Rhenium-188 Labeled Radiopharmaceuticals: Current Clinical Applications in Oncology and Promising Perspectives.

Rhenium-188 (188Re) is a high energy beta-emitting radioisotope with a short 16.9 h physical half-life, which has been shown to be a very attractive candidate for use in therapeutic nuclear medicine. The high beta emission has an average energy of 784 keV and a maximum energy of 2.12 MeV, sufficient to penetrate and destroy targeted abnormal tissues. In addition, the low-abundant gamma emission of 155 keV (15%) is efficient for imaging and for dosimetric calculations. These key characteristics identify 188Re as an important therapeutic radioisotope for routine clinical use. Moreover, the highly reproducible on-demand availability of 188Re from the 188W/188Re generator system is an important feature and permits installation in hospital-based or central radiopharmacies for cost-effective availability of no-carrier-added (NCA) 188Re. Rhenium-188 and technetium-99 m exhibit similar chemical properties and represent a "theranostic pair." Thus, preparation and targeting of 188Re agents for therapy is similar to imaging agents prepared with 99mTc, the most commonly used diagnostic radionuclide. Over the last three decades, radiopharmaceuticals based on 188Re-labeled small molecules, including peptides, antibodies, Lipiodol and particulates have been reported. The successful application of these 188Re-labeled therapeutic radiopharmaceuticals has been reported in multiple early phase clinical trials for the management of various primary tumors, bone metastasis, rheumatoid arthritis, and endocoronary interventions. This article reviews the use of 188Re-radiopharmaceuticals which have been investigated in patients for cancer treatment, demonstrating that 188Re represents a cost effective alternative for routine clinical use in comparison to more expensive and/or less readily available therapeutic radioisotopes.

Granulomatosis with polyangiitis and multiple bilateral cranial nerve palsies: a diagnostic challenge.

BACKGROUND: Granulomatosis with polyangiitis is characterized by vasculitis of small and medium sized vessels and non-caseating granulomas with head and neck symptoms in 95% of those affected. Cranial nerve palsies are rare; while, chronic rhinosinusitis and ear problems are common. CASE REPORT: We describe the serious course and the diagnostic challenge of a patient with granulomatosis with polyangiitis of bilateral mastoids and the right temporal lobe. Initially, the patient showed metachronous bilateral facial palsy with chronic mastoiditis. Repeated surgeries and rheumatologic examinations did not determine a diagnosis. The patient developed additional cranial nerve palsies. Due to progression into the temporal lobe, we removed the affected parts. After 6 months, the diagnosis was revealed by histology. RESULTS AND CONCLUSION: Granulomatosis with polyangiitis is a diagnostic challenge. Persistent reevaluations were necessary for a final diagnosis and to limit the life-threatening disease. Once diagnosed, therapy began with the standard FAUCI-Scheme.

Targeted radionuclide therapy--an overview.

Radionuclide therapy (RNT) based on the concept of delivering cytotoxic levels of radiation to disease sites is one of the rapidly growing fields of nuclear medicine. Unlike conventional external beam therapy, RNT targets diseases at the cellular level rather than on a gross anatomical level. This concept is a blend of a tracer moiety that mediates a site specific accumulation followed by induction of cytotoxicity with the short-range biological effectiveness of particulate radiations. Knowledge of the biochemical reactions taking place at cellular levels has stimulated the development of sophisticated molecular carriers, catalyzing a shift towards using more specific targeting radiolabelled agents. There is also improved understanding of factors of importance for choice of appropriate radionuclides based on availability, the types of emissions, linear energy transfer (LET), and physical half-life. This article discusses the applications of radionuclide therapy for treatment of cancer as well as other diseases. The primary objective of this review is to provide an overview on the role of radionuclide therapy in the treatment of different diseases such as polycythaemia, thyroid malignancies, metastatic bone pain, radiation synovectomy, hepatocellular carcinoma (HCC), neuroendocrine tumors (NETs), non-Hodgkin's lymphoma (NHL) and others. In addition, recent developments on the systematic approach in designing treatment regimens as well as recent progress, challenges and future perspectives are discussed. An examination of the progress of radionuclide therapy indicates that although a rapid stride has been made for treating hematological tumors, the development for treating solid tumors has, so far, been limited. However, the emergence of novel tumor-specific targeting agents coupled with successful characterization of new target structures would be expected to pave the way for future treatment for such tumors.

