Mariza Vorster

Advances in imaging of tuberculosis: the role of ¹⁸F-FDG PET and PET/CT.

Purpose of review To review the main applications, advantages and limitations of 18F-FDG PET and PET/computed tomography (CT), and some other tracers in imaging of tuberculosis (TB). Recent findings In pulmonary TB, granulomas typically demonstrate increased 18F-FDG uptake, and areas of active TB can be differentiated from old or inactive disease by dual time point imaging. However, standardized uptake value measurements are high in both TB and malignant lesions, with significant overlap that limits their usefulness. In extrapulmonary TB, 18F-FDG PET detects more tuberculous lesions than CT, is of value in assessing response to tuberculostatic treatment, and helps in diagnosing spinal infection and identifying TB-related spondylitis; however, again, differentiation of malignant versus TB lymph node involvement is problematic. 18F-FDG PET can also be considered a marker of disease status in patients with HIV and TB co-infection. Overall, evaluation of treatment response is potentially the most important clinical application of 18F-FDG PET in TB, owing to its ability to distinguish active from inactive disease. Summary 18F-FDG PET and PET/CT may assist early diagnosis and facilitate differentiation between malignancies and TB, identification of extrapulmonary TB, staging of TB, and assessment of treatment response.

Results of a Prospective Multicenter International Atomic Energy Agency Sentinel Node Trial on the Value of SPECT/CT Over Planar Imaging in Various Malignancies

We aimed to assess the additional value of SPECT/CT over planar lymphoscintigraphy (PI) in sentinel node (SN) detection in malignancies with different lymphatic drainage such as breast cancer, melanoma, and pelvic tumors. Methods: From 2010 to 2013, 1,508 patients were recruited in a multicenter study: 1,182 breast cancer, 262 melanoma, and 64 pelvic malignancies (prostate, cervix, penis, vulva). PI was followed by SPECT/CT 1–3 h after injection of 99mTc-colloid particles. Surgery was performed the same or next day. Results: Significantly more SNs were detected by SPECT/CT for breast cancer (2,165 vs. 1,892), melanoma (602 vs. 532), and pelvic cancer (195 vs. 138), all P < 0.001. The drainage basin mismatch between PI and SPECT/CT was 16.5% for breast cancer, 11.1% for melanoma, and 51.6% for pelvic cancers. Surgical adjustment was 17% for breast cancer, 37% for melanoma, and 65.6% for pelvic cancer. Conclusion: SPECT/CT detected more SNs and changed the drainage territory, leading to surgical adjustments in a considerable number of patients in all malignancies studied but especially in the pelvic cancer group because of this groups deep lymphatic drainage. We recommend SPECT/CT in all breast cancer patients with no SN visualized on PI, all patients with melanoma of the head and neck or trunk, all patients with pelvic malignancies, and those breast cancer and melanoma patients with unexpected drainage on PI.

68 Ga-PSMA imaging of metastatic breast cancer

Ga-labelled prostate-specific membrane antigen (PSMA) is rapidly emerging as a significant step forward in the diagnosis of recurrent prostate cancer, based on the fact that PSMA is a type II transmembrane protein with high expression in prostate carcinoma cells [1, 2]. Recently it has been demonstrated to accumulate in metastatic clear-cell renal cell carcinoma [3] and interestingly several studies have provided evidence that PSMA is also expressed in the tumour-associated vasculature of primary breast cancers and distant metastases [4, 5]. We report the case of a 33-year-old woman with metastatic breast carcinoma who underwent Ga-PSMA and F-FDG PET/CT imaging for restaging and evaluation of the most appropriate therapeutic option. Images demonstrated intense and extensive skeletal uptake in the axial and appendicular skeleton with liver metastases. Concordance of Ga-PSMA and F-FDG lesions suggests that Ga-PSMA may provide helpful prognostic information. Furthermore, Ga-PSMA-avid metastatic sites may in future aid in selecting tumours with high PSMA expression for PSMA-directed therapy.

Development of a Single Vial Kit Solution for Radiolabeling of 68Ga-DKFZ-PSMA-11 and Its Performance in Prostate Cancer Patients.

