Nuclear Medicine and Cancer Theragnostics: Basic Concepts.

Cancer theragnostics is a novel approach that combines diagnostic imaging and radionuclide therapy. It is based on the use of a pair of radiopharmaceuticals, one optimized for positron emission tomography imaging through linkage to a proper radionuclide, and the other bearing an alpha- or beta-emitter isotope that can induce significant damage to cancer cells. In recent years, the use of theragnostics in nuclear medicine clinical practice has increased considerably, and thus investigation has focused on the identification of novel radionuclides that can bind to molecular targets that are typically dysregulated in different cancers. The major advantages of the theragnostic approach include the elimination of multi-step procedures, reduced adverse effects to normal tissues, early diagnosis, better predictive responses, and personalized patient care. This review aims to discuss emerging theragnostic molecules that have been investigated in a series of human malignancies, including gliomas, thyroid cancer, neuroendocrine tumors, cholangiocarcinoma, and prostate cancer, as well as potent and recently introduced molecular targets, like cell-surface receptors, kinases, and cell adhesion proteins. Furthermore, special reference has been made to copper radionuclides as theragnostic agents and their radiopharmaceutical applications since they present promising alternatives to the well-studied gallium-68 and lutetium-177.

Myocardial Ischemia on MPI SPECT in a Patient with Acute Myeloid Leukemia Without Significant Coronary Artery Disease.

Herein, we report the case of a 56-year-old male patient with acute myeloid leukemia (AML) in remission who had asymptomatic myocardial ischemia on myocardial perfusion imaging and transthoracic echocardiography. Angiography did not reveal any significant coronary artery disease. Although the etiology is not entirely clear, this case suggested that myocardial perfusion imaging should be considered in patients with AML who received idarubicin to screen for possible myocardial dysfunction.

Hamstring Muscle Cramp Visualized on Bone Single-Photon Emission Computed Tomography/Computed Tomography Hybrid Imaging.

ABSTRACT: It is well recognized that bone-seeking radiotracers localize in muscles sustaining an injury from various causes (e.g., strenuous physical activity, trauma, hereditary myopathies, inflammatory myositides, medications, electrical burns, etc.). This report presents the case of an active 50-yr-old man (body mass index = 29) that was recently referred to our nuclear medicine department for bone scintigraphy, for the skeletal staging of a newly diagnosed prostate adenocarcinoma. The scan findings were unremarkable for its oncological indication but revealed extraosseous radiotracer absorption in the medial region of the hamstrings bilaterally. Hybrid scintitomography (single-photon emission computed tomography) with computed tomography indicated that this uptake involved the semitendinosus muscle. On a more meticulous repeat history questioning, he recalled experiencing muscle cramps on both posterior thighs 5 days earlier, during intense work-related physical activity (plumbing) under warm environmental conditions. The combination of strenuous exercise with likely dehydration contributed to bilateral self-limiting heat cramps of the hamstrings, leading to an inconsequential localized minor rhabdomyolysis that was discovered coincidentally a few days later during a bone scan. Although extraskeletal absorption of bone-seeking radiotracers in muscles is widely documented as a result of exertion or injury, this is the first report of radiotracer absorption induced by cramping.

Myocardial perfusion SPECT as a potential mediator on circulating chromogranin A in patients with old myocardial infarction.

OBJECTIVE: Chromogranin A (CgA) is a soluble polypeptide stored within and released from secretory granules of endocrine and other cell types (including cardiomyocytes); CgA appears to be a marker of the overall neuroendocrine activity. Increased levels of serum CgA have been found not only in patients with neuroendocrine neoplasms but also with other malignancies, hypertension, myocardial infarction, heart, or renal failure. SUBJECTS AND METHODS: A population of 307 patients (202 males, 105 females) was enrolled. The study group consisted of 118 individuals (38.4%) with myocardial infarction more than one year old (MI group); the remaining 189 (61.6%) had no known heart disease (control group). All patients underwent myocardial perfusion scintigraphy (MPS) after blood withdrawal for serum CgA measurement. To test whether a possible effect of old infarction on serum CgA is mediated by MPS findings, we employed analysis of covariance for three distinct categories of left ventricular (LV) perfusion deficits as dichotomous predictors: (1) any-type deficits (abnormal MPS); (2) reversible deficits (ischemia); and (3) fixed deficits (scar). RESULTS: In all three MPS conditions, the effect of age, gender, and LV ejection fraction (EFLV) on serum CgA was statistically significant: women exhibited higher CgA levels than men (P=0.008-0.023), whereas increasing age and decreasing EFLV were associated with increasing CgA (all P<0.001). Conversely, no statistically significant differences in mean CgA levels were found between MI patients and normal controls with either abnormal MPS, scar, or ischemia, or their degree and extent. CONCLUSION: Although serum CgA is significantly associated with age, gender, and EFLV in patients with an old MI, no association was found between CgA levels and either old MI history or MPS findings. The verified involvement of circulating CgA in the acute/subacute phase of infarction appears to be blunted in infarctions older than a year.

