differed significantly (P < 0.001) between patients with benign and malignant lesions, with patients with cancer demonstrating decreased BPE in the contralateral tumor-free breast. FGT approached but did not reach significance (P = 0.055). BPU was 1.5 for patients with minimal BPE, 1.9 for mild BPE, 2.2 for moderate BPE, and 1.9 for marked BPE. BPU differed significantly between patients with benign lesions (mean, 1.9) and patients with malignant lesions (mean, 1.8) (P < 0.001). Mean apparent diffusion coefficient did not differ between groups (P = 0.19). Conclusion: Differences in multiparametric 18F-FDG PET/MRI biomarkers, obtained from contralateral tumor-free breast tissue, exist between patients with benign and patients with malignant breast tumors. Contralateral BPE, BPU, and FGT are decreased in breast cancer patients and may potentially serve as imaging biomarkers for the presence of malignancy.

    更新日期:2020-01-02
  • Pulmonary Lymphangitic Carcinomatosis: Diagnostic Performance of High-Resolution CT and 18F-FDG PET/CT in Correlation with Clinical Pathologic Outcome
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Mario Jreige; Vincent Dunet; Igor Letovanec; John O. Prior; Reto A. Meuli; Catherine Beigelman-Aubry; Niklaus Schaefer

    The rationale of this study was to investigate the performance of high-resolution CT (HRCT) versus 18F-FDG PET/CT for the diagnosis of pulmonary lymphangitic carcinomatosis (PLC). Methods: In this retrospective institution-approved study, 94 patients addressed for initial staging of lung cancer with suspicion of PLC were included. Using double-blind analysis, we assessed the presence of signs favoring PLC on HRCT (smooth or nodular septal lines, subpleural nodularity, peribronchovascular thickening, satellite nodules, lymph node enlargement, and pleural effusion). 18F-FDG PET/CT images were reviewed to qualitatively evaluate peritumoral uptake and to quantify tracer uptake in the tumoral and peritumoral areas. Histology performed on surgical specimens served as the gold standard for all patients. Results: Among 94 included patients, 73% (69/94) had histologically confirmed PLC. Peribronchovascular thickening, lymph node involvement, and increased peritumoral uptake were more often present in patients with PLC (P < 0.009). Metabolic variables, including tumor SUVmax, SUVmean, metabolic tumor volume, and total lesion glycolysis, as well as peritumoral SUVmax, SUVmean, and their respective ratios to background, were significantly higher in the PLC group than in the non-PLC group (P ≤ 0.0039). Sensitivity, specificity, and area under the receiver-operating-characteristic curve for peribronchovascular thickening (69%, 83%, and 0.76, respectively; 95% confidence interval [95%CI], 0.67–0.85) and increased peritumoral uptake (94%, 84%, and 0.89, respectively; 95%CI, 0.81–0.97) were similar (P = 0.054). For detecting PLC, sensitivity, specificity, and area under the receiver-operating-characteristic curve were significantly higher, at 97%, 92%, and 0.98, respectively (95%CI, 0.96–1.00), for peritumoral SUVmax and 94%, 88%, and 0.96, respectively (95%CI, 0.92–1.00), for peritumoral SUVmean (all P ≤ 0.025). Conclusion: Qualitative evaluation of 18F-FDG PET/CT and HRCT perform similarly for the diagnosis of PLC, with both being outperformed by 18F-FDG PET/CT quantitative parameters.

    更新日期:2020-01-02
  • Predictive Role of Temporal Changes in Intratumoral Metabolic Heterogeneity During Palliative Chemotherapy in Patients with Advanced Pancreatic Cancer: A Prospective Cohort Study
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Shin Hye Yoo; Seo Young Kang; Gi Jeong Cheon; Do-Youn Oh; Yung-Jue Bang

    Metabolic intratumoral heterogeneity (ITH) is known to be related to cancer treatment outcome. However, information on the temporal changes in metabolic ITH during chemotherapy and the correlations between metabolic changes and treatment outcomes in patients with pancreatic cancer is sparse. We aimed to analyze the temporal changes in metabolic ITH and the predictive role of its changes in advanced pancreatic cancer patients who underwent palliative chemotherapy. Methods: We prospectively enrolled patients with unresectable locally advanced or metastatic pancreatic cancer before first-line palliative chemotherapy. 18F-FDG PET was performed at baseline and at the first response follow-up. SUVs, volumetric parameters, and textural features of the primary pancreatic tumor were analyzed. Relationships between the parameters at baseline and first follow-up were assessed, as well as changes in the parameters with treatment response, progression-free survival (PFS), and overall survival (OS). Results: Among 63 enrolled patients, the best objective response rate was 25.8% (95% confidence interval [CI], 14.6%–37.0%). The median PFS and OS were 7.1 mo (95% CI, 5.1–9.7 mo) and 10.1 mo (95% CI, 8.6–12.7 mo), respectively. Most parameters changed significantly during the first-line chemotherapy, in a way of reducing ITH. Metabolic ITH was more profoundly reduced in responders than in nonresponders. Multiple Cox regression analysis identified high baseline compacity (P = 0.023) and smaller decreases in SUVpeak (P = 0.007) and entropy gray-level cooccurrence matrix (P = 0.033) to be independently associated with poor PFS. Patients with a high carbohydrate antigen 19-9 (P = 0.042), high pretreatment SUVpeak (P = 0.008), and high coefficient of variance at first follow-up (P = 0.04) showed worse OS. Conclusion: Reduction in metabolic ITH during palliative chemotherapy in advanced pancreatic cancer patients is associated with treatment response and might be predictive of PFS and OS.

    更新日期:2020-01-02
  • 18F-FDG PET Dissemination Features in Diffuse Large B-Cell Lymphoma Are Predictive of Outcome
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Anne-Ségolène Cottereau; Christophe Nioche; Anne-Sophie Dirand; Jérôme Clerc; Franck Morschhauser; Olivier Casasnovas; Michel Meignan; Irène Buvat

    We assessed the predictive value of new radiomic features characterizing lesion dissemination in baseline 18F-FDG PET and tested whether combining them with baseline metabolic tumor volume (MTV) could improve prediction of progression-free survival (PFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) patients. Methods: From the LNH073B trial (NCT00498043), patients with advanced-stage DLCBL and 18F-FDG PET/CT images available for review were selected. MTV and several radiomic features, including the distance between the 2 lesions that were farthest apart (Dmaxpatient), were calculated. Receiver-operating-characteristic analysis was used to determine the optimal cutoff for quantitative variables, and Kaplan–Meier survival analyses were performed. Results: With a median age of 46 y, 95 patients were enrolled, half of them treated with R-CHOP biweekly (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and the other half with R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone), with no significant impact on outcome. Median MTV and Dmaxpatient were 375 cm3 and 45 cm, respectively. The median follow-up was 44 mo. High MTV and Dmaxpatient were adverse factors for PFS (P = 0.027 and P = 0.0003, respectively) and for OS (P = 0.0007 and P = 0.0095, respectively). In multivariate analysis, only Dmaxpatient was significantly associated with PFS (P = 0.0014) whereas both factors remained significant for OS (P = 0.037 and P = 0.0029, respectively). Combining MTV (>384 cm3) and Dmaxpatient (>58 cm) yielded 3 risk groups for PFS (P = 0.0003) and OS (P = 0.0011): high with 2 adverse factors (4-y PFS and OS of 50% and 53%, respectively, n = 18), low with no adverse factor (94% and 97%, n = 36), and an intermediate category with 1 adverse factor (73% and 88%, n = 41). Conclusion: Combining MTV with a parameter reflecting the tumor burden dissemination further improves DLBCL patient risk stratification at staging.

    更新日期:2020-01-02
  • Lymph Node Involvement in Treatment-Naïve Prostate Cancer Patients: Correlation of PSMA PET/CT Imaging and Roach Formula in 280 Men in Radiotherapeutic Management
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Stefan A. Koerber; Gerald Stach; Clemens Kratochwil; Matthias F. Haefner; Henrik Rathke; Klaus Herfarth; Klaus Kopka; Tim Holland-Letz; Peter L. Choyke; Uwe Haberkorn; Juergen Debus; Frederik L. Giesel

    The importance of prostate-specific membrane antigen (PSMA) PET/CT for primary staging of treatment-naïve prostate cancer patients is still under debate. Therefore, the present study aimed to evaluate the role of PSMA PET/CT in detecting nodal metastases in a large cohort of men and compare imaging results with the risk of lymph node involvement based on the Roach formula. Methods: In total, 280 men with newly diagnosed prostate carcinoma were included in the present study. For all patients, PSMA PET/CT was performed for primary staging. Median age was 67 y (range, 38–84 y), and 84% of all patients were classified as high-risk according to the d’Amico criteria. The risk of lymph node involvement was calculated using the Roach formula and compared with the PSMA PET/CT results. Results: PSMA-positive nodes were detected in 90 of 280 men (32.1%). Although most nodal metastases occurred within the pelvis, 36.0% were in extrapelvic sites. In 9 patients (3.2%), nodal metastases occurred in the Virchow node. After comparison of PSMA data with the results of the Roach formula, an area under the curve of 0.781 was obtained for the Roach predictions. Conclusion: For treatment-naïve prostate cancer patients, PSMA PET/CT is well suited for the detection of nodal metastases. However, the original Roach formula can still be used for a quick assessment of potential lymphatic spread in daily clinical routine.

    更新日期:2020-01-02
  • Matched-Pair Comparison of 68Ga-PSMA-11 PET/CT and 18F-PSMA-1007 PET/CT: Frequency of Pitfalls and Detection Efficacy in Biochemical Recurrence After Radical Prostatectomy
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Isabel Rauscher; Markus Krönke; Michael König; Andrei Gafita; Tobias Maurer; Thomas Horn; Kilian Schiller; Wolfgang Weber; Matthias Eiber

    18F-labeled prostate-specific membrane antigen (PSMA)–ligand PET has several principal advantages over 68Ga-PSMA-11. The purpose of this retrospective study was to evaluate the frequency of non–tumor-related uptake and the detection efficacy comparing 68Ga-PSMA-11 PET/CT and 18F-PSMA-1007 PET/CT in recurrent prostate cancer (PC) patients. Methods: The study included 102 patients with biochemically recurrent PC after radical prostatectomy undergoing 18F-PSMA-1007 PET/CT imaging. On the basis of various clinical variables, patients with corresponding 68Ga-PSMA-11 PET/CT scans were matched. All PET/CT scans (n = 204) were reviewed by 1 nuclear medicine physician. First, all PET-positive lesions were noted. Then, lesions suspected of being recurrent PC were differentiated from lesions attributed to a benign origin on the basis of known pitfalls and information from CT. For each region, the SUVmax of the lesion with the highest PSMA-ligand uptake was noted. Detection rates were determined, and SUVmax was compared separately for 68Ga-PSMA-11 and 18F-PSMA-1007. Results: In total, 18F-PSMA-1007 PET and 68Ga-PSMA-11 PET revealed 369 and 178 PSMA-ligand–positive lesions, respectively. 18F-PSMA-1007 PET revealed approximately 5 times more lesions attributed to a benign origin than did 68Ga-PSMA-11 PET (245 vs. 52 lesions, respectively). The benign lesions most frequently observed were ganglia, unspecific lymph node, and bone lesions, at a rate of 43%, 31%, and 24% for 18F-PSMA-1007 PET and 29%, 42%, and 27% for 68Ga-PSMA-11 PET, respectively. The SUVmax of lesions attributed to a benign origin was significantly higher (P < 0.0001) for 18F-PSMA-1007 PET. Further, a similar number of lesions was attributed to recurrent PC (124/369 for 18F-PSMA-1007 PET and 126/178 for 68Ga-PSMA-11 PET). Conclusion: The number of lesions with increased PSMA-ligand uptake attributed to a benign origin is considerably higher for 18F-PSMA-1007 PET than for 68Ga-PSMA-11 PET. This finding indicates the need for sophisticated reader training emphasizing known pitfalls and reporting within the clinical context.

    更新日期:2020-01-02
  • Prospective Evaluation of PSMA-Targeted 18F-DCFPyL PET/CT in Men with Biochemical Failure After Radical Prostatectomy for Prostate Cancer
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Steven P. Rowe; Scott P. Campbell; Margarita Mana-Ay; Zsolt Szabo; Mohamad E. Allaf; Kenneth J. Pienta; Martin G. Pomper; Ashley E. Ross; Michael A. Gorin

    Our purpose is to provide the results of a prospective study evaluating prostate-specific membrane antigen–targeted 18F-DCFPyL (2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) PET/CT in patients with biochemical failure after radical prostatectomy for prostate cancer (PCa). Methods: Thirty-one patients with postprostatectomy serum prostate-specific antigen (PSA) levels of at least 0.2 ng/mL and negative conventional imaging results were enrolled in this study and imaged with 18F-DCFPyL PET/CT. A consensus central review identified foci of radiotracer uptake consistent with sites of PCa. Descriptive statistics were used. Results: Twenty-one patients (67.7%) had at least 1 finding on 18F-DCFPyL PET/CT consistent with a site of PCa. Imaging was positive in 59.1% of patients with a PSA level of less than 1.0 ng/mL and in 88.9% of patients with a PSA level of more than 1.0 ng/mL. The median SUVmax across all lesions was 11.6 (range, 1.5–57.6). Conclusion: In this prospective study using the prostate-specific membrane antigen–targeted PET agent 18F-DCFPyL, most patients with biochemical failure after radical prostatectomy had foci of suggestive uptake, even at low serum PSA levels.

    更新日期:2020-01-02
  • Predictors of Overall and Disease-Free Survival in Metastatic Castration-Resistant Prostate Cancer Patients Receiving 225Ac-PSMA-617 Radioligand Therapy
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Mike Sathekge; Frank Bruchertseifer; Mariza Vorster; Ismaheel O. Lawal; Otto Knoesen; Johncy Mahapane; Cindy Davis; Florette Reyneke; Alex Maes; Clemens Kratochwil; Thabo Lengana; Frederik L. Giesel; Christophe Van de Wiele; Alfred Morgenstern

    Metastatic prostate carcinoma overexpresses prostate-specific membrane antigen (PSMA), making this antigen a suitable target for radioligand therapy of the disease. Here we report on our experience with a series of 73 castration-resistant prostate carcinoma patients treated with 225Ac-PSMA-617, identifying variables predictive for overall survival (OS) and progression-free survival (PFS) after 225Ac-PSMA-617 treatment. Methods: 225Ac-PSMA-617 was administered to patients who had metastatic castration-resistant prostate carcinoma and who had exhausted available therapy options for their disease. Full blood count, glomerular filtration rate, and liver function test were obtained at baseline and on follow-up for evaluation of toxicity. 68Ga-PSMA PET/CT was obtained at baseline, before every treatment cycle, and on follow-up for selection of patients for treatment, to determine the activity of the treatment agent to be administered, and for response assessment. Serial prostate-specific antigen (PSA) was obtained for PSA response assessment. Results: Seventy-three men (mean age, 69 y; range, 45–85 y) with metastatic castration-resistant prostate carcinoma were treated with 210 cycles of 225Ac-PSMA-617. In 70% of patients, a PSA decline of greater than or equal to 50% was obtained; 82% of patients had any PSA decline. In 29% of patients, all lesions on 68Ga-PSMA PET resolved in response to treatment. During follow-up, 23 patients experienced disease progression, whereas 13 patients died from their disease. The estimated median PFS and OS were 15.2 mo (95% CI, 13.1–17.4) and 18 mo (95% CI, 16.2–19.9), respectively. In univariate analyses, factors such as baseline PSA, any PSA decline, PSA decline of greater than or equal to 50%, prior chemotherapy, prior radiation therapy, and baseline hemoglobin level were associated with longer PFS and OS (all Ps < 0.05). In multivariate analyses, there was a negative association between prior 177Lu-PSMA therapy and PFS, and a positive association between PSA decline of greater or equal to 50% and PFS. Only a PSA decline of greater than or equal to 50% remained significantly associated with OS on multivariate analyses. Xerostomia was seen in 85% of patients but was not severe enough to warrant discontinuing treatment. Anemia was seen in 27 patients; no patients had grade IV bone marrow toxicity. Renal failure of grade III or IV was seen in 5 patients with baseline renal impairment. Conclusion: In this study, a PSA decline of greater than or equal to 50% after treatment with 225Ac-PSMA-617 was proven by multivariate analyses to be significantly associated with OS and PFS. Furthermore, previous 177Lu-PSMA treatment was negatively associated with PFS in both univariate and multivariate analyses.

