Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. Recently, we started the first-in-human treatment with an α-radionuclide–labeled PSMA ligand. Although the case series is still ongoing, we here report in advance about two patients in highly challenging clinical situations who showed a complete response to 225Ac-PSMA-617 therapy. Methods:68Ga-PSMA-11 PET/CT validated the presence of the PSMA-positive tumor phenotype. A 100-kBq activity of 225Ac-PSMA-617 per kilogram of body weight was administered bimonthly. Prostate-specific antigen response and hematologic toxicity were measured at least every 4 wk. Restaging was performed with 68Ga-PSMA-11 PET/CT. Results: Both patients experienced a prostate-specific antigen decline to below the measurable level and showed a complete response on imaging. No relevant hematologic toxicity was observed. Xerostomia was the only mentionable clinical side effect. Conclusion: Targeted α-therapy with 225Ac-PSMA-617, although still experimental, obviously has strong potential to significantly benefit advanced-stage prostate cancer patients.

https://jnm.snmjournals.org/content/jnumed/57/12/1941.full.pdf

225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer.

Neuroblastoma is a type of cancer that most often affects children. Neuroblastoma occurs when immature nerve cells called neuroblasts become abnormal and multiply uncontrollably to form a tumor. Most commonly, the tumor originates in the nerve tissue of the adrenal gland located above each kidney. Other common sites for tumors to form include the nerve tissue in the abdomen, chest, neck, or pelvis. Neuroblastoma can spread (metastasize) to other parts of the body such as the bones, liver, or skin.

Neuroblastoma

The aim of this study was to develop a treatment protocol for 225Ac-PSMA-617 α-radiation therapy in advanced-stage, metastatic castration-resistant prostate cancer patients with prostate-specific membrane antigen (PSMA)-positive tumor phenotype. Methods: A dosimetry estimate was calculated on the basis of time-activity curves derived from serially obtained 177Lu-PSMA-617 scans extrapolated to the physical half-life of 225Ac, assuming instant decay of unstable daughter nuclides. Salvage therapies empirically conducted with 50 (n = 4), 100 (n = 4), 150 (n = 2), and 200 kBq/kg (n = 4) of 225Ac-PSMA-617 were evaluated retrospectively regarding toxicity and treatment response. Eight of 14 patients received further cycles in either 2- or 4-mo intervals with identical or deescalated activities. Results: Dosimetry estimates for 1 MBq of 225Ac-PSMA-617 assuming a relative biologic effectiveness of 5 revealed mean doses of 2.3 Sv for salivary glands, 0.7 Sv for kidneys, and 0.05 Sv for red marrow that are composed of 99.4% α, 0.5% β, and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose-limiting toxicity if treatment activity exceeded 100 kBq/kg per cycle. At 100 kBq/kg, the duration of prostate-specific antigen decline was less than 4 mo, but if therapy was repeated every 2 mo patients experienced additive antitumor effects. Treatment activities of 50 kBq/kg were without toxicity but induced insufficient antitumor response in these high-tumor-burden patients. Remarkable antitumor activity by means of objective radiologic response or tumor marker decline was observed in 9 of 11 evaluable patients. Conclusion: For advanced-stage patients, a treatment activity of 100 kBq/kg of 225Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.

https://jnm.snmjournals.org/content/jnumed/58/10/1624.full.pdf

Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding.

We evaluated the potential usefulness of [68Ga]Ga-DOTA-FAPI-04 positron emission tomography/computed tomography (PET/CT) for the diagnosis of primary and metastatic lesions in various types of cancer, compared with [18F] FDG PET/CT. A total of 75 patients with various types of cancer underwent contemporaneous [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT either for an initial assessment or for recurrence detection. Tumour uptake was quantified by the maximum standard uptake value (SUVmax). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of [18F] FDG and [68Ga]Ga-DOTA-FAPI-04 PET/CT were calculated and compared to evaluate the diagnostic efficacy. The study cohort consisted of 75 patients (47 males and 28 females; median age, 61.5 years; age range, 32–85 years). Fifty-four patients with 12 different tumour entities underwent paired [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT for initial assessment, while the other 21 patients underwent paired scans for recurrence detection. [68Ga]Ga-DOTA-FAPI-04 PET/CT was able to clearly identify 12 types of malignant tumours with favourable tumour-to-background contrast, which resulted in a higher detection rate of primary tumours than did [18F] FDG PET/CT (98.2% vs. 82.1%, P = 0.021). Meanwhile, [68Ga]Ga-DOTA-FAPI-04 PET/CT showed a better sensitivity than [18F] FDG PET/CT in the detection of lymph nodes (86.4% vs. 45.5%, P = 0.004) and bone and visceral metastases (83.8% vs. 59.5%, P = 0.004). [68Ga]Ga-DOTA-FAPI-04 PET/CT showed a superior diagnostic efficacy than [18F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer, especially in identifying liver metastases, peritoneal carcinomatosis, and brain tumours.

Comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer.

Pheochromocytomas (PHEO) (1–3) are catecholamineproducing tumors that arise from chromaffin cells. PHEO are mostly situated within the adrenal medulla, although in about 9–23% of cases, tumors develop from extraadrenal chromaffin tissue (adjacent to sympathetic ganglia of the neck, mediastinum, abdomen, and pelvis) and are often referred to as paragangliomas (4–6). PHEO situated in the adrenal gland are identified more commonly than those in extraadrenal tissues, because clinicians usually focus on the adrenal gland as a main source of catecholamine production. Although they usually choose a proper imaging technique to attempt the localization of PHEO in the adrenal gland, they are often confused as to which algorithm to follow and what technique to choose for the detection of extraadrenal PHEO. Furthermore, physicians often neglect the facts that up to approximately 25% of patients with apparent sporadic PHEO may, in fact, be carriers of germline mutations, indicating hereditary disease with a predisposition for extraadrenal, often multifocal, PHEO (7); that in children, multifocal and extraadrenal PHEO are found in up to 30–43% of cases (6, 8–12); that malignant PHEO account for up to 26–35% of cases (13–18); that the prevalence of malignancy in sporadic adrenal PHEO is 9% (5); and that about 10% of patients with PHEO present with metastatic disease at the time of their initial work-up (19). After initial failed surgery, patients with metastatic PHEO are commonly reevaluated using metaiodobenzylguanidine (MIBG) scintigraphy, a modality that should actually be performed before surgery to confirm that a tumor was indeed a PHEO (5–9% of the population harbor an adrenal tumor, most commonly a benign adenoma) (20–22) or to rule out metastatic disease. These patients are then reoperated upon, suffering additional surgery-related complications and substantial financial expenses. Some clinicians consider the presence of sporadic unilateral small PHEO as indicative of benign disease. This was concluded in older studies of series of patients with PHEO (23–25). However, more recent works from large series of patients with benign and malignant disease in the United States and Europe do not support this view; rather, they support the opinion that there are no absolute clinical, imaging, or laboratory criteria to predict malignancy and clinical course of PHEO (5, 16, 19, 26–32). Nevertheless, PHEO tumors with a diameter larger than 5 cm have a higher potential to metastasize, and such patients should be followed more frequently (33). Consequently, it seems that ruling out metastatic PHEO before initial surgery would be useful, because the detection of other lesions may dramatically affect treatment and follow-up. Localization of PHEO should be attempted using at least two imaging modalities. Anatomical imaging studies [computed tomography (CT) and magnetic resonance imaging (MRI)] should be combined with functional (nuclear medicine) imaging studies for optimal results to locate primary, recurrent, or metastatic PHEO. Functional imaging studies (enabled by the presence of the noradrenergic transporter system on PHEO cells) include [I]or [I]MIBG scintigraphy, 6-[F]fluorodopamine ([F]DA), [F]dihydroxyphenylalanine ([F]DOPA), [C]hydroxyephedrine, and [C]epinephrine positron emission tomography (PET) (34–38). Chromaffin cells in various neuroendocrine tissues [such as PHEO, but also medullary thyroid carcinoma (MTC)] express the plasma membrane norepinephrine transporter and the intracellular vesicular monoamine transporter. The norepinephrine transporter is responsible for the cellular uptake of both MIBG (39) and [F]DA (36). We have recently shown that [F]DA PET scanning could theoretically represent yet another imaging modality for the detection of MTCs (40) because MTC cells often express the norepinephrine transporter and concentrate MIBG (41). In most cases, functional imaging modalities are either able to confirm that a tumor is a PHEO or can lead to further diagnostic work-up. For example, in a patient with positive plasma metanephrines and MIBG imaging studies showing uptake in extraadrenal locations, the possible presence of Abbreviations: CT, Computed tomography; DA, dopamine; DOPA, dihydroxyphenylalanine; DTPA, diaminetriaminepentacetate; FDG, fluorodeoxyglucose; HU, Hounsfield units; MEN 2, multiple endocrine neoplasia type 2; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; MTC, medullary thyroid carcinoma; Octreoscan, somatostatin receptor scintigraphy with [I]Tyr3-octreotide or [In]diaminetriaminepentacetate-octreotide; PET, positron emission tomography; PHEO, pheochromocytoma; SPECT, single photon emission computed tomography; U/S, ultrasound.