Is there a role for Gallium-67 SPECT in distinguishing progression and pseudoprogresion in oncologic patients receiving immunotherapy?

Immuno-oncology (IO) with immune checkpoint inhibitors (ICIs) is the new landmark in cancer treatment. However, due to its economical-related burden and the possibility of tumor pseudoprogression with late response patterns, it is imperative to find new ways for early discrimination of patients with IO-sensitive versus IO-resistant disease. ICI-mediated antitumor responses depend on tumor immune infiltration by T-cells capable of recognizing and killing tumor cells. Nevertheless, patients may experience different responses to immunotherapy according to their tumor microenvironment and inflammatory infiltration. T-cell infiltrated tumors are referred to as 'hot' and are potential candidates for a good response to ICIs, whereas 'cold' are those tumors lacking T-cell infiltration and exhibit a narrow likelihood of response to IO therapy. Gallium-67 (67Ga) scintigraphy may hold potential for separating 'hot' from 'cold' tumors, thus providing an imaging tool to distinguish 'hot' ICI-induced pseudoprogression from real early 'cold' progression. Even so, various tumors (lymphomas, lung cancer, breast cancer, hepatoma, malignant melanoma) exhibit an inherent affinity for 67Ga that is independent of the ICI-induced immune infiltration, and this raises issues about false positivity. For that reason, future investigational studies to evaluate the prospective role of this radiotracer in the early prediction of ICI response should be confined to tumors with an inherently low 67Ga affinity (thyroid carcinoma, gastrointestinal and genitourinary tract tumors). We describe our experience with a patient with recurrent metastatic lung adenocarcinoma under ICI therapy that was submitted to 67Ga scanning for a fever of unknown origin and we discuss the aforementioned topics, alongside current imaging trends and future perspectives in the field.

Quality of life and tolerance to mental pain scale in cancer patients subjected to bone scan.

PURPOSE: To evaluate the impact of psychiatric co-morbidities on the quality of life-36 (QoL36) and tolerance to mental pain scale (TMPS) questionnaire of cancer patients administered in the Laboratory of Nuclear Medicine prior to a bone scan to rule out metastatic disease. METHODS: A group of 40 consecutive cancer patients (24 prostate, 12 breast and 4 with other cancers) were subjected to bone scan (BS) to rule out metastatic disease. Each patient received QoL36 and TMPS questionnaire prior to BS. RESULTS: There were low QoL and TMPS scores in all patient groups. The average QoL36 questionnaire score was 43,71 (23-70) (normal values considered >90). The average TMPS scores for prostate cancer patients was 55.42 (21-96), for breast cancer patients 63.42 (44-83) and for the other cancer patients 58.25 (48-68). Female patients with breast cancer had statistically higher tolerance to mental pain compared to patients with prostate cancer. Both tests were independently important for evaluation of the psychological status of the patients. There was no significant correlation of either QoL or TMPS with age, sex or disease duration. CONCLUSIONS: Cancer patients exhibited low QoL and TMPS, independent of sex, age, cancer type and disease duration. Multi-modality psychological support may be needed for these patients.

The contribution of metabolic parameters of FDG PET/CT prior and during therapy of adult patients with lymphomas.

Lymphomas are the most common hematological malignancies and are further distinguished in Hodgkin lymphoma (HL) and non-Hodgkin (NHL). For staging purposes and for assessing response to treatment, the Lugano classification is currently used, both for HL and NHL patients, whereas for the assessment of prognosis, several prognostic systems exist, such as the international prognostic index (IPI) and revised-IPI for diffuse large B cell lymphomas, follicular lymphoma IPI (FLIPI)-1 and 2 for follicular lymphomas, and the international prognostic score for advanced HL. The aim of this systematic review was to determine the significance of the metabolic FDG PET/CT parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), in monitoring therapeutic interventions and prognostic outcome of patients with HL and NHL. We performed a systematic search on the literature and selection of articles concerning treatment evaluation, response and survival in association with MTV and TLG in patients with lymphomas. Our review documented that in most studies, baseline MTV and TLG were predictive of treatment response, progression-free survival (PFS) and overall survival (OS) for both HL and NHL patients. There were conflicting results for the value of interim determination of MTV and TLG. Our conclusion was that combination of baseline MTV and TLG parameters with prognostic scoring systems, such as IPI, or FLIPI-1 and -2, will add additional predictive power for response and prognosis in lymphoma patients.