    更新日期:2020-01-02
  • Development of Novel PSMA Ligands for Imaging and Therapy with Copper Isotopes
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    José Carlos dos Santos; Barbro Beijer; Ulrike Bauder-Wüst; Martin Schäfer; Karin Leotta; Matthias Eder; Martina Benešová; Christian Kleist; Frederik Giesel; Clemens Kratochwil; Klaus Kopka; Uwe Haberkorn; Walter Mier

    Prostate-specific membrane antigen (PSMA)–binding tracers have been shown to be promising agents for the specific targeting of prostate tumors. On labeling with the short-lived isotopes 18F and 68Ga, excellent molecular imaging performance is achieved. This potential could be further exploited using long-lived isotopes. Because of the favorable half-life of 64Cu, tracers labeled with this PET nuclide could solve logistic problems. Moreover, this isotope provides a theranostic pair with the therapeutic copper isotope 67Cu. Hence, 9 novel tracers that combine dedicated copper chelators with the PSMA-specific urea-based binding motif were developed. Methods: The precursors were obtained by solid-phase synthesis. The purity and molecular weight of the PSMA ligands were confirmed by high-performance liquid chromatography and liquid chromatography–mass spectrometry. The compounds were labeled with 64Cu, with a radiolabeling yield of more than 99%. Competitive cell binding assays and internalization assays were performed with C4-2 cells, a subline of the PSMA-positive cell line LNCaP (human lymph node carcinoma of the prostate). In vitro serum stability, the stability of 64Cu-CA003 in blood, and the in vivo fate of neat 64Cu-chloride or 64Cu-CA003 were determined to prove whether the stability of the radiolabeled compounds is sufficient to ensure no significant loss of copper during the targeting process. For PET imaging and biodistribution studies, a C4-2 tumor–bearing mouse model was used. Results: The radiolabeled 64Cu-PSMA ligands showed high serum stability. All PSMA ligands showed high inhibition potencies, with equilibrium inhibition constants in the low nanomolar range. 64Cu-CA003 and 64Cu-CA005 showed high internalization ratios (34.6% ± 2.8 and 18.6% ± 4.4, respectively). Both the in vitro serum stability determination and the in vivo characterization of the main radiolabeled compounds confirmed that, except for 64Cu-PSMA-617, all compounds showed high serum stability within the observation period of 24 h. Small-animal PET imaging demonstrated high tumor uptake within 20 min. Organ distribution studies confirmed high specific uptake in the tumor, with 30.8 ± 12.6 percentage injected dose (%ID)/g at 1 h after injection. Rapid clearance from the kidneys was observed—a decrease from 67.0 ± 20.9 %ID/g at 1 h after injection to 7.5 ± 8.51 %ID/g at 24 h after injection (in the case of CA003). The performance of CA003, the compound with the best preclinical properties, was assessed in a first patient. In line with its preclinical data, PET imaging resulted in clear visualization of the cancer lesions, with high contrast. Conclusion: The 64Cu-labeled PSMA ligands are promising agents to target PSMA and visualize PSMA-positive tumor lesions as shown in preclinical evaluation by small-animal PET studies, organ distribution, and a patient application. Most importantly, the images obtained at 20 h enabled delineation of unclear lesions, showing that the compounds fulfill the prerequisite for dosimetry in the course of therapy planning with 67Cu. Thus, we suggest clinical use of copper-labeled CA003 for diagnostics and radiotherapy of prostate cancer.

    更新日期:2020-01-02
  • Preclinical Evaluation of 203/212Pb-Labeled Low-Molecular-Weight Compounds for Targeted Radiopharmaceutical Therapy of Prostate Cancer
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Sangeeta Ray Banerjee; Il Minn; Vivek Kumar; Anders Josefsson; Ala Lisok; Mary Brummet; Jian Chen; Ana P. Kiess; Kwamena Baidoo; Cory Brayton; Ronnie C. Mease; Martin Brechbiel; George Sgouros; Robert F. Hobbs; Martin G. Pomper

    Targeted radiopharmaceutical therapy (TRT) using α-particle radiation is a promising approach for treating both large and micrometastatic lesions. We developed prostate-specific membrane antigen (PSMA)–targeted low-molecular-weight agents for 212Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate, 203Pb. Methods: Five rationally designed low-molecular-weight ligands (L1-L5) were synthesized using the lysine-urea-glutamate scaffold, and PSMA inhibition constants were determined. Tissue biodistribution and SPECT/CT imaging of 203Pb-L1–203Pb-L5 were performed on mice bearing PSMA(+) PC3 PIP and PSMA(−) PC3 flu flank xenografts. The absorbed radiation dose of the corresponding 212Pb-labeled analogs was determined using the biodistribution data. Antitumor efficacy of 212Pb-L2 was evaluated in PSMA(+) PC3 PIP and PSMA(−) PC3 flu tumor models and in the PSMA(+) luciferase-expressing micrometastatic model. 212Pb-L2 was also evaluated for dose-escalated, long-term toxicity. Results: All new ligands were obtained in high yield and purity. PSMA inhibitory activities ranged from 0.10 to 17 nM. 203Pb-L1–203Pb-L5 were synthesized in high radiochemical yield and specific activity. Whole-body clearance of 203Pb-L1–203Pb-L5 was fast. The absorbed dose coefficients (mGy/kBq) of the tumor and kidneys were highest for 203Pb-L5 (31.0, 15.2) and lowest for 203Pb-L2 (8.0, 4.2). The tumor-to-kidney absorbed dose ratio was higher for 203Pb-L3 (3.2) and 203Pb-L4 (3.6) than for the other agents, but with lower tumor-to-blood ratios. PSMA(+) tumor lesions were visualized through SPECT/CT as early as 0.5 h after injection. A proof-of-concept therapy study with a single administration of 212Pb-L2 demonstrated dose-dependent inhibition of tumor growth in the PSMA(+) flank tumor model. 212Pb-L2 also demonstrated an increased survival benefit in the micrometastatic model compared with 177Lu-PSMA-617. Long-term toxicity studies in healthy, immunocompetent CD-1 mice revealed kidney as the dose-limiting organ. Conclusion: 203Pb-L1–203Pb-L5 demonstrated favorable pharmacokinetics for 212Pb-based TRT. The antitumor efficacy of 212Pb-L2 supports the corresponding 203Pb/212Pb theranostic pair for PSMA-based α-particle TRT in advanced PC.

    更新日期:2020-01-02
  • Dose-Dependent Growth Delay of Breast Cancer Xenografts in the Bone Marrow of Mice Treated with 223Ra: The Role of Bystander Effects and Their Potential for Therapy
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Calvin N. Leung; Brian S. Canter; Didier Rajon; Tom A. Bäck; J. Christopher Fritton; Edouard I. Azzam; Roger W. Howell

    The role of radiation-induced bystander effects in radiation therapy remains unclear. With renewed interest in therapy with α-particle emitters, and their potential for sterilizing disseminated tumor cells (DTCs), it is critical to determine the contribution of bystander effects to the overall response so they can be leveraged for maximum clinical benefit. Methods: Female Foxn1nu athymic nude mice were administered 0, 50, or 600 kBq/kg 223RaCl2 to create bystander conditions. At 24 hours after administration, MDA-MB-231 or MCF-7 human breast cancer cells expressing luciferase were injected into the tibial marrow compartment. Tumor burden was tracked weekly via bioluminescence. Results: The MDA-MB-231 xenografts were observed to have a 10-day growth delay in the 600 kBq/kg treatment group only. In contrast, MCF-7 cells had 7- and 65-day growth delays in the 50 and 600 kBq/kg groups, respectively. Histologic imaging of the tibial marrow compartment, α-camera imaging, and Monte Carlo dosimetry modeling revealed DTCs both within and beyond the range of the α-particles emitted from 223Ra in bone for both MCF-7 and MDA-MB-231 cells. Conclusion: Taken together, these results support the participation of 223Ra-induced antiproliferative/cytotoxic bystander effects in delayed growth of DTC xenografts. They indicate that the delay depends on the injected activity and therefore is dose-dependent. They suggest using 223RaCl2 as an adjuvant treatment for select patients at early stages of breast cancer.

    更新日期:2020-01-02
  • Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: 18F-BCPP-EF, 11C-SA-4503, and 11C-UCB-J
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Ayla Mansur; Eugenii A. Rabiner; Robert A. Comley; Yvonne Lewis; Lefkos T. Middleton; Mickael Huiban; Jan Passchier; Hideo Tsukada; Roger N. Gunn; Laurent Martarello; Robert A. Comley; Laigao Chen; Adam Schwarz; Karl Schmidt; Paul Matthews; Marios Politis; Jonathan Rohrer; David Brooks; James Rowe

    Mitochondrial complex 1 is involved in maintaining brain bioenergetics; σ-1 receptor responds to neuronal stress; and synaptic vesicle protein 2A reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here, we characterize the kinetic behavior of 3 PET radioligands—18F-BCPP-EF, 11C-SA-4503, and 11C-UCB-J—for the measurement of mitochondrial complex 1, σ-1 receptor, and synaptic vesicle protein 2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. Methods: Twelve human subjects underwent dynamic PET scans with each radioligand, including associated arterial blood sampling. A range of kinetic models was investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. Results: All 3 radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution were multilinear analysis 1 (MA1) and the 2-tissue-compartment model for 18F-BCPP-EF, MA1 for 11C-SA-4503, and both MA1 and the 1-tissue-compartment model for 11C-UCB-J. Acquisition times of 70, 80, and 60 min for 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, respectively, provided good estimates of regional volume of distribution values. An effect of age was observed on 18F-BCPP-EF and 11C-UCB-J signal in the caudate. Conclusion: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases.

    更新日期:2020-01-02
  • Prediction of Tumor Control in 90Y Radioembolization by Logit Models with PET/CT-Based Dose Metrics
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Yuni K. Dewaraja; Theresa Devasia; Ravi K. Kaza; Justin K. Mikell; Dawn Owen; Peter L. Roberson; Matthew J. Schipper

    The aim of this work was to develop models for tumor control probability (TCP) in radioembolization with 90Y PET/CT–derived radiobiologic dose metrics. Methods: Patients with primary liver cancer or liver metastases who underwent radioembolization with glass microspheres were imaged with 90Y PET/CT for voxel-level dosimetry to determine lesion absorbed dose (AD) metrics, biological effective dose (BED) metrics, equivalent uniform dose, and equivalent uniform BED for 28 treatments (89 lesions). The lesion dose–shrinkage correlation was assessed on the basis of RECIST and, when available, modified RECIST (mRECIST) at first follow-up. For a subset with mRECIST, logit regression TCP models were fit via maximum likelihood to relate lesion-level binary response to the dose metrics. As an exploratory analysis, the nontumoral liver dose–toxicity relationship was also evaluated. Results: Lesion dose–shrinkage analysis showed that there were no significant differences between model parameters for primary and metastatic subgroups and that correlation coefficients were superior with mRECIST. Therefore, subsequent TCP analysis was performed for the combined group using mRECIST only. The overall lesion-level mRECIST response rate was 57%. The AD and BED metrics yielding 50% TCP were 292 and 441 Gy, respectively. All dose metrics considered for TCP modeling, including mean AD, were significantly associated with the probability of response, with high areas under the curve (0.87–0.90, P < 0.0001) and high sensitivity (>0.75) and specificity (>0.83) calculated using a threshold corresponding to 50% TCP. Because nonuniform AD deposition by microspheres cannot be determined by PET at a microscopic scale, radiosensitivity values extracted here by fitting models to clinical response data were substantially lower than reported for in vitro cell cultures or for external-beam radiotherapy clinical studies. There was no correlation between nontumoral liver AD and toxicity measures. Conclusion: Despite the heterogeneous patient cohort, logistic regression TCP models showed a strong association between various dose metrics and the probability of response. The performance of mean AD was comparable to that of radiobiologic dose metrics that involve more complex calculations. These results demonstrate the importance of considering TCP in treatment planning for radioembolization.

    更新日期:2020-01-02
  • PET-Based Human Dosimetry of 68Ga-NODAGA-Exendin-4, a Tracer for β-Cell Imaging
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Marti Boss; Mijke Buitinga; Tom J.P. Jansen; Maarten Brom; Eric P. Visser; Martin Gotthardt

    68Ga-NODAGA-exendin-4 is a promising tracer for β-cell imaging using PET/CT. Possible applications include preoperative visualization of insulinomas and discrimination between focal and diffuse forms of congenital hyperinsulinism. There is also a significant role for this tracer in extending our knowledge on the role of β-cell mass in the pathophysiology of type 1 and type 2 diabetes by enabling noninvasive quantification of tracer uptake as a measure for β-cell mass. Calculating radiation doses from this tracer is important to assess its safety for use in patients (including young children) with benign diseases and healthy individuals. Methods: Six patients with hyperinsulinemic hypoglycemia were included. After intravenous injection of 100 MBq of the tracer, 4 successive PET/CT scans were obtained at 30, 60, 120, and 240 min after injection. Tracer activity in the pancreas, kidneys, duodenum, and remainder of the body were determined, and time-integrated activity coefficients for the measured organs were calculated. OLINDA/EXM software, version 1.1, was applied to calculate radiation doses using the reference adult male and female models and to estimate radiation doses to children. Results: The mean total effective dose for adults was very low (0.71 ± 0.07 mSv for a standard injected dose of 100 MBq). The organ with the highest absorbed dose was the kidney (47.3 ± 10.2 mGy/100 MBq). The estimated effective dose was 2.32 ± 0.32 mSv for an injected dose of 20 MBq in newborns. This dose decreased to 0.77 ± 0.11 mSv/20 MBq for 1-y-old children and 0.59 ± 0.05 mSv for an injected dose of 30 MBq in 5-y-old children. Conclusion: Our human PET/CT-based dosimetric calculations show that the effective radiation doses from the novel tracer 68Ga-NODAGA-exendin-4 are very low for adults and children. The doses are lower than reported for other polypeptide tracers such as somatostatin analogs (2.1–2.6 mSv/100 MBq) and are beneficial for application as a research tool, especially when repeated examinations are needed.

