Andreas Hertel

Positron Emission Tomography (PET) for Staging and Evaluation of Response to Treatment in Patients with Hodgkin's Disease

Forty two examinations utilizing F-18 FDG-PET were performed in 23 patients with Hodgkins disease to study for involved lymphoma regions and compared to conventional staging procedures. Twenty stagings were performed at diagnosis of untreated Hodgkins disease or at first relapse, and 22 restagings during and after chemoradiotherapy. At diagnosis in 5 of 20 patients PET and other procedures revealed different extranodal manifestations and in 3 patients established different clinical staging. PET seemed to be accurate in the assessment of lymphoma involvement in nodal sites. During follow up, in 10 out of 22 investigations different results and discrepancy were recorded, mostly due to the different extent of F-18-FDG metabolism in residual masses in lymphatic tissues compared to CT, X-ray or ultrasonography. The results indicate that PET may have advantages in the assessment of remissions in nodal sites. Less conclusive results were observed with regard to extranodal involvement or inflammatory disease. In conclusion PET may be sufficient for the staging of the majority of patients with Hodgkins disease and particularly for assessing remission status in nodal sites, but PET may have disadvantages in the evaluation of extranodal lymphoma and inflammatory disease.

Comparison of metabolic and receptor imaging in recurrent medullary thyroid carcinoma with histopathological findings

Abstract. Early diagnosis of metastases of medullary thyroid carcinoma (MTC) provides the optimal condition for curative outcome. The aim of this study was to appraise the detection of metastases in patients with recurrent MTC using [111In-DTPA-d-Phe1]-pentetreotide and pentavalent technetium-99m dimercaptosuccinic acid [99mTc(V)-DMSA] in comparison with histopathological findings. Eighteen MTC patients with persistently elevated tumour marker (calcitonin, carcinoembryonic antigen) levels underwent somatostatin receptor scintigraphy using [111In-DTPA-d-Phe1]-pentetreotide (222 MBq) with early (4xa0h after injection) and delayed (24xa0h) whole-body scans and single-photon emission tomography (SPET) imaging. Metabolic whole-body and SPET imaging using 500xa0MBq 99mTc(V)-DMSA was performed 4xa0h after injection. Metabolic and receptor imaging revealed 51 sites of focal accumulation in the 18 patients investigated. Comparison with histological findings revealed that metabolic and receptor imaging had a sensitivity of 84% for the diagnosis of MTC. Using [111In-DTPA-d-Phe1]-pentetreotide, SPET discovered four lymph node metastases in two patients in whom planar views had previously identified only one lymph node metastasis, and provided no new information in the other 16 patients. In comparison, SPET studies [using 99mTc(V)-DMSA] additionally localized eight lymph node metastases in four patients and confirmed the diagnosis of hepatic metastases (n=5) in another patient in whom conventional imaging modalities and planar views had previously detected only three liver metastases. Overall, lesion detection sensitivities for 99mTc(V)-DMSA and [111In-DTPA-d-Phe1]-pentetreotide were 69% and 29%, respectively. Five surgically removed foci were adjudged false-positive with respect to MTC metastases. False-positve results were caused by lymphadenitis, an enchondroma and a pheochromocytoma (histologically proven). The smallest lesion identified by metabolic imaging was a 6xa0mm in diameter lymph node metastasis located in the upper mediastinum. Somatostatin receptor scintigraphy only demonstrated tumour sizes more than 1xa0cm in diameter. These preliminary results suggest that the combination of metabolic [99mTc(V)-DMSA] and receptor ([111In-DTPA-d-Phe1]-pentetreotide) imaging is more sensitive for tumour localization in patients with recurrent MTC than the use of only one radiopharmaceutical. However, neither 99mTc(V)-DMSA nor [111In-DTPA-d-Phe1]-pentetreotide is specific for MTC and false-positive scintigraphic findings have to be considered. Furthermore, somatostatin receptor scintigraphy cannot visualize small tumour sites (<1xa0cm). Further studies are needed to evaluate the role of combined metabolic and receptor imaging in the management of patients with recurrent MTC.

