Samuel Samnick

Striatal FP-CIT uptake differs in the subtypes of early Parkinson's disease.

Summary.In idiopathic Parkinson’s disease (PD), a tremor-dominant type (TDT), an akinetic-rigid type (ART), and a mixed type (MT) are distinguished. We compared cerebral [I-123]FP-CIT SPECT in the PD subtypes (67 patients Hoehn and Yahr stage 1:26 with ART, 19 with MT, 22 with TDT). We measured the ratios putamen/occipital lobe binding and caudate nucleus/occipital lobe binding. Parkinsonian motor symptoms were quantified by UPDRS motor scale. In both putamen and caudate nucleus contralateral to the clinically affected body side TDT patients showed a significantly higher FP-CIT uptake than ART or MT patients (ANOVA; p<0.01). Contralateral putamen and caudate nucleus FP-CIT uptake correlated significantly with severity of rigidity (p<0.01) and hypokinesia (p<0.01) but not with severity of resting or postural tremor (p>0.05). The missing correlation between striatal FP-CIT uptake and tremor suggests, that further systems besides the nigrostriatal dopaminergic system may contribute to generation of parkinsonian tremor.

FP-CIT and MIBG scintigraphy in early Parkinson's disease

Methods provided by nuclear medicine may be helpful in diagnosis of Parkinsons disease (PD). For that purpose, the sensitivity of iodine‐123 metaiodobenzylguanidine ([123I]MIBG) scintigraphy and [123I]FP‐CIT single photon emission computed tomography (SPECT) was studied in patients with PD onset (Hoehn and Yahr Stage 1). Cerebral [123I]FP‐CIT and cardiac [123I]MIBG scintigraphy were carried out in 18 patients with idiopathic Parkinsons disease, according to Hoehn and Yahr Stage 1. For quantification purposes, we calculated the striatum/posterior lobe binding of FP‐CIT and the heart‐to‐mediastinum (H/M) count ratio regarding MIBG scintigraphy. In 15 of 18 patients, we observed markedly reduced or asymmetric striatal FP‐CIT tracer accumulation. FP‐CIT binding of the affected striatum was significantly lower as compared with that of the unaffected side. Striatal FP‐CIT binding correlated significantly with the motor part of the Unified Parkinsons disease rating scale (UPDRS) but not with age, disease duration, or gender. MIBG scintigraphy delivered significant pathological results in 13 of 18 patients. There was no significant correlation between the H/M ratio relating to MIBG scintigraphy and the motor part of UPDRS, age, disease duration, or gender; however, binding of striatal FP‐CIT correlated significantly with cardiac MIBG accumulation. According to the clinical criteria, it might be difficult to prove the diagnosis of PD in patients with slight symptoms and in these cases, FP‐CIT SPECT and MIBG scintigraphy may contribute to the early diagnosis of PD. In addition, the functional loss of nigrostriatal and cardiac sympathetic neurons seems to be coupled closely.

Myocardial sympathetic degeneration correlates with clinical phenotype of Parkinson's disease

In idiopathic Parkinsons disease (PD), different clinical subtypes are distinguished due to predominant motor symptoms: a tremor‐dominant type (TDT), an akinetic rigid type (ART), and a mixed type (MT). We compared myocardial sympathetic innervation, measured by MIBG scintigraphy, in different subtypes of PD at early and advanced stages of PD. We applied MIBG scintigraphy in 102 patients with PD. About 57 patients were at Hoehn and Yahr (H&Y) stage 1, 22 at H&Y stage 2, and 23 at H&Y stages 3 and 4. For quantification of myocardial MIBG uptake, the heart‐to‐mediastinum (H/M) count‐ratio was calculated. At all H&Y stages, myocardial MIBG uptake was significantly higher in TDT patients than in ART or MT patients (P < 0.05; ANOVA). Furthermore, at each H&Y stage, myocardial MIBG uptake correlated significantly with severity of hypokinesia (P < 0.05; Spearmans correlation) and rigidity (P < 0.05), but not with severity of resting or postural tremor. The significant correlation between myocardial sympathetic degeneration and severity of hypokinesia and rigidity suggests that myocardial sympathetic degeneration and hypokinetic‐rigid symptoms develop in a closely coupled manner in early as well as advanced PD. No such correlation can be found between myocardial sympathetic degeneration and parkinsonian tremor.

