Cardiac molecular pathways influenced by doxorubicin treatment in mice.

Doxorubicin (DOX) is a potent chemotherapeutic with distinct cardiotoxic properties. Understanding the underlying cardiotoxic mechanisms on a molecular level would enable the early detection of cardiotoxicity and implementation of prophylactic treatment. Our goal was to map the patterns of different radiopharmaceuticals as surrogate markers of specific metabolic pathways induced by chemotherapy. Therefore, cardiac distribution of 99mTc-sestamibi, 99mTc-Annexin V, 99mTc-glucaric acid and [18F]FDG and cardiac expression of Bcl-2, caspase-3 and -8, TUNEL, HIF-1α, and p53 were assessed in response to DOX exposure in mice. A total of 80 mice (64 treated, 16 controls) were evaluated. All radiopharmaceuticals showed significantly increased uptake compared to controls, with peak cardiac uptake after one (99mTc-Annexin V), two (99mTc-sestamibi), three ([18F]FDG), or four (99mTc-glucaric acid) cycles of DOX. Strong correlations (p < 0.01) were observed between 99mTc-Annexin V, caspase 3 and 8, and TUNEL, and between [18F]FDG and HIF-1α. This suggests that the cardiac DOX response starts with apoptosis at low exposure levels, as indicated by 99mTc-Annexin V and histological apoptosis markers. Late process membrane disintegration can possibly be detected by 99mTc-sestamibi and 99mTc-glucaric acid. [18F]FDG signifies an early adaptive response to DOX, which can be further exploited clinically in the near future.

Phase I clinical trial of 99mTc-etarfolatide, an imaging agent for folate receptor in healthy Japanese adults.

OBJECTIVE: Technetium etarfolatide ((99m)Tc-EF) is a radioactive diagnostic imaging agent that was developed to assess the expression of folate receptors in tumors. Administering folic acid prior to the administration of (99m)Tc-EF has been shown to improve SPECT images. Here, we conducted a phase I clinical trial to assess the safety, pharmacokinetics, and radiation dosimetry of (99m)Tc-EF injection following pre-administration of folic acid in healthy Japanese male adults. METHODS: Six healthy Japanese male adults were enrolled in the study. Folic acid was intravenously administered, followed 1-3 min later by an intravenous injection of (99m)Tc-EF (740 MBq ± 20 %). Assessments of subjective symptoms and objective findings, electrocardiograms, physical examination, and laboratory tests were performed before and up to 7 days after the injection to assess the safety of (99m)Tc-EF. Blood and urine collections and whole-body planar imaging were conducted at various time points up to 24 h after the injection to assess the pharmacokinetics of (99m)Tc-EF. The internal radiation dosimetry was calculated based on the pharmacokinetics results using the MIRD method. RESULTS: Five adverse events were observed in three subjects (50 %) after administration of the folic acid and (99m)Tc-EF, while these events were mild and non-serious. Of those five events, three were considered to be related to the administered agents. The radioactivity in blood rapidly decreased and showed a biphasic profile. The activity of (99m)Tc-EF at 5 min post injection was largest in the bone marrow, followed by the liver and kidneys, and had decreased within 24 h in all organs/tissues without appreciable retention. The pharmacokinetics results suggested that (99m)Tc-EF was mainly eliminated by kidney. The results also suggested that when administered at 925 MBq of (99m)Tc-EF, which is the maximum dose generally used for clinical trials in other countries, the corresponding effective dose of (99m)Tc-EF is equal to or less than those determined for the current radioactive diagnostic imaging agents. CONCLUSIONS: The results of this study assessing the safety and radiation dosimetry of (99m)Tc-EF with folic acid pre-administration suggested that folic acid and (99m)Tc-EF should be appropriate for further studies. No pharmacokinetics concerns were noted.

Comparison of DMSA scan 99 m and EC scan 99 m in diagnosis of cortical defect and differential renal function.