    更新日期:2020-01-02
  • PET Imaging of Tumor PD-L1 Expression with a Highly Specific Nonblocking Single-Domain Antibody
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Gaochao Lv; Xiaorong Sun; Ling Qiu; Yan Sun; Ke Li; Qingzhu Liu; Qi Zhao; Songbing Qin; Jianguo Lin

    Although immunotherapy through programmed death 1/programmed death ligand 1 (PD-1/PD-L1) checkpoint blockade has shown impressive clinical outcomes, not all patients respond to it. Recent studies have demonstrated that the expression level of PD-L1 in tumors is one of the factors that correlate with PD-1/PD-L1 checkpoint blockade therapy. Herein, a 68Ga-labeled single-domain antibody tracer, 68Ga-NOTA-Nb109, was designed and developed for specific and noninvasive imaging of PD-L1 expression in a melanoma-bearing mouse model. Methods: The single-domain antibody Nb109 was labeled with the radionuclide 68Ga through a NOTA chelator. An in vitro binding assay was performed to assess the affinity and binding epitope of Nb109 to PD-L1. The clinical application value of 68Ga-NOTA-Nb109 was evaluated by a stability assay; by biodistribution and pharmacokinetics studies; and by PET imaging, autoradiography, and immunohistochemical staining studies on tumor-bearing models with differences in PD-L1 expression. Results: 68Ga-NOTA-Nb109 was obtained with a radiochemical yield of more than 95% and radiochemical purity of more than 98% in 10 min. It showed a highly specific affinity for PD-L1, with an equilibrium dissociation constant of 2.9 × 10−9 M. A competitive binding assay indicated Nb109 to have a binding epitope different from that of PD-1 and PD-L1 antibody. All biodistribution, PET imaging, autoradiography, and immunohistochemical staining studies revealed that 68Ga-NOTA-Nb109 specifically accumulated in A375-hPD-L1 tumor, with a maximum uptake of 5.0% ± 0.35% injected dose/g at 1 h. Conclusion: 68Ga-NOTA-Nb109 holds great potential for noninvasive PET imaging of the PD-L1 status in tumors and for timely evaluation of the effect of immune checkpoint targeting treatment.

    更新日期:2020-01-02
  • 64Cu PET Imaging of the CXCR4 Chemokine Receptor Using a Cross-Bridged Cyclam Bis-Tetraazamacrocyclic Antagonist
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Benjamin P. Burke; Cecilia S. Miranda; Rhiannon E. Lee; Isaline Renard; Shubhanchi Nigam; Gonçalo S. Clemente; Thomas D’Huys; Torsten Ruest; Juozas Domarkas; James A. Thompson; Timothy J. Hubin; Dominique Schols; Christopher J. Cawthorne; Stephen J. Archibald

    Expression of the chemokine receptor chemokine C-X-C motif receptor 4 (CXCR4) plays an important role in cancer metastasis, in autoimmune diseases, and during stem cell–based repair processes after stroke and myocardial infarction. Previously reported PET imaging agents targeting CXCR4 suffer from either high nonspecific uptake or bind only to the human form of the receptor. The objective of this study was to develop a high-stability 64Cu-labeled small-molecule PET agent for imaging both human and murine CXCR4 chemokine receptors. Methods: Synthesis, radiochemistry, stability and radioligand binding assays were performed for the novel tracer 64Cu-CuCB-bicyclam. In vivo dynamic PET studies were performed on mice bearing U87 (CXCR4 low-expressing) and U87.CXCR4 (human-CXCR4 high-expressing) tumors. Biodistribution and receptor blocking studies were performed on CD1-IGS immunocompetent mice. CXCR4 expression on tumor and liver disaggregates was confirmed using a combination of immunohistochemistry, quantitative polymerase chain reaction, and Western blot. Results: 64Cu-CuCB-bicyclam has a high affinity for both the human and the murine variants of the CXCR4 receptor (half-maximal inhibitory concentration, 8 nM [human]/2 nM [murine]) and can be obtained from the parent chelator that has low affinity. In vitro and in vivo studies demonstrate specific uptake in CXCR4-expressing cells that can be blocked by more than 90% using a higher-affinity antagonist, with limited uptake in non–CXCR4-expressing organs and high in vivo stability. The tracer was also able to selectively displace the CXCR4 antagonists AMD3100 and AMD3465 from the liver. Conclusion: The tetraazamacrocyclic small molecule 64Cu-CuCB-bicyclam has been shown to be an imaging agent for the CXCR4 receptor that is likely to be applicable across a range of species. It has high affinity and stability and is suitable for preclinical research in immunocompetent murine models.

    更新日期:2020-01-02
  • Image Quality and Semiquantitative Measurements on the Biograph Vision PET/CT System: Initial Experiences and Comparison with the Biograph mCT
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Joyce van Sluis; Ronald Boellaard; Ananthi Somasundaram; Paul H. van Snick; Ronald J.H. Borra; Rudi A.J.O. Dierckx; Gilles N. Stormezand; Andor W.J.M. Glaudemans; Walter Noordzij

    In May 2018, the Biograph Vision PET/CT system was installed at the University Medical Center Groningen. This study evaluated the initial experiences with this new PET/CT system in terms of perceived image quality and semiquantitative analysis in comparison to the Biograph mCT as a reference. Methods: In total, 20 oncologic patients were enrolled and received a single 3 MBq/kg injected dose of 18F-FDG followed by a dual-imaging PET scan. Ten patients were scanned on the Biograph mCT first, whereas the other 10 patients were scanned on the Biograph Vision first. The locally preferred clinically reconstructed images were blindly reviewed by 3 nuclear medicine physicians and scored (using a Likert scale of 1–5) on tumor lesion demarcation, overall image quality, and image noise. In addition, these clinically reconstructed images were used for semiquantitative analysis by measurement of SUVs in tumor lesions. Images acquired using reconstructions conform with the European Association of Nuclear Medicine Research Ltd. (EARL) specifications were also used for measurements of SUV in tumor lesions and healthy tissues for comparison between systems. Results: The 18F-FDG dose received by the 14 men and 6 women (age range, 36–84; mean ± SD, 61 ± 16 y) ranged from 145 to 405 MBq (mean ± SD, 268 ± 59.3). Images acquired on the Biograph Vision were scored significantly higher on tumor lesion demarcation, overall image quality, and image noise than images acquired on the Biograph mCT (P < 0.001). The overall interreader agreement showed a Fleiss κ of 0.61 (95% confidence interval, 0.53–0.70). Furthermore, the SUVs in tumor lesions and healthy tissues agreed well (within 95%) between PET/CT systems, particularly when EARL-compliant reconstructions were used on both systems. Conclusion: In this initial study, the Biograph Vision showed improved image quality compared with the Biograph mCT in terms of lesion demarcation, overall image quality, and visually assessed signal-to-noise ratio. The 2 systems are comparable in semiquantitatively assessed image biomarkers in both healthy tissues and tumor lesions. Improved quantitative performance may, however, be feasible using the clinically optimized reconstruction settings.

    更新日期:2020-01-02
  • PennPET Explorer: Design and Preliminary Performance of a Whole-Body Imager
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Joel S. Karp; Varsha Viswanath; Michael J. Geagan; Gerd Muehllehner; Austin R. Pantel; Michael J. Parma; Amy E. Perkins; Jeffrey P. Schmall; Matthew E. Werner; Margaret E. Daube-Witherspoon

    We report on the development of the PennPET Explorer whole-body imager. Methods: The PennPET Explorer is a multiring system designed with a long axial field of view. The imager is scalable and comprises multiple 22.9-cm-long ring segments, each with 18 detector modules based on a commercial digital silicon photomultiplier. A prototype 3-segment imager has been completed and tested with an active 64-cm axial field of view. Results: The instrument design is described, and its physical performance measurements are presented. These include sensitivity of 55 kcps/MBq, spatial resolution of 4.0 mm, energy resolution of 12%, timing resolution of 256 ps, and a noise-equivalent count rate above 1,000 kcps beyond 30 kBq/mL. After an evaluation of lesion torso phantoms to characterize quantitative accuracy, human studies were performed on healthy volunteers. Conclusion: The physical performance measurements validated the system design and led to high-quality human studies.

    更新日期:2020-01-02
  • PennPET Explorer: Human Imaging on a Whole-Body Imager
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Austin R. Pantel; Varsha Viswanath; Margaret E. Daube-Witherspoon; Jacob G. Dubroff; Gerd Muehllehner; Michael J. Parma; Daniel A. Pryma; Erin K. Schubert; David A. Mankoff; Joel S. Karp

    The PennPET Explorer, a prototype whole-body imager currently operating with a 64-cm axial field of view, can image the major body organs simultaneously with higher sensitivity than that of commercial devices. We report here the initial human imaging studies on the PennPET Explorer, with each study designed to test specific capabilities of the device. Methods: Healthy subjects were imaged with FDG on the PennPET Explorer. Subsequently, clinical subjects with disease were imaged with 18F-FDG and 68Ga-DOTATATE, and research subjects were imaged with experimental radiotracers. Results: We demonstrated the ability to scan for a shorter duration or, alternatively, with less activity, without a compromise in image quality. Delayed images, up to 10 half-lives with 18F-FDG, revealed biologic insight and supported the ability to track biologic processes over time. In a clinical subject, the PennPET Explorer better delineated the extent of 18F-FDG–avid disease. In a second clinical study with 68Ga-DOTATATE, we demonstrated comparable diagnostic image quality between the PennPET scan and the clinical scan, but with one fifth the activity. Dynamic imaging studies captured relatively noise-free input functions for kinetic modeling approaches. Additional studies with experimental research radiotracers illustrated the benefits from the combination of large axial coverage and high sensitivity. Conclusion: These studies provided a proof of concept for many proposed applications for a PET scanner with a long axial field of view.

    更新日期:2020-01-02
  • Multi-Isotope Capabilities of a Small-Animal Multi-Pinhole SPECT System
    J Nucl. Med. (IF 7.354) Pub Date : 2020-01-01
    Mathias Lukas; Anne Kluge; Nicola Beindorff; Winfried Brenner

    The quantitative accuracy and image quality of multi-isotope SPECT is affected by various hardware-related perturbations. The present study evaluates the simultaneous acquisition of multiple isotopes using a multiplexed multi-pinhole SPECT system, assesses the extent of different error sources, and proposes experimental procedures for its objective characterization. Methods: Phantom measurements with single-, dual- and triple-isotope combinations of 99mTc, 111In, 123I, 177Lu, and 201Tl were performed with the NanoSPECT/CTPLUS to evaluate system energy resolution, count rate performance, sensitivity, collimator penetration, hardware versus object scatter, spectral crosstalk, spatial resolution, spatial registration accuracy, image uniformity, image noise, and image quality. Results: The intrinsic detector properties were suitable for the simultaneous acquisition of up to 3 isotopes with limitations for count rates exceeding 104 kcps and γ-energies lower than 75 keV. Spectral crosstalk between isotopes was more likely mediated by hardware than by source scatter and was strongly dependent on the isotope combination. Simultaneous multi-isotope acquisitions slightly degraded spatial resolution and image uniformity for spatially superimposed but not for spatially separated activity distributions while the background noise level was increased for all multi-isotope studies. For particular isotopes, collimator penetration and x-ray fluorescence contributed a significant portion of error. Conclusion: The NanoSPECT/CTPLUS enables the simultaneous acquisition of 3 radioisotopes with high quantitative accuracy and only little loss of image quality when the activity ratio is adapted to isotope-specific count rate sensitivities and when the system calibration is performed with phantoms of appropriate size.

    更新日期:2020-01-02
  • Molecular Imaging with Reporter Genes: Has Its Promise Been Delivered?
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Inna Serganova; Ronald G. Blasberg

    The first reporter systems were developed in the early 1980s and were based on measuring the activity of an enzyme—as a surrogate measure of promoter-driven transcriptional activity—which is now known as a reporter gene system. The initial objective and application of reporter techniques was to analyze the activity of a specific promoter (namely, the expression of a gene that is under the regulation of the specific promoter that is linked to the reporter gene). This system allows visualization of specific promoter activity with great sensitivity. In general, there are 2 classes of reporter systems: constitutively expressed (always-on) reporter constructs used for cell tracking, and inducible reporter systems sensitive to endogenous signaling molecules and transcription factors that characterize specific tissues, tumors, or signaling pathways. This review traces the development of different reporter systems, using fluorescent and bioluminescent proteins as well as radionuclide-based reporter systems. The development and application of radionuclide-based reporter systems is the focus of this review. The question at the end of the review is whether the “promise” of reporter gene imaging has been realized. What is required for moving forward with radionuclide-based reporter systems, and what is required for successful translation to clinical applications?

    更新日期:2019-12-02
  • Long-Term Clinical and Neuronuclear Imaging Sequelae of Cancer Therapy, Trauma, and Brain Injury
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    April Alcantara; Gholam R. Berenji; Carole S. Scherling; Beata Durcanova; Daniel Diaz-Aguilar; Daniel H.S. Silverman

    Neuronuclear imaging has been used for several decades in the study of primary neurodegenerative conditions, such as dementia and parkinsonian syndromes, both for research and for clinical purposes. There has been a relative paucity of applications of neuronuclear imaging to evaluate nonneurodegenerative conditions that can also have long-term effects on cognition and function. This article summarizes clinical and imaging aspects of 3 such conditions that have garnered considerable attention in recent years: cancer- and chemotherapy-related cognitive impairment, posttraumatic stress disorder, and traumatic brain injury. Further, we describe current research using neuroimaging tools aimed to better understand the relationships between the clinical presentations and brain structure and function in these conditions.

    更新日期:2019-12-02
  • Targeting P-Selectin Adhesion Molecule in Molecular Imaging: P-Selectin Expression as a Valuable Imaging Biomarker of Inflammation in Cardiovascular Disease
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Lydia A. Perkins; Carolyn J. Anderson; Enrico M. Novelli

    P-selectin is an adhesion molecule translocated to the surface of endothelial cells and platelets under inflammatory stimuli, and its potential as a biomarker in inflammatory conditions has driven preclinical studies to investigate its application for molecular imaging of inflammation. Clinical imaging of P-selectin expression for disease characterization could have an important role in stratifying patients and determining treatment strategies. The objective of this review is to outline the role of P-selectin in cardiovascular inflammatory conditions and its translation as an early inflammatory biomarker for several molecular imaging modalities for diagnostic purposes and therapeutic planning.

    更新日期:2019-12-02
  • Prospective Evaluation of a Tumor Control Probability Model Based on Dynamic 18F-FMISO PET for Head and Neck Cancer Radiotherapy
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Daniela Thorwarth; Stefan Welz; David Mönnich; Christina Pfannenberg; Konstantin Nikolaou; Matthias Reimold; Christian La Fougère; Gerald Reischl; Paul-Stefan Mauz; Frank Paulsen; Markus Alber; Claus Belka; Daniel Zips

    Our purpose was to evaluate an imaging parameter–response relationship between the extent of tumor hypoxia quantified by dynamic 18F-fluoromisonidazole (18F-FMISO) PET/CT and the risk of relapse after radiotherapy in patients with head and neck cancer. Methods: Before a prospective cohort of 25 head and neck cancer patients started radiotherapy, they were examined with dynamic 18F-FMISO PET/CT 0–240 min after tracer injection. 18F-FMISO image parameters, including a hypoxia metric, MFMISO, derived from pharmacokinetic modeling of dynamic 18F-FMISO and maximum tumor-to-muscle ratio (TMRmax) at 4 h after injection, gross tumor volume (GTV), relative hypoxic volume based on MFMISO, and a logistic regression model combining GTV and TMRmax, were assessed and compared with a previous training cohort (n = 15). Dynamic 18F-FMISO was used to validate a tumor control probability model based on MFMISO. The prognostic potential with respect to local control of all potential parameters was validated using the concordance index for univariate Cox regression models determined from the training cohort, in addition to Kaplan–Meier analysis including the log-rank test. Results: The tumor control probability model was confirmed, indicating that dynamic 18F-FMISO allows stratification of patients into different risk groups according to radiotherapy outcome. In this study, MFMISO was the only parameter that was confirmed as prognostic in the independent validation cohort (concordance index, 0.71; P = 0.004). All other investigated parameters, such as TMRmax, GTV, relative hypoxic volume, and the combination of GTV and TMRmax, were not able to stratify patient groups according to outcome in this validation cohort (P = not statistically significant). Conclusion: In this study, the relationship between MFMISO and the risk of relapse was prospectively validated. The data support further evaluation and external validation of dynamic 18F-FMISO PET/CT as a promising method for patient stratification and hypoxia-based radiotherapy personalization, including dose painting.