Rhenium-188: availability from the (188)W/(188)Re generator and status of current applications.

Rhenium-188 is one of the most readily available generator derived and useful radionuclides for therapy emitting ß(-) particles (2.12 MeV, 71.1% and 1.965 MeV, 25.6%) and imageable gammas (155 keV, 15.1%). The (188)W/(188)Re generator is an ideal source for the long term (4-6 months) continuous availability of no carrier added (nca) (188)Re suitable for the preparation of radiopharmaceuticals for radionuclide therapy. The challenges associated with the double neutron capture route of production of the parent (188)W radionuclide have been a major impediment in the progress of application of (188)Re. Tungsten-188 of adequate specific activity can be prepared only in 2-3 of the high flux reactors operating in the World. Several useful technologies have been developed for the preparation of clinical grade (188)W/(188)Re generators. Since the specific activity of (188)W used in the generator is relatively low 185 GBq( < 5 Ci)/g], the eluted (188)ReO(4)(-) can have low radioactive concentration often insufficient for radiopharmaceutical preparation. However, several efficient post elution concentration techniques have been developed that yield clinically useful (188)ReO(4)(-) solutions. Rhenium-188 has been used for the preparation of therapeutic radiopharmaceuticals for the management of diseases such as bone metastasis, rheumatoid arthritis and primary cancers. Several early phase clinical studies using radiopharmaceuticals based on (188)Re-labeled phosphonates, antibodies, peptides, lipiodol and particulates have been reported. This article reviews the availability and use of (188)Re including a discussion of why broader use of (188)Re has not progressed as expected as a popular radionuclide for therapy.

[Use of a mechatronic robotic camera holding system in head and neck surgery]. / Anwendung eines aktiven Haltearms in der endoskopischen Kopf-Hals-Chirurgie.

BACKGROUND: It has been shown that a third hand is useful for holding the endoscope during endoscopic surgery so that both hands of the surgeon are free for instrumentation. MATERIAL AND METHODS: Experimental tests were performed with the mechatronic robotic camera holding system Soloassist on anatomical specimens in the area of the nose, nasopharynx and larynx. RESULTS: An ergonomic set-up and the practical application are easily possible. The third hand enables a still and clear picture without undesired camera movement and all instruments can be controlled by the surgeon. There would appear to be some room for improvement as the working area is limited due to an additional instrument. The camera holding system shows a very high velocity for head and neck surgery. CONCLUSION: Until the active holder can be used regularly in clinical practice in the field of head and neck surgery, more technical modifications have to be implemented.

[Modification of the retrolabyrinthine approach with hearing preservation in CPA tumors]. / Modifizierter retrolabyrinthärer Zugangsweg bei Kleinhirnbrückenwinkeltumoren zum Hörerhalt.

BACKGROUND: In an anatomical study including a CT scan of the cadaver sections by means of a virtual model analysis the option of a modified retrolabyrinthine passage to the cerebellopontine angle (CPA) preserving the Saccus endolymphaticus and the upper petrosus sinus was analysed. METHODS: Due to the individual anatomical variations of the petrosus bone the results showed several limitations with regard to the retrolabyrintine passage to the CPA. The smallest distance between the dura of the posterior fossa and the posterior semicircular canal measured in a high resolution CT was of particular importance as to how much room was available for the surgical manipulation in the retrolabyrinthine space. As the back side angle to the petrosus bone is much flatter in a translabyrinthine approach than in a retrosigmoidal approach the internal auditory canal needed to be controlled by using a 30 degree endoscope. RESULTS: In five patients the translabyrinthine approach was modified by temporarily preserving the labyrinth in an effort to remove the CPA tumors. Based on our clinical experience and on the findings of the anatomical and radiological studies we eventually removed the CPA tumors type B2 or C3 in three patients preserving hearing by using a modified retrolabyrinthine approach.