Evaluation of l-3-[123I]iodo-α-methyltyrosine SPET and [18F]fluorodeoxyglucose PET in the detection and grading of recurrences in patients pretreated for gliomas at follow-up: a comparative study with stereotactic biopsy

Abstract. Based on the results of stereotactic biopsy, we evaluated in a prospective fashion the efficiency of l-3-[123I]iodo-α-methyltyrosine-single-photon emission tomography (SPET) and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in the detection and grading of recurrences in patients previously treated for gliomas. The patient population comprised 30 individuals, nine with astrocytomas of grade II, ten with astrocytomas of grade IV, three with oligoastrocytomas of grade II, six with oligodendrogliomas of grade II and two with anaplastic oligodendrogliomas of grade III) suspected of recurrence and scheduled for further treatment. IMT SPET data were acquired using either by dual-or a triple-headed SPET camera, Multispect 2/3. FDG uptake was measured with an ECAT ART PET camera. Two independent observers classified PET and SPET images as positive or negative for tumour tissue. Uptake of FDG and IMT was evaluated visually and, in the case of IMT, also quantitatively by calculating the ratios between tracer accumulation in the lesion and the unaffected contralateral regions of reference using the region of interest (ROI) technique. The PET and SPET results were compared with the histopathological findings obtained either by stereotactic biopsy or in one case by open surgery. Glucose metabolism and amino acid uptake of recurrences of brain tumours as assessed by FDG-PET and IMT-SPET correlated highly with the histopathological findings. Based on the histopathological data, FDG-PET and IMT-SPET findings confirmed recurrence in all cases of high-grade gliomas (IV). A difference could be demonstrated in low-grade (II–III) tumour recurrences. True-positive IMT-SPET results were found in 86% of grade III and 75% of grade II recurrences, whereas FDG-PET yielded a sensitivity of 71% in tumours of grade III and 50% in those of grade II. With respect to the grade of malignancy of brain tumours at recurrence, IMT-SPET, in contrast to FDG-PET, does not permit adequate in vivo grading of non-mixed brain tumours of astrocytic or oligodendroglial origin. However, in this study FDG-PET did not permit discrimination between upgrading of low-grade oligoastrocytomas (II) into anaplastic oligodendrogliomas (III) and upgrading into glioblastomas (IV) The results of this study indicate that FDG-PET and IMT-SPET are equivalent to stereotactic biopsy in their ability to identify high-grade tumours at recurrence. IMT-SPET proved to be superior to FDG-PET in confirming low-grade recurrences. In the case of suspected progression of the grade of malignancy in ordinary gliomas, FDG-PET correlated significantly with the histopathological grading, whereas IMT-SPET did not. However, tumour grading by FDG-PET has a limitation in mixed brain tumours in that it is not possible to discriminate between progression of the oligo- versus the astrocytic tumour entity. In this case histopathological evaluation of the tumour grade remains necessary.

Preparation and investigation of tumor affinity, uptake kinetic and transport mechanism of iodine-123-labelled amino acid derivatives in human pancreatic carcinoma and glioblastoma cells

In developing radioiodinated agents for pancreatic and brain tumor imaging by single photon emission tomography (SPET), we prepared p-amino-3-[123I]iodo-l-phenylalanine (IAPA), p-[123I]iodo-l-phenylalanine (IPA), L-8-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (ITIC) and L-3-[123I]iodo-alpha-methyl-tyrosine (IMT) in radiochemical yields up to 95%, and we investigated their uptake in human pancreatic carcinoma and glioblastoma cells as well as the mechanisms promoting the tumor uptake. The radiopharmaceutical uptake into tumor cells was rapid (t(1/2) < or = 5 min) and temperature- and pH-dependent. The radioactivity concentration in tumor cells varied from 10 to 33% of the total activity (105-310 cpm/1000 cells) following a 30-min incubation at 37 degrees C (pH 7.4). In comparison, accumulation of the radiopharmaceuticals into normal brain and pancreatic tissue remained relatively low. Depolarizing the plasma membrane potential in high K+ buffer significantly altered the radioactivity concentration in the tumor cells, suggesting that membrane potential plays a certain role in the cellular uptake. Competitive inhibition experiments with specific amino acid transport inhibitors indicated that the uptake of IAPA, IPA and IMT into human pancreatic carcinoma and glioblastoma cells is predominantly mediated by the L and ASC transport systems, while no substantial involvement of the transport system A in their tumor uptake could be demonstrated. In contrast, results of the present investigation indicated that ITIC is not taken up into tumor cells via the common neutral amino acid carrier systems, including the A, L and ASC system. Furthermore, preloading with naturally occurring L-amino acids failed to stimulate the cellular uptake of the radiopharmaceuticals. These data indicate that the investigated radiopharmaceuticals exhibit interesting characteristics with promise for in vivo tumor investigations to ascertain their potential as radioligands for glioma and pancreatic carcinoma imaging by SPET.

