The influence of sentinel lymph node tumour burden on additional lymph node involvement and disease-free survival in cutaneous melanoma--a retrospective analysis of 392 cases.

Twenty per cent of sentinel lymph node (SLN)-positive melanoma patients have positive non-SLN lymph nodes in completion lymph node dissection (CLND). We investigated SLN tumour load, non-sentinel positivity and disease-free survival (DFS) to assess whether certain patients could be spared CLND. Sentinel lymph node biopsy was performed on 392 patients between 1999 and 2005. Median observation period was 38.8 months. Sentinel lymph node tumour load did not predict non-SLN positivity: 30.8% of patients with SLN macrometastases (> or =2 mm) and 16.4% with micrometastases (< or =2 mm) had non-SLN positivity (P=0.09). Tumour recurrences after positive SLNs were more than twice as frequent for SLN macrometastases (51.3%) than for micrometastases (24.6%) (P=0.005). For patients with SLN micrometastases, the DFS analysis was worse (P=0.003) when comparing those with positive non-SLNs (60% recurrences) to those without (17.6% recurrences). This difference did not translate into significant differences in DFS: patients with SLN micrometastasis, either with (P=0.022) or without additional positive non-SLNs (P<0.0001), fared worse than patients with tumour-free SLNs. The 2-mm cutoff for SLN tumour load accurately predicts differences in DFS. Non-SLN positivity in CLND, however, cannot be predicted. Therefore, contrary to other studies, no recommendations concerning discontinuation of CLND based on SLN tumour load can be deduced.

St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4.

BACKGROUND: St John's Wort (hypericum perforatum) is an herbal medicine that is frequently used for therapy of mild depression. Recently, St John's Wort was reported to substantially decrease blood/plasma concentrations and efficacy of cyclosporine (INN, ciclosporin), indinavir, and digoxin. In this study we investigated the mechanisms of these St John's Wort-induced drug interactions. METHODS AND RESULTS: In a preclinical study, the administration of St John's Wort extract to rats during 14 days resulted in a 3.8-fold increase of intestinal P-glycoprotein/Mdrl expression and in a 2.5-fold increase in hepatic CYP3A2 expression (Western blot analyses). In a clinical study, the administration of St John's Wort extract to 8 healthy male volunteers during 14 days resulted in an 18% decrease of digoxin exposure after a single digoxin dose (0.5 mg), in 1.4- and 1.5-fold increased expressions of duodenal P-glycoprotein/MDR1 and CYP3A4, respectively, and in a 1.4-fold increase in the functional activity of hepatic CYP3A4 (14C-erythromycin breath test). CONCLUSIONS: These results indicate direct inducing effects of St John's Wort on intestinal P-glycoprotein/MDR1 (in rats and humans), hepatic CYP3A2 (in rats), and intestinal and hepatic CYP3A4 (in humans). Therefore the results provide a mechanistic explanation for the previously observed drug interactions in patients and support the importance of intestinal P-glycoprotein/MDR1 in addition to intestinal and hepatic CYP3A4 for overall drug absorption and disposition in humans.

Whole-body PET: physiological and artifactual fluorodeoxyglucose accumulations.

UNLABELLED: The purpose of this study was to semiquantitatively identify artifactual and physiological soft-tissue accumulations in whole-body FDG-PET scans with the aim of defining their frequency and anatomic distribution. METHODS: Fifty whole-body FDG-PET scans performed for the staging of malignant melanoma were obtained from transaxial scans and reconstructed without absorption correction by filtered backprojection in the form of coronal and sagittal sections. The patients were asked to stay n.p.o. for at least 4 hr and interrogated about their physical activity prior to injection and until scanning. Classification of FDG organ accumulations was done using grades 0-6. Means and standard deviations on this scale were then calculated for multiple organs and muscle groups and tabulated. RESULTS: On this grading scale, viscera showed uptake grades between 1.7 +/- 0.5 and 2.05 +/- 1.0. Except for the intestines, the activity in these organs was homogeneously distributed. Relatively high average uptake values of 2.0-4.2 (s.d. > or = 2.3) were found in various muscle groups, especially the orbital musculature. Myocardial uptake was visible in 90% of the scans. Reconstruction artifacts were seen around the renal collecting system and the bladder. CONCLUSION: Most of the "normal" accumulations of FDG in nonattenuation corrected whole-body PET are readily recognized and distinct from the usually focal FDG accumulation associated with metastatic disease, but the diagnostician must be familiar with them. Muscular FDG uptake is related to physical activity prior and immediately following injection and can be minimized by proper patient instructions and positioning.