INTRODUCTION: Diagnosis of renal cortical lesions by radioisotopes in nuclear medicine is one of the most common techniques and procedures can be performed by different radiotracer. However, all these materials are accurate in determining kidney function, but there are differences between them in the field. The purpose of this study was to evaluate the effectiveness of EC scans compared with DMSA scan in the detection of cortical lesions and DRF. METHODS: 65 cases, which have been referred for various reasons, for DMSA scans were enrolled. Patients 1 week after DMSA scan with the previous consent of the EC being scanned. The results were compared in terms of convergence as well as sensitivity, specificity, positive and negative predictive value of EC with respect to the results of DMSA scan. RESULTS: PPV of EC was 100%, negative predictive value of EC was 68.75%, sensitivity of EC was 90.74% and specificity of EC was 100% in the detection of cortical lesions. DMSA scan and EC convergence rates result in cortical lesions in our study was high. DISCUSSION: We suggest EC scan as an alternative to reduce the cost of therapy and radiation, but considering the benefits of DMSA scan, it could remain the gold standard method of diagnosis. 

Comparison of effective dose and lifetime risk of cancer incidence of CT attenuation correction acquisitions and radiopharmaceutical administration for myocardial perfusion imaging.

OBJECTIVE: To measure the organ dose and calculate effective dose from CT attenuation correction (CTAC) acquisitions from four commonly used gamma camera single photon emission CT/CT systems. METHODS: CTAC dosimetry data was collected using thermoluminescent dosemeters on GE Healthcare's Infinia™ Hawkeye™ (GE Healthcare, Buckinghamshire, UK) four- and single-slice systems, Siemens Symbia™ T6 (Siemens Healthcare, Erlangen, Germany) and the Philips Precedence (Philips Healthcare, Amsterdam, Netherlands). Organ and effective dose from the administration of (99m)Tc-tetrofosmin and (99m)Tc-sestamibi were calculated using International Commission of Radiological Protection reports 80 and 106. Using these data, the lifetime biological risk was calculated. RESULTS: The Siemens Symbia gave the lowest CTAC dose (1.8 mSv) followed by the GE Infinia Hawkeye single-slice (1.9 mSv), GE Infinia Hawkeye four-slice (2.5 mSv) and Philips Precedence v. 3.0. Doses were significantly lower than the calculated doses from radiopharmaceutical administration (11 and 14 mSv for (99m)Tc-tetrofosmin and (99m)Tc-sestamibi, respectively). Overall lifetime biological risks were lower, which suggests that using CTAC data posed minimal risk to the patient. Comparison of data for breast tissue demonstrated a higher risk than that from the radiopharmaceutical administration. CONCLUSION: CTAC doses were confirmed to be much lower than those from radiopharmaceutical administration. The localized nature of the CTAC exposure compared to the radiopharmaceutical biological distribution indicated dose and risk to the breast to be higher. ADVANCES IN KNOWLEDGE: This research proved that CTAC is a comparatively low-dose acquisition. However, it has been shown that there is increased risk for breast tissue especially in the younger patients. As per legislation, justification is required and CTAC should only be used in situations that demonstrate sufficient net benefit.

[99mTc]demotensin VI: biodistribution and initial clinical results in tumor patients of a pilot/phase I study.

PURPOSE: Neurotensin subtype 1 receptor overexpression is found in a variety of human tumors. The aim of this pilot/phase I study was to assess the safety profile, pharmacokinetics, and imaging characteristics of (99m)Tc-Demotensin VI in tumor patients. METHODS: Scintigraphy with (99m)Tc-Demotensin VI was performed in 14 patients (2 female and 12 male) with advanced tumor stages. The diagnoses were pancreatic adenocarcinoma (n=4), small cell lung cancer (SCLC) (n=4), non-small cell lung cancer (NSCLC) (n=4), and colon carcinoma (n=2). Patients were injected with 500-550 MBq (99m)Tc-Demotensin VI. Blood samples were taken at various time points and urine was also collected up to 24 hours post-injection (p.i.) Planar images were acquired at 15-30 minutes, 1-2 hours, 4 hours, and 24 hours p.i. with additional SPECT imaging at 4 hours. RESULTS: Radiochemical purity always exceeded 95% up to 4 hours. Urinary and blood excretion was rapid with 5.05% ID (mean: n=5) in plasma after 4 hours. No side effects were observed after injection of (99m)Tc-Demotensin VI. Focal tracer accumulation was observed in 3 patients with brain metastases due to NSCLC, although specificity of this uptake could not be proven. Further, no tumor-related findings were observed. Although stability tests in human plasma revealed that (99m)Tc-Demotensin VI remained intact up to 2 hours incubation, ex vivo urine analysis indicated rapid metabolism. CONCLUSION: (99m)Tc-Demotensin VI was well tolerated by patients and showed favorable pharmacokinetics; however, tumor targeting was limited to brain metastases. Further studies on stability issues and receptor characterization in tumors are warranted to introduce neurotensin receptors (NTSR) imaging into the clinic.