Investigation of iodine-123-labelled amino acid derivatives for imaging cerebral gliomas: uptake in human glioma cells and evaluation in stereotactically implanted C6 glioma rats

Abstract. In developing iodine-123-labelled amino acid derivatives for imaging cerebral gliomas by single-photon emission tomography (SPET), we compared p-[123I]iodo-l-phenylalanine (IPA), l-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (ITIC) and l-3-[123I]iodo-α-methyltyrosine (IMT) with regard to their uptake in human glioblastoma T99 and T3868 cells, and thereafter studied the mechanisms promoting the cellular uptake. The potential of the 123I-iodinated agents for use as SPET radiopharmaceuticals was evaluated in healthy experimental rats as well as in rats with stereotactically implanted C6 gliomas. The radiopharmaceutical uptake into glioblastoma cells was rapid, temperature and pH dependent, and linear during the first 5xa0min. Equilibrium was reached after 15–20xa0min, except in the case of ITIC, the initial uptake of which gradually decreased from 15xa0min onwards. The radioactivity concentration in glioma cells following 30-min incubation at 37°C (pH 7.4) varied from 11% to 35% of the total activity per million cells (ITIC < IMT ≤ IPA). Competitive inhibition experiments using α-(methylamino)-isobutyric acid and 2-amino-2-norbornane-carboxylic acid, known as specific substrates for systems A and L, respectively, as well as representative amino acids preferentially transported by system ASC, indicated that IPA, like IMT, is predominantly mediated by the L and ASC transport systems, while no significant involvement of the A transport system could be demonstrated. By contrast, none of the three principal neutral amino acid transport systems (A, L and ASC) appear to be substantially involved in the uptake of ITIC into glioblastoma cells. Analysis of uptake under conditions that change the cell membrane potential, i.e. in high K+ medium, showed that the membrane potential plays an important role in ITIC uptake. Alteration of the mitochondrial activity by means of valinomycin or nigericin induces a slight increase or decrease in the radiopharmaceutical uptake, suggesting a minor contribution of the mitochondria in the uptake. IPA, IMT and ITIC passed the blood-brain barrier, and thereafter showed efflux from the brain. The radioactivity concentration in healthy rat brain 15xa0min following intravenous injection varied from 0.07% (ITIC) to 0.27% ID/g (IPA). In comparison, the brain uptake in the stereotactically implanted C6 glioma rats was substantially higher (up to 1.10% ID/g 15xa0min p.i.), with tumour-to-background ratios greater than 4. These data indicate that IPA and ITIC, like IMT, exhibit interesting biological characteristics which hold promise for in vivo brain tumour investigations by SPET.

Intra-individual comparison of p-[123I]-iodo-L-phenylalanine and L-3-[123I]-iodo-α-methyl-tyrosine for SPECT imaging of gliomas

ObjectivesRadioactive amino-acids accumulate in gliomas even with an intact blood-brain-barrier. L-3-[123I]-iodo-α-methyl-tyrosine (IMT) is well established for SPECT imaging of gliomas. Recently, we introduced p-[123I]-iodo-L-phenylalanine (IPA) for the characterisation of brain lesions. This study compares both tracers in glioma patients.MethodsEleven patients with gliomas (1 WHO grade 1, 5 grade 2, 1 grade 3, 2 grade 4 gliomas, 1 unconfirmed upgrading and 1 post-therapeutic non-neoplastic lesion) underwent SPECT imaging with IPA (early and delayed acquisitions at 30 min and 3 h) and IMT (early only). Maximum tumour-to-brain ratios (TBR) were calculated using region-of-interest analysis to assess uptake of IMT and IPA. Imaging results were compared to histopathological findings.ResultsEarly TBRs of IMT and IPA were strongly correlated (ru2009=u20090.828, pu2009=u20090.002). TBRs were higher for IMT than IPA (1.95±0.50 versus 1.79±0.42; pu2009<u20090.05), but independent from tumour cell density (pu2009>u20090.1). Visual interpretation by different observers was more concordant for IMT-SPECT than IPA-SPECT (kappa 1.0 versus 0.774). No differences in early TBRs were observed between low-grade and high-grade gliomas for IMT (1.97±0.53 versus 2.21±0.44, pu2009>u20090.5) or IPA (1.70±0.23 versus 2.21±0.56, pu2009=u20090.167) with a trend to higher TBRs in low-grade tumours for IMT (pu2009=u20090.093). In contrast to the known wash-out of IMT, we observed persistent accumulation of IPA in gliomas.ConclusionsIPA shows lower TBRs than IMT, especially in low-grade tumours, so IMT should be preferred for the delineation of low-grade gliomas by SPECT imaging. Due to its prolonged retention, however, IPA remains promising for therapeutic use in gliomas after labelling with I-131.