Can response to partial sleep deprivation in depressed patients be predicted by regional changes of cerebral blood flow

The possible predictive value of regional cerebral perfusion patterns with respect to the response to partial sleep deprivation (PSD) was evaluated in 15 major depressive patients (mean age = 54.9 years, mean Hamilton depression score = 21.6). Patients were studied with single photon emission computed tomography with technetium-99 m-D,L-hexamethyl-propylene amine oxime. Scans were performed on the morning before and after (at 08.00 h) PSD. Responders to PSD had significantly higher perfusion in the right orbitofrontal cortex than did non-responders before PSD. Multiple regression analysis indicated that right orbitofrontal/basal cingulate perfusion (r = -0.77, P < 0.001) before PSD, and left inferior temporal perfusion (r = 0.59, P = 0.01) after PSD, were fairly accurate predictors of change in Hamilton depression scores. Thus, it appears that the orbitofrontal cortex and the cingulate are involved in PSD and may serve as predictors of therapeutic response.

Evaluation of the effects of total sleep deprivation on cerebral blood flow using single photon emission computerized tomography

HMPAO‐single photon emission computerized tomography (SPECT) is a useful technique in studying cerebral blood flow (CBF). This method is suitable to evaluate the differences of CBF with reference to total sleep deprivation (TSD) within 24 h because of the short half‐life of the radiopharmaceutical compound. In the present study, CBF before and after TSD was analysed in patients suffering from major depression. The morning before and after TSD, Tc‐HMPAO‐SPECT was performed in 20 patients. Hamilton Rating Scale for Depression scores and subjective ratings were obtained daily. Eleven patients responded to TSD; 9 were nonresponders. The main finding was a significant left temporal and mainly right parietal increase of CBF, which was observed in the responders only. CBF values and the severity of depression correlated inversely.

Multimodal imaging of residual function and compensatory resource allocation in cortical atrophy: a case study of parietal lobe function in a patient with Huntington's disease

In a case of Huntingtons disease (HD) with dementia and pronounced parieto-frontal atrophy, the functional state of the affected regions was investigated using functional magnetic resonance imaging (fMRI) and fluorodeoxyglucose-positron emission tomography (FDG-PET). It was observed that although parietal areas showed extensive atrophy and reduced resting glucose metabolism, the patient performed with similar accuracy but with longer response time in a visuospatial task compared with healthy control subjects. At the same time, the blood oxygen level-dependent (BOLD) fMRI signal in these areas, which are involved in visuospatial processing, showed a similar task-dependent modulation as in control subjects. The signal amplitude (signal percent change) of the task-dependent activation was even higher for the HD patient than in the control group. This residual functionality of parietal areas involved in visuospatial processing could account for the patients performance in the task concerned, which contrasted with his poor performance in other cognitive tasks. The increased percent-signal change suggests that a higher neuronal effort was necessary to reach a similar degree of accuracy as in control subjects, fitting well with the longer reaction time. We propose that fMRI should be considered as a tool for the assessment of functionality of morphologically abnormal cortex and for the investigation of compensatory resource allocation in neurodegenerative disorders.

PET with 2-[F-18]-Fluoro-2-Deoxy-D-Glucose (FDG) in Patients with Cancer of Unknown Primary (CUP): Influence on Patients' Diagnostic and Therapeutic Management

25 patients with cancer of unknown primary (CUP) were studied using PET-FDG. Whole-body-PET scans were performed based on previous morphological information. All patients underwent conventional diagnostic modalities prior to and after the PET-study. True positive results were obtained in 12/25 patients (48%) and the primary identified by PET was confirmed by further procedures. True negative results were obtained in 8/25 patients (32%) and no primary tumor was found by PET or other clinical investigations. False positive results were obtained in 5/25 patients (20%). No false negative results were obtained. In 11 patients having CT compared with PET the primary tumor was exclusively localized by PET in 8 patients (73%) and also by CT in 3 patients (27%); CT was unable to identify the tumor in 8/11 patients detected by PET. PET affected management and directed treatment in 11/25 patients (44%). The sensitivity of PET-FDG was 100%, specificity 61%. These observations demonstrate that PET-FDG is a highly sensitive method to detect CUP. Correctly classified patients in an early stage of disease may lead to benefit from a more targeted therapy with prolonged survival time. In cases of advanced disease PET might not decisively influence survival time.