Phase 1 study to identify tumour hypoxia in patients with head and neck cancer using technetium-99m BRU 59-21.

The aim of this study was to assess the safety and biodistribution of technetium-99m BRU 59-21, a novel radioactively labelled 2-nitro-imidazole hypoxic marker, in head and neck cancer patients and to correlate uptake with pimonidazole staining. (99m)Tc-BRU 59-21 was administered intravenously (mean dose 824 MBq, range 780-857 MBq) to ten head and neck cancer patients scheduled for primary surgery, and whole-body images and SPET scans were then obtained. Uptake of radioactivity in the regions of interest was determined and tumour to normal tissue ratios were calculated after correlative evaluation with MRI/CT. Twelve to 16 h before surgery (up to 2 weeks after the scan), patients received pimonidazole intravenously. Tumour sections were stained immunohistochemically for pimonidazole binding. No serious adverse events were reported. In five patients there were ten adverse events, which were mild in intensity and resolved completely without intervention. Uptake of (99m)Tc-BRU 59-21 was observed in eight of the ten primary tumours. Tumour to normal tissue ratios on the SPET scans for primary tumour and lymph nodes increased from 1.8 (range 0.9-2.7) to 2.1 (range 0.8-3.7) between 30 min and 3 h post injection. Tumour to normal tissue ratios in the primary tumour were significantly correlated with pimonidazole staining for SPET scans performed 30 min and 3 h post injection ( P=0.016 and P=0.037, respectively). When primary tumour and involved lymph nodes were considered in conjunction, correlation between the tumour to normal tissue ratio and pimonidazole staining was observed for early ( P<0.001) but not for late SPET scans ( P=0.076). However, late scans showed better tumour delineation than early scans. Administration of (99m)Tc-BRU 59-21 in head and neck cancer patients appears to be safe and feasible. Uptake and retention in tumour tissue was observed, suggestive of tumour hypoxia, and this was supported by correlations with staining for the hypoxic marker pimonidazole.

Localizing infection with a technetium-99m-labeled peptide: initial results.

In vitro-labeled leukocyte imaging is useful for the detection of infection, but an in vivo labeling method is preferable. This study sought to evaluate the safety and efficacy of a leukocyte-avid peptide for the detection of infection, to determine the effects of peptide dose on performance and to compare the peptide with in vitro-labeled leukocytes. A 23-amino acid peptide, P483, containing the platelet factor-4 heparin-binding sequence, was labeled with 99mTc and complexed with heparin (P483H). Thirty patients were injected with 29 microg (n = 11), 145 microg (n = 10) or 290 microg (n = 9) of labeled peptide, and imaged 15 min and 90-120 min later. Early and late images were interpreted individually and jointly. Twenty patients underwent (111)In-labeled leukocyte scintigraphy. Fourteen patients had infection: osteomyelitis (n = 7), vascular graft (n = 2), abscess (n = 2), joint replacement (n = 1), surgical wound (n = 1) and pneumonia (n = 1). There were 10 adverse events in six patients; all were mild and resolved spontaneously, and without any intervention. The sensitivity, specificity and accuracy were the same for both early and late imaging: 0.86, 0.81 and 0.83, respectively. Interpreting early and late images together did not improve the results. No relationship between peptide dose and study accuracy was found. In patients undergoing both examinations, the accuracies of the peptide and in vitro-labeled leukocyte imaging were identical: 0.80. In summary, 99mTc-P483H safely, rapidly and accurately detected focal infection, was comparable with in vitro-labeled leukocyte imaging and therefore merits further investigation.

99Tc(m) labelled HL91 versus computed tomography and biopsy for the visualization of tumour recurrence of squamous head and neck carcinoma.