Production of Sn-117m in the BR2 high-flux reactor.

The BR2 reactor is a 100MW(th) high-flux 'materials testing reactor', which produces a wide range of radioisotopes for various applications in nuclear medicine and industry. Tin-117m ((117m)Sn), a promising radionuclide for therapeutic applications, and its production have been validated in the BR2 reactor. In contrast to therapeutic beta emitters, (117m)Sn decays via isomeric transition with the emission of monoenergetic conversion electrons which are effective for metastatic bone pain palliation and radiosynovectomy with lesser damage to the bone marrow and the healthy tissues. Furthermore, the emitted gamma photons are ideal for imaging and dosimetry.

[Significance of emissary veins in surgical treatment of temporal paragangliomas]. / Stellenwert emissarischer Venen bei der operativen Therapie temporaler Paragangliome.

With the surgical removal of temporal paraganglioma, possible changes of the cerebral blood pathways of the Circle of Willis should be considered. If the cerebral blood drains dominates unilaterally and the pathway of drainage over the Bulbus venae jugularis is inadequate due to vessel malformation or variations or by intraluminal tumor growth, as for instance of temporal paragangliomas, collateral emissary vessels can take over this function by an extraordinary large lumen extension. Ignorance of such a characteristic venous drainage can lead to hemorrhagic apoplexia when such originally redundant veins are sacrificed. A presurgical angiography is, therefore, indicated. In case of vessel malformations or variations the use of computer-assisted surgery could be helpful to preserve such native emissary veins at the bony skull base, such as the condylar emissary vein in the case of a transcondylar infralabyrinthine approach.

Use of the Oak Ridge National Laboratory tungsten-188/rhenium-188 generator for preparation of the rhenium-188 HDD/lipiodol complex for trans-arterial liver cancer therapy.

This work describes the installation, use, and quality control (QC) of the alumina-based tungsten-188 ((188)W)/rhenium-188 ((188)Re) generators provided by the Oak Ridge National Laboratory (ORNL). In addition, methods used for concentration of the (188)Re-perrhenate bolus and preparation of (188)Re-labeled HDD (4-hexadecyl-2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol) for trans-arterial administration for therapy of nonresectable liver cancer also are described. The (188)W/(188)Re generator has a long useful shelf-life of several months and is a convenient on-site (188)Re production system. (188)Re has excellent therapeutic and imaging properties (T(1/2) 16.9 hours; E(betamax) 2.12 MeV; 155-keV gamma ray, 15%) and is cost effectively obtained on demand by saline elution of the generator. The clinical efficacy of a variety of (188)Re-labeled agents has been demonstrated for several therapeutic applications. Because of the favorable physical properties of (188)Re, several (188)Re-labeled agents are being developed and evaluated for the treatment of nonresectable/refractory liver cancer. (188)Re-labeled HDD has been the most widely studied of these agents for this application and has been introduced into clinical trials at a number of institutions. The trans-arterial administration of (188)Re-labeled agents for treatment of inoperable liver cancer requires use of high-level (1-2 Ci) (188)W/(188)Re generators. The handling of such high levels of (188)Re imposes radiological precautions normally not encountered in a radiopharmacy and adequate care and ALARA (ie, "As Low As Reasonably Achievable") principles must be followed. The ORNL generator provides consistently high (188)Re yields (>75%) and low (188)W parent breakthrough (<10(-3)%) over an extended shelf-life of several months. However, the high elution volumes (20-40 mL for 1-2 Ci generators) can require concentration of the (188)Re bolus by postelution passage through silver cation chloride trapping columns used in the cost-effective tandem cation/anion column system. The silver column removes the high levels of chloride anion as insoluble AgCl, thus allowing subsequent specific trapping of the perrhenate anion on the small (QMA SeaPak) anion column. This method permits subsequent elution of (188)Re-perrhenate with a small volume of saline, providing a very high activity-concentration solution. Because the (188)Re-specific volume-activity concentration continually decreases with time, the tandem system is especially effective method for extending the useful generator shelf-life. Low elution flow rates (<1 mL/min) minimize any high back pressure which may be encountered during generator/tandem column elution when using tightly packed, small-particle-size commercial columns. In-house preparation of silver cation columns is recommended since the chloride trapping capacity is essentially unlimited, it is inexpensive and not limited in availability to any one supplier, and back pressure can be eliminated by the use of larger particles. Methods for the preparation of (188)Re-HDD have been optimized and this agent can be obtained in high yield (80%).

