[Response evaluation in nuclear medicine : Criteria, results and pitfalls]. / Nuklearmedizinische Responsebeurteilung : Kriterien, Ergebnisse und Pitfalls.

CLINICAL/METHODICAL ISSUE: Established criteria to categorize metabolic tumor response to cytotoxic chemotherapies may not be suited to capture the effects of therapy with immune checkpoint inhibitors (ICI) or with kinase inhibitors (KI), such as BRAF or MEK inhibitors. NUCLEAR MEDICINE STANDARD METHODS: To assess the metabolic response to cytotoxic chemotherapy by positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG), the criteria of the European Organization for Research and Treatment of Cancer (EORTC) and the positron emission tomography response criteria in solid tumors (PERCIST) were conceived. The salient features of both criteria are detailed in a comparative way. PERFORMANCE AND ACHIEVEMENTS: To date only retrospective data exist for the evaluation of therapies with either ICI or KI. They show that response to ICI cannot be reliably determined using the established criteria. Employing the EORTC criteria the responses to KI can be adequately ascertained so that the metabolic tumor response in FDG-PET is regarded as a surrogate marker for the efficacy of these drugs. PRACTICAL RECOMMENDATIONS: Tumor response to therapy with ICI cannot at present be assessed with FDG-PET. Responses to BRAF and MEK inhibitors are, however, assessable using the criteria that were originally developed to evaluate responses to cytotoxic chemotherapy.

[Staging of cutaneous malignant melanoma by CT]. / CT-Staging kutaner maligner Melanome.

Malignant melanomas are a challenge in radiological imaging diagnostics as they may metastasize into every organ and tissue. Cross-sectional imaging, in particular positron emission tomography computed tomography (PET/CT) and whole body magnetic resonance imaging (MRI), are considered the standards in the staging of melanomas. Because of its excellent availability CT, however, remains a widely employed staging modality. Familiarity with the manifold CT morphology of metastasized melanomas as it is described here is essential when interpreting dedicated CT and in addition useful when interpreting PET/CT results. In individual cases CT can assist in the detection of transient metastases. In the detection of locoregional lymph node metastases CT has a median sensitivity and specificity in meta-analyses of at best 61 % and 97 %, respectively, which is inferior to the performance of ultrasound (96 % and 99 %, respectively). According to meta-analyses, in the assessment of systemic tumor spread CT can detect the majority of metastases with a sensitivity and specificity of 51-63 % and 69-78 %, respectively, which is inferior to MRI and PET/CT. Therefore, if an exact staging is required for critical management decisions, MRI or PET/CT should be employed whenever possible.

The indication for gamma probe-guided surgery of spinal osteoid osteomas.

The standard treatment for osteoid osteomas is CT-guided radiofrequency ablation (RFA). This minimally invasive procedure is effective in terms of pain reduction as well as the recurrence rate. Nevertheless, the use for spinal lesions is limited due to a possible thermal damage of neural structures. Although the literature is contradictory, RFA should only be used when a cortical shell between the lesion and the spinal canal is existent. We present seven cases (five males, two females, mean age 23 years) with spinal osteoid osteoma in which RFA was not applicable and open resection with the use of probe-guided surgery (PGS) was performed. The principle of PGS is that after preoperative bone scintigraphy, a handheld radiation probe is used intraoperatively for tumour localisation. Here, exposure and bone resection can be minimised and completeness of tumour excision may be estimated. At the initial measurement we found a hot-spot (maximum count-rate) in all patients and after tumour resection, the signal decreased by a mean of 68% in the operative field. After a mean follow-up of 17 months one patient had residual pain but no patient had signs of tumour recurrence. The authors recommend to use PGS for those spinal osteoid osteomas where RFA is not applicable and intraoperative localisation--and here complete resection--of the tumour is difficult.

99mTcO(BAT-NI), a novel nitroimidazole tracer: in vivo uptake studies in ischaemic myocardium.