Planar coincidence scintigraphy and PET in staging malignant melanoma.

UNLABELLED: This study describes a comparison of simulated planar positron coincidence scintigraphy (PCS) with PET in the whole-body staging of patients with malignant melanoma using 2-18F-fluoro-2-deoxy-D-glucose (FDG). METHODS: In 55 patients with either known metastatic or newly diagnosed malignant melanoma, whole-body PET scanning was performed on a conventional full-ring dedicated PET tomograph, and multiaxial sections were obtained. Furthermore, anteroposterior projection images simulating images of a dual-head Anger camera operating in coincidence mode were obtained from the PET raw data. Each study was evaluated separately and blindly. Imaging findings were confirmed by biopsy or by at least one imaging modality in addition to PET. RESULTS: A total of 108 lesions were evaluated, of which 76 proved to be melanoma metastases. Whole-body PET correctly demonstrated 68 metastases, 6 lesions were classified as questionable metastases and 2 were missed. Whole-body PCS correctly demonstrated 14 metastases, 22 lesions were classified as questionable metastases and 40 metastases were missed. The sensitivities of whole-body PET and whole-body PCS were 89% and 18%, respectively. In PCS lesions in regions of high background activity, such as in the abdomen, were missed more often than in PET (p < 0.05). The tumor-to-background contrast was generally lower in PCS than in PET. A further decrease in PCS detection was found in lesions of < 22 mm in diameter. CONCLUSION: The lack of sensitivity precludes the clinical use of whole-body PCS in staging malignant melanoma.

Detection of extrathoracic metastases by positron emission tomography in lung cancer.

BACKGROUND: Accurate staging of non-small cell lung cancer is essential for treatment planning. We evaluated in a prospective study the role of whole-body 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in mediastinal nodal staging with a positive predictive value of 96%. The study was continued to further evaluate the value of whole-body FDG PET in detecting unexpected extrathoracic metastases (ETMs) in patients qualifying for surgical treatment by conventional staging. METHODS: One hundred patients underwent clinical evaluation, chest and upper abdominal computed tomography scan, mediastinoscopy (lymph nodes greater than 1 cm on computed tomography), and routine laboratory tests. In 94 patients with stage IIIa or less and 6 with suspected N3 a whole-body FDG PET was performed. If clinical signs of ETMs were present additional diagnostic methods were applied. All findings in the FDG PET were confirmed histologically or radiologically. RESULTS: Unexpected ETMs were detected in 13 (14%) of 94 patients (stage IIIa or less) at 14 sites. In addition 6 of 94 patients were restaged up to N3 after PET. The suspected N3 disease (stage IIIb) on computed tomography was confirmed by PET in all 6 patients. There was no false positive finding of ETM. Weight loss was correlated with the occurrence of ETM: more than 5 kg, 5 of 13 patients (38%); more than 10 kg, 4 of 6 patients (67%). Pathologic laboratory findings were not predictive for ETM. CONCLUSIONS: Whole-body FDG PET improves detection of ETMs in patients with non-small cell lung cancer otherwise elegible for operation. In 14% of patients (stage IIIa or less), ETMs were detected, and in total, 20% of the patients were understaged.

Non-invasive assessment of tumour cell proliferation with positron emission tomography and [76Br]bromodeoxyuridine.

