[Molecular breast imaging. An update]. / Molekulare Brustbildgebung. Ein Update.

CLINICAL/METHODICAL ISSUE: The aim of molecular imaging is to visualize and quantify biological, physiological and pathological processes at cellular and molecular levels. Molecular imaging using various techniques has recently become established in breast imaging. STANDARD RADIOLOGICAL METHODS: Currently molecular imaging techniques comprise multiparametric magnetic resonance imaging (MRI) using dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted imaging (DWI), proton MR spectroscopy ((1)H-MRSI), nuclear imaging by breast-specific gamma imaging (BSGI), positron emission tomography (PET) and positron emission mammography (PEM) and combinations of techniques (e.g. PET-CT and multiparametric PET-MRI). METHODICAL INNOVATIONS: Recently, novel techniques for molecular imaging of breast tumors, such as sodium imaging ((23)Na-MRI), phosphorus spectroscopy ((31)P-MRSI) and hyperpolarized MRI as well as specific radiotracers have been developed and are currently under investigation. PRACTICAL RECOMMENDATIONS: It can be expected that molecular imaging of breast tumors will enable a simultaneous assessment of the multiple metabolic and molecular processes involved in cancer development and thus an improved detection, characterization, staging and monitoring of response to treatment will become possible.

[Diagnose importance of multiparametric magnetic resonance tomography for prostate cancer]. / Stellenwert der multiparametrischen Magnetresonanztomographie beim Prostatakarzinom.

Prostate cancer is biologically and clinically a heterogeneous disease which makes imaging evaluation challenging. Magnetic resonance imaging (MRI) has considerable potential to improve prostate cancer detection and characterization. Until recently morphologic MRI has not been routinely incorporated into clinical care because of its limitation to detect, localize and characterize prostate cancer. Performing prostate gland MRI using functional techniques has the potential to provide unique information regarding tumor behavior, including treatment response. In order for multiparametric MRI data to have an impact on patient management, the collected data need to be relayed to clinicians in a standardized way for image construction, analysis and interpretation. This will ensure that patients are treated effectively and in the most appropriate way. Scoring systems similar to those employed successfully for breast imaging need to be developed.

[Magnetic resonance tomography-guided interventional procedure for diagnosis of prostate cancer]. / MRT-gezielte interventionelle Verfahren zur Abklärung des Prostatakarzinoms.

In recent years magnetic resonance imaging (MRI) has been increasingly established in the diagnosis of prostate cancer in addition to transrectal ultrasonography (TRUS). The use of T2-weighted imaging allows an exact delineation of the zonal anatomy of the prostate and its surrounding structures. Other MR imaging tools, such as dynamic contrast-enhanced T1-weighted imaging or diffusion-weighted imaging allow an inference of the biochemical characteristics (multiparametric MRI). Prostate cancer, which could only be diagnosed using MR imaging or lesions suspected as being prostate cancer, which are localized in the anterior aspect of the prostate and were missed with repetitive TRUS biopsy, need to undergo MR guided biopsy. Recent studies have shown a good correlation between MR imaging and histopathology of specimens collected by MR-guided biopsy. Improved lesion targeting is therefore possible with MR-guided biopsy. So far data suggest that MR-guided biopsy of the prostate is a promising alternative diagnostic tool to TRUS-guided biopsy.

FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo.

This study aimed to test whether [(18)F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg(-1) per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses >or=5 mg kg(-1) per day (tumour volume treated vs control (T/C): 51% for 5 mg kg(-1) per day and 57% for 15 mg kg(-1) per day). Correspondingly, doses >or=5 mg kg(-1) per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg(-1) per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg(-1) per day and 52% for 15 mg kg(-1) per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials.

Familial hemiplegic migraine: follow-up findings of diffusion-weighted magnetic resonance imaging (MRI), perfusion-MRI and [99mTc] HMPAO-SPECT in a patient with prolonged hemiplegic aura.