Validation of brain tumour imaging with p-[123I]iodo-l-phenylalanine and SPECT

PurposeThe aims of this prospective study were to validate single-photon emission computed tomography (SPECT) with p-[123I]iodo-l-phenylalanine (IPA) in brain tumours and to evaluate its potential for the characterisation of indeterminate brain lesions.MethodsIn 45 patients with indeterminate brain lesions or suspected progression of glioma, amino acid uptake was studied using IPA-SPECT and compared with the final diagnosis established by biopsy or serial imaging. After image fusion of IPA-SPECT and magnetic resonance imaging, the presence of tumour was visually determined by two independent observers. IPA uptake was quantified as the ratio between maximum uptake in the suspicious lesion and mean uptake in unaffected brain.ResultsPrimary brain tumours were present in 35 cases (12 low-grade and 23 high-grade gliomas). Non-neoplastic brain lesions were confirmed in seven cases (three dysplasias, three inflammatory lesions, one lesion after effective therapy). Visual analysis showed a high concordance between the two observers (kappa=0.90, p<0.001), with sensitivity and specificity of 86% and 100% for the discrimination of primary brain tumours and non-neoplastic lesions. At 30xa0min p.i., IPA uptake in primary brain tumours was higher than that in non-neoplastic lesions (1.70±0.36 vs 1.14±0.18, p<0.05). Brain metastases showed no increased uptake (1.13±0.22, n=3). The persistent retention of IPA in low-grade gliomas without disruption of the blood–brain barrier was visualised up to 24xa0h p.i. Low-grade and high-grade gliomas showed equivalent IPA uptake (1.72±0.37 vs 1.67±0.36 at 30xa0min, p=0.745).ConclusionIPA shows long and specific retention in gliomas. IPA is a promising and safe radiopharmaceutical for the visualisation of gliomas and the characterisation of indeterminate brain lesions.

p-[123I]iodo-l-phenylalanine for detection of pancreatic cancer: basic investigations of the uptake characteristics in primary human pancreatic tumour cells and evaluation in in vivo models of human pancreatic adenocarcinoma

Pancreatic cancer is associated with the worst 5-year survival rate of any human cancer. This high mortality is due, in part, to difficulties in establishing early and accurate diagnosis. Because most tumours share the ability to accumulate amino acids more effectively than normal tissues and any other pathology, assessment of amino acid transport in tumour cells using radiolabelled amino acids has become one of the most promising tools for tumour imaging. This study investigated the potential of p-[123I]iodo-l-phenylalanine (IPA) for detection of pancreatic cancer by single-photon emission tomography. IPA affinity for pancreatic tumour was investigated in human pancreatic adenocarcinoma PaCa44 and PanC1 cells, followed by analysis of the underlying mechanisms of tracer accumulation in neoplastic cells. Thereafter, IPA was evaluated for targeting of pancreatic tumours using SCID mice engrafted with primary human pancreatic adenocarcinoma cells, as well as in acute inflammation models in immunocompetent mice and rats. IPA accumulated intensively in human pancreatic tumour cells. Radioactivity accumulation in tumour cells following a 30-min incubation at 37°C/pHxa07.4 varied from 41% to 58% of the total loaded activity per 106 cells. The cellular uptake was temperature and pH dependent and predominantly mediated by specific carriers for neutral amino acids, namely the sodium-independent and l-leucine-preferring (L-system) transporter and the alanine-, serine- and cysteine-preferring (ASC-system) transporter. Protein incorporation was less than 8%. Biodistribution studies showed rapid localization of the tracer to tumours, reaching 10%±2.5% to 15%±3% of the injected dose per gram (I.D./g) in heterotopic tumours compared with 17%±3.5% to 22%±4.3% I.D./g in the orthotopic tumours, at 60 and 240xa0min post injection of IPA, respectively. In contrast, IPA uptake in the gastrointestinal tract and areas of inflammation remained moderate and decreased with time. Excellent tumour detection was obtained by gamma camera imaging. The specific and high-level targeting of IPA to tumour and the negligible uptake in the gastrointestinal tract and areas of inflammation indicate that p-[123I]iodo-l-phenylalanine is a promising tracer for differential diagnosis of pancreatic cancer.