    更新日期:2019-12-02
  • 18F-Choline PET/mpMRI for Detection of Clinically Significant Prostate Cancer: Part 2. Cost-Effectiveness Analysis
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Christine L. Barnett; Matthew S. Davenport; Jeffrey S. Montgomery; Lakshmi Priya Kunju; Brian T. Denton; Morand Piert

    The objective of this study was to evaluate the cost-effectiveness of 18F-choline PET/multiparametric MRI (mpMRI) versus mpMRI alone for the detection of primary prostate cancer with a Gleason score of greater than or equal to 3 + 4 in men with elevated prostate-specific antigen levels. Methods: A Markov model of prostate cancer onset and progression was used to estimate the health and economic consequences of 18F-choline PET/mpMRI for the detection of primary prostate cancer with a Gleason score of greater than or equal to 3 + 4 in men with elevated prostate-specific antigen levels. Multiple simultaneous hybrid 18F-choline PET/mpMRI strategies were evaluated using Likert or Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) scoring; the first was biopsy for Likert 5 mpMRI lesions or Likert 3–4 lesions with 18F-choline target-to-background ratios of greater than or equal to 1.58, and the second was biopsy for PI-RADSv2 5 mpMRI lesions or PI-RADSv2 3–4 mpMRI lesions with 18F-choline target-to-background ratios of greater than or equal to 1.58. These strategies were compared with universal standard biopsy, mpMRI alone with biopsy only for PI-RADSv2 3–5 lesions, and mpMRI alone with biopsy only for Likert 4–5 lesions. For each mpMRI strategy, either no biopsy or standard biopsy could be performed after negative mpMRI results were obtained. Deaths averted, quality-adjusted life years (QALYs), cost, and incremental cost-effectiveness ratios were estimated for each strategy. Results: When the results of 18F-choline PET/mpMRI were negative, performing a standard biopsy was more expensive and had lower QALYs than performing no biopsy. The best screening strategy among those considered in this study performed hybrid 18F-choline PET/mpMRI with Likert scoring on men with elevated PSA, performed combined biopsy (targeted biopsy and standard 12-core biopsy) for men with positive imaging results, and no biopsy for men with negative imaging results ($22,706/QALY gained relative to mpMRI alone); this strategy reduced the number of biopsies by 35% in comparison to mpMRI alone. When the same policies were compared using PI-RADSv2 instead of Likert scoring, hybrid 18F-choline PET/mpMRI cost $46,867/QALY gained relative to mpMRI alone. In a threshold analysis, the best strategy among those considered remained cost-effective when the sensitivity and specificity of PET/mpMRI and combined biopsy (targeted biopsy and standard 12-core biopsy) were simultaneously reduced by 20 percentage points. Conclusion: 18F-choline PET/mpMRI for the detection of primary prostate cancer with a Gleason score of greater than or equal to 3 + 4 is cost-effective and can reduce the number of unneeded biopsies in comparison to mpMRI alone.

    更新日期:2019-12-02
  • No Added Value of 18F-Sodium Fluoride PET/CT for the Detection of Bone Metastases in Patients with Newly Diagnosed Prostate Cancer with Normal Bone Scintigraphy
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Helle D. Zacho; Mads R. Jochumsen; Niels C. Langkilde; Jesper C. Mortensen; Christian Haarmark; Helle W. Hendel; Jørgen B. Jensen; Lars J. Petersen

    The aim of this study was to determine if additional 18F-sodium fluoride PET/CT (NaF PET/CT) improves the prognostic accuracy in the initial staging of prostate cancer patients with normal bone scintigraphy undergoing prostatectomy. Methods: A prospective cohort study examined NaF PET/CT in intermediate- or high-risk prostate cancer with negative bone scintigraphy who were scheduled for prostatectomy. Biochemical response: PSA levels < 0.2 ng/mL at 6 wk and 6 mo postoperatively, PSA level ≥ 0.2 ng/mL was biochemical failure. Results: Eighty-one patients were included in the study; 75 patients (93%) achieved biochemical responses, 6 patients had biochemical failure. NaF PET/CT indicated bone metastasis in 1 patient (1.2%), was equivocal in 7 patients (8.6%), without bone metastases in 73 patients (90.1%). Eight patients with bone metastases or equivocal results on NaF PET/CT exhibited biochemical responses. All patients with biochemical failure had negative NaF PET/CT and bone scintigraphy for bone metastases. Conclusion: NaF PET/CT has no added value for bone staging in intermediate- and high-risk prostate cancer patients with normal bone scintigraphy results undergoing prostatectomy.

    更新日期:2019-12-02
  • A Prospective Observational Study to Evaluate the Effects of Long-Acting Somatostatin Analogs on 68Ga-DOTATATE Uptake in Patients with Neuroendocrine Tumors
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Anni Gålne; Helen Almquist; Martin Almquist; Cecilia Hindorf; Tomas Ohlsson; Erik Nordenström; Anna Sundlöv; Elin Trägårdh

    Patients with neuroendocrine tumors (NETs) are often treated with somatostatin analogs (SSAs) for control of symptoms and tumor growth. Such therapy could theoretically lead to misinterpretation of somatostatin receptor imaging with 68Ga-DOTATATE PET/CT by interfering with tracer–receptor binding. Guidelines recommend an interval of 3–4 wk between the last dose and imaging. The aim of this study was to evaluate if long-acting (LA) SSA treatment changes the uptake of 68Ga-DOTATATE in patients with NETs. Methods: From 2013 to 2016, 296 patients with, or under evaluation for, NETs were included in this prospective observational study. The effect of LA SSA on tracer uptake was evaluated in 2 main patient populations: those undergoing 68Ga-DOTATATE PET/CT before starting LA SSA treatment and at least once afterward, and those receiving ongoing LA SSA therapy, in whom the effect of the interval between the last dose of LA SSA and the PET/CT exam was analyzed. A third, explorative, analysis was performed to evaluate if clinical disease progression, regression, or stable tumor status changed the uptake of 68Ga-DOTATATE. In the 3 analyses, measurements of SUVmax in normal liver and tumor lesions were compared. Results: The median SUVmax in normal liver was significantly higher before treatment (8.6; interquartile range, 7.4–10.2) than after treatment initiation (6.0; 4.7–8.0) (P < 0.001). No significant changes in SUVmax were seen in tumor lesions after treatment initiation. No significant differences in SUVmax were found in normal liver or tumor lesions dependent on the interval between last dose of LA SSA and PET/CT. Conclusion: Treatment with LA SSA does not change SUVmax in tumor lesions, whereas SUVmax in normal liver is significantly lower after treatment. The findings have implications for interpretation of 68Ga-DOTATATE PET/CT for response assessment after SSA therapy and for guidelines on discontinuation of treatment before PET/CT.

    更新日期:2019-12-02
  • 68Ga-Pentixafor PET/CT for Imaging of Chemokine Receptor 4 Expression in Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma: Comparison to 18F-FDG PET/CT
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Yaping Luo; Xinxin Cao; Qingqing Pan; Jian Li; Jun Feng; Fang Li

    18F-FDG PET/CT has some limitations in the evaluation of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL), an indolent B-cell lymphoma that primarily involves the bone marrow. Because there is a high level of chemokine receptor 4 expression in the B cells of WM/LPL patients, we performed a prospective cohort study to evaluate the performance of 68Ga-pentixafor, which targets chemokine receptor 4 in WM/LPL, and to compare it with the performance of 18F-FDG. Methods: Seventeen patients with WM/LPL were recruited. All patients underwent both 68Ga-pentixafor PET/CT and 18F-FDG PET/CT. A positive PET/CT result was defined as the presence of focal lesions with positive PET results or diffuse bone marrow patterns (uptake > liver). The rates of positive results for PET/CT scans of bone marrow, lymph nodes, and other extramedullary involvement were statistically compared. Results: 68Ga-pentixafor PET/CT had a higher rate of positive results than 18F-FDG PET/CT (100% vs. 58.8%; P = 0.023) in the recruited WM/LPL patients. The sensitivities of 68Ga-pentixafor PET/CT and 18F-FDG PET/CT for detecting bone marrow involvement were 94.1% and 58.8%, respectively (P = 0.077). In terms of detecting lymph node involvement, 68Ga-pentixafor PET/CT had a significantly higher rate of positive results than 18F-FDG PET/CT (76.5% vs. 11.8%; P = 0.003). In addition, 68Ga-pentixafor detected more paramedullary and central nervous system involvement than 18F-FDG. Conclusion: 68Ga-pentixafor might be a promising imaging agent for the assessment of WM/LPL.

    更新日期:2019-12-02
  • Simplified Methods for Quantification of 18F-DCFPyL Uptake in Patients with Prostate Cancer
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Bernard H.E. Jansen; Maqsood Yaqub; Jens Voortman; Matthijs C.F. Cysouw; Albert D. Windhorst; Robert C. Schuit; Gerbrand M. Kramer; Alfons J.M. van den Eertwegh; Lothar A. Schwarte; N. Harry Hendrikse; André N. Vis; Reindert J.A. van Moorselaar; Otto S. Hoekstra; Ronald Boellaard; Daniela E. Oprea-Lager

    Radiolabeled prostate-specific membrane antigen (PSMA) PET has demonstrated promising results for prostate cancer (PCa) imaging. Quantification of PSMA radiotracer uptake is desired as it enables reliable interpretation of PET images, use of PSMA uptake as an imaging biomarker for tumor characterization, and evaluation of treatment effects. The aim of this study was to perform a full pharmacokinetic analysis of 2-(3-(1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL), a second-generation 18F-labeled PSMA ligand. On the basis of the pharmacokinetic analysis (reference method), simplified methods for quantification of 18F-DCFPyL uptake were validated. Methods: Eight patients with metastasized PCa were included. Dynamic PET acquisitions were performed at 0–60 and 90–120 min after injection of a median dose of 313 MBq of 18F-DCFPyL (range, 292–314 MBq). Continuous and manual arterial blood sampling provided calibrated plasma tracer input functions. Time–activity curves were derived for each PCa metastasis, and 18F-DCFPyL kinetics were described using standard plasma input tissue-compartment models. Simplified methods for quantification of 18F-DCFPyL uptake (SUVs; tumor-to-blood ratios [TBRs]) were correlated with kinetic parameter estimates obtained from full pharmacokinetic analysis. Results: In total, 46 metastases were evaluated. A reversible 2-tissue-compartment model was preferred for 18F-DCFPyL kinetics in 59% of the metastases. The observed k4 was small, however, resulting in nearly irreversible kinetics during the course of the PET study. Hence, k4 was fixated (0.015) and net influx rate, Ki, was preferred as the reference kinetic parameter. Whole-blood TBR provided an excellent correlation with Ki from full kinetic analysis (R2 = 0.97). This TBR could be simplified further by replacing the blood samples with an image-based, single measurement of blood activity in the ascending aorta (image-based TBR, R2 = 0.96). SUV correlated poorly with Ki (R2 = 0.47 and R2 = 0.60 for SUV normalized to body weight and lean body mass, respectively), most likely because of deviant blood activity concentrations (i.e., tumor tracer input) in patients with higher tumor volumes. Conclusion: 18F-DCFPyL kinetics in PCa metastases are best described by a reversible 2-tissue-compartment model. Image-based TBRs were validated as a simplified method to quantify 18F-DCFPyL uptake and might be applied to clinical, whole-body PET scans. SUV does not provide reliable quantification of 18F-DCFPyL uptake.

    更新日期:2019-12-02
  • Radiation Dosimetry and Biodistribution of 18F-PSMA-11 for PET Imaging of Prostate Cancer
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Sarah Piron; Kathia De Man; Nick Van Laeken; Yves D’Asseler; Klaus Bacher; Ken Kersemans; Piet Ost; Karel Decaestecker; Pieter Deseyne; Valérie Fonteyne; Nicolaas Lumen; Eric Achten; Boudewijn Brans; Filip De Vos

    Prostate-specific membrane antigen (PSMA) is highly overexpressed in prostate cancer. Many PSMA analog radiotracers for PET/CT prostate cancer staging have been developed, such as 68Ga-PSMA-11. This radiotracer has achieved good results in multiple clinical trials, but because of the superior imaging characteristics of 18F-fluoride, 18F-PSMA-11 was developed. The aim of this study was to evaluate the administration safety and radiation dosimetry of 18F-PSMA-11. Methods: Six patients (aged 62–68 y; mean, 66 ± 2 y) with suspected prostate cancer recurrence after previous treatment were administered 2 MBq of 18F-PSMA-11 per kilogram of body weight and then underwent low-dose PET/CT imaging at 0, 20, 50, 90, and 300 min after injection. To evaluate the safety of administration, vital parameters were monitored. To assess toxicity, full blood count and biochemical parameters were determined. According to the latest International Commission on Radiological Protection recommendations, radiation dosimetry analysis was performed using IDAC-Dose 2.1. For blood activity measurement, small samples of venous blood were collected at various time points after injection. The unbound 18F-fluoride fraction was determined in plasma at 20, 50, and 90 min after administration to evaluate the defluorination rate of 18F-PSMA-11. Results: After injection, 18F-PSMA-11 cleared rapidly from the blood. At 5 h after injection, 29.0% ± 5.9% of the activity was excreted in urine. The free 18F fraction in plasma increased from 9.7% ± 1.0% 20 min after injection to 22.2% ± 1.5% 90 min after injection. The highest tracer uptake was observed in kidneys, bladder, spleen, and liver. No study drug–related adverse events were observed. The calculated mean effective dose was 12.8 ± 0.6 μSv/MBq. Conclusion: 18F-PSMA-11 can be safely administered and results in a mean effective dose of 12.8 ± 0.6 μSv/MBq. Therefore, the total radiation dose is lower than for other PSMA PET agents and in the same range as 18F-DCFPyL.

    更新日期:2019-12-02
  • Molecular Imaging of Fibroblast Activity After Myocardial Infarction Using a 68Ga-Labeled Fibroblast Activation Protein Inhibitor, FAPI-04
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Zohreh Varasteh; Sarajo Mohanta; Stephanie Robu; Miriam Braeuer; Yuanfang Li; Negar Omidvari; Geoffrey Topping; Ting Sun; Stephan G. Nekolla; Antonia Richter; Christian Weber; Andreas Habenicht; Uwe A. Haberkorn; Wolfgang A. Weber

    Heart failure remains a major source of late morbidity and mortality after myocardial infarction (MI). The temporospatial presence of activated fibroblasts in the injured myocardium predicts the quality of cardiac remodeling after MI. Therefore, monitoring of activated fibroblasts is of great interest for studying cardiac remodeling after MI. Fibroblast activation protein (FAP) expression is upregulated in activated fibroblasts. This study investigated the feasibility of imaging activated fibroblasts with a new 68Ga-labeled FAP inhibitor (68Ga-FAPI-04) for PET imaging of fibroblast activation in a preclinical model of MI. Methods: MI and sham-operated rats were scanned with 68Ga-FAPI-04 PET/CT (1, 3, 6, 14, 23, and 30 d after MI) and with 18F-FDG (3 d after MI). Dynamic 68Ga-FAPI-04 PET and blocking studies were performed on MI rats 7 d after coronary ligation. After in vivo scans, the animals were euthanized and their hearts harvested for ex vivo analyses. Cryosections were prepared for autoradiography, hematoxylin and eosin (H&E), and immunofluorescence staining. Results: 68Ga-FAPI-04 uptake in the injured myocardium peaked on day 6 after coronary ligation. The tracer accumulated intensely in the MI territory, as identified by decreased 18F-FDG uptake and confirmed by PET/MR and H&E staining. Autoradiography and H&E staining of cross-sections revealed that 68Ga-FAPI-04 accumulated mainly at the border zone of the infarcted myocardium. In contrast, there was only minimal uptake in the infarct of the blocked rats, comparable to the uptake in the remote noninfarcted myocardium (PET image–derived ratio of infarct uptake to remote uptake: 6 ± 2). Immunofluorescence staining confirmed the presence of FAP-positive myofibroblasts in the injured myocardium. Morphometric analysis of the whole-heart sections demonstrated 3- and 8-fold higher FAP-positive fibroblast density in the border zone than in the infarct center and remote area, respectively. Conclusion: 68Ga-FAPI-04 represents a promising radiotracer for in vivo imaging of post-MI fibroblast activation. Noninvasive imaging of activated fibroblasts may have significant diagnostic and prognostic value, which could aid clinical management of patients after MI.