[Primary B-cell non-Hodgkin lymphoma of the internal auditory canal: case report and literature review]. / Primäres B-Zell-Non-Hodgkin-Lymphom des inneren Gehörgangs: Fallbericht und Literaturübersicht.

A primary non-Hodgkin lymphoma (NHL) of the internal auditory canal or the cerebellopontine angle is an absolute rarity, even among the unusual lesions encountered there. Schwannomas or meningiomas account for approximately 90-95% of the tumors of the cerebellopontine angle and the internal auditory canal. Atypical symptoms, such as facial nerve palsy or rapid progression, require differential diagnostics to identify less frequent entities. However, clinical symptoms or the image morphology cannot confirm the diagnosis of a lymphoma. If a malignant process is suspected during surgical exploration, an immediate intraoperative biopsy can give important clues for appropriate treatment. The course, diagnostics, and therapy of a rare case of primary B-cell NHL of the internal auditory canal are reported here.

Highlights of the European Association of Nuclear Medicine Congress, Athens, Greece, 30 September to 4 October 2006.

The 2006 EANM Congress, held in Athens, Greece, was once again a major event in the nuclear medicine scientific and educational calendar. The scientific programme, which included the second biennial ISRTRD meeting, confirmed the major developments taking place in (1) the diagnostic and prognostic uses of nuclear medicine imaging (both in PET and in single-photon studies), (2) radionuclide therapies, (3) radiochemistry and radiopharmacy, and (4) physics. This paper outlines the major findings in each of these areas.

[Craniofacial fibrous dysplasia: scan policy or surgery?]. / Kraniofaziale Fibröse Dysplasie: Observieren oder Operieren?

BACKGROUND: The aetiologic correlations of fibrous dysplasia (FD) are more and more decoded by molecular biology, improved imaging procedures, and the use of computer assisted surgery--thus a review of present diagnostics and therapy methods is evaluated. METHOD: The valid methods of diagnostic and therapy procedures of craniofacial FD were retrospectively analysed in a collective of 9 patients in consideration of literature. The criteria of the decision for diagnosis and surgical procedures were evaluated. RESULTS: According to the literature, diagnosis was ascertained with modern CT and MRI scans. Bone scintigraphy was only used additionally in particular questions. In case of unclear radiological findings histomorphological procedures were used complementarily to distinguish FD from other bone tumors. The aim of surgical intervention was to reduce pain, to restore the function in compression symptoms, to recover original ostia, or to restore the natural geometry of the face. CONCLUSIONS: Current imaging procedures allow differential diagnosis from other benign bone tumors but also from malignancies. The therapy of FD is conservative (wait and scan) or operative in dependence on the localisation, the extension and the clinical manifestations of the disease. In the future molecular biological methods could function as supporting instrument for diagnosis if histomorphological results are not meaningful.

Influence of ionizing radiation on nucleus 24 cochlear implants.