Prostate-specific membrane antigen (PSMA), a type II glycoprotein, is highly expressed in almost all prostate cancers. By playing such a universal role in the disease, PSMA provides a target for diagnostic imaging of prostate cancer using positron emission tomography/computed tomography (PET/CT). The PSMA-targeting ligand Glu-NH-CO-NH-Lys-(Ahx)-HBED-CC (DKFZ-PSMA-11) has superior imaging properties and allows for highly-specific complexation of the generator-based radioisotope Gallium-68 (68Ga). However, only module-based radiolabeling procedures are currently available. This study intended to develop a single vial kit solution to radiolabel buffered DKFZ-PSMA-11 with 68Ga. A 68Ge/68Ga-generator was utilized to yield 68GaCl3 and major aspects of the kit development were assessed, such as radiolabeling performance, quality assurance, and stability. The final product was injected into patients with prostate cancer for PET/CT imaging and the kit performance was evaluated on the basis of the expected biodistribution, lesion detection, and dose optimization. Kits containing 5 nmol DKFZ-PSMA-11 showed rapid, quantitative 68Ga-complexation and all quality measurements met the release criteria for human application. The increased precursor content did not compromise the ability of 68Ga-DKFZ-PSMA-11 PET/CT to detect primary prostate cancer and its advanced lymphatic- and metastatic lesions. The 68Ga-DKFZ-PSMA-11 kit is a robust, ready-to-use diagnostic agent in prostate cancer with high diagnostic performance.

68Ga-PSMA-HBED-CC PET imaging in breast carcinoma patients

BackgroundTo report on imaging findings using 68Ga-PSMA-HBED-CC PET in a series of 19 breast carcinoma patients.Methods68Ga-PSMA-HBED-CC PET imaging results obtained were compared to routinely performed staging examinations and analyzed as to lesion location and progesterone receptor status.ResultsOut of 81 tumor lesions identified, 84% were identified on 68Ga-PSMA-HBED-CC PET. 68Ga-PSMA-HBED-CC SUVmean values of distant metastases proved significantly higher (mean, 6.86, SD, 5.68) when compared to those of primary or local recurrences (mean, 2.45, SD, 2.55, p = 0.04) or involved lymph nodes (mean, 3.18, SD, 1.79, p = 0.011). SUVmean values of progesterone receptor-positive lesions proved not significantly different from progesterone receptor-negative lesions. SUV values derived from FDG PET/CT, available in seven patients, and 68Ga-PSMA-HBED-CC PET/CT imaging proved weakly correlated (r = 0.407, p = 0.015).Conclusions68Ga-PSMA-HBED-CC PET/CT imaging in breast carcinoma confirms the reported considerable variation of PSMA expression on human solid tumors using immunohistochemistry.

213Bi-PSMA-617 targeted alpha-radionuclide therapy in metastatic castration-resistant prostate cancer

Prostate-specific membrane antigen radioligand therapy (PSMA-RLT) with Lu-PSMA holds great promise as a safe treatment option in patients with metastasized castration-resistant prostate cancer (mCRPC) with appropriate selection [1]. This approach, together with GaPSMA PET/CT, is an excellent example of theranostic nuclear medicine [2]. However, more structured data have recently shown that despite a marked response to PSMARLT, some patients are refractory to Lu-radioligand therapy [2, 3]. Fortunately recent studies have demonstrated that targeted α-radiation therapy with Ac-PSMA can significantly benefit mCRPC patients [4]. Similarly, BiDOTATOC may be able to break the radioresistance to βemitters while simultaneously reducing haematological toxicity in patients with diffuse red marrow infiltration by neuroendocrine tumour [5]. We present the first-in-human treatment concept with Bi-PSMA-617 in a patient with mCRPC that was progressive under conventional therapy. The patient was treated with two cycles of Bi-PSMA-617 with a cumulative activity of 592 MBq. Restaging with GaPSMA PET/CT after 11 months showed a remarkable molecular imaging response. This pat ient a lso

Nuclear medicine imaging in tuberculosis using commercially available radiopharmaceuticals