Current Approaches and Recommended Algorithm for the Diagnostic Localization of Pheochromocytoma

124Iodine (124I) with its 4.2 d half-life is particularly attractive for in vivo detection and quantification of longer-term biological and physiological processes; the long half-life of 124I is especially suited for prolonged time in vivo studies of high molecular weight compounds uptake. Numerous small molecules and larger compounds like proteins and antibodies have been successfully labeled with 124I. Advances in radionuclide production allow the effective availability of sufficient quantities of 124I on small biomedical cyclotrons for molecular imaging purposes. Radioiodination chemistry with 124I relies on well-established radioiodine labeling methods, which consists mainly in nucleophilic and electrophilic substitution reactions. The physical characteristics of 124I permit taking advantages of the higher PET image quality. The availability of new molecules that may be targeted with 124I represents one of the more interesting reasons for the attention in nuclear medicine. We aim to discuss all iodine radioisotopes application focusing on 124I, which seems to be the most promising for its half-life, radiation emissions, and stability, allowing several applications in oncological and nononcological fields.

/pdf/124iodine-a-longer-life-positron-emitter-isotope-new-1t68l5i674.pdf

124Iodine: A Longer-Life Positron Emitter Isotope—New Opportunities in Molecular Imaging

Skeletal metastases occur in many patients with different kinds of malignant tumors, especially in advance stage of breast cancer (in 47%–85% of patients), prostate cancer (33–85%), and lung cancer (32%–60%). The management of painful skeletal metastases is complicated and should be carried out by a multidisciplinary approach including conventional analgesics, antitumor therapy (chemo- and hormone therapy), osteoclast-inhibitory agents (bisphosphonates), corticosteroids, external-beam radiotherapy, surgery, and nuclear medicine therapy. The nuclear medicine therapy for palliation of pain from bone metastases is a systemic radionuclide therapy based on the use of radiopharmaceuticals. In several studies the efficacy of bone-seeking radiopharmaceuticals have been demonstrated in terms of pain reduction from diffuse skeletal metastases. In this review, we will summarize the current literature on bone-seeking radiopharmaceuticals for the treatment of painful bone metastases (Phosphorus-32, Strontium-...

Radiometabolic treatment of bone-metastasizing cancer: from 186rhenium to 223radium.

Objectives To investigate the role of whole-body fluorine-18-2-deoxy-2-fluoro- d -glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the identification of peritoneal carcinomatosis in patients with ovarian cancer (OC). Material and methods Seventy-nine patients with histologically proven stages III–IV OC who underwent 18F-FDG PET/CT were studied retrospectively. We considered group A as 51 patients who also underwent computed-tomography with contrast-enhancement (CECT), and group B as 35 patients who had also been tested for biomarker Ca-125. Sensitivity, specificity, accuracy, positive predictive values (PPV) and negative predictive values (NPV) of 18F-FDG PET/CT as compared to CECT and to Ca-125 were evaluated. Results 18F-FDG PET/CT’ sensitivity, specificity, accuracy, PPV and NPV for all 79 patients were: 85%, 92.31%, 88.61%, 91.89% and 85.71%, respectively. 18F-FDG PET/CT sensitivity in group A was 78.6%, while it was 53.6% for CECT. 18F-FDG PET/CT specificity, calculated in the same group, was 91.3%, while that of CECT was 60.9% (statistically significant difference, McNemar 4, P = 0.039). Accuracy was 84.3% and 56.9%, respectively. 18F-FDG PET/CT’ sensitivity in group B was 86.4%, while that of Ca-125 was 81.8% (no statistical difference, McNemar 0, P = 1). 18F-FDG PET/CT specificity in group B was 84.6% while that of Ca-125 was 38.5% (clear but not statistically significant difference, McNemar 3.12, P = 0.070). Accuracy calculated in the same group was 85.7% for 18F-FDG PET/CT and 65.7% for Ca-125. Conclusion 18F-FDG PET/CT is a useful diagnostic tool when peritoneal biopsy cannot be performed and it can better select those who are candidates for adjuvant chemotherapy.

