Sven N. Reske

Use of Positron Emission Tomography for Response Assessment of Lymphoma: Consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma

PURPOSE To develop guidelines for performing and interpreting positron emission tomography (PET) imaging for treatment assessment in patients with lymphoma both in clinical practice and in clinical trials. METHODS An International Harmonization Project (IHP) was convened to discuss standardization of clinical trial parameters in lymphoma. An imaging subcommittee developed consensus recommendations based on published PET literature and the collective expertise of its members in the use of PET in lymphoma. Only recommendations subsequently endorsed by all IHP subcommittees were adopted. RECOMMENDATIONS PET after completion of therapy should be performed at least 3 weeks, and preferably at 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Visual assessment alone is adequate for interpreting PET findings as positive or negative when assessing response after completion of therapy. Mediastinal blood pool activity is recommended as the reference background activity to define PET positivity for a residual mass > or = 2 cm in greatest transverse diameter, regardless of its location. A smaller residual mass or a normal sized lymph node (ie, < or = 1 x 1 cm in diameter) should be considered positive if its activity is above that of the surrounding background. Specific criteria for defining PET positivity in the liver, spleen, lung, and bone marrow are also proposed. Use of attenuation-corrected PET is strongly encouraged. Use of PET for treatment monitoring during a course of therapy should only be done in a clinical trial or as part of a prospective registry.

Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL-PET study

Preclinical studies suggest ropinirole (a D2/D3 dopamine agonist) may be neuroprotective in Parkinsons disease (PD), and a pilot clinical study using 18F‐dopa positron emission tomography (PET) suggested a slower loss of striatal dopamine storage with ropinirole compared with levodopa. This prospective, 2‐year, randomized, double‐blind, multinational study compared the rates of loss of dopamine‐terminal function in de novo patients with clinical and 18F‐dopa PET evidence of early PD, randomized 1 to 1 to receive either ropinirole or levodopa. The primary outcome measure was reduction in putamen 18F‐dopa uptake (Ki) between baseline and 2‐year PET. Of 186, 162 randomized patients were eligible for analysis. A blinded, central, region‐of‐interest analysis showed a significantly lower reduction (p = 0.022) in putamen Ki over 2 years with ropinirole (−13.4%; n = 68) compared with levodopa (−20.3%; n = 59; 95% confidence interval [CI], 0.65–13.06). Statistical parametric mapping localized lesser reductions in 18F‐dopa uptake in the putamen and substantia nigra with ropinirole. The greatest Ki decrease in each group was in the putamen (ropinirole, −14.1%; levodopa, −22.9%; 95% CI, 4.24–13.3), but the decrease was significantly lower with ropinirole compared with levodopa (p < 0.001). Ropinirole is associated with slower progression of PD than levodopa as assessed by 18F‐dopa PET. Ann Neurol 2003

FDG-PET for clinical use. Results of the 3rd German Interdisciplinary Consensus Conference, "Onko-PET III", 21 July and 19 September 2000.

Abstract. Positron emission tomography (PET) is the most powerful molecular imaging technique currently available for clinical use. Because deranged tumour metabolism is a common finding in many malignancies, PET is frequently used for tissue characterisation, staging and therapy control. Four previous consensus studies in Germany, performed up to 1997, have established indications for fluorine-18 fluoro-2-deoxy-D-glucose (FDG) PET in oncology, neurology and cardiology. More than 10,000 references on FDG-PET have been published in the meantime, mostly on oncological issues. Therefore, it was the aim of the present paper to provide an update on the clinical use of FDG-PET in oncology. For this purpose a systematic literature search was performed in all common medical literature databases. All hits were manually checked and abstracts, case reports, technically oriented papers and reviews were excluded from analysis. A questionnaire comprising 24 items was developed for standardised quality assessment according to evidence-based medicine (EBM) criteria. We selected 533 papers for further review by an interdisciplinary panel of 58 experts from oncology, radiology and nuclear medicine. Clinical use was judged according to the following grading scheme: 1a, established clinical use; 1b, clinical use probable; 2, useful in individual cases; 3, not yet assessable owing to missing or incomplete data; 4, clinical use rare (either as inferred from theoretical considerations or as demonstrated by published studies). Of the 533 papers selected, 122 references with 7,092 documented patients fulfilled the EBM criteria for detailed review. The results of these studies were tabulated and are available at www.nucmed-ulm.de. Clinical indications (grade 1a or 1b) were established for differentiating benign from malignant lesions in pulmonary nodules, pancreatic masses and residual masses after chemotherapy in malignant lymphoma. Staging was improved by FDG-PET in oesophageal cancer, breast cancer, head and neck cancer, lung cancer, malignant lymphoma and malignant melanoma. Effectiveness of radio- and/or chemotherapy could be better controlled in Hodgkins disease and high-grade non-Hodgkins lymphoma. Restaging was improved in relapsing thyroid cancer, colorectal cancer, head and neck cancer, lung cancer and malignant melanoma. In summary, the efficiency of FDG-PET was studied in several thousand patients with malignant tumours and was found to be well documented in the international high-quality peer-reviewed literature. There are clear-cut clinical indications for FDG-PET in diagnosis, staging and therapy control, and the technique can help to improve the management of many patients with cancer.