A Novel Technetium-99M Labeled Monoclonal Antibody (174H.64) For Staging Head and Neck Cancer by Immuno-Spect

A novel murine monoclonal antibody (MAb 174H.64) was labeled with 99mTc by a direct method. MAb 174H.64 detects a cytokeratin-associated antigen which is expressed by over 90% of all squamous cell carcinomas. Panendoscopy, sonography and computerized tomography scan were performed in all cases as well as magnetic resonance imaging (in selected patients). Pre-operative immunoscintigraphy was performed in 21 patients with histologically proven primary carcinomas (18 with remaining primary tumors and 3 with lymph node recurrences). Scintigraphic images were obtained 4-6 h after injection of 1.1 GBq of the 99mTc-labeled antibody (2 mg). Late images were acquired 18 to 24 h after injection. Single-Photon-Emission-Computed Tomography (SPECT) of the head and thorax was performed in all patients. The primary tumors were immunoscintigraphically visualized in all 18 patients with remaining primary tumor. Fifteen of 18 loco-regional lymph node metastases were visualized by immunoscintigraphy (the smallest lesions had a diameter of < 1 cm), in one patient lymph node metastases were detected by immunoscan only. Two metastatically involved lymph nodes were identified by histology only (micrometastases). Distant metastases were present in 3 patients, of which two were identified by immunoscintigraphy. Immuno-SPECT according to this method was a sensitive and specific imaging modality for preoperative staging of patients with squamous cell carcinoma of the head and neck and detected lymph node metastases with higher accuracy than conventional clinical and imaging modalities.

Follow-Up in Carriers of the ‘MELAS’ Mutation without Strokes

Eight carriers of the A3243G mutation of mitochondrial DNA without stroke-like episodes were monitored for up to 7 years in clinical and metabolic studies, by magnetic resonance imaging (MRI) and positron emission tomography (PET). None developed mitochondrial encephalopathy (MELAS), but 2 developed diabetes mellitus, 1 terminal kidney failure and 2 cardiomyopathy. One patient improved markedly under ubiquinone. Electroencephalography showed progressive slowing in 2 cases, but electrophysiological tests and MRI were otherwise noncontributary. PET showed widespread cortical and basal ganglion metabolic deficits in 6 cases. We conclude that internal medical complications are more common than MELAS in adult carriers of the mutation. PET findings, firstly reported in such patients, suggest that chronic subclinical encephalopathy is very frequent, and PET may play a role in monitoring in the future.

A Preliminary Study on the Functional Analysis of Peripheral Blood Lymphocytes from Ovarian Cancer Patients Developing Hama after Immunoscintigraphy

In the follow-up of ovarian cancer patients, rising levels of the tumor-associated antigen CA 125 are an indication for immunoscintigraphy. Human anti-mouse antibodies (HAMA) are frequently found after immunoscintigraphy with murine MAb directed against CA 125. Since we observed that patients developing high HAMA-levels in serum remained free of tumor or had stable disease, we examined the cytotoxic activity of peripheral blood lymphocytes (PBL) by a fluorescence-based assay. Our results demonstrate that PBLs of patients with high anti-idiotypic antibodies show an increased cytotoxic activity (by a factor of 4) compared to those of patients with low HAMA levels. The clinical course of the patients after the first injection of murine monoclonal antibody was observed over a period of 1 to 3 years. Improvement or deterioration of patients ‘ clinical condition corresponded with the results obtained by functional analysis. Further investigations concerning the course of cytotoxic activity in HAMA-positive patients will have to clarify HAMAs role in the immune response.

Positron Emission Tomography–Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial

Purpose Interim positron emission tomography (PET) using the tracer, [18F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP-plus rituximab (R-CHOP) in CD20-positive lymphomas-followed by a PET scan that was evaluated using the ΔSUVmax method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitts lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.