Role of 18F-FDG PET/CT in diagnosing peritoneal carcinomatosis in the restaging of patient with ovarian cancer as compared to contrast enhanced CT and tumor marker Ca-125

Constipation and fecal incontinence can severely affect quality of life for patients, particularly when simultaneously present. Malone antegrade colonic enema enables periodic colonic emptying, thus preventing uncontrolled passage of feces and constipation. Eleven patients with fecal incontinence and severe constipation or perineal colostomy after Miles’ operation underwent a modified Marsh and Kiff ileostomy for antegrade colonic enema. Before and after surgery, the patients were fully evaluated for gastrointestinal functions, including gallbladder and stomach emptying time, H2-breath test, colonic transit time, dynamic defecography, and anorectal manometry. The severity of incontinence and constipation was scored preoperatively and postoperatively by using the American Medical System score and Cleveland Clinic Constipation scale, respectively, whereas the quality of life was measured by the Gastrointestinal Quality of Life Index. The surgical technique involved division of the terminal ileum 10 to 15 cm from the ileocecal valve, anastomosis and intussusception of the ileum with the cecum, narrowing of the ileal conduit with a linear stapler, and a small, introflexed ileostomy with an advanced skin flap. During the postoperative period, the mean American Medical System score decreased significantly from 77 to 11 (P < 0.01) and the mean Cleveland Clinic Constipation score from 23 to 8.5 (P < 0.01) with a significant improvement of quality of life. Antegrade colonic enema did not affect gallbladder, gastric, or orocecal transit time, which remained comparable with baseline. Colonic scintigraphy showed that antegrade colonic enema was efficient to clean the whole colon and rectum, leaving only 24 (range, 6–40) percent of the initial radioactivity after 30 minutes. Ileal manometry confirmed the presence of a high-pressure zone, preventing accidental reflux. Modified Marsh and Kiff technique is a safe and effective surgical option to treat patients with combined fecal incontinence and severe constipation and those with perineal colostomy after Miles. It should be recommended as a last option before colostomy.

Long-Term Functional Assessment of Antegrade Colonic Enema for Combined Incontinence and Constipation Using a Modified Marsh and Kiff Technique

Anomalous coronary arteries (ACAs) may be clinically silent and totally benign or associated with catastrophic and fatal presentations. It has been postulated that the proximal course of an ACA is a decisive factor in risk stratification and surgical approach. Particularly, a course between the aorta and pulmonary trunk carries a high risk of major adverse events. We sought to evaluate the anatomic course of documented ACAs by transesophageal echocardiography (TEE) and to study their functional importance using stress‐rest 99mTc-sestamibi (99mTcMIBI) myocardial perfusion SPECT. Methods: From a cohort of patients undergoing coronary angiography in our department between January 1997 and April 2003, we selected 14 with ACAs but without CAD (9 men and 5 women; mean age, 50.7 14.6 y). All patients underwent TEE and stress‐rest 99m Tc-MIBI myocardial perfusion SPECT. Results: TEE correctly identified the origin of all ACAs and revealed an anomalous course between the great vessels in 5 patients. At exercise myocardial perfusion SPECT, 4 of 14 patients demonstrated a reversible myocardial perfusion defect. All these patients had an anomalous course between the aorta and pulmonary artery. Conclusion: In this study, 4 of 5 (80%) anomalous courses between the aorta and pulmonary artery were associated with the finding of a reversible perfusion defect on stress‐rest SPECT. An integrated evaluation of anatomic course and hemodynamic importance could be useful in the management of ACA.

http://jnm.snmjournals.org/content/45/4/532.full.pdf

Domenico Rubini

Papers

124Iodine: A Longer-Life Positron Emitter Isotope—New Opportunities in Molecular Imaging

Radiometabolic treatment of bone-metastasizing cancer: from 186rhenium to 223radium.

Role of 18F-FDG PET/CT in diagnosing peritoneal carcinomatosis in the restaging of patient with ovarian cancer as compared to contrast enhanced CT and tumor marker Ca-125

Long-Term Functional Assessment of Antegrade Colonic Enema for Combined Incontinence and Constipation Using a Modified Marsh and Kiff Technique

Stress-Rest Myocardial Perfusion SPECT for Functional Assessment of Coronary Arteries with Anomalous Origin or Course