Myocardial perfusion single-photon emission tomography (SPET) performed with cationic technetium-99m complexes indicates ischaemic areas as cold lesions. By contrast, nitroimidazole derivatives labelled with fluorine-18 or (99m)Tc have recently shown promising results for hot spot imaging of ischaemic myocardium. This study evaluates (99m)TcO(BAT-NI), a new (99m)Tc complex comprising the nitroimidazole ligand, 2,10-dimercapto-2,10-dimethyl-4,8-diaza-6-[4-(2-nitroimidazolyl)butyl]undecane, in a low-flow in vivo model of myocardial ischaemia in thoracotomised rats. To elucidate the influence of the 2-nitroimidazole group on ischaemia-induced uptake, comparisons with ligand derivatives were performed where (a) the 2-nitro group was deleted [(99m)TcO(BAT-I)], (b) the 2-nitroimidazole functionality was replaced by a Br atom [(99m)TcO(BAT-Br)] and (c) the (99m)TcO(BAT) moiety was replaced by an iodine-125 iodophenoxybutyl ligand ((125)IP-NI). The radiolabelled compounds were i.v. injected 15 min after reducing resting myocardial blood flow by 50-60% and the uptake of radioactivity was assessed 90 min post injection. Autoradiography of left ventricular short-axis slices showed median uptake ratios of ischaemic/non-ischaemic myocardium (I/N) of 3.4, 4.5 and 3.4 for (99m)TcO(BAT-NI), (99m)TcO(BAT-I) and (99m)TcO(BAT-Br), respectively. In contrast, (125)IP-NI was not preferentially taken up by ischaemic myocardium. Accumulation of (99m)TcO(BAT-NI) in ischaemic heart regions was comparable to that in the liver. Biodistribution studies showed a median uptake of 0.65% ID/g of (99m)TcO(BAT-NI) in ischaemic tissue and an I/N of 3.3. On planar images of the thorax and upper abdomen the ischaemic hearts were visualised faintly; the median heart to lung count ratio for (99m)TcO(BAT-NI) was 1.7, and the median heart to liver count ratio was 1.0. We conclude that uptake of (99m)TcO(BAT-NI) in ischaemic myocardium does not depend on the nitroimidazole moiety but is intrinsic to the BAT complex. Clinical use of the (99m)TcO(BAT)-labelled tracers seems unlikely owing to their low uptake and their low ischaemic tissue contrast on planar images in vivo.

[Static-dynamic MR urography. Comparison with excretory urography and scintigraphy in experimentally-induced urinary tract obstruction]. / Statisch-dynamische MR-Urographie. Vergleich mit Ausscheidungsurographie und Szintigraphie bei experimentell induzierter Harntransportstörung (HTS).

PURPOSE: To assess the diagnostic value of combined static-dynamic MR urography (MRU) for the functional-morphological evaluation of experimentally induced urinary tract obstruction. METHODS: Static-dynamic MRU--combination study with a respiratory-triggered 3D-IR-TSE sequence and a dynamic 2D-FFE sequence after Gd-DTPA and furosemide--was obtained in comparison with 99mTc-MAG3 diuretic renal scintigraphy (DRS), excretory urography (EU) and ultrasound (US) in 29 healthy piglets and in 20 piglets with surgically induced ureteric stenosis (total of 50 postoperative examination blocks). RESULTS: MRU allowed complete depiction of the urinary tract in all controls, in operated piglets the stenosis was always correctly identified. Quality of MRU was superior to EU in 36 of 43 comparative studies. Calculation of single kidney function from parenchymal renograms, and assessment of urinary excretion from whole-kidney renograms resulted in a highly significant agreement of MRU with DRS. CONCLUSION: Static-dynamic MR urography allows excellent depiction of experimentally induced urinary tract obstruction, and reliable assessment of individual renal function and urinary excretion. Two advantages of the method stand out, it does not require radiation and it permits a functional-morphological correlation.

Combined static-dynamic MR urography for the simultaneous evaluation of morphology and function in urinary tract obstruction. I. Evaluation of the normal status in an animal model.