Beitrag der Nuklearmedizin zur Diagnostik des Hirntumorrezidivs und der zerebralen Radionekrose

ZusammenfassungZiel der Studie: Die Beurteilung des Hirntumorrezidivs und der davon differentialdiagnostisch abzugrenzenden posttherapeutisch bedingten benignen Veränderungen nach operativer Resektion und/oder Radiatio stellt eine Herausforderung sowohl für die morphologisch orientierten (cCT/MRT) als auch die funktionell bildgebenden Verfahren (SPECT/PET) dar. Anhand einer Literaturübersicht und der hier vorgestellten Daten des eigenen Patientenguts soll die diagnostische Effizienz von L-3-[123I]Iodo-α-methyltyrosin-SPECT (IMT-SPECT) und [18F]-Fluorodeoxyglucose-PET (FDG-PET) im Rahmen der Rezidivdiagnostik und dem In-vivo Grading primärer Hirntumoren aufgezeigt werden.nn Patienten: 39 Patienten im Alter zwischen 26 und 67 Jahren, bei denen im Rahmen der Nachsorge der Verdacht auf das Vorliegen eines Tumorrezidivs nach vorangegangener operativer Resektion und/oder Radiatio bestand, wurden zur weiteren Abklärung einer IMT-SPECT- und FDG-PET Diagnostik zugeführt. Bei 34/39 Patienten lag ein Rezidiv vor, in 12 Fällen ein zusätzlicher Grading-Wandel. Mit FDG-PET und IMT-SPECT konnten alle Tumoren höheren Malignitätsgrads nachgewiesen werden. Im Vergleich zu FDG zeigte IMT eine höhere Sensitivität, niedriggradige Rezidive zu bestätigen. FDG-PET ist im Gegensatz zu IMT-SPECT in der Rezidivdiagnostik hinsichtlich des nichtinvasiven Gradings Methode der Wahl. Sowohl die PET als auch die SPECT-Befunde ermöglichten zwischen einem Rezidiv und der Radionekrose zu differenzieren. Bei 2 Patienten führte die nuklearmedizinische Diagnostik zum Nachweis eines Rezidivs, in 1 weiteren Fall wurde eine Radionekrose bestätigt.nn Diskussion: Zusammenfassend belegen die Ergebnisse insbesondere im Fall unklarer cCT/MRT-Befunde, daß mit der IMT-SPECT in der Rezidivdiagnostik und der FDG-PET bei Verdacht auf einen Grading-Wandel entscheidende diagnostische Zusatzinformationen gewonnen werden.SummaryThe evaluation of brain tumor recurrence and therapy-induced benign changes following surgery and/or irradiation is a diagnostic challenge for imaging methods based on either morphology (cCT/MRI) or function (SPECT/PET). Current literature and the present data of our own patients demonstrate the diagnostic efficiency of IMT-SPECT and FDG-PET in the detection of recurrence and in-vivo grading. Thirty-nine patients suspected of brain tumor recurrence at follow-up were studied by FDG-PET and IMT-SPECT. Thirty-four of 39 patients showed recurrences; in 12 cases even a change in the grade of malignancy was observed. All high-grade recurrences could be confirmed by either methods. IMT-SPECT showed a higher sensitivity in detecting low-grade tumors at recurrence. In contrast to IMT-SPECT, FDG-PET supports sufficient in-vivo grading. Both methods can be used to differentiate between tumor recurrence and radionecrosis. In conclusion the results of our study demonstrate the efficiency of IMT-SPECT and FDG-PET in confirming recurrences and determining the actual tumor grade.