In oncology, a number of new potential therapeutic modalities, including gene targeting, are currently under investigation. To evaluate their response at a preclinical level, a non-invasive method providing information about cell proliferation would be highly valuable. The growth fraction can be assessed by the incorporation of thymidine into the DNA of S-phase cells. We report the use of the thymidine analogue bromodeoxyuridine (BrUdR) labelled with bromide-76 (76Br) in positron emission tomography (PET). PET scans using [76Br]BrUdR were performed in seven patients with metastatic melanoma. The in vitro cell proliferation in these metastases (n = 7) was compared with immunohistochemically evaluated cell proliferation using anti-bromo-deoxyuridine and MIB-1 antibodies after excision. Blood samples were taken to analyse the kinetics of the radiopharmaceutical. The accumulation of [76Br]BrUdR in PET correlated significantly with the immunohistochemically assessment of S-phase and cycling cells. In one patient a clinically unexpected metastases was found on [76Br]BrUdR-PET which became evident 4 weeks later. Analysis of blood samples showed a fast disappearance of [76Br]BrUdR; 30 min after injection free bromide was the main form of radioactivity, resulting in a high background activity. Assessment of cell proliferation using [76Br]BrUdR is hampered because of fast debromation and high background activity. The results are thus rather the effect of the increased circulation in more rapidly proliferating metastases than Incorporation of [76Br]BrUdR into proliferating cells.

D1 dopamine receptors are not expressed in human melanoma.

D1 dopamine receptor mRNA has been demonstrated in mouse melanoma cells, and the expression of these G-protein-coupled receptors in human melanoma was therefore presumed when dopamine receptor binding radiopharmaceuticals were found to be useful for the detection of metastases in whole-body scintigraphy. The aim of this study was thus to investigate if D1 dopamine receptor mRNA or protein could be directly demonstrated in melanoma cells. The presence of D1 dopamine receptor mRNA was investigated in six human melanoma cell lines from metastases using reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, in vitro binding assays with the D1 dopamine receptor agonist 125I-Sch 23982 were performed in 19 melanoma metastases. No D1 dopamine receptor mRNA could be detected by RT-PCR. All melanotic metastases were found to accumulate 125I-Sch 23982, with the presence of binding sites and intensity of 125I-Sch 23982 labelling correlating to the amount of melanin present in the metastases. Two amelanotic melanomas did not accumulate 125I-Sch 23982. D1 dopamine receptors could not be detected by means of RT-PCR or in vitro binding assays in human melanomas. Detection of antagonists is best explained by non-specific binding to melanin.

Bronchoscopic radioisotope injection for sentinel lymph-node mapping in potentially resectable non-small-cell lung cancer.

OBJECTIVE: Prospective study to evaluate the feasibility of a preoperative bronchoscopic radioisotope application, followed by conventional sentinel lymph-node (SLN) identification and to investigate the occurrence and distribution of micrometastases in relation to SLN activity. METHODS: Twenty patients with a mean age of 63 years and proven clinical stage T1-3 N0-1 non-small-cell lung cancer (NSCLC) were included. A dosage of 80MBq radiolabeled technetium-99m nanocolloid was endoscopically administrated on intubated patients in the operation theatre. At thoracotomy, scintigraphic readings of both the primary tumor and hilar and mediastinal lymph-node stations were obtained with a hand-held gamma-counter. Patients underwent lung resection and mediastinal lymphadenectomy. Radiolabeled nodes were also examined separately on back-table. SLNs were defined as the hottest nodes or nodes with at least one-tenth of the radioactivity of the hottest nodes. SLNs pathologic assessment included standard examination using hematoxylin and eosin staining on step sections and immunohistochemistry (ICH) for cytokeratins. RESULTS: Identification of SLNs was possible in 19/20 (95%) patients after bronchoscopic radioisotope application. In 7/19 (37%) patients, a unique SLN was identified, whereas in 12/19 (63%) patients, nodes from two different stations could be classified as SLNs. Metastatic nodal disease was found in 9/19 (47%) patients. ICH revealed micrometastases in 2/12 (17%) patients, initially classified nodal negative. Pathologic negative SLNs were a predictor for absence of metastatic nodal disease after mediastinal lymphadenectomy. No complication related to the procedure was observed. CONCLUSION: Our preliminary results suggest that preoperative bronchoscopic radioisotope injection for SLN identification is a safe and simple method, improving accuracy of SLN detection in comparison to intraoperative technique. The absence of metastases in the SLNs seems to predict a negative nodal status accurately.