18-F-fluorodeoxyglucose-positron emission tomography as a new approach to detect lymphomatous bone marrow.

PURPOSE Bone marrow involvement in patients with malignant lymphoma is considered a sign of generalized disease with less favorable prognosis. Bone marrow biopsy (BMB), which represents the standard diagnostic procedure, however, is associated with a high rate of false-negative findings, which may lead to errors in management. The present study was undertaken to investigate the efficacy of positron emission tomography (PET) with 18-F-fluorodeoxyglucose (FDG-PET) as a new method to evaluate bone marrow involvement in patients with malignant lymphoma. METHODS Seventy-eight consecutive, untreated patients with either non-Hodgkins lymphoma (NHL; n = 39) or Hodgkins disease (HD; n = 39) were prospectively evaluated. Static FDG-PET imaging was performed following application of 270 MBq (F-18)-FDG. Attenuation correction was performed in 63 of 78 patients. Visual evaluation was performed by two examiners unaware of the clinical data. Material for BMB (70 bilateral, 8 unilateral) was obtained from the posterior iliac crest. Discordant results of PET and biopsy were settled, when possible, on the basis of further biopsy or magnetic resonance imaging (MRI). RESULTS In addition to seven concordant positive and 57 concordant negative findings, biopsy revealed another four cases with bone marrow involvement not detectable by FDG-PET analysis (+5.1%). On the contrary, PET showed bone marrow areas of intensive FDG uptake that suggested bone marrow lymphoma in 10 patients with negative biopsies (+12.8%). In eight patients, FDG-PET findings were confirmed by either histologic verification (n = 4), MRI (n = 2), polymerase chain reaction (PCR) for rearranged immunoglobulin H sequences (n = 1), or clinical presentation (n = 1). Two cases remained unresolved. CONCLUSION The results indicate that FDG-PET has a high potential to detect bone marrow involvement in malignant lymphoma. Besides confirming lesions found at BMB, FDG-PET provided additional information, which, in eight of 78 patients (10.3%), led to an upgrade of the tumor stage.

Fluorine-18 2-deoxy-2-fluoro-D-glucose PET in the preoperative staging of breast cancer: comparison with the standard staging procedures.

The present study compared the diagnostic accuracy of fluorine-18 2-deoxy-2-fluoro-D-glucose positron emission tomography (FDG-PET) with conventional staging techniques. The differentiation between malignant and benign lesions and the detection of multifocal disease, axillary and internal lymph node involvement, and distant metastases were evaluated. One hundred and seventeen female patients were prospectively examined using FDG-PET and conventional staging methods such as chest X-ray, ultrasonography of the breast and liver, mammography and bone scintigraphy. All patients were examined on a modern full-ring PET scanner. Histopathological analysis of resected specimens was employed as the reference method. The readers of FDG-PET were blinded to the results of the other imaging methods and to the site of the breast tumour. The sensitivity and specificity of FDG-PET in detecting malignant breast lesions were 93% and 75% respectively. FDG-PET was twofold more sensitive (sensitivity 63%, specificity 95%) in detecting multifocal lesions than the combination of mammography and ultrasonography (sensitivity 32%, specificity 93%). Sensitivity and specificity of FDG-PET in detecting axillary lymph node metastases were 79% and 92% (41% and 96% for clinical evaluation). FDG-PET correctly indicated distant metastases in seven patients. False-positive or false-negative findings were not encountered with FDG-PET. Chest X-ray was false-negative in three of five patients with lung metastases. Bone scintigraphy was false-positive in four patients. Three patients were upstaged since FDG-PET detected distant metastases missed with the standard staging procedure. It is concluded that, compared with the imaging methods currently employed for initial staging, FDG-PET is as accurate in interpreting the primary tumour and more accurate in screening for lymph node metastases and distant metastases. Due to a false-negative rate of 20% in detecting axillary lymph node metastases, FDG-PET cannot replace histological evaluation of axillary status.