Familial hemiplegic migraine (FHM) is a rare inherited autosomal dominant disorder. Migraine aura may last up to several weeks and then resolve without sequel. We report a 21-year-old male with FHM since the age of 3 years. Diffusion-weighted magnetic resonance imaging (DWI), perfusion-MR imaging (P-MRI) and [99mTc] hexamethyl-propyleneamine-oxime-single photon emission tomography (HMPAO-SPECT) were performed on day 2, when he was somnolent with right-sided hemiplegia, on day 9 when a mild hemiparesis was still present and on day 24 after recovery. The right central region showed normal findings in DWI, whereas P-MRI and SPECT revealed hyperperfusion on day 2, less marked on day 9, and normal findings on day 24. In conclusion, this case report indicates for the first time, by means of SPECT, P-MRI and DWI studies, that even extremely long-lasting migraine aura is not associated with cerebral ischaemia. Therefore, it supports the revised International Headache Society criteria where the term 'persistent' aura is proposed.

[Radiation exposure around patients after administration of 123-MIBG]. / Strahlenexposition im Umfeld von Patienten nach 123I-MIBG-Applikation.

AIM: Estimation of the radiation exposure to neighbouring patients, personnel and relatives deriving from patients undergoing 123I-MIBG scintigraphy. METHODS: For scintigraphic studies, 16 patients with suspected pheocromocytoma were injected with 340 +/- 30 MBq 123I-MIBG. Dose rates were measured at a distance of 0.5 m, 1 m, and 2 m after 10 min, 3 h, 21 h, 45 h, and 68 h using three calibrated portable radiation detectors. The emasured values were background corrected. RESULTS: Ten minutes after injection the dose rate was 10.5 microS/h at a distance of 0.5 m, 3.78 microS/h at 1 m, and 0.95 microS/h at 2 m. The effective half-life was estimated to 8.68 +/- 0.15 h. The maximum dose in a distance of 1 m for neighbouring patients was 46 microS/h, for personnel in a ward 27 microS/h, and to relatives in a distance of 2 m 12 microS/h. CONCLUSION: This study demonstrates that the calculated exposure to people around patients after 123I-MIBG injection is well below the maximum permissible annual dose limit of 1 mSv for not professionally exposed persons.

Effects of chemotherapeutic agents on expression of somatostatin receptors in pancreatic tumor cells.

UNLABELLED: Specific tumors express high amounts of receptors for somatostatin (SST), providing the basis for imaging and treatment using radiolabeled SST analogs. However, little is known about the potential influence of cytotoxic drugs on SST receptor (SSTR) expression in malignant cells. METHODS: To study the interaction between cytotoxic drugs and SSTR expression, the pancreatic cancer-derived tumor cell lines BxPC-3, Panc-1, Capan-1, and ASPC-1 were exposed to a range of cytotoxic drugs in vitro: Gemcitabine, 5-fluorouracil, cisplatin (cis-diaminedichloroplatinum [II]), camptothecin, mitomycin C, and doxorubicin were checked for changes in binding characteristics of the SSTR ligand (111)In-1,4,7,10-tetraazacyclododecane- N,N',N",N"'-tetraacetic acid-lanreotide (DOTA-LAN). Chemosensitivity was quantitated by measurements of reduction in cell numbers, changes in cell cycle distribution, and appearance of apoptotic subG1 (subG1/0 cell DNA content) cells. RESULTS: Cells were treated with gemcitabine (1.0 or 2.0 microg/mL), 5-fluorouracil (65-520 microg/mL), camptothecin (1.5 or 3 microg/mL), mitomycin C (0.1 or 0.2 microg/mL), and doxorubicin (1.0 or 2.0 microg/mL). Each of the chemotherapeutic agents induced a loss of high-affinity receptors. In addition, gemcitabine caused a reduction of low-affinity receptors in BxPC-3, Panc-1, and ASPC-1 cells. Mitomycin C, camptothecin, and 5-fluorouracil also induced an overexpression of low-affinity receptors. In cells pretreated with cisplatin (2-10 microg/mL), binding of DOTA-LAN was increased. Excluding gemcitabine, the increase in low-affinity binding sites exhibits a weak correlation with apoptosis (r(2) = 0.62). For gemcitabine, these effects were reversed after 4 d of recovery of the cell lines, eventually revealing overexpression of low- and high-affinity sites for BxPC-3 and Panc-1 cells and low-affinity sites for ASPC-1 cells. CONCLUSION: Our results clearly show that the pancreatic tumor lines reduce the expression of high-affinity DOTA-LAN binding sites during application of chemotherapeutic drugs, which is accompanied by variable overexpression of low-affinity binding sites. In the case of gemcitabine, SSTRs are overexpressed during recovery from drug exposure within 4 d. These findings may have implications on the interpretation of scintigraphic results obtained by receptor ligands.