[The value of 3-phase skeletal scintigraphy for early diagnosis of Sudeck disease]. / Wertigkeit der Drei-Phasen-Skelettszintigraphie zur Frühdiagnostik des Morbus Sudeck.

PURPOSE: In a prospective study the value of the three-phase bone scintigraphy in the early diagnosis of Sudeck's atrophy was analysed. MATERIAL AND METHODS: 137 patients with the clinical suspicion on Sudeck's atrophy in stage I were examined. By means of the clinical course and additional examinations (block response), pain experts confirmed the diagnosis separately. RESULTS: With the findings of hyperperfusion of all 5 phalanges, homogeneous hyperaemia of the affected hand or the foot and periarticular increased uptake of the whole extremity a reliable diagnosis of Sudeck's atrophy was possible. The sensitivity was 95.9%, the specificity 100%. With bone scintigraphy Sudeck's atrophy could be clearly differentiated from an inactivity atrophy. CONCLUSION: Three-phase bone scintigraphy is an excellent tool for the objective diagnosis of Sudeck's atrophy in stage I.

[The clinical relevance of anti-CEA immunoscintigraphy with the 99mTc-labelled monoclonal antibody BW 431/26. A critical assessment after 119 studies]. / Klinische Relevanz der Anti-CEA-Immunszintigraphie mit dem 99mTc-markierten monoklonalen Antikörper BW 431/26. Kritische Bestandsaufnahme nach 119 Untersuchungen.

The results of 119 radioimmunoscintigraphies (RIS) in 113 patients with the 99mTc-labeled monoclonal anti-CEA-antibody BW 431/26 (Behring) have been analysed. The aim of our study was the estimation of the method's sensitivity and specificity under different aspects to find out for which indications and questions the 99mTc-RIS is useful. Colorectal primary tumours in 19 patients were scintigraphically detected with a sensitivity of 83% and a specificity of 100%; 3 out of 7 other tumour sites were localised correctly. 55 patients were examined during the follow-up of colorectal cancer. There were 17 out of 22 true positive findings of local recurrences (sensitivity 77%, specificity 88%). Liver metastases were imaged as hot lesions with only 41% sensitivity and 86% specificity. The detection of extrahepatic tumour sites is difficult because of the persistently high blood-pool activity of the monoclonal antibody and, in the pelvic area, the unspecific bowel activity. Skeletal metastases were recognised in 7 out of 9 cases. In 14 patients with other non-colorectal carcinomas, RIS was successful in single cases. It is not helpful, however, when searching for tumours of unknown origin or for the screening of patients with elevated CEA levels without tumour history. The high technical, methodological and time effort required by RIS is justified in the follow-up of cancer patients when conventional diagnostic procedures are inconclusive or the status of morphological findings remains unclear. The use of RIS as an unspecific screening tool in tumour diagnosis must be rejected because of the not completely explored risks of the examination. Repeated applications of monoclonal antibodies require controls of the patients' HAMA titers before performing RIS.

[Dopamine-D2 receptor scintigraphy with 123I-iodobenzofuran in malignant melanoma]. / Dopamin-D2-Rezeptorszintigraphie mit 123I-Jodbenzofuran beim malignen Melanom.