Diagnosis and treatment of limbic encephalitis in the cancer patient.

Limbic encephalitis is an inflammatory process involving the limbic structures of the brain, manifested with short-term memory deficits, confusion, depression and seizures. It is usually a paraneoplastic condition but it may also appear as a nonparaneoplastic syndrome. Patients with this condition may exhibit a variety of antibodies in their serum or/and cerebrospinal fluid targeting basement membrane components that bind to a variety of neurotransmitter receptors such as α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and GABA B and proteins associated to the ion channels such as LGI1, Caspr2 or intracellular components. Flurodeoxyglucose PET/computed tomography usually demonstrates increased uptake in the limbic structures, and it may reveal the site of the primary tumor. Treatment consists of tumor removal if possible. Symptomatic treatment includes steroids, gamma immune globulin, plasma exchange, immunosuppressive therapies and anti-epileptic drugs. Prognosis is better when it is associated with antibodies against basement membrane rather than intracellular antibodies.

Principles and current trends in the correlative evaluation of glioma with advanced MRI techniques and PET

Cerebral gliomas comprise a heterogeneous group of primary neoplasms of the central nervous system, representing a signifcant cause of cancer morbidity and mortality. Contrast-enhanced magnetic resonance imaging (MRI) is paramount for identifying structural brain abnormalities related to the development of gliomas. Although morphological MRI remains the current standard of care for initial diagnostic workup, surgical planning, monitoring therapy response and surveillance during follow-up, it is rather diffcult to define tumor grade and boundaries and to assess response to radiochemotherapy solely by contrast-enhancement, due to a variety of factors influencing blood-brain barrier (BBB) permeability and contrast agent distribution. The nature of a lesion lies beyond often misleading gross structural patterns, down to the cellular and molecular level, hence the imaging techniques of advanced multimodal MRI and positron emission tomography (PET) have emerged to provide critical non-invasive insight into the underlying biology of primary brain cancer. Out of the various PET radiotracers, labeled amino acids are of particular significance due to their non-dependency on BBB disruption to reach glioma cells and their excellent tumor-to-background contrast. After discussing the basic imaging principles of MR perfusion, diffusion, spectroscopy and PET in glioma, this review focuses on the correlative imaging with amino acid PET and advanced MRI techniques in tumor grading and staging, in guiding stereotactic biopsy and surgical excision and in assessing therapy response, post-therapy surveillance and prognosis. Lastly, a reference is made on the expanding availability of integrated PET/MRI systems and the resulting benefits of simultaneous image acquisition.

Myocardial ischemia in female patients with rheumatoid arthritis assessed with single photon emission tomography-myocardial perfusion imaging.

BACKGROUND: Non-specific cardiac symptoms in female patients with rheumatoid arthritis (RA) could indicate early cardiovascular disease. MATERIALS AND METHODS: Myocardial perfusion imaging (MPI), with 99mTc tetrofosmin stress-rest single photon emission computer tomography (SPECT), in 13 RA female patients with atypical cardiac symptoms, was compared to 44 weight- and age-matched females with similar cardiac complaints (control group). Smoking, hypertension, diabetes mellitus, dyslipidemia, obesity and cardiac heredity were recorded and compared between the study and control group. MPI was assessed using 17 segment polar map and with a scale of 0 to 5 scoring. RESULTS: Patients with RA demonstrated higher cardiovascular risk (46%) compared to control individuals (17%). In addition, patients with RA had more irreversible myocardial ischemic abnormalities in their MPI than the control group. Dyslipidemia and obesity was found more frequent in RA patients with MPI SSS ≥ 4. CONCLUSION: RA patients with atypical cardiac complaints are at higher risk for cardiovascular disease; early detection and monitoring of this patient group could potentially reverse or successfully manage the consequences of the upcoming cardiovascular disease.

Radiotherapy for breast cancer induced long-term diminished accumulation of radiotracer on bone scan of the irradiated ribs.