    更新日期:2019-12-02
  • Imaging of Chemotherapy-Induced Acute Cardiotoxicity with 18F-Labeled Lipophilic Cations
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Stuart P. McCluskey; Anna Haslop; Christopher Coello; Roger N. Gunn; Edward W. Tate; Richard Southworth; Christophe Plisson; Nicholas J. Long; Lisa A. Wells

    Many chemotherapy agents are toxic to the heart, such that increasing numbers of cancer survivors are now living with the potentially lethal cardiovascular consequences of their treatment. Earlier and more sensitive detection of chemotherapy-induced cardiotoxicity may allow improved treatment strategies and increase long-term survival. Lipophilic cation PET tracers may be suitable for early detection of cardiotoxicity. This study aimed to evaluate an 18F-labeled lipophilic phosphonium cation, [1-(2-18F-fluoroethyl),1H[1,2,3]triazole-4-ethylene]triphenylphosphonium bromide (18F-MitoPhos), as a cardiac imaging agent, comparing it with leading PET and SPECT lipophilic cationic tracers before further assessing its potential for imaging cardiotoxicity in an acute doxorubicin model. Methods: Cardiac uptake and response to decreased mitochondrial membrane potential of 18F-MitoPhos and 99mTc-sestamibi were tested in isolated perfused rat hearts. Baseline pharmacokinetic profiles of 18F-MitoPhos and 18F-fluorobenzyltriphenylphosphonium and their response to acute doxorubicin-induced cardiotoxicity were assessed in rats in vivo (10, 15, or 20 mg of doxorubicin per kilogram, intravenously, 48 h beforehand). Results: Cardiac retention of 18F-MitoPhos was more than double that of 99mTc-sestamibi in isolated perfused rat hearts. A favorable biodistribution of 18F-MitoPhos in vivo was observed, with heart-to-tissue ratios of 304 ± 186, 11.2 ± 1.2, and 3.8 ± 0.6 for plasma, liver, and lung, respectively (60 min). A significant dose-dependent loss of cardiac retention of 18F-MitoPhos was observed on doxorubicin treatment, with average cardiac SUV from 30 to 60 min (mean ± SD) decreasing from 3.5 ± 0.5 (control) to 1.8 ± 0.1 (doxorubicin, 20 mg/kg). Other assessed biomarkers showed no alterations. Conclusion: 18F-MitoPhos showed pharmacokinetic parameters suitable for cardiac imaging. A significant dose response of cardiac uptake to doxorubicin treatment was observed before detectable biomarker alterations. 18F-MitoPhos is therefore a promising tracer for imaging chemotherapy-induced cardiotoxicity. To our knowledge, this is the first demonstration of radiolabeled lipophilic cations being used for the PET imaging of chemotherapy-induced cardiotoxicity and indicates the potential application of these compounds in this area.

    更新日期:2019-12-02
  • Presynaptic Striatal Dopaminergic Function in Atypical Parkinsonism: A Metaanalysis of Imaging Studies
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Valtteri Kaasinen; Tuomas Kankare; Juho Joutsa; Tero Vahlberg

    Multiple-system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS) have signs and symptoms overlapping those of Parkinson disease (PD), complicating their clinical diagnosis. Although presynaptic dopaminergic brain imaging with PET and SPECT is clinically widely used for patients with suspected PD, the benefit of functional imaging in atypical parkinsonism syndromes remains unclear. We compared striatal presynaptic dopaminergic function in MSA parkinsonism variant (MSA-P), MSA cerebellar variant (MSA-C), PSP, CBS, and PD using combined quantitative data from all published studies. Methods: The PubMed database was searched from inception to August 2018 for the terms “dopamine” OR “dopaminergic” AND “PET” OR “SPECT” OR “SPET” and keywords related to PD, MSA, PSP, and CBS. In total, 1,711 publications were identified. PET or SPECT studies comparing patients with atypical parkinsonism to another diagnostic group (PD, MSA, PSP, or CBS) were included. Tracers for dopamine transporter (DAT), aromatic amino acid decarboxylase (AADC), or vesicular monoamine type 2 were investigated. Tracer binding data were extracted from the original articles. Heterogeneity of the data was examined using I2 statistics, and a random-effects model was used to summarize data. Hedges g was used as an estimator of effect size in group comparisons. Results are reported according to PRISMA guidelines. Results: Thirty-five studies (29 DAT, 6 AADC, no vesicular monoamine type 2 studies) with 356 MSA-P patients, 204 PSP patients, 79 CBS patients, and 62 MSA-C patients were included in the metaanalysis. Caudate nucleus and putamen DAT function was clearly lower in PSP than in PD (caudate: 34.1% difference, g = −1.08, 95% confidence interval [CI] = −1.52 to −0.64; putamen: 18.2%, g = −0.86, 95% CI = −1.50 to −0.21) and MSA-P (striatum: 31.4%, g = −0.70, 95% CI = −1.21 to −0.19) and was clearly lower in MSA-P than in MSA-C (striatum: 46.0%, g = 1.46, 95% CI = 0.23 to 2.68). Although not significant because of limited data, aromatic l-AADC results paralleled the DAT findings. Conclusion: Striatal presynaptic DAT function is clearly lower in PSP patients than in PD and MSA-P patients and is clearly lower in MSA-P patients than in MSA-C patients.

    更新日期:2019-12-02
  • Limits for Reduction of Acquisition Time and Administered Activity in 18F-FDG PET Studies of Alzheimer Dementia and Frontotemporal Dementia
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Florian Schiller; Lars Frings; Johannes Thurow; Philipp T. Meyer; Michael Mix

    We evaluated the effect of a reduced acquisition time for 18F-FDG PET studies of Alzheimer dementia (AD) and frontotemporal dementia (FTD) to derive a limit for reductions of acquisition time (improving patient compliance) and administered activity (lowering the radiation dose) with uncompromised diagnostic outcome. Methods: We included patients with a clinical diagnosis of AD (n = 13) or FTD (n = 12) who were examined with 18F-FDG PET/CT after injection of 210 ± 9 MBq of 18F-FDG. List-mode data were reconstructed over various time intervals simulating reduced acquisition times or administered activities. Volume-of-interest–based and voxelwise statistical analyses including group contrasts were performed for 15 different acquisition times ranging from 10 min to 2 s. In addition, masked visual reads were obtained from 3 readers independently for 7 different acquisition times down to 30 s, providing a diagnosis of either AD or FTD and the individual diagnostic certainty. Results: Regional mean uptake changed by less than 5% at a reduced acquisition time down to 1 min in all regions and patients except for the posterior cingulate cortex of 1 patient. Voxelwise group contrasts suggest a sufficient measurement time of only 2 min, for which the number of significant voxels decreased by merely 5% while maintaining their spatial pattern. In 450 visual reads at reduced times, no change in the original diagnosis was observed. The diagnostic certainty showed only a very slow and mild decline, with small effect sizes (Cohen’s d) of 0.3, at acquisition times of 3 and 2 min compared with the original results at 10 min. Conclusion: Statistical results at a region and voxel level, as well as single-subject visual reads, reveal a considerable potential to reduce the typical 10-min acquisition time (by a factor of 4) without compromising diagnostic quality. Conversely, our data suggest that for a given acquisition time of 10 min and a similar effect size, the administered activity may be reduced to 50 MBq, resulting in an effective dose of less than 1 mSv for the PET examination.

    更新日期:2019-12-02
  • A Fully Automatic Technique for Precise Localization and Quantification of Amyloid-β PET Scans
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Mouna Tahmi; Wassim Bou-Zeid; Qolamreza R. Razlighi

    Spatial heterogeneity in the accumulation of amyloid-β plaques throughout the brain during asymptomatic as well as clinical stages of Alzheimer disease calls for precise localization and quantification of this protein using PET imaging. To address this need, we have developed and evaluated a technique that quantifies the extent of amyloid-β pathology on a millimeter-by-millimeter scale in the brain with unprecedented precision using data from PET scans. Methods: An intermodal and intrasubject registration with normalized mutual information as the cost function was used to transform all FreeSurfer neuroanatomic labels into PET image space, which were subsequently used to compute regional SUV ratio (SUVR). We have evaluated our technique using postmortem histopathologic staining data from 52 older participants as the standard-of-truth measurement. Results: Our method resulted in consistently and significantly higher SUVRs in comparison to the conventional method in almost all regions of interest. A 2-way ANOVA revealed a significant main effect of method as well as a significant interaction effect of method on the relationship between computed SUVR and histopathologic staining score. Conclusion: These findings suggest that processing the amyloid-β PET data in subjects’ native space can improve the accuracy of the computed SUVRs, as they are more closely associated with the histopathologic staining data than are the results of the conventional approach.

    更新日期:2019-12-02
  • In Vivo Synaptic Density Imaging with 11C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Takuya Toyonaga; Levi M. Smith; Sjoerd J. Finnema; Jean-Dominique Gallezot; Mika Naganawa; Jason Bini; Tim Mulnix; Zhengxin Cai; Jim Ropchan; Yiyun Huang; Stephen M. Strittmatter; Richard E. Carson

    11C-UCB-J is a new PET tracer for synaptic density imaging. Recently, we conducted 11C-UCB-J PET on patients with mild cognitive impairment or early Alzheimer disease (AD) and found a 41% decrease in specific binding in the hippocampus compared with healthy subjects. We hypothesized that 11C-UCB-J may have potential to be a general biomarker for evaluating AD treatment effects via monitoring of synaptic density changes. In this study, we performed longitudinal 11C-UCB-J PET on AD mice to measure the treatment effects of saracatinib, which previously demonstrated synaptic changes with postmortem methods. Methods: Nine wild-type (WT) mice and 9 amyloid precursor protein and presenilin 1 double-transgenic (APPswe/PS1ΔE9 [APP/PS1]) mice underwent 3 11C-UCB-J PET measurements: at baseline, after treatment, and during drug washout. After baseline measurements, saracatinib, a Fyn kinase inhibitor currently in clinical development for AD treatment, was administered by oral gavage for 41 ± 11 d. Treatment-phase measurements were performed on the last day of treatment, and washout-phase measurements occurred more than 27 d after the end of treatment. SUVs from 30 to 60 min after injection of 11C-UCB-J were calculated and normalized by the whole-brain (WB) or brain stem (BS) average values as SUV ratio (SUVR(WB) or SUVR-1(BS)). Results: Hippocampal SUVR(WB) at baseline was significantly lower in APP/PS1 than WT mice (APP/PS1: 1.11 ± 0.04, WT: 1.15 ± 0.02, P = 0.033, unpaired t test). Using SUVR-1(BS) in the hippocampus, there was also a significant difference at baseline (APP/PS1: 0.48 ± 0.13, WT: 0.65 ± 0.10, P = 0.017, unpaired t test). After treatment with saracatinib, hippocampal SUVR(WB) in APP/PS1 mice was significantly increased (P = 0.037, paired t test). A trend-level treatment effect was seen with hippocampal SUVR-1(BS). Saracatinib treatment effects may persist, as there were no significant differences between WT and APP/PS1 mice after drug washout. Conclusion: On the basis of the 11C-UCB-J PET results, hippocampal synaptic density was lower in APP/PS1 mice than in WT mice at baseline, and this deficit was normalized by treatment with saracatinib. These results support the use of 11C-UCB-J PET to identify disease-specific synaptic deficits and to monitor treatment effects in AD.

    更新日期:2019-12-02
  • Longitudinal PET Monitoring of Amyloidosis and Microglial Activation in a Second-Generation Amyloid-β Mouse Model
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Christian Sacher; Tanja Blume; Leonie Beyer; Finn Peters; Florian Eckenweber; Carmelo Sgobio; Maximilian Deussing; Nathalie L. Albert; Marcus Unterrainer; Simon Lindner; Franz-Josef Gildehaus; Barbara von Ungern-Sternberg; Irena Brzak; Ulf Neumann; Takashi Saito; Takaomi C. Saido; Peter Bartenstein; Axel Rominger; Jochen Herms; Matthias Brendel

    Nonphysiologic overexpression of amyloid-β (Aβ) precursor protein in common transgenic Aβ mouse models of Alzheimer disease likely hampers their translational potential. The novel AppNL-G-F mouse incorporates a mutated knock-in, potentially presenting an improved model of Alzheimer disease for Aβ-targeting treatment trials. We aimed to establish serial small-animal PET of amyloidosis and neuroinflammation in AppNL-G-F mice as a tool for therapy monitoring. Methods: AppNL-G-F mice (20 homozygous and 21 heterogeneous) and 12 age-matched wild-type mice were investigated longitudinally from 2.5 to 10 mo of age with 18F-florbetaben Aβ PET and 18F-GE-180 18-kDa translocator protein (TSPO) PET. Voxelwise analysis of SUV ratio images was performed using statistical parametric mapping. All mice underwent a Morris water maze test of spatial learning after their final scan. Quantification of fibrillar Aβ and activated microglia by immunohistochemistry and biochemistry served for validation of the PET results. Results: The periaqueductal gray emerged as a suitable pseudo reference tissue for both tracers. Homozygous AppNL-G-F mice had a rising SUV ratio in cortex and hippocampus for Aβ (+9.1%, +3.8%) and TSPO (+19.8%, +14.2%) PET from 2.5 to 10 mo of age (all P < 0.05), whereas heterozygous AppNL-G-F mice did not show significant changes with age. Significant voxelwise clusters of Aβ deposition and microglial activation in homozygous mice appeared at 5 mo of age. Immunohistochemical and biochemical findings correlated strongly with the PET data. Water maze escape latency was significantly elevated in homozygous AppNL-G-F mice compared with wild-type at 10 mo of age and was associated with high TSPO binding. Conclusion: Longitudinal PET in AppNL-G-F knock-in mice enables monitoring of amyloidogenesis and neuroinflammation in homozygous mice but is insensitive to minor changes in heterozygous animals. The combination of PET with behavioral tasks in AppNL-G-F treatment trials is poised to provide important insights in preclinical drug development.