In this paper, data available on nuclear medicine imaging using commercially available radiopharmaceuticals for the differentiation, staging, and prediction or assessment of the response to treatment in tuberculosis (TB) are reviewed. Limited available studies suggest that single photon emission computed tomography (SPECT) using either 201Tl, 99mTc-sestamibi, or 99mTc-tetrofosmin is accurate (≥85%) and has a high negative predictive value (≥90%) for the differentiation of TB from carcinoma in patients presenting with a solitary pulmonary nodule (SPN). The criteria for detection of TB on 201Tl SPECT are nondepiction of the suspicious lesion in the delayed image or a negative retention index [washout on the delayed images (3–4 h postinjection) vs. the early image (5–15 min postinjection)] and a comparable-to-background uptake on 99mTc-sestamibi or 99mTc-tetrofosmin SPECT. Another SPECT tracer of potential interest for the differentiation of TB from malignant SPN that warrants further exploration, is N-isopropyl-p-[123I]iodoamphetamine (123I-IMP). In contrast, 18F-fluorodeoxyglucose (18F-FDG) PET is unable to differentiate malignancy from TB and thus cannot be used as a tool to reduce futile biopsy/thoracotomy in these patients. A limited number of studies have reported on the potential of nuclear medicine imaging in assessment of the extent of disease in patients with extrapulmonary TB using 67Ga-citrate SPECT and 18F-FDG PET, respectively. 67Ga-citrate SPECT was shown to be as sensitive as bone scintigraphy for the detection of bone infection and was found to be complementary to computed tomography (CT) imaging. 18F-FDG PET was found to be significantly more efficient when compared with CT, respectively, in over half of patients for the identification of sites of lymph node involvement that were missed by CT and often the only sites of extrapulmonary TB identified. Unfortunately, 18F-FDG PET findings did not lead to alterations in treatment planning in any of the patients under study. Additional studies confirming these findings are urgently required. Similar to the setting of SPN, 18F-FDG PET cannot differentiate malignant lymph node involvement from lymph node involvement by TB. These results and the recent findings of Demura and colleagues using 18F-FDG PET further suggest that nuclear medicine imaging techniques could be used for the evaluation of therapeutic response. Prospective studies, focusing on specific subgroups of patients in whom such an imaging approach might be clinically relevant, for example in multidrug-resistant TB patients, are warranted. In acquired immunodeficiency syndrome patients, 67Ga scintigraphy proved to be a reliable and sensitive method for the primary detection and follow-up of opportunistic pneumonias, including TB. Combining 201Tl scintigraphy with 67Ga scintigraphy was shown to increase the specificity for both pulmonary and extrapulmonary TB, which is a 67Ga(+) and 201Tl(−) mismatch pattern in acquired immunodeficiency syndrome patients that is specific for mycobacterial infections. Finally, the results obtained using both SPECT and PET indicate that nuclear medicine could be an important noninvasive method for the determination of disease activity, detection of extrapulmonary TB, and determination of response to therapy.

Metastatic Prostate Carcinoma Presenting as a Superscan on 68Ga-PSMA PET/CT.

We describe the finding of a metastatic superscan detected by Ga-PSMA PET/CT imaging. A 63-year-old man with metastatic prostate carcinoma underwent Ga-PSMA PET/CT imaging for staging and evaluation of the most appropriate therapeutic option. Images demonstrated diffuse and extensive skeletal uptake in the axial and appendicular skeleton, corresponding to the typical red marrow distribution. Intense soft tissue uptake was also seen in the prostate and multiple pelvic and abdominal lymph nodes.

Gallium-68: a systematic review of its nononcological applications.

The increased availability of PET facilities worldwide has sparked renewed interest in the use of generator-produced tracers such as gallium-68 (68Ga). Imaging with 68Ga provides exciting opportunities in terms of new ligand-labelling possibilities and the exploration of novel clinical applications. The aim of the study was to summarize and appraise what has been published on the clinical applications of 68Ga outside oncology practice. This systematic review was based on the PRISMA guidelines. Databases searched include PubMed, Medline, Scopus, Web of Science and Google Scholar. The following search strategy was used: ‘68Ga’ OR ‘68Gallium’ (all fields) NOT the following (title and abstract): Oncology/NET/neuroendocrine tumour/tumor/DOTATOC, DOTATATE, DOTANOC. These results were further limited to English publications, which resulted in 205 publications on PubMed. After duplicates and irrelevant articles were removed, 72 publications remained for inclusion. Only those studies in which compounds were labelled with 68Ga for applications other than in oncology-related indications were included. Publications in which the focus was on oncology-related applications of 68Ga imaging or in which the emphasis was on aspects relating to generators, radiochemistry or physics were excluded. Although a multitude of tracers have been labelled with 68Ga over several decades, it has not been established in routine clinical practice yet. In addition, neuroendocrine and other oncological applications have dominated the field until relatively recently following reports of applications in infection and inflammation. The majority of publications to date involve small numbers of subjects in mainly preclinical settings. Differences in methodology preclude grouping of studies to reach a clear conclusion. There is wide scope for 68Ga tracer application outside oncological practice, which remains greatly underutilized. Larger clinical trials are needed to validate these applications.

Metabolic Imaging of Infection

Metabolic imaging has come to occupy a prominent place in the diagnosis and management of microbial infection. Molecular probes available for infection imaging have undergone a rapid evolution starting with nonspecific agents that accumulate similarly in infection, sterile inflammation, and neoplastic tissue and then extending to more targeted probes that seek to identify specific microbial species. This focus review describes the metabolic and molecular imaging techniques currently available for clinical use in infection imaging and those that have demonstrated promising results in preclinical studies with the potential for clinical applications.