Radiotherapy may result in long term effects and composition alterations in bones. Bone scintigraphy after radiotherapy may demonstrate decreased skeletal uptake; however, this is a transient effect with bone scan normalized after a few years. We describe a case of a 31-year-old female patient treated for left breast cancer with chemotherapy and radiotherapy, exhibiting reduced and diffuse diphosphonate uptake in the heavily irradiated sections of left ribs, even twelve years post-treatment. Similarly, quantitative computed tomography indicated altered bone composition. To our knowledge this is the first case describing such a long radiation side effect in breast cancer treatment.

Performance of 18F-FDG, 11C-Methionine, and 18F-FET PET for Glioma Grading: A Meta-analysis.

PURPOSE: Gliomas constitute the most frequent primary brain tumors. Glioblastoma, the most common and malignant glioma in adults, has dismal prognosis with any current therapy. On the other hand, low-grade gliomas, the second most common type of gliomas, are potentially curative with appropriate treatment. METHODS: We conducted a meta-analysis to assess the performance of PET tracers with the best available evidence, namely, fluorodeoxyglucose (FDG), C-methionine (MET), and F-fluoroethyltyrosine (FET), in differentiating low- from high-grade gliomas. RESULTS: Twenty-three studies with a total of 994 participants were included in this meta-analysis. The pooled sensitivities of both MET PET and FET PET were found to be significantly higher than of FDG PET (94%, 88%, and 63% respectively, P < 0.001). The pooled specificity of FDG PET was found to be significantly greater compared with both MET PET and FET PET (89%, 55%, and 57%, respectively; P = 0.002). Fluorodeoxyglucose PET was superior in terms of higher positive likelihood ratio values compared with both FET PET and MET PET. CONCLUSIONS: This meta-analysis indicated that both MET and FET were superior to FDG in terms of sensitivity for identifying glioma grade.

Skull Base Metastasis Revealed by Bone Scintigraphy in a Patient With Hypoglossal Nerve Palsy.

Even though different imaging modalities are available in sole or in combination for the optimal detection of bone metastases, whole-body bone scintigraphy (BS) in a single session seems to be advantageous. We present an 80-year-old male with unilateral left hypoglossal nerve palsy (HNP) and no other focal deficits on neurological examination. Initial brain computed tomography (CT) scan revealed no pathological findings, while the subsequent cranial CT and magnetic resonance imaging (MRI) scans uncovered only mild nonspecific sclerotic lesions in left occipital condyle. All laboratory examinations were within normal limits, except for an elevated alkaline phosphatase (170 U/L) and a markedly increased prostate-specific antigen (609 ng/mL). The patient underwent whole-body BS with technetium-99m that revealed increased radiotracer deposition compatible with metastases in multiple foci, including the left occipital condyle. Prostate biopsy confirmed the diagnosis of prostate adenocarcinoma. Our case suggests that a complete and thorough workup for hidden malignancies should be performed in all patients with HNP, even in the absence of a finding in brain neuroimaging. Bone scintigraphy is an essential investigation that should be considered in uncertain cases of HNP, and especially in those with negative CT and MRI scans.

Huge Abdominal Photopenic Area Due to Kidney Cyst Imaged by Bone Scintigraphy in a Prostate Cancer Patient.

Bone scintigraphy is a method of choice in evaluating metastatic disease in patients with prostatic cancer. We describe the case of a 77-year-old man who was subjected to bone scan for evaluation of secondary metastatic disease due to an elevated prostatic-specific antigen level (7.2). Bone scintigraphy demonstrated a huge photopenic area in the left upper abdominal area, as a result of a huge kidney cyst (15 × 13 cm).

Radiation Necrosis, Pseudoprogression, Pseudoresponse, and Tumor Recurrence: Imaging Challenges for the Evaluation of Treated Gliomas.

Glioblastoma (GBM) is the most common primary malignant type of brain neoplasm in adults and carries a dismal prognosis. The current standard of care for GBM is surgical excision followed by radiation therapy (RT) with concurrent and adjuvant temozolomide-based chemotherapy (TMZ) by six additional cycles. In addition, antiangiogenic therapy with an antivascular endothelial growth factor (VEGF) agent has been used for recurrent glioblastoma. Over the last years, new posttreatment entities such as pseudoprogression and pseudoresponse have been recognized, apart from radiation necrosis. This review article focuses on the role of different imaging techniques such as conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), dynamic contrast enhancement (DCE-MRI) and dynamic susceptibility contrast (DSE-MRI) perfusion, magnetic resonance spectroscopy (MRS), and PET/SPECT in differentiation of such treatment-related changes from tumor recurrence.