    更新日期:2019-12-02
  • Biodistribution and Dosimetry of Intraventricularly Administered 124I-Omburtamab in Patients with Metastatic Leptomeningeal Tumors
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Neeta Pandit-Taskar; Pat B. Zanzonico; Kim Kramer; Milan Grkovski; Edward K. Fung; Weiji Shi; Zhigang Zhang; Serge K. Lyashchenko; Alex M. Fung; Keith S. Pentlow; Jorge A. Carrasquillo; Jason S. Lewis; Steven M. Larson; Nai-Kong V. Cheung; John L. Humm

    Radiation dose estimations are key for optimizing therapies. We studied the role of 124I-omburtamab (8H9) given intraventricularly in assessing the distribution and radiation doses before 131I-omburtamab therapy in patients with metastatic leptomeningeal disease and compared it with the estimates from cerebrospinal fluid (CSF) sampling. Methods: Patients with histologically proven malignancy and metastatic disease to the central nervous system or leptomeninges who met eligibility criteria for 131I-omburtamab therapy underwent immuno-PET imaging with 124I-8H9 followed by 131I-8H9 antibody therapy. Patients were imaged with approximately 74 MBq of intraventricular 124I-omburtamab via an Ommaya reservoir. Whole-body PET images were acquired at approximately 4, 24, and 48 h after administration and analyzed for dosimetry calculations. Peripheral blood and CSF samples were obtained at multiple time points for dosimetry estimation. Results: Forty-two patients with complete dosimetry and therapy data were analyzed. 124I-omburtamab PET–based radiation dosimetry estimations revealed mean (±SD) absorbed dose to the CSF for 131I-8H9 of 0.62 ± 0.40 cGy/MBq, compared with 2.22 ± 2.19 cGy/MBq based on 124I-omburtamab CSF samples and 1.53 ± 1.37 cGy/MBq based on 131I-omburtamab CSF samples. The mean absorbed dose to the blood was 0.051 ± 0.11 cGy/MBq for 124I-omburtamab samples and 0.07 ± 0.04 cGy/MBq for 131I-omburtamab samples. The effective whole-body radiation dose for 124I-omburtamab was 0.49 ± 0.27 mSv/MBq. The mean whole-body clearance half-time was 44.98 ± 16.29 h. Conclusion: PET imaging with 124I-omburtamab antibody administered intraventricularly allows for noninvasive estimation of dose to CSF and normal organs. High CSF-to-blood absorbed-dose ratios are noted, allowing for an improved therapeutic index to leptomeningeal disease and reduced systemic doses. PET imaging–based estimates were less variable and more reliable than CSF sample–based dosimetry.

    更新日期:2019-12-02
  • PARaDIM: A PHITS-Based Monte Carlo Tool for Internal Dosimetry with Tetrahedral Mesh Computational Phantoms
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Lukas M. Carter; Troy M. Crawford; Tatsuhiko Sato; Takuya Furuta; Chansoo Choi; Chan Hyeong Kim; Justin L. Brown; Wesley E. Bolch; Pat B. Zanzonico; Jason S. Lewis

    Mesh-type and voxel-based computational phantoms comprise the current state of the art for internal dose assessment via Monte Carlo simulations but excel in different aspects, with mesh-type phantoms offering advantages over their voxel counterparts in terms of their flexibility and realistic representation of detailed patient- or subject-specific anatomy. We have developed PARaDIM (pronounced “paradigm”: Particle and Heavy Ion Transport Code System–Based Application for Radionuclide Dosimetry in Meshes), a freeware application for implementing tetrahedral mesh-type phantoms in absorbed dose calculations. It considers all medically relevant radionuclides, including α, β, γ, positron, and Auger/conversion electron emitters, and handles calculation of mean dose to individual regions, as well as 3-dimensional dose distributions for visualization and analysis in a variety of medical imaging software. This work describes the development of PARaDIM, documents the measures taken to test and validate its performance, and presents examples of its uses. Methods: Human, small-animal, and cell-level dose calculations were performed with PARaDIM and the results compared with those of widely accepted dosimetry programs and literature data. Several tetrahedral phantoms were developed or adapted using computer-aided modeling techniques for these comparisons. Results: For human dose calculations, agreement of PARaDIM with OLINDA 2.0 was good—within 10%–20% for most organs—despite geometric differences among the phantoms tested. Agreement with MIRDcell for cell-level S value calculations was within 5% in most cases. Conclusion: PARaDIM extends the use of Monte Carlo dose calculations to the broader community in nuclear medicine by providing a user-friendly graphical user interface for calculation setup and execution. PARaDIM leverages the enhanced anatomic realism provided by advanced computational reference phantoms or bespoke image-derived phantoms to enable improved assessments of radiation doses in a variety of radiopharmaceutical use cases, research, and preclinical development. PARaDIM can be downloaded freely at www.paradim-dose.org.

    更新日期:2019-12-02
  • The Characterization of 18F-hGTS13 for Molecular Imaging of xC− Transporter Activity with PET
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Corinne Beinat; Gayatri Gowrishankar; Bin Shen; Israt S. Alam; Elise Robinson; Tom Haywood; Chirag B. Patel; Emily Carmen Azevedo; Jessa B. Castillo; Ohad Ilovich; Norman Koglin; Heribert Schmitt-Willich; Mathias Berndt; Andre Mueller; Marion Zerna; Ananth Srinivasan; Sanjiv Sam Gambhir

    The aim of this study was development of an improved PET radiotracer for measuring xC− activity with increased tumor uptake and reduced uptake in inflammatory cells compared with (S)-4-(3-18F-fluoropropyl)-l-glutamate (18F-FSPG). Methods: A racemic glutamate derivative, 18F-hGTS13, was evaluated in cell culture and animal tumor models. 18F-hGTS13 was separated into C5 epimers, and the corresponding 18F-hGTS13-isomer1 and 18F-hGTS13-isomer2 were evaluated in H460 tumor–bearing rats. Preliminary studies investigated the cellular uptake of 18F-hGTS13-isomer2 in multiple immune cell populations and states. Results: 18F-hGTS13 demonstrated excellent H460 tumor visualization with high tumor-to-background ratios, confirmed by ex vivo biodistribution studies. Tumor-associated radioactivity was significantly higher for 18F-hGTS13 (7.5 ± 0.9 percentage injected dose [%ID]/g, n = 3) than for 18F-FSPG (4.6 ± 0.7 %ID/g, n = 3, P = 0.01). 18F-hGTS13-isomer2 exhibited excellent H460 tumor visualization (6.3 ± 1.1 %ID/g, n = 3) and significantly reduced uptake in multiple immune cell populations relative to 18F-FSPG. 18F-hGTS13-isomer2 exhibited increased liver uptake relative to 18F-FSPG (4.6 ± 0.8 vs. 0.7 ± 0.01 %ID/g), limiting its application in hepatocellular carcinoma. Conclusion: 18F-hGTS13-isomer2 is a new PET radiotracer for molecular imaging of xC− activity that may provide information on tumor oxidation states. 18F-hGTS13-isomer2 has potential for clinical translation for imaging cancers of the thorax because of the low background signal in healthy tissue.

    更新日期:2019-12-02
  • Performance Evaluation of a High-Resolution Nonhuman Primate PET/CT System
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Zsolt Sarnyai; Kálmán Nagy; Gergely Patay; Milán Molnár; Göran Rosenqvist; Miklós Tóth; Akihiro Takano; Balázs Gulyás; Péter Major; Christer Halldin; Andrea Varrone

    The LFER 150 PET/CT device (large–field-of-view extreme-resolution portable research imager) is a system for nonhuman primate (NHP) imaging. The objective of this study was to evaluate the performance of the system using the National Electrical Manufacturers Association NU 4-2008 standard protocol. As a preliminary in vivo evaluation of the system, a PET measurement in an NHP was also performed. Methods: Resolution, sensitivity, image quality, and noise-equivalent count rate (NECR) were measured. NECR measurement was performed with a ratlike phantom and a monkeylike phantom. A Derenzo phantom experiment was performed to test the resolution using 3-dimensional ordered-subset expectation maximization reconstruction. One cynomolgus monkey (4.5 kg, intravenous ketamine/xylazine anesthesia) was examined with the dopamine transporter radioligand 18F-FE-PE2I (94 MBq) to evaluate the in vivo performance of the system. List-mode PET data acquired for 93 min were reconstructed into 38 frames with the Tera-Tomo 3-dimensional engine. Binding potential for caudate nucleus, putamen, and substantia nigra was evaluated using the simplified reference tissue model. Results: Radial full-width half-maximum resolution using Fourier rebinning and a 2-dimensional filtered backprojection algorithm was less than 2.2 mm and less than 3.2 mm in the central 60-mm-diameter and 140-mm-diameter regions, respectively. Maximum sensitivity in the 400- to 600-keV and 250- to 750-keV energy windows was 30.03 cps/kBq (3.3%) and 49.11 cps/kBq (5.4%), respectively. The uniformity in the image-quality phantom was 3.3%, and the spillover ratio for air and water was 0.1. The peak of the NECR curve was 430 kcps (at 115 MBq) with the ratlike phantom and 78 kcps (at 139 MBq) with the monkeylike phantom. Rods of the Derenzo phantom with 1-mm diameter could be distinguished by eye. In the NHP experiment, binding potentials in the caudate, putamen, and substantia nigra (4.9, 4.9, and 1, respectively) were similar to those previously reported using the same radioligand and a high-resolution research tomograph. Conclusion: The results obtained from phantom experiments and 1 representative PET measurement in an NHP confirm that the LFER 150 is a high-resolution PET/CT system with suitable performance for brain imaging in NHPs.

    更新日期:2019-12-02
  • 89Zr-Immuno-PET: Toward a Noninvasive Clinical Tool to Measure Target Engagement of Therapeutic Antibodies In Vivo
    J Nucl. Med. (IF 7.354) Pub Date : 2019-12-01
    Yvonne W.S. Jauw; Joseph A. O’Donoghue; Josée M. Zijlstra; Otto S. Hoekstra; C. Willemien Menke-van der Houven van Oordt; Franck Morschhauser; Jorge A. Carrasquillo; Sonja Zweegman; Neeta Pandit-Taskar; Adriaan A. Lammertsma; Guus. A.M.S. van Dongen; Ronald Boellaard; Wolfgang A. Weber; Marc C. Huisman

    89Zr-immuno-PET is a promising noninvasive clinical tool that measures target engagement of monoclonal antibodies (mAbs) to predict toxicity in normal tissues and efficacy in tumors. Quantification of 89Zr-immuno-PET will need to move beyond SUVs, since total uptake may contain a significant non–target-specific contribution. Nonspecific uptake is reversible (e.g., blood volume) or irreversible (due to 89Zr-residualization after mAb degradation). The aim of this study was to assess nonspecific uptake in normal tissues as a first critical step toward quantification of target engagement in normal tissues and tumors using 89Zr-immuno-PET. Methods: Data from clinical studies with 4 89Zr-labeled intact IgG1 antibodies were collected, resulting in a total of 128 PET scans (1–7 d after injection from 36 patients: 89Zr-obinutuzumab [n = 9], 89Zr-cetuximab [n = 7], 89Zr-huJ591 [n = 10], and 89Zr-trastuzumab [n = 10] [denoted as 89Zr-anti-CD20, 89Zr-anti-EGFR, 89Zr-anti-PSMA and 89Zr-anti-HER2, respectively]). Nonspecific uptake was defined as uptake measured in tissues without known target expression. Patlak graphical evaluation of transfer constants was used to estimate the reversible (Vt) and irreversible (Ki) contributions to the total measured uptake for the kidney, liver, lung, and spleen. Baseline values were calculated per tissue combining all mAbs without target expression (kidney: 89Zr-anti-CD20, 89Zr-anti-EGFR, and 89Zr-anti-HER2; liver: 89Zr-anti-CD20; lung: 89Zr-anti-CD20, 89Zr-anti-EGFR, and 89Zr-anti-PSMA; spleen: 89Zr-anti-EGFR and 89Zr-anti-HER2). Results: For the kidney, liver, lung, and spleen, baseline Vt was 0.20, 0.24, 0.09, and 0.24 mL⋅cm−3, respectively, and baseline Ki was 0.7, 1.1, 0.2 and 0.5 μL⋅g−1⋅h−1, respectively. For 89Zr-anti-PSMA, a 4-fold higher Ki was observed for the kidney, indicating target engagement. In this case, nonspecific uptake accounted for 66%, 34%, and 22% of the total signal in the kidney at 1, 3, and 7 d after injection, respectively. Conclusion: This study shows that nonspecific uptake of mAbs for tissues without target expression can be quantified using 89Zr-immuno-PET at multiple time points. These results form a crucial base for measurement of target engagement by therapeutic antibodies in vivo with 89Zr-immuno-PET. For future studies, a pilot phase including at least 3 scans at 1 or more days after injection is required to assess nonspecific uptake as a function of time, to optimize study design for detection of target engagement.

    更新日期:2019-12-02
  • Is the Vision of Radioligand Therapy for Prostate Cancer Becoming a Reality? An Overview of the Phase III VISION Trial and Its Importance for the Future of Theranostics
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Kambiz Rahbar; Lisa Bodei; Michael J. Morris

    Prostate-specific membrane antigen (PSMA) is of considerable interest as a target for diagnostics and therapy of prostate cancer patients. PSMA-targeted imaging has demonstrable value in guiding the management of the clinical evolution of prostatic cancer. The use of PSMA-targeted therapy using 177Lu-labeled PSMA-617 is similarly effective and is progressing toward approval. The phase III VISION trial represents the largest well-designed and executed study of a theranostic pair. This article provides an overview of the phase III trial and delineates the different study arms and their implications in the assessment of efficacy. The VISION (phase III) trial will provide data of critical value to the field of theranostics and especially the field of prostatic cancer management.

    更新日期:2019-11-04
  • Quantitative Clinical Nuclear Cardiology, Part 1: Established Applications
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Ernest V. Garcia; Piotr Slomka; Jonathan B. Moody; Guido Germano; Edward P. Ficaro

    SPECT myocardial perfusion imaging has attained widespread clinical acceptance as a standard of care for patients with known or suspected coronary artery disease. A significant contribution to this success has been the use of computer techniques to provide objective quantitative assessment in the standardization of the interpretation of these studies. Software platforms have been developed as a pipeline to provide the quantitative algorithms researched, developed and validated to be clinically useful so diagnosticians everywhere can benefit from these tools. The goal of this continuing medical education article (part 1) is to describe the many quantitative tools that are clinically established and, more importantly, how clinicians should use them routinely in interpretation, clinical management, and therapy guidance for patients with coronary artery disease.

    更新日期:2019-11-04
  • Imaging Patients with Metastatic Castration-Resistant Prostate Cancer Using 89Zr-DFO-MSTP2109A Anti-STEAP1 Antibody
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Jorge A. Carrasquillo; Bernard M. Fine; Neeta Pandit-Taskar; Steven M. Larson; Stephen E. Fleming; Josef J. Fox; Sarah M. Cheal; Joseph A. O’Donoghue; Shutian Ruan; Govind Ragupathi; Serge K. Lyashchenko; John L. Humm; Howard I. Scher; Mithat Gönen; Simon P. Williams; Daniel C. Danila; Michael J. Morris

    Six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a relatively newly identified target in prostate cancer. We evaluated the ability of PET/CT with 89Zr-DFO-MSTP2109A, an antibody that recognizes STEAP1, to detect lesions in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: Nineteen mCRPC patients were prospectively imaged using approximately 185 MBq/10 mg of 89Zr-DFO-MSTP2109A. 89Zr-DFO-MSTP2109A PET/CT images obtained 4–7 d after injection were compared with bone and CT scans. Uptake in lesions was measured. Fifteen patients were treated with an antibody–drug conjugate (ADC) based on MSTP2109A; ADC treatment–related data were correlated with tumor uptake by PET imaging. Bone or soft-tissue biopsy samples were evaluated. Results: No significant toxicity occurred. Excellent uptake was observed in bone and soft-tissue disease. Median SUVmax was 20.6 in bone and 16.8 in soft tissue. Sixteen of 17 lesions biopsied were positive on 89Zr-DFO-MSTP2109A, and all sites were histologically positive (1 on repeat biopsy). Bayesian analysis resulted in a best estimate of 86% of histologically positive lesions being true-positive on imaging (95% confidence interval, 75%–100%). There was no correlation between SUVmax tumor uptake and STEAP1 immunohistochemistry, survival after ADC treatment, number of ADC treatment cycles, or change in prostate-specific antigen level. Conclusion: 89Zr-DFO-MSTP2109A is well tolerated and shows localization in mCRPC sites in bone and soft tissue. Given the high SUV in tumor and localization of a large number of lesions, this reagent warrants further exploration as a companion diagnostic in patients undergoing STEAP1-directed therapy.