In recent publications dopamine-D2 receptor scintigraphy with benzamides was postulated for specific imaging of melanoma. In a prospective study the value of 123I-iodobenzofuran (IBF), a highly specific and affine dopamine-D2 receptor ligand was evaluated for the detection of melanoma metastases. With IBF-D2 receptor scintigraphy only 2 of 17 melanoma metastases could be detected. The interpretation of the abdomen was impaired by the hepatobiliary and renal excretion of the radionuclide. The ratio striatum/frontal cortex of 2.75 +/- 0.49 3 h p.i. demonstrated a high D2-receptor binding of the ligand. IBF-D2-receptor scintigraphy is not suitable as a method of staging melanoma.

[123I-alpha-methyltyrosine scintigraphy in malignant melanoma]. / 123I-alpha-Methyltyrosin-Szintigraphie beim malignen Melanom.

AIM: The aim of the study was to evaluate the ranking of the scintigraphy with L-3-123I-alpha-methyltyrosine (123I-AMT) in metastasized melanoma. METHODS: 26 metastases and one primary tumor of a malignant melanoma in six patients were examined with 123I-AMT whole-body scintigraphy and SPECT. Positron Emission Tomography with 2-18F-fluoro-2-desoxy-D-glucose (18F-FDG) was used as the golden standard. RESULTS: With 123I-AMT-SPECT 8/10 metastases in the thorax > 1.6 cm were detected (ratio T/NT 1.2-1.8), metastases < 1.6 cm were not detectable with SPECT. In 123I-AMT whole-body scintigraphy not one lesion showed a positive tumor uptake. CONCLUSION: In single cases 123I-AMT scintigraphy can be helpful in staging of malignant melanoma.

MR imaging versus alternative imaging techniques.

MR imaging is the method of choice in evaluating a large number of soft-tissue abnormalities; however, it has certain draw-backs, some of which may make other imaging methods more suitable. MR imaging is more expensive than alternative imaging methods; it may not be affordable for screening purposes and for diagnoses obtainable by less expensive imaging methods. In addition, immediate scheduling is not always possible for MR imaging, and an MR scanner may not be available close to the patient's home, which may be important for imaging follow-up. These factors support the use of other imaging modalities, with sonography frequently being the appropriate choice. In some situations, mainly in the presence of certain biomedical implants and devices, MR imaging is contraindicated. Additionally, under some circumstances patient access may be difficult during MR imaging; sonography and CT therefore are preferable (as for imaging guided biopsy). Moreover, some artifacts, such as motion artifacts, may have less relevance in other imaging methods (such as sonography), which may be important in noncooperative patients and children. MR imaging may not be specific in tumors and infection; this deficiency is shared with most alternative imaging methods, with the exception of scintigraphy in selected indications. Lastly, standard radiography and CT commonly are superior to MR imaging in diagnosing calcification and abnormalities of cortical bone. Consequently, in selected cases and for screening purposes, methods other than MR imaging should be considered for depicting soft-tissue structures.

Sentinel lymph node evaluation in squamous cell carcinoma of the head and neck.

OBJECTIVE: The aim of our study was to assess the feasibility of sentinel lymph node (SLN) radiolocalization in N0 neck in squamous cell head and neck carcinoma and its predictive value for occult metastasis. STUDY DESIGN: Nineteen patients of an open prospective trial. SETTING: After peritumoral injection of a 99m Tc labeled radiocolloid, the SLN was localized preoperatively by lymphoscintigraphy and intraoperatively through the intact skin by a hand-held gamma-probe. The histology of the SLN and the nodes of the elective neck dissection were compared. RESULTS: Localization of the SLN by lymphoscintigraphy was possible in 18 of 19, and with the hand-held gamma-probe in all 19 patients. Six SLN revealed occult metastatic disease. No skip metastasis were found in the 13 neck specimen with negative SLN. CONCLUSION: SLN evaluation in N0 neck in squamous cell carcinoma of the head and neck is accurately feasible and seems to adequately predict the presence of occult metastasis.