This phase I pilot study reports on (1) the safety and feasibility of 99Tc(m)-HL91, an amine oxime core radioligand that has shown oxygen dependent binding, and imaging; and (2) its usefulness for the visualization of local tumour recurrence of a biopsy proven squamous cell carcinoma of the head and neck (SCCHN) as compared to spiral computed tomogaphy (CT) and biopsy. Nine men (mean age 33 years, range 34-74 years) were prospectively included. For safety measurements, vital signs were recorded and serum chemical analysis carried out, with a complete blood cell count and urine analysis, and an ECG was performed prior to injection of 99Tc(m)-HL91 and repeated during the investigation. Single photon emission computed tomography (SPECT) scans of the head and neck, and of a standard, were performed at 2 h and 4 h post-injection of 740 MBq 99Tc(m)-HL91. Tumour-to-normal tissue background (T/N) ratios and percentage uptake were measured for all 99Tc(m)-HL91 scans. Spiral CT scans were obtained using a Somaton 4+ Siemens scanner within 1 week from the 99Tc(m)-HL91 scans. Based on CT and the 99Tc(m)-HL91 scan findings guided biopsies were performed. No adverse or subjective side effects were noticed. Vital signs, ECG findings, clinical laboratory, blood and urine assays remained stable in all patients. Spiral CT suggested local recurrence in 5/9 patients accompanied by nodal involvement in three, all of which proved positive on biopsy. 99Tc(m)-HL91 scintigraphy was false positive in one patient and true positive (TP) in 3/5 local recurrences and two out of three sites of lymph node involvement depicted by spiral CT. The mean T/N ratios at 2 h and 4 h in TPs were 1.28 (range 1.1-1.66) and 1.40 (range 1.0-1.6), respectively. The corresponding absolute percentages of 99Tc(m)-HL91 lesional uptake at 2 h and 4 h were mu = 0.05% (SD = 0.03%) and mu = 0.048% (SD = 0.035%). The findings suggest 99Tc(m)-HL91 is a safe radioligand and that metabolic binding in a large fraction but not all of local SCCHN recurrences may be expected. The inference that tumour 99Tc(m)-HL91 avidity could be a non-invasive measure of tumour hypoxia deserves however independent confirmation with needle oximetry.

Safety and efficacy of arcitumomab imaging in colorectal cancer after repeated administration.

UNLABELLED: In pivotal phase III clinical trials for detecting recurrent or metastatic colorectal cancer, most patients received a single arcitumomab injection. However, the early detection of postsurgical recurrence or metastases with arcitumomab will necessitate serial studies for surveillance. We present immunogenicity, safety, and imaging data supporting the use of multiple administrations of arcitumomab. METHODS: Human antimouse antibody (HAMA) response, adverse events, clinical laboratory values, and diagnostic imaging results were evaluated in 44 patients (24 men, 20 women; age range, 2878 y) after repeated arcitumomab administration (44 second and 3 third injections). Most patients initially had Dukes' class B or C colorectal cancer and had known or occult disease recurrence and elevated serum carcinoembryonic antigen levels at the time of the repeated injection. RESULTS: At the repeated injection, in no patient did elevated HAMA titers develop, hematology and serum chemistry changes were clinically insignificant, and only 1 adverse event (eosinophilia) was judged at least possibly related to arcitumomab. Arcitumomab imaging results at the second injection were comparable with those obtained in phase III trials after a single injection of arcitumomab, having a 78% per-lesion concordance with CT in the abdomen and pelvis and a 73% sensitivity and 94% specificity based on 9 patients with cancer confirmed surgically at 11 anatomic sites and excluded at 16 sites. CONCLUSION: These data indicate that at least 2 injections of arcitumomab can be given safely to patients with colorectal cancer, without increased immunogenicity and with imaging efficacy equivalent to the first administration.

Tc-99m-PEG-Liposomes for the evaluation of colitis in Crohn's disease.