111In-DOTA-lanreotide scintigraphy in patients with tumors of the lung.

UNLABELLED: Imaging with radiolabeled somatostatin (SST) analogs has recently been established for the localization of various human SST receptor (hsstr)-positive tumors, including neuroendocrine tumors, lymphomas, and non-small cell lung cancer (NSCLC). METHODS: 111In-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-lanreotide (DOTA-LAN) scintigraphy (150 MBq; 7 nmol per patient) was performed on 47 patients (28 patients with primary tumors, 19 patients with lung metastases from other tumors) to evaluate the tumor binding in patients with histologically confirmed lung cancer. A group of 27 tumor patients without documented lung lesions served as the control group. Early and delayed planar and SPECT images were acquired. Whole-body scintigraphy was performed at 0.5, 4-6, 24, and 48 h after injection for tumor dose estimation. In addition, hsstr subtype expression and radioligand binding characteristics were studied in vitro using lung tumor samples (n = 15). RESULTS: 111In-DOTA-LAN indicated the primary lung tumor in 16 of 16 NSCLC patients. Lymph node metastases were visualized in 6 of 6 NSCLC patients, and bone metastases were seen in 3 of 3 NSCLC patients. 111In-DOTA-LAN scintigraphy indicated lung carcinoid in 5 of 5 patients and small cell lung cancer lesions in 6 of 6 patients. Multiple lung metastases were shown in all 6 patients with non-Hodgkin's lymphoma and in the 1 patient with Hodgkin's disease, 5 of 5 colorectal adenocarcinoma patients, 4 of 4 carcinoid patients, 2 of 2 neuroendocrine carcinoma (NEC) patients, and 1 of 1 angiosarcoma patient. Pulmonary tumor sites not indicated by CT or MRI were visualized in 6 of 47 tumor patients (i.e., 13%; lung metastases in 1 carcinoid patient and 1 NEC patient, lymph node metastases in 1 carcinoid patient and 2 NSCLC patients, bone metastases in 1 carcinoid patient). The estimated lung tumor dose ranged between 0.2 and 5 mGy/MBq. Focal lung uptake of 111In-DOTA-LAN was not observed in any of the 27 control patients. In vitro binding studies indicated high-affinity binding sites for 111In-DOTA-LAN in NSCLC samples (dissociation constants, 0.5 and 4 nmol/L) with predominant expression of hsstr4. CONCLUSION: 111In-DOTA-LAN yields high tumor binding for various human lung tumors. Consecutively, radiopeptide therapy may offer a potential new treatment alternative for some lung tumor patients.

Phase II study of merbarone (NSC 336628) in patients with advanced gastric carcinoma.

Merbarone, 5-(N-phenylcarboxamido)-2-thiobarbituric acid (NSC 336628), is a derivative of barbituric acid and represents a unique class of antineoplastic agents. We treated 16 patients with advanced gastric carcinoma in a phase II study of merbarone. All patients were previously untreated with chemotherapy or biological therapy. The starting dose of merbarone was 1000mg/m2 infused over 24 hr for 5 consecutive days every 21 days. A median of two courses (range, 1-7) was given. None of the patients achieved a complete or partial response; however, 3 patients achieved a transient minor response. Toxicity was mild to moderate in most patients, but 1 patient died of treatment-related neutropenia and sepsis. Our data suggest that merbarone at this dose and schedule is inactive against gastric carcinoma. The evidence of minor response suggests that analog research may be worthwhile to pursue.