Effect of 6 months of growth hormone treatment in young children with Prader-Willi syndrome.

Nine prepubertal children with Prader-Willi syndrome were treated with growth hormone (GH; 24 IU/m2/week) for 6 months. Mean height increased by 0.8 SD and mean weight for height decreased by 0.7 SD over this 6-month treatment period. Body fat, measured by dual-energy X-ray absorptiometry, decreased by 22.5% over the period of GH treatment, whereas fat-free mass increased by 14%. These preliminary results indicate that GH is effective in increasing height and normalizing body composition in patients with Prader-Willi syndrome.

[Quantitative nuclear medicine kidney diagnosis with kidney tubule traversing radioisotopes]. / Quantitative nuklearmedizinische Nierendiagnostik mit tubulär sezernierten Radiopharmazeutika.

In modern nuclear medicine, renal function scintigraphy has been improved and its range of applications extended by the development of new radiopharmaceuticals (iodine-123-hippuran, technetium-99m-MAG3) combining the properties of short half-life, favourable radiation energy and high renal clearance. Three significant advantages recommend the use of scintigraphic methods: 1. Being non-invasive and non-nephrotoxic, the examinations do not affect the patient. The radiation exposure the patient is subjected to is about the same as with a comparable X-ray investigation or, with respect to the reproductive glands, even lower. Allergic reactions do not occur. 2. In contrast to the situation with other imaging methods, the functional defect itself (and not only secondary changes in the morphology) can mostly be detected. Not only diffuse alterations, but also defined functional lesions of a small part of a kidney, can be diagnosed. 3. Various renal parameters can be calculated more accurately than with any other routine clinical method. The radioisotopic methods discussed yield reliable results with excellent reproducibility concerning glomerular filtration rate, effective renal plasma flow, side-to-side functional ratio, renal perfusion, and urine drainage. Most of these parameters can be obtained by means of a single investigation. These radioisotopic methods make it possible to detect or exclude a wide range of functional lesions of the kidneys and the urinary tract, which are often due to non-specific symptoms. In addition, they allow answers to highly specific clinical and scientific questions in nephrology and urology.

[Detection of primarily unrecognized fractures in severely injured patients by skeletal scintigraphy]. / Nachweis von primär nicht erkannten Frakturen bei Schwerverletzten durch Skelettszintigraphie.

Even in despite of diligent investigation clinical and radiological diagnostics can leave fractures unrecognized in seriously injured patients. Bone-scans of 53 patients revealed 68 additional fractures. In 45% of all cases the initial diagnosis was altered, 19% resulted in therapeutical consequences. Routine diagnostics should be supplemented by a bone-scan if clinical and radiological findings are not in line. A bone-scan can exclude any osseous lesion and can survey the full extent of injuries especially in the disoriented or unconscious patient.

[The impact of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) on planning of radiotherapy]. / Vliianie pozitronnoi émissionnoi tomografii s 18F-ftorodeoksigliukozoi na planirovanie luchevoi terapii.

AIM: To determine the impact of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) on patient management in radiotherapy. MATERIAL AND METHODS: One hundred sixty-nine consecutive patients with different malignant tumors were analyzed. Whole-body FDG-PET was performed for staging before radiotherapy. The strategy of radiotherapy before and after PET scanning was compared and the change in the treatment management determined. RESULTS: In 47(28%) of 169 patients PET results changed patient management in radiotherapy. In 19 patients (11%) radiotherapy was not performed after PET. In 16 patients (10%) PET results changed the intention of radiation treatment (curative/palliative). Correction of radiation dose was made in 16 patients (10%). Correction of the volume of the exposure area was made in 12 patients (7%). Tumor outside the field of view was missed in only 2 patients with a regional PET scan. CONCLUSION: In this retrospective analysis the information provided by FDG-PET contributes to a substantial change in radiotherapy strategy.