HYPOTHESIS: To evaluate the influence of conventional or hyperfractionated radiotherapy on Nucleus CI24M or CI24R(CS) implant systems. BACKGROUND: As a consequence of more than 70,000 cochlear implant recipients worldwide, the potential need for radiotherapy is an issue requiring consideration by both implantees and implantation centers. Conditions requiring radiotherapy of the head may include head, neck, or brain tumors. METHODS: The study examines the effect of ionizing radiation on cochlear implant function. The implanted devices examined were the Nucleus CI24M and Nucleus CI24R(CS). In a modeled study, two implants of each type were treated with fraction schemes most frequently used in clinical routine (e.g., conventional fractionation [total dose, 120 Gy] and hyperfractionation [total dose, 116 Gy]). Parameters quantified were the implant output amplitude changes at high and low current level (current levels 255 and 100, respectively), the charge balance of the biphasic pulse, and the accuracy of the impedance telemetry function. RESULTS: Within the clinically relevant dose range (< 80 Gy), implant function in all four devices was normal. Failure occurred in one Nucleus CI24R(CS) device treated with hyperfractionation. A dramatic drop in the output amplitude at 106 Gy was observed, and the impedance measurement failed at a total dose of 111 Gy. CONCLUSION: The results suggest that conventional or hyperfractionated radiotherapy can be applied safely at Nucleus CI24M or CI24R(CS) implant systems in a patient-like setting. Therefore, the authors propose that the results of the study can be applicable in clinical practice.

Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: tandomized phase II trial with the new, high-energy radiopharmaceutical rhenium-188 hydroxyethylidenediphosphonate.

PURPOSE: We investigated the effect of repeated bone-targeted therapy with rhenium-188 hydroxyethylidenediphosphonate (HEDP) in patients with progressive, hormone-resistant prostate carcinoma and bone pain. The aim of this study was to determine the pain palliation and the antitumor effect of rhenium-188 HEDP treatments. PATIENTS AND METHODS: Sixty-four patients were randomly assigned to one of two groups for radionuclide therapy with rhenium-188 HEDP; patients of group A received a single injection, patients of group B received two injections (interval, 8 weeks). After therapy, patients were followed-up by assessment of pain palliation and clinical outcome until death. RESULTS: In both groups, toxicity was low, with moderate thrombopenia and leukopenia (maximum common toxicity criteria grade of 2). The effectiveness of rhenium-188 HEDP for pain palliation was better in the repeated treatment group (group B), with a response rate and time of response of 92% and 5.66 months, respectively (P =.006 and P =.001). In group B, 11 (39%) of 28 patients had a prostate-specific antigen decrease of more than 50% for at least 8 weeks, compared with two (7%) of 30 patients in the single-injection group (group A). The median times to progression of group A and group B were 2.3 months (range, 0 to 12.2 months) and 7.0 months (range, 0 to 24.1 months), respectively (P =.0013), and the median overall survival times were 7.0 months (range, 1.3 to 36.7 months) and 12.7 months (range, 4.1 to 32.2 months), respectively (P =.043). CONCLUSION: Compared with single-injection therapy, repeated bone-targeted therapy with rhenium-188 HEDP administered to patients with advanced progressive hormone-refractory prostate carcinoma enhanced pain palliation and improved progression-free and overall survival. Larger studies are justified to further evaluate the use of rhenium-188 HEDP.

The impact of overexpression and deficiency of fatty acid translocase (FAT)/CD36.

Fatty acid translocase (FAT)/CD36 has been associated with diverse normal and pathologic processes. These include scavenger receptor functions (uptake of apoptotic cells and modified lipid), lipid metabolism and fatty acid transport, adhesion, angiogenesis, modulation of inflammation, transforming growth factor-beta activation, atherosclerosis, diabetes and cardiomyopathy. Although CD36 was identified more than 25 years ago, it is only with the advent of recent genetic technology that in vivo evidence has emerged for its physiologic and pathologic relevance. As these in vivo studies are expanded, we will gain further insight into the mechanism(s) by which CD36 transmits a cellular signal, and this will allow the design of specific therapeutics that impact on a particular function of CD36.