OBJECTIVE: A new approach, combined static-dynamic MR urography is evaluated to determine its potential utility for the functional-morphological diagnosis of paediatric urinary tract obstruction. In this initial investigation we sought to evaluate the procedure by imaging the urinary tract of piglets. MATERIALS AND METHODS: Twenty-nine healthy piglets were studied with MR urography (MRU), 99mTc-MAG3 diuretic renal scintigraphy (DRS), ultrasound (US) and excretory urography (EU). The functional and morphological findings were compared. For MRU we combined a respiration-triggered 3D-IR-TSE sequence and a dynamic 2D-FFE sequence after Gd-DTPA injection. RESULTS: MRU depicted the complete urinary tract with superior image quality compared to EU. Calculation of time-intensity curves from the dynamic sequence permitted determination of single kidney function from parenchymal ROIs and urinary excretion using the whole kidney ROI. MRU and DRS showed significant agreement in the assessment of both single kidney function and urinary excretion. Disturbances of urinary drainage were generally caused by an overfilled bladder. CONCLUSIONS: Combined static-dynamic MRU is well suited for the depiction of the complete urinary tract and for the determination of individual kidney function and urinary excretion in the piglet.

Combined static-dynamic MR urography for the simultaneous evaluation of morphology and function in urinary tract obstruction. II. Findings in experimentally induced ureteric stenosis.

PURPOSE: To assess the diagnostic value of combined static-dynamic MR urography (MRU) for the functional-morphological evaluation of experimentally induced urinary tract obstruction in the piglet. MATERIALS AND METHODS: In 20 piglets unilateral ureteric stenosis was created operatively. Post-surgery repeated comparative examinations were obtained with MRU, diuretic renal scintigraphy (DRS), excretory urography (EU) and ultrasound (US). MRU was performed as a combination study with a static 3D-IR-TSE sequence and a dynamic 2D-FFE sequence after Gd-DTPA with frusemide administration. RESULTS: MRU allowed complete depiction of the prestenotic urinary tract and of the stenosis in all cases. In 43 comparative studies MRU was superior to EU in 36, EU to MRU in 2. When single kidney function was calculated with both MRU and DRS, results were highly correlated (r = 0.92). When urinary excretion was compared, significant agreement was achieved with concordant findings in 86% and slightly discordant results in 12%. CONCLUSIONS: Static-dynamic MR urography permits excellent depiction of experimentally induced urinary tract obstruction in piglets and reliable assessment of individual renal function and urinary excretion. Two advantages of the method stand out--it does not require radiation and it permits functional-morphological correlation.

[Ultrasound imaging of the sentinel lymph node in malignant melanoma]. / Sonographie des Sentinel-Lymphknotens bei malignem Melanom.

BACKGROUND AND OBJECTIVE: In the therapy of malignant melanoma sentinel lymph node(SLN) excision has assumed increased importance. The localization of the sentinel node is possible by lymphoscintigraphy and gamma probe guidance. Aim of the study was to prove whether SLN can be identified sonographically. PATIENTS/METHODS: 23 patients (16 women, 7 men; average age 42.7 years) with malignant melanoma required SLN excision. Before the patient underwent lymphoscintigraphy, sonography of the regional lymph nodes was performed. The position of lymph nodes (LN) with asymmetrical extension of the cortical substance was marked cutaneously according to the probe position in two axis (M1). During lymphoscintigraphy the gamma probe position orthograd to the skin with the highest count rate was marked (M2). Then a second sonography of the region was performed. RESULTS: In all patients M1 and M2 marked the same point. During the operation the sonographically documented position of the SLN could be confirmed in all cases. The second sonography after the lymphoscintigraphy showed a more blurred distinction between the cortical substance and the center of the lymph nodes. CONCLUSIONS: Our results show that sonography allows an identification of SLN. We think that the preoperative sonography of the SLN is an important supplementary method in addition to lymphoscintigraphy.

Trapping and metabolism of radioiodinated PHIPA 3-10 in the rat myocardium.