    更新日期:2019-11-04
  • Prediction of Time to Hormonal Treatment Failure in Metastatic Castration-Sensitive Prostate Cancer with 18F-FDG PET/CT
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Hossein Jadvar; Erik M. Velez; Bhushan Desai; Lingyun Ji; Patrick M. Colletti; David I. Quinn

    The aim of this prospective investigation was to assess the association of 18F-FDG PET/CT with time to hormonal treatment failure (THTF) in men with metastatic castration-sensitive prostate cancer. Methods: 76 men with metastatic castration-sensitive prostate cancer recruited from 2005 to 2011 underwent 18F-FDG PET/CT and were followed prospectively for THTF, defined as treatment change to chemotherapy or death. Patients who had not switched to chemotherapy were censored at the last follow-up date (median of 36 mo; range, 12–108 mo). Cox regression analyses were performed to examine the association between PET/CT measurements: sum of SUVmax, maximum SUVmax, and average SUVmax for up to 10 of the most active lesions and THTF. Survival probabilities were based on the Kaplan–Meier method. Results: 43 patients had hormonal treatment failure, and 8 died without documented treatment failure. Median THTF was 26.5 mo (95% confidence interval [CI], 15.5–46.6 mo). The THTF-free probability at 5 y was 35% ± 6%. On univariate analysis, all PET parameters, including number of lesions, were statistically significant for THTF. In a reduced multivariate model accounting for clinical variables, only sum of SUVmax (hazard ratio, 1.01; 95% CI, 1.002–1.03; P = 0.024) and number of lesions (hazard ratio, 1.18; 95% CI, 1.08–1.29; P < 0.001) were independently associated with THTF. When sum of SUVmax was grouped into quartile ranges, there was a significantly worse survival probability for patients in the fourth-quartile range than in the first, with a univariate hazard ratio of 6.2 (95% CI, 2.8–13.6; P < 0.001). Conclusion: Sum of SUVmax and number of lesions derived from 18F-FDG PET/CT provide independent prognostic information on THTF in men with metastatic castration-sensitive prostate cancer.

    更新日期:2019-11-04
  • 18F-Fluciclovine Parameters on Targeted Prostate Biopsy Associated with True Positivity in Recurrent Prostate Cancer
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Olayinka A. Abiodun-Ojo; Akinyemi A. Akintayo; Oladunni O. Akin-Akintayo; Funmilayo I. Tade; Peter T. Nieh; Viraj A. Master; Mehrdad Alemozaffar; Adeboye O. Osunkoya; Mark M. Goodman; Baowei Fei; David M. Schuster

    We evaluated 18F-fluciclovine uptake parameters that correlate with true positivity for local recurrence in non–prostatectomy-treated patients. Methods: Twenty-one patients (prostate-specific antigen level, 7.4 ± 6.8 ng/mL) with biochemical recurrence after nonprostatectomy local therapy (radiotherapy and cryotherapy) underwent dual–time-point 18F-fluciclovine (364.1 ± 37.7 MBq) PET/CT from pelvis to diaphragm. Prostatic uptake over background was delineated and coregistered to a prostate-biopsy–planning ultrasound. Transrectal biopsies of 18F-fluciclovine–defined targets were completed using a 3-dimensional visualization and navigation platform. Histologic analyses of lesions were completed. Lesion characteristics including SUVmax, target-to-background ratio (TBR), uptake pattern, and subjective reader’s suspicion level were compared between true-positive (malignant) and false-positive (benign) lesions. Univariate analysis was used to determine the association between PET and histologic findings. Receiver-operating-characteristic curves were plotted to determine discriminatory cutoffs for TBR. Statistical significance was set at a P value of less than 0.05. Results: Fifty lesions were identified in 21 patients on PET. Seventeen of 50 (34.0%) targeted lesions in 10 of 21 patients were positive for malignancy. True-positive lesions had a significantly higher SUVmax (6.62 ± 1.70 vs. 4.92 ± 1.27), marrow TBR (2.57 ± 0.81 vs. 1.69 ± 0.51), and blood-pool TBR (4.10 ± 1.17 vs. 2.99 ± 1.01) than false-positive lesions at the early time point (P < 0.01) and remained significant at the delayed time point, except for blood-pool TBR. Focal uptake (odds ratio, 12.07; 95% confidence interval, 2.98–48.80; P < 0.01) and subjective highest suspicion level (odds ratio, 10.91; 95% confidence interval, 1.19–99.69; P = 0.03) correlated with true positivity. Using the receiver-operating-characteristic curve, optimal cutoffs for marrow TBR were 1.9 (area under the curve, 0.82) and 1.8 (area under the curve, 0.85) at early and delayed imaging, respectively. With these cutoffs, 15 of 17 malignant lesions were identified at both time points; however, fewer false-positive lesions were detected at the delayed time point (5/33) than at the early time point (11/33). Conclusion: True positivity of 18F-fluciclovine–targeted prostate biopsy in non–prostatectomy-treated patients correlates with focal uptake, TBR (blood pool and marrow), and subjective highest suspicion level. A marrow TBR of 1.9 at the early time point and 1.8 at the delayed time point had optimal discriminating capabilities. Despite the relatively low intraprostate positive predictive value (34.0%) with 18F-fluciclovine, application of these parameters to interpretative criteria may improve true positivity in the treated prostate.

    更新日期:2019-11-04
  • 18F-FDG PET/MRI for Therapy Response Assessment of Isolated Limb Perfusion in Patients with Soft-Tissue Sarcomas
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Johannes Grueneisen; Benedikt Schaarschmidt; Aydin Demircioglu; Michal Chodyla; Ole Martin; Stefanie Bertram; Axel Wetter; Sebastian Bauer; Wolfgang Peter Fendler; Lars Podleska; Michael Forsting; Ken Herrmann; Lale Umutlu

    Our purpose was to assess the diagnostic potential of simultaneously acquired 18F-FDG PET and MRI data sets for therapy response assessment of isolated limb perfusion (ILP) in patients with soft-tissue sarcomas (STS). Methods: In total, 45 patients with histopathologically verified STS were prospectively enrolled for an integrated 18F-FDG PET/MRI examination before and after ILP. Therapy response was assessed based on different MRI- and PET-derived morphologic (RECIST and the MR-adapted Choi criteria) and metabolic (PERCIST) criteria. In addition, a regression model was used combining relative changes in quantitative variables to predict treatment response under ILP. Histopathologic results after subsequent tumor resection served as the reference standard, and patients were categorized as responders or nonresponders on the basis of the 6-stage regression scale by Salzer-Kuntschik. Results: Histopathologic analysis categorized 27 patients as responders (grades I–III) and 18 patients as nonresponders (grades IV–VI). Calculated sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were 22%, 89%, 75%, 43%, and 49% for RECIST; 70%, 44%, 66%, 50%, and 60% for the Choi criteria; and 85%, 78%, 85%, 78%, and 82% for PERCIST. Receiver-operating-characteristic analysis revealed an area under the curve (AUC) of 0.56 for RECIST, 0.57 for the Choi criteria, and 0.82 for PERCIST. The combined regression model revealed higher values (AUC, 0.90) than for the stand-alone analysis, however, differences to metabolic parameters did not reach significance (P value: 0.067). Conclusion: Our study demonstrates the superiority of 18F-FDG PET over MRI data sets for response assessment of STS under neoadjuvant ILP. In a clinical setting, MRI delivers valuable information for presurgical assessment. Therefore, combining 18F-FDG PET and MRI data may enable more reliable treatment planning and therapy monitoring of STS.

    更新日期:2019-11-04
  • Metabolic Biomarker–Based BRAFV600 Mutation Association and Prediction in Melanoma
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Hanna Saadani; Bernies van der Hiel; Else A. Aalbersberg; Ioannis Zavrakidis; John B.A.G. Haanen; Otto S. Hoekstra; Ronald Boellaard; Marcel P.M. Stokkel

    The aim of this study was to associate and predict B-rapidly accelerated fibrosarcoma valine 600 (BRAFV600) mutation status with both conventional and radiomics 18F-FDG PET/CT features, while exploring several methods of feature selection in melanoma radiomics. Methods: Seventy unresectable stage III–IV melanoma patients who underwent a baseline 18F-FDG PET/CT scan were identified. Patients were assigned to the BRAFV600 group or BRAF wild-type group according to mutational status. 18F-FDG uptake quantification was performed by semiautomatic lesion delineation. Four hundred eighty radiomics features and 4 conventional PET features (SUVmax, SUVmean, SUVpeak, and total lesion glycolysis) were extracted per lesion. Six different methods of feature selection were implemented, and 10-fold cross-validated predictive models were built for each. Model performances were evaluated with areas under the curve (AUCs) for the receiver operating characteristic curves. Results: Thirty-five BRAFV600 mutated patients (100 lesions) and 35 BRAF wild-type patients (79 lesions) were analyzed. AUCs predicting the BRAFV600 mutation varied from 0.54 to 0.62 and were susceptible to feature selection method. The best AUCs were achieved by feature selection based on literature, a penalized binary logistic regression model, and random forest model. No significant difference was found between the BRAFV600 and BRAF wild-type group in conventional PET features or predictive value. Conclusion: BRAFV600 mutation status is not associated with, nor can it be predicted with, conventional PET features, whereas radiomics features were of low predictive value (AUC = 0.62). We showed feature selection methods to influence predictive model performance, describing and evaluating 6 unique methods. Detecting BRAFV600 status in melanoma based on 18F-FDG PET/CT alone does not yet provide clinically relevant knowledge.

    更新日期:2019-11-04
  • Accuracy of 18F-FDG PET/CT in Predicting Residual Disease After Neoadjuvant Chemoradiotherapy for Esophageal Cancer
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Maria J. Valkema; Bo Jan Noordman; Bas P.L. Wijnhoven; Manon C.W. Spaander; Katharina Biermann; Sjoerd M. Lagarde; Roel J. Bennink; Wendy M.J. Schreurs; Mark J. Roef; Monique G.G. Hobbelink; Marcel J.R. Janssen; Laura H. Graven; J. Jan B. van Lanschot; Roelf Valkema

    Our purpose was to prospectively investigate optimal evaluation of qualitative and quantitative 18F-FDG PET/CT in response evaluations 12–14 wk after neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer patients. Methods: This was a side study of the prospective diagnostic pre-SANO trial. 18F-FDG PET/CT scans at baseline and at 12–14 wk after nCRT were qualitatively assessed for the presence of tumor. Maximum SUVs normalized for lean body mass (SULmax) were measured in all scans. The primary endpoint was the proportion of false-negative patients with tumor regression grade (TRG) 3–4 (>10% vital residual tumor) in qualitative and quantitative analyses. Receiver-operating-characteristic curve analysis for TRG1 versus TRG3–4 using SULmax, SULmax tumor-to-esophagus ratio, and Δ%SULmax was performed to define optimal cutoffs. Secondary endpoints were sensitivity, specificity, negative predictive value, and positive predictive value for TRG1 versus TRG2–4. Results: In total, 129 of 219 patients were analyzed. Qualitative 18F-FDG PET/CT was unable to detect TRG3–4 in 15% of patients. Sensitivity, specificity, negative predictive value, and positive predictive value in qualitative analysis for detecting TRG1 versus TRG2–4 was 80%, 37%, 42%, and 77%, respectively. In 18 of 190 patients (10%) with follow-up scans after nCRT, 18F-FDG PET/CT identified new interval metastases. Quantitative parameters did not detect TRG3–4 tumor in 27%–61% of patients. The optimal cutoff for detecting TRG1 versus TRG2–4 was a post-nCRT SULmax of 2.93 (area under receiver-operating-characteristic curve, 0.70). Conclusion: Qualitative and quantitative analyses of 18F-FDG PET/CT are unable to accurately detect TRG3–4 and to discriminate substantial residual disease from benign inflammation-induced 18F-FDG uptake after nCRT. However, 18F-FDG PET/CT is useful for the detection of interval metastases and might become useful in an active surveillance strategy with serial 18F-FDG PET/CT scanning.

    更新日期:2019-11-04
  • 18F-FDG PET/CT Is an Early Predictor of Pathologic Tumor Response and Survival After Preoperative Radiochemotherapy with Bevacizumab in High-Risk Locally Advanced Rectal Cancer
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Antonio Avallone; Luigi Aloj; Biagio Pecori; Corradina Caracò; Alfonso De Stefano; Fabiana Tatangelo; Lucrezia Silvestro; Vincenza Granata; Francesco Bianco; Carmela Romano; Francesca Di Gennaro; Alfredo Budillon; Antonella Petrillo; Paolo Muto; Gerardo Botti; Paolo Delrio; Secondo Lastoria

    There is an unmet need for predictive biomarkers of the clinical benefit of antiangiogenic drugs. The aim of the present study was to prospectively evaluate the value of 18F-FDG PET/CT performed during and after preoperative chemoradiotherapy with bevacizumab for the prediction of complete pathologic tumor regression and survival in patients with MRI-defined high-risk locally advanced rectal cancer. Methods: Sixty-one patients treated in a nonrandomized phase II study (BRANCH) with concomitant or sequential (4 d before chemoradiotherapy) administration of bevacizumab with preoperative chemoradiotherapy were included. 18F-FDG PET/CT was performed at baseline, 11 d after the beginning of chemoradiotherapy (early), and before surgery (late). Metabolic changes were compared with pathologic complete tumor regression (TRG1) versus incomplete tumor regression (TRG2–TRG5), progression-free survival, cancer-specific survival, and overall survival. Receiver-operating-characteristic curves were calculated for those 18F-FDG PET/CT parameters that significantly correlated with TRG1. Results: Early total-lesion glycolysis and its percentage change compared with baseline (ΔTLG-early) could discriminate TRG1 from TRG2–TRG5. Only receiver-operating-characteristic analysis of ΔTLG-early showed an area under the curve greater than 0.7 (0.76), with an optimal cutoff at 59.5% (80% sensitivity, 71.4% specificity), for identifying TRG1. Late metabolic assessment could not discriminate between the 2 groups. After a median follow-up of 98 mo (range, 77–132 mo), metabolic responders (ΔTLG-early ≥ 59.5%) demonstrated a significantly higher 10-y progression-free survival (89.3% vs. 63.6%, P = 0.02) and cancer-specific survival (92.9% vs. 72.6%, P = 0.04) than incomplete metabolic responders. Conclusion: Our results suggest that early metabolic response can act as a surrogate marker of the benefit of antiangiogenic therapy. The findings provide further support for the use of early 18F-FDG PET/CT evaluation to predict pathologic response and survival in the preoperative treatment of patients with locally advanced rectal cancer. ΔTLG-early showed the best accuracy in predicting tumor regression and may be particularly useful in guiding treatment-modifying decisions during preoperative chemoradiotherapy based on expected response.