In the present study, the potential role of 99mTc-PEG-liposome to determine the extent and severity of active disease of Crohn's colitis was investigated. Patients suspected of having an exacerbation of Crohn's disease underwent a 99mTc-PEG-liposome scan (740 MBq, imaging at 4 and 24 h p.i.). A barium enema or endoscopy was performed as the standard verification procedure. Disease activity indices (Clinical Disease Activity Index and Van Hees Activity Index) were calculated. In seven patients positive images of colon segments affected by Crohn's colitis were obtained using 99mTc-PEG-liposomes. Only a moderate relation between 99mTc-liposome scan grading and verification procedures was found (Spearman rank r = 0.22). In accordance with previous studies, no significant correlation was found between the clinical disease activity indices and the verification procedures. This study was prematurely terminated because of unacceptable side-effects in 3 out of 9 patients, which occured almost immediately after starting the infusion. The complaints consisted of dyspnea and facial erythema. The symptoms were self-limiting when the infusion was stopped. In conclusion, the extent of Crohn's colitis can be established non-invasively with 99mTc-PEG-liposome scintigraphy. However, in view of the encountered side-effects, the PEG-liposomal preparation may have to be modified.

99Tcm-citrate: a new bone imaging radiopharmaceutical.

99Tcm-citrate has been shown to incorporate irreversibly in the skeleton with a biodistribution different to that on a conventional bone scan. The aims of this study were to confirm the bone-imaging properties of 99Tcm-citrate, to identify the variabilities influencing its skeletal uptake, to compare its uptake in bone with that of 99Tcm-MDP and to assess its possible role in bone scintigraphy. Appropriate animal and human studies (n = 45) were conducted. The 3 h lesion-to-bone ratio of 99Tcm-citrate was compared with that of 99Tcm-MDP in more than 150 lesions, including osteoblastic sites (Group A), lesions undergoing treatment or healing (Group B), and degenerative or old healed lesions (Group C). The uptake ratio was classified as concordant (< 20% variation), mildly discordant (20-50% variation) or significantly discordant (> 50% variation). Animal experiments showed most bone uptake of 99Tcm-citrate when prepared at a pH of 6.0-6.5. The two radiopharmaceuticals appeared to compete for bone uptake, suggesting related but different sites of bone accumulation. The 99Tcm-citrate/99Tcm-MDP uptake ratio in Group A was concordant (mean +/- S.D. = 0.92 +/- 0.15), while Group C lesions had a significantly lower 99Tcm-citrate/99Tcm-MDP uptake ratio (0.34 +/- 0.24, P < 0.01). A comparison of Group B lesions showed wide variation in intensity and area of involvement in many lesions (uptake ratio < 0.5 or > 1.5 in 13 of 30 sites). We conclude that 99Tcm-citrate has a different site of bone localization than phosphonates, possibly in the organic matrix. Although its skeletal uptake is lower than that of 99Tcm-MDP, it may have better specificity in differentiating osteoblastic from degenerated or healed bony lesions, and therefore be useful in predicting healing of bone secondaries, fractures or osteomyelitic lesions.

Technetium-99m antimyosin antibody (3-48) myocardial imaging: human biodistribution, safety and clinical results in detection of acute myocardial infarction.

Technetium-99m antimyosin (99mTc-AM) antibody imaging may have significant advantages over indium-111 antimyosin in clinical practice. The purpose of this study was to determine the human biodistribution, the safety profile and the sensitivity of 99mTc-AM (3-48) imaging in the detection of both Q-wave and non-Q-wave myocardial infarction (MI). Biodistribution and safety parameters were mainly determined in 12 normal healthy volunteers while 40 patients with proven MI (22 Q-wave, 18 non-Q-wave) were injected with 99mTc-AM (20-25 mCi) between 5 h and 7 days after the onset of acute chest pain. Three standard planar views were performed at 6 h and at 24 h post injection. Both sets of images were completed in 33 patients while two patients were imaged only at 6 h, three patients only at 18 h and one at 18 and 24 h. One patient was not imaged. Vital signs and ECG were recorded and blood samples for haematology, biochemistry and human antimurine antibodies (HAMA) and urinalysis were obtained in all volunteers and patients. No serious adverse reactions or side-effects attributable to 99mTc-AM have been reported. No volunteers or patients developed allergic reactions or significant increases in HAMA titres. Reading of 99mTc-AM imaging was performed by two blinded experienced observers. The sensitivity of 99mTc-AM in the detection of MI was 100% (21/21) for Q-wave and 83.3% (15/18) for non-Q-wave infarctions. The overall sensitivity was 92.3% (36/39). The three false-negative cases were inferoposterior MI. A certain degree of uptake focalization was seen in 26 out of 35 (74.2%) at 6 h. At 24 h, two patients (5.8%) did not show 99mTc-AM uptake while 22 (64.7%) showed intense focal uptake, seven (20.6%) moderate uptake and 3 (8.9%) slight uptake. It is concluded that 99mTc-AM (3-48) imaging is safe and shows high sensitivity in the detection of both Q-wave and non-Q-wave MI even with early imaging (6 h post injection). These promising results warrant further clinical investigation.