UNLABELLED: PHIPA 3-10 [13-(4'-iodophenyl)-3-(p-phenylene)tridecanoic acid] is a p-phenylene-bridged, radioiodinated omega-phenyl fatty acid that has recently been developed to study coronary artery disease or cardiomyopathies. Here, we demonstrate that PHIPA 3-10 exhibits the characteristics of a long-chain fatty acid, including its ability to be efficiently taken up by myocytes and to function as a substrate for beta-oxidation before it is trapped. METHODS: Myocardial metabolism of carrier-added and carrier-free 131I-PHIPA 3-10 preparations were investigated in rats in vivo and in isolated Langendorff rat hearts. Heart extracts were analyzed by high-performance liquid chromatography, negative-ion electrospray mass spectrometry and investigation of intracellular distribution using density-gradient centrifugation. RESULTS: A single, rapidly formed metabolite was found in the heart extract and also, surprisingly, in the hydrolyzed lipids. The total amount of metabolite increased from 43% to 51% between 15 and 60 min postinjection. By high-performance liquid chromatography comparison with synthetic potential catabolites, the metabolite was assigned the name PHIPA 1-10 [11-(4'-iodophenyl)-1-(p-phenylene)undecanoic acid] and was the product of one beta-oxidation cycle. Additional proof was obtained from the mass spectrometric analysis of the metabolite formed in vivo. The formation of this metabolite could be suppressed by Etomoxir, a carnitine palmitoyl transferase I inhibitor, indicating beta-oxidation of 131I-PHIPA 3-10 in mitochondria. Final evidence for the involvement of mitochondria in the degradation of 131I-PHIPA 3-10 was obtained by density-gradient centrifugation of homogenized rat heart tissue. The position of the labeled free PHIPA 3-10 and free metabolite peaked within the fraction containing mainly mitochondria. CONCLUSION: In spite of its bulky structure, 131I-PHIPA 3-10 is extracted by the myocardium in a manner similar to the extraction of the unmodified fatty acid analog, IPPA. The retention of PHIPA 3-10 in heart muscle results from the presence of the p-phenylene group, which prevents more than one beta-oxidation cycle. Intracellular free PHIPA 3-10 and free PHIPA 1-10 are present in the mitochondria, whereas most of the esterified metabolite was found in the cytosolic lipid pool. Hence, the rapid appearance of PHIPA 1-10 in the lipid pool must be accounted for by mitochondrial leakage or by an unknown in-out transport system.

Localization of endothelin ETA and ETB receptor-mediated constriction in the renal microcirculation of rats.

1. The aim of the study was to visualize endothelin-1 (ET-1)-mediated constriction in renal vessels of cortical and juxtamedullary glomeruli in the split hydronephrotic rat kidney in vivo and to functionally characterize the ET receptor subtypes involved. 2. ET-1 (10(-9) M) constricted preglomerular vessels (by 6-18%) and efferent arterioles (by 11-13%), and decreased glomerular blood flow (GBF, by 55%) of cortical and juxtamedullary glomeruli. 3. The ETA antagonist BQ-123 (10(-6) M), as well as the ETB antagonist BQ-788 (2 x 10(-7) M) and IRL 1038 (10(-6) M), shifted the concentration-response curve of GBF for ET-1 to the right by one order of magnitude. While BQ-123 antagonized ET-1 constriction only in preglomerular vessels, BQ-788 and IRL 1038 were effective both in preglomerular vessels and efferent arterioles. 4. The ETB agonist IRL 1620 (10(-8) M) reduced GBF by 50% and constricted efferent arterioles (by 20-33%) about two times more than preglomerular vessels (by 6-14%). 5. Our results suggest that in renal cortical and juxtamedullary vessels of rats, ET-1-induced preglomerular vasoconstriction is mediated by ETA and ETB receptors, while efferent vasoconstriction is predominantly mediated by ETB receptors, which might have important consequences for the regulation of glomerular filtration pressure by ET.

Endothelin and endothelium-derived relaxing factor control of basal renovascular tone in hydronephrotic rat kidneys.