    更新日期:2019-11-04
  • Temporal Modulation of HER2 Membrane Availability Increases Pertuzumab Uptake and Pretargeted Molecular Imaging of Gastric Tumors
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Patrícia M.R. Pereira; Komal Mandleywala; Ashwin Ragupathi; Lukas M. Carter; Jeroen A.C.M. Goos; Yelena Y. Janjigian; Jason S. Lewis

    Human epidermal growth factor receptor 2 (HER2) is used as a tumor biomarker and therapeutic target. Pertuzumab is an anti-HER2 antibody, and its binding to tumor cells requires HER2 to be present at the cell membrane. However, the cellular distribution of HER2 protein in gastric tumors is dynamic, and HER2 internalization decreases antibody binding to tumor cells. These features preclude the use of pretargeted strategies for molecular imaging and therapy. We explored the pharmacological modulation of HER2 endocytosis as a strategy to improve pertuzumab uptake in HER2-positive gastric tumors and allow the use of a pretargeted imaging approach. Methods: We conducted in vitro and in vivo studies with NCI-N87 gastric cancer cells to determine how HER2 endocytosis affects pertuzumab binding to tumor cells. Lovastatin, a clinically approved cholesterol-lowering drug, was used to modulate caveolae-mediated HER2 endocytosis. Results: Administration of lovastatin to NCI-N87 cancer cells resulted in significant accumulation of non-activated HER2 dimers at the cell surface. Pretreatment of NCI-N87 cells with lovastatin increased in vitro specific accumulation of membrane-bound 89Zr-labeled pertuzumab. Lovastatin-enhanced pertuzumab tumor uptake was also observed in NCI-N87 gastric cancer xenografts, allowing tumor detection as early as 4 h and high-contrast images at 48 h after tracer administration via PET. Temporal enhancement of HER2 membrane availability by lovastatin allowed imaging of cell surface HER2 with transcyclooctene-conjugated antibodies and 18F-labeled tetrazine. Conclusion: Temporal pharmacological modulation of membrane HER2 may be clinically relevant and exploitable for pretargeted molecular imaging and therapy in gastric tumors.

    更新日期:2019-11-04
  • 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer Patients with a Single Functioning Kidney
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Jingjing Zhang; Harshad R. Kulkarni; Aviral Singh; Christiane Schuchardt; Karin Niepsch; Thomas Langbein; Richard P. Baum

    The aim of this study was to assess the safety, tolerability, and effects on renal function as well as therapeutic efficacy of prostate-specific membrane antigen (PSMA)–targeted radioligand therapy (PRLT) using 177Lu-labeled PSMA-617 in patients with metastatic castration-resistant prostate cancer and a single functioning kidney before PRLT. Methods: Sixteen patients (aged 53–78 y; mean age, 64.7 ± 6.5 y) with a single functioning kidney received PRLT with 177Lu-PSMA-617 between March 2015 and October 2018. All parameters of renal function (serum creatinine, blood urea nitrogen, and electrolytes) were prospectively documented in a structured database and analyzed before each PRLT cycle and in follow-up. Renal function was further quantified by measuring tubular extraction rate (TER) using 99mTc-mercaptoacetyltriglycine renal scintigraphy. Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Kaplan–Meier analysis was performed to obtain the progression-free survival and overall survival. Results: The median administered activity was 22.1 GBq (range, 15.4–33.8 GBq). The calculated absorbed radiation dose to the kidney per cycle was 5.3 ± 2.1 Gy (0.81 ± 0.32 Gy/GBq). Renal function was already impaired at baseline in 43.7% of patients, including CTCAE grade 1 renal impairment in 25.0% and CTCAE grade 2 in 18.8%. Grade 1 and 2 renal impairment, respectively, were present in 37.5% and 6.3% of the patients after the first PRLT cycle and in 31.3% and 12.5% after the second cycle. No CTCAE grade 3 or 4 nephrotoxicity was observed during or after treatment. There was no significant change in either TER or the ratio of TER to lower-limit TER after the last cycle of treatment (P > 0.05). The median PFS was 8.1 mo based on both the criteria of the European Organization for Research and Treatment of Cancer and RECIST. The median overall survival has yet to be reached with a median follow-up time of 19.3 mo (range, 5.8–45.3 mo). Conclusion: In patients with a single functioning kidney, 177Lu-PSMA-617 PRLT is feasible, seems to be effective, and is well tolerated, without any signs of acute or subacute nephrotoxicity during a mean follow-up of nearly 2 y (and up to 45.3 mo). Further long-term follow-up of this special patient group is warranted.

    更新日期:2019-11-04
  • A Prospective Study on 18F-DCFPyL PSMA PET/CT Imaging in Biochemical Recurrence of Prostate Cancer
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Etienne Rousseau; Don Wilson; Frédéric Lacroix-Poisson; Andra Krauze; Kim Chi; Martin Gleave; Michael McKenzie; Scott Tyldesley; S. Larry Goldenberg; François Bénard

    18F-DCFPyL (2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid), a prostate-specific membrane antigen–targeting radiotracer, has shown promise as a prostate cancer imaging radiotracer. We evaluated the safety, sensitivity, and impact on patient management of 18F-DCFPyL in the setting of biochemical recurrence of prostate cancer. Methods: Subjects with prostate cancer and biochemical recurrence after radical prostatectomy or curative-intent radiotherapy were included in this prospective study. The subjects underwent 18F-DCFPyL PET/CT imaging. The localization and number of lesions were recorded. The uptake characteristics of the 5 most active lesions were measured. A pre- and posttest questionnaire was sent to treating physicians to assess the impact on management. Results: One hundred thirty subjects were evaluated. 18F-DCFPyL PET/CT localized recurrent prostate cancer in 60% of cases with a prostate-specific antigen (PSA) level of ≥0.4 to <0.5, 78% with a level of ≥0.5 to <1.0, 72% with a level of ≥1.0 to <2.0, and 92% with a level of ≥2.0. Many subjects had few lesions (1 lesion in 40.8%, 2 in 8.5%, and 3 in 4.6%). The number of lesions was significantly related to PSA by ANOVA, but there was a large overlap in the PSA values for number of lesion categories. Total lesion uptake was also significantly related to PSA level. A change in treatment intent occurred in 65.5% of subjects, disease stage changed in 65.5%, and management plans changed in 87.3%. Twenty-two subjects reported mild adverse events after the scan; all resolved completely. Conclusion: 18F-DCFPyL PET/CT is safe and sensitive for the localization of biochemical recurrence of prostate cancer. This test improved decision making for referring oncologists and changed management for most subjects.

    更新日期:2019-11-04
  • Impact of 18F-PSMA-1007 Uptake in Prostate Cancer Using Different Peptide Concentrations: Preclinical PET/CT Study on Mice
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Fumihiko Soeda; Tadashi Watabe; Sadahiro Naka; Yuwei Liu; Genki Horitsugi; Oliver C. Neels; Klaus Kopka; Mitsuaki Tatsumi; Eku Shimosegawa; Frederik L. Giesel; Jun Hatazawa

    PET radioligands with low molar activity (MA) may underestimate the quantity of the target of interest because of competitive binding of the target with unlabeled ligand. The aim of this study was to evaluate the change in the whole-body distribution of 18F-PSMA-1007 targeting prostate-specific membrane antigen (PSMA) when solutions with different peptide concentrations are used. Methods: Mouse xenograft models of LNCaP (PSMA-positive prostate cancer) (n = 18) were prepared and divided into 3 groups according to the peptide concentration injected: a high-MA group (1,013 ± 146 GBq/μmol; n = 6), a medium-MA group (100.7 ± 23.1 GBq/μmol; n = 6), and a low-MA group (10.80 ± 2.84 GBq/μmol; n = 6). Static PET scans were performed 1 h after injection (scan duration, 10 min). SUVmean in tumor and normal organs was compared by the multiple-comparison test. Immunohistochemical staining and Western blot analysis were performed to confirm expression of PSMA in tumor, salivary gland, and kidney. Results: The low-MA group (SUVmean, 1.12 ± 0.30) showed significantly lower uptake of 18F-PSMA-1007 in tumor than did the high-MA group (1.97 ± 0.77) and the medium-MA group (1.81 ± 0.57). On the other hand, in salivary gland, both the low-MA group (SUVmean, 0.24 ± 0.04) and the medium-MA group (0.57 ± 0.08) showed significantly lower uptake than the high MA group (1.27 ± 0.28). The tumor-to-salivary gland SUVmean ratio was 1.73 ± 0.55 in the high-MA group, 3.16 ± 0.86 in the medium-MA group, and 4.78 ± 1.29 in the low-MA group. The immunohistochemical staining and Western blot analysis revealed significant overexpression of PSMA in tumor and low expression in salivary gland and kidney. Conclusion: A decrease in the MA level of the injected 18F-PSMA-1007 solution resulted in decreased uptake in tumor and, to a greater degree, in normal salivary gland. Thus, there is a possibility of minimizing the adverse effects in salivary gland by setting an appropriate MA level in PSMA-targeting therapy.

    更新日期:2019-11-04
  • Recombinant α1-Microglobulin Is a Potential Kidney Protector in 177Lu-Octreotate Treatment of Neuroendocrine Tumors
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Charlotte K. Andersson; Emman Shubbar; Emil Schüler; Bo Åkerström; Magnus Gram; Eva B. Forssell-Aronsson

    Treatment of neuroendocrine tumors with 177Lu-octreotate results in prolonged survival and improved quality of life for the patient. However, the treatment is today limited by side effects on kidney and bone marrow, and complete tumor remission is rarely seen. A possible way to minimize dose-limiting toxicity and to optimize this treatment method is to use radioprotectors in conjunction with radiotherapy. A recombinant form of α1-microglobulin (rA1M) was recently shown to preserve kidney structure and function after 177Lu-octreotate injection in mice and was suggested as a radioprotector in peptide receptor radionuclide therapy. The aims of this work were to investigate the influence of rA1M on the in vivo biokinetics of 177Lu-octreotate, with a focus on tumor tissue, and to study the impact of rA1M on the therapeutic response in tumor tissue subjected to 177Lu-octreotate treatment. Methods: The biodistribution of 177Lu-octreotate was examined in BALB/c nude mice with GOT2 tumors 1–168 h after injection with either 177Lu-octreotate or coadministration of 177Lu-octreotate and rA1M. The effects of rA1M on the tumor response after 177Lu-octreotate treatment were studied in BALB/c nude mice with GOT1 tumors. Three groups of mice were administered rA1M, 177Lu-octreotate, or both. Another group served as untreated controls. Tumor volume was measured to follow the treatment effects. Results: No statistically significant difference in biodistribution of 177Lu was observed between the groups receiving 177Lu-octreotate or coinjection of 177Lu-octreotate and rA1M. The therapy study showed a decrease in mean tumor volume during the first 2 wk for both the 177Lu-octreotate group and the coadministration group, followed by tumor regrowth. No statistically significant difference between the groups was found. Conclusion: rA1M did not negatively impact absorbed dose to tumor or therapeutic response in combination with 177Lu-octreotate and may be a promising kidney protector during 177Lu-octreotate treatment of patients with neuroendocrine tumors.

    更新日期:2019-11-04
  • Dual-Time-Point 18F-Fluorocholine PET/CT in Parathyroid Imaging
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Wouter A.M. Broos; Maurits Wondergem; Friso M. van der Zant; Remco J.J. Knol

    18F-fluorocholine (18F-FCH) PET/CT is a promising and increasingly used scan technique in the preoperative imaging of parathyroid adenoma. Several acquisition methods have been evaluated in the literature, but the optimal image acquisition time point after administration of the tracer is still under debate. Methods: Patients who had hyperparathyroidism, underwent dual-time-point 18F-FCH PET/CT (image acquisition, 5 min; 60 min after injection), and had histologically proven pathologic parathyroid glands were retrospectively included in the study. Early and late images were compared both visually and quantitatively. Results: Sixty-four patients were included, and a total of 71 parathyroid glands were surgically removed. Visually, there were no differences between early and late images of hyperfunctioning parathyroid glands in 44 patients (69%); in 13 patients (20%), visualization on early images was better; in 6 patients (9%), visualization of hyperfunctioning glands was best on late images; and in 1 patient (2%), the lesion was exclusively visualized on late images. For the total cohort, there was a significant decrease in 18F-FCH uptake in the glands on late versus early time points (P = 0.001), but there was a significant increase in the ratio of parathyroid uptake to thyroid uptake (P = 0.037). The group of patients with better visualization on early images showed a decrease over time in both parathyroid uptake and the ratio of parathyroid uptake to thyroid uptake, significant in comparison to those in both the group with better visualization at later time points and the group in which visualization was similar at both time points (P values of 0.000–0.018). There were no significant differences in 18F-FCH uptake and the ratio of parathyroid uptake to thyroid uptake between the latter 2 groups (P values of 0.200–0.709). Conclusion: In most patients (89%), hyperfunctioning parathyroid glands were adequately visualized on early imaging; however, in a subset of patients (11%), such glands were best visualized at later time points. Therefore, we recommend the acquisition of dual-time-point images in parathyroid imaging with 18F-FCH PET/CT or the creation of an opportunity to acquire additional late images after review of early images when findings are inconclusive.

    更新日期:2019-11-04
  • Progressive Tau Accumulation in Alzheimer Disease: 2-Year Follow-up Study
    J Nucl. Med. (IF 7.354) Pub Date : 2019-11-01
    Hanna Cho; Jae Yong Choi; Hye Sun Lee; Jae Hoon Lee; Young Hoon Ryu; Myung Sik Lee; Clifford R. Jack, Jr.; Chul Hyoung Lyoo

    Tau PET enables in vivo visualization and quantitation of tau accumulation in Alzheimer disease (AD). In cross-sectional tau PET studies, tau burden reflects disease severity and phenotypic variation. We investigated longitudinal changes in cortical tau accumulation and their association with cognitive decline in patients with AD. Methods: We enrolled 107 participants (45 amyloid-β–negative cognitively unimpaired [CU−], 7 amyloid-β–positive cognitively unimpaired [CU+], 31 with prodromal AD [mild cognitive impairment; MCI+], and 24 with AD dementia [DEM+]) who completed 2 baseline PET scans (18F-flortaucipir and 18F-florbetaben), MRI, and neuropsychologic tests. All participants underwent the same assessments after 2 y. After correcting for partial-volume effect, we created SUV ratio (SUVR) images. By using a linear mixed-effect model, we investigated the changes in SUVR across time within each group. We also investigated a correlation between the progression of tau accumulation and cognitive decline. Results: In contrast to no change in global cortical SUVR in the CU− and CU+ groups during the 2-y period, global cortical SUVR increased by 0.06 (2.9%) in the MCI+ group and 0.19 (8.0%) in the DEM+ group at follow-up. The MCI+ group was associated with additional tau accumulation predominantly in the medial and inferior temporal cortices, whereas the DEM+ group showed increases in the lateral temporal cortex. Progressive tau accumulation occurred in the diffuse cortical areas in the MCI+ patients who developed dementia and the DEM+ patients who showed deterioration of global cognition, whereas there was only a small increase of additional tau accumulation in the lateral temporal cortex in those who did not show worsening of cognition. Deterioration of global cognition and language functions was associated with progression of diffuse tau accumulation in the association neocortex. Conclusion: Progressive tau accumulation occurs in prodromal AD and DEM patients in the cortical areas at different levels of tau accumulation. Progression of cognitive dysfunction may be related to the additional tau accumulation in regions of higher Braak stage. 18F-flortaucipir PET is an imaging biomarker for monitoring the progression of AD.

    更新日期:2019-11-04
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