Stereoselective synthesis, in vitro, and initial in vivo evaluation of 1-methylpiperidin-4-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (IPIP): a novel radioiodinated molecular probe with high affinity for the muscarinic receptor.

1-Methylpiperidin-4-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (IPIP, Fig. 1) was investigated as a potential radioiodinated molecular probe targeted to the muscarinic receptor complex. The IPIP stereoisomers were synthesized via a chiral intermediate in >95% enantiomeric excess. The R-isomers demonstrated a M(1) to M(2) subtype selectivity of approximately 3 to 1 and the S-isomers demonstrated non-subtype selective binding in vitro. IPIP was radiolabeled with iodide-125 with an average radiochemical yield of 74.4% (+/-14.8, n = 5), specific activities >800 mCi/micromol, and radiochemical purities >97%. In vivo the Z-isomers demonstrated high uniform cerebral uptake suggesting non-subtype selective binding. In contrast, E-R-IPIP, after allowing a low uptake in M(2) rich areas to clear, demonstrated a retention of activity in M(1) and M(4) rich cerebral regions. In addition, the cerebral uptake of E-R-IPIP and Z-S-IPIP were inhibited by 70-90% via pretreatment with R-QNB, an established muscarinic antagonist. An ex vivo metabolism study demonstrated Z-S-IPIP was stable at the receptor site with an absence of radiolabeled metabolites.

Efficacy of Re-188-labelled sulphur colloid on prolongation of survival time in melanoma-bearing animals.

UNLABELLED: In this study, the effectiveness of a 188Re labeled sulfur colloid with two particle size ranges was used to evaluate the effectiveness of this agent on melanoma tumors in mice in terms of animal lifespan. METHODS: Two separate group of animals were used for investigating biodistribution and survival time. A total of 188 B16F10-melanoma-bearing BDF(1) mice were injected intraperitoneally with 3.7 MBq (0.1mCi)/2mL of radiolabeled sulfur colloid ten days after intraperitoneal inoculation of 5x10(5) B16F10 melanoma cells/2ml. For group 1, 30 mice were sacrificed at 1, 4, 24, 48 and 72 hours for biodistribution studies. In group 2, 158 mice were divided into 9 groups (n=16 approximately 18/groups)each receiving respectively tumor alone, tumor with normal saline, cold colloid or hot colloid with 16, 23, 31, 46, 62, or 124 MBq activity. Each of these colloid groups was further divided into two groups, one receiving smaller particle sizes (<3 microm:80.4 +/-7.2%, colloid 1) and the other receiving larger particle sizes (<3 microm:12.3+/-1.0%, colloid 2). The animals were checked daily until death and their survival recorded. RESULTS: Colloid 2 showed higher accumulation in almost all tissues, the highest accumulation organ was tumor ( approximately 40%), then spleen ( approximately 20%), stomach ( approximately 15%), diaphragm ( approximately 3%), and liver ( approximately 2%). There was a significant increase in survival time with increasing amount of the larger-particle-size colloid. Administered levels of 16-31 MBq/mouse were most efficacious and with higher amounts the survival times decreased significantly below that of the controls. There was a significant difference in the dose-response curves for the two preparations. Protection factors (1/Relative-risk) of nearly 5 were achieved using the larger colloid size, and nearly 30 using the smaller colloid size. An amount of 16-31 MBq of the colloid 2 was the optimal activity in these studies. On the one hand, the survival data agreed well with the biodistribution data, where higher accumulation was found in tumor with colloid 2. CONCLUSION: Rhenium-188 offers on-site availability, medium half-life, higher beta-particle energy of 2.12 MeV for therapy and emission of 155keV gamma photon suitable for imaging. The present study demonstrated that 188Re-sulfur colloid is an effective agent in controlling tumor cells in the abdominal cavity in animals.