1. In order to investigate the control of renal vascular tone by endothelin (ET) and endothelium-derived relaxing factor (EDRF) under basal conditions, we infused intravenously anti-ET-1/3 antibodies (a-ET-1/3) and NG-nitro-L-arginine methyl ester (L-NAME) in split hydronephrotic rat kidneys. 2. A 25 min I.V. infusion of a-ET-1/3 (4.0 x 10(-13) mol kg-1 min-1) induced a time-dependent vasodilatation of arcuate (16.5%) and interlobular arteries (18.6%) as well as an increase of glomerular blood flow (GBF) by 32%. 3. Inhibition of EDRF synthesis by L-NAME produced a marked vasoconstriction of arcuate arteries (17.1%) and efferent (20.1%) arterioles and a decrease of GBF by 43%. 4. Co-infusion of a-ET-1/3 and L-NAME induced efferent vasoconstriction by 19.5%, whereas preglomerular vessel diameters remained unchanged. 5. The specificity of a-ET-1/3 effects was confirmed by simultaneous I.V. application of a-ET-1/3 and ET-1 (160 ng I.V.) which produced no significant vascular effects. Injection of ET-1 alone constricted arcuate arteries and decreased glomerular blood flow by 25%. 6. Experiments in normal rat kidneys with a-ET-1/3 I.V. revealed an increase of renal blood flow by 21%. 7. Our results demonstrate a physiological control of basal vascular tone in larger preglomerular arterioles by ET and EDRF. Efferent arteriolar tone is predominantly controlled by EDRF.

Influence of endothelium-derived relaxing factor on renal microvessels and pressure-dependent vasodilation.

The influence of endothelium-derived relaxing factor (EDRF) on renal microvessels and autoregulation was visualized in vivo, in the split hydronephrotic kidney of rats. EDRF synthesis was inhibited by local administration of 10(-5) M NG-nitro-L-arginine methyl ester (L-NAME). Diameters of arcuate arteries decreased by 17%. In cortical vessels efferent arterioles constricted more (13-16%) than interlobular arteries and afferent arterioles (7-12%). Cortical glomerular blood flow (GBF) decreased by 46% after L-NAME. A similar behavior of blood flow and vascular diameters was also observed in juxtamedullary (JM) arterioles. The responses to acetylcholine but not to sodium nitroprusside were attenuated after L-NAME. After local administration of L-arginine (10(-3) M) diameters of all vessels and GBF increased, vascular responses to L-NAME were blunted. Stepwise reduction of renal perfusion pressure revealed that autoregulation was preserved in cortical vessels after L-NAME. In JM arterioles, which do not autoregulate in female Wistar rats, autoregulation of GBF was enhanced after L-NAME. These data suggest that tonic formation of EDRF influences basal renal hemodynamics to a considerable extent. EDRF may also impair autoregulation of JM glomeruli without disturbing autoregulation of cortical glomeruli.

Different responses of cortical and juxtamedullary arterioles to norepinephrine and angiotensin II.

Cortical (C) and juxtamedullary (JM) glomerular blood flow were measured with intravitalmicroscopic techniques in the split hydronephrotic kidney of female Wistar rats under Inactin anesthesia. Intravenous injection of small, equivalent pressor doses of norepinephrine (NE) and angiotensin II (Ang II) reduced the diameter of C afferent arterioles by -16 +/- 2.4% and -14 +/- 1.9%, respectively, whereas that of JM afferent arterioles was reduced by only -3.8 +/- 2.7% and -3.8 +/- 1.5%. Blood flow under NE and Ang II was reduced in C glomeruli by -42 +/- 4.9% and -37 +/- 4.0%, respectively, but in JM glomeruli was reduced by -10 +/- 6.2% and -8.6 +/- 2.9% of control. Perfusion pressure reduction during NE or Ang II infusion to preinfusion values revealed autoregulatory behavior only in C glomeruli. In a second series of experiments cyclooxygenase inhibition by local administration of indomethacin (2.8 x 10(-5) M) induced C and JM vasoconstriction. The effects of NE and Ang II during local application of indomethacin were variable but different responsiveness of C and JM vessels disappeared. We assume that the differences in NE and Ang II responsiveness between C and JM vessels under control conditions are caused by a high prostaglandin content or sensitivity, particularly of JM vessels in the hydronephrotic kidney.