Adverse reactions and drug interactions with radiopharmaceuticals.

Adverse reactions to radiopharmaceuticals are comparatively few in number. Various estimates quote an incident rate of 1 to 6 reactions per 100,000 injections. Other figures quoted are 1 in 800 for the bone-seeking radiopharmaceutical methylene diphosphonate, and 1 in 400 for the lung visualisation agent macroaggregated albumin. The very low numbers of reported adverse effects probably reflect the tiny amounts of material which are used in the formulation of radiopharmaceuticals. Adverse reactions to radiopharmaceuticals are usually mild and transient and require little or no medical treatment. A few reactions involve respiratory or circulatory collapse or loss of consciousness. Several fatalities have been reported with the liver scanning agent 99mTc (technetium 99m)-albumin colloid. Clinical manifestations may be categorised under the headings of vasomotor effects i.e. faintness, pallor, diaphoresis or hypotension, and anaphylactoid effects such as nausea, dermographism, wheezing, bronchospasm, erythema and pruritus. The most prominent group of radiopharmaceuticals that have been reported to produce adverse events are the diphosphonates, which are used for scanning the skeleton. Typical diphosphonate reactions include erythema (especially over the extremities), nausea, vomiting and malaise. The onset of reaction is usually 2 to 3 hours after injection. The second group of radiopharmaceuticals which give rise to adverse events are the colloids, which are used for liver and spleen scintigraphy. Typical colloid reactions include pallor, nausea, flush and pulse changes. Adverse events may also occur as a result of the patient's medication interfering with the disposition of the radiopharmaceutical. Although not usually hazardous or dangerous, such events may be so pronounced that a marked deviation in the expected pharmacokinetics may occur. Drug interactions can be conveniently categorised under the headings of unusual handling of the radiopharmaceutical because of pharmacological action, genuine in vivo interaction between the medication and radiopharmaceutical, drug-induced disease and interaction between the radiopharmaceutical and catheters or syringes. The most serious drug interactions are those where the patient is taking cortisone or cytotoxic agents prior to tumour scintigraphy. Other important effects occur in patients undergoing bone scanning who are receiving iron preparations. Nifedipine has been reported to produce quite severe problems in scanning, including difficulties in the radiolabelling of red cells (for cardiac scintigraphy), and other effects where the drug appears to prevent the transport of bone-seeking materials into the skeleton. Many drugs alter hormonal status and these effects may produce marked deviations from the expected biodistribution. Diethylstilbestrol (stilboestrol), digitalis, gonadotrophins, phenothiazines and cimetidine all increase estrogen levels in high doses.(ABSTRACT TRUNCATED AT 400 WORDS)

Radiation dose rates from adult patients undergoing nuclear medicine investigations.

Adult patients undergoing nuclear medicine investigations may subsequently come into close contact with members of the public and hospital staff. In order to expand the available dosimetry and derive appropriate recommendations, dose rates were measured at 0.1, 0.5 and 1.0 m from 80 adult patients just before they left the nuclear medicine department after undergoing one of eight 99Tcm studies, an 123I thyroid, an 111In leucocyte or a 201Tl cardiac scan. The maximum departure dose rates at these distances of 150, 30 and 7.3 microSv h-1 were greater than those found in similar published studies of adult and paediatric patients. To limit the dose to an infant to less than 1 mSv, an 111In leucocyte scan is the only investigation for which it may be necessary to restrict close contact between the infant and a radioactive parent, depending on the dose rate near the surface of the patient, the parent's habits and how fretful is the infant. It is unlikely that a ward nurse will receive a dose of 60 microSv in a working day if caring for just one radioactive adult patient, unless the patient is classified as totally helpless and has undergone a 99Tcm marrow, bone or brain scan. The data and revised calculations of effective exposure times based on a total close contact time of 9 h in every 24 h period should allow worst case estimates of radiation dose to be made and recommendations to be formulated for other circumstances, including any future legislative changes in dose limits or derived levels.