Early Detection and Accurate Description of Extent of Metastatic Bone Disease in Breast Cancer With Fluoride Ion and Positron Emission Tomography

PURPOSE Previous studies have shown that bone metastases are revealed by magnetic resonance imaging (MRI) or bone marrow scintigraphy several months before they are visible by conventional bone scintigraphy (BS). We present a new approach for detecting bone metastases in patients with breast cancer. We compared findings obtained with fluoride ion (F-18) and positron emission tomography (PET) with those obtained with conventional BS. PATIENTS AND METHODS Thirty-four breast cancer patients were prospectively examined using F-18-PET and conventional BS. F-18-PET and BS were performed within 3 weeks of each other. Metastatic bone disease was previously known to be present in six patients and was suspected (bone pain or increasing levels of tumor markers, Ca(2+), alkaline phosphatase) in 28 patients. Both imaging modalities were compared by patient-by-patient analysis and lesion-by-lesion analysis, using a five-point scale for receiver operating characteristic (ROC) curve analysis. A panel of reference methods was used, including MRI (28 patients), planar x-ray (17 patients), and spiral computed tomography (four patients). RESULTS With F-18-PET, 64 bone metastases were detected in 17 patients. Only 29 metastases were detected in 11 patients with BS. As a result of F-18-PET imaging, clinical management was changed in four patients (11.7%). For F-18-PET, the area under the ROC curve was 0.99 on a lesion basis (for BS, it was 0.74; P <.05) and 1.00 on a patient basis (for BS, it was 0.82; P <.05). CONCLUSION F-18-PET demonstrates a very early bone reaction when small bone marrow metastases are present, allowing accurate detection of breast cancer bone metastases. This accurate detection has a significant effect on clinical management, compared with the effect on management brought about by detection with conventional BS.

FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters

Abstract. The aim of this study was to evaluate the possible correlation between preoperative FDG-PET results in human breast cancer and the prognostic markers Ki-67, c-erb B2, p53, oestrogen/progesterone receptor status, axillary lymph node status, tumour size and tumour grading. Seventy-five female patients with breast cancer were included in this prospective study. Patient selection was independent of tumour size and the suspected clinical stage of disease. A high-resolution full-ring scanner (Siemens ECAT HR+) was used for PET imaging. The FDG uptake of breast tumours was calculated as the tumour to background ratio (TBR). In resected cancer tissue specimens, the proliferative fraction was evaluated by Ki-67 immunostaining. Additionally, immunostaining of the prognostic markers c-erb B2, p53, and progesterone and oestrogen receptors was performed. Haematoxylin and eosin-stained sections were used for tumour grading. Correlations between FDG uptake and prognostic markers were assumed to be significant at P<0.05 using the Mann-Whitney U test. In ductal breast cancer, mean TBR was 17.3 (median 7.7, range 1.6–122.7), while in lobular cancer it was 6.5 (median 3.7, range 1.4–22.7). Mean proliferative fraction (% Ki-67 positive tumour cells) was 15%±13.8% (median 10%, range 0%–60%). Twenty-three carcinomas showed <5% Ki-67 positive tumour cells. Statistical analysis indicated a positive correlation between FDG uptake and proliferative index in ductal breast cancer (P<0.0001, r=0.63). By contrast, there was no correlation between FDG uptake and c-erb B2 (P=0.79), p53 (P=0.92), tumour grading (P=0.09), oestrogen receptor status (P=0.41), progesterone receptor status (P=0.34), axillary lymph node status (P=0.90) and tumour size (P=0.3). It is concluded that FDG uptake is significantly higher in ductal breast cancer than in lobular cancer (P<0.05). FDG uptake correlates with proliferative activity assessed by Ki-67 immunostaining (P<0.05). A significant correlation with the other prognostic markers, however, could not be demonstrated.

Gene silencing by adenovirus-delivered siRNA

RNA interference is the process that double‐stranded RNA induces the homology‐dependent degradation of cognate mRNA mediated by 21–23 nucleotide short interfering RNA (siRNA). Here, we describe a simple virus vector for efficient delivery of siRNA into mammalian cells utilizing the well‐defined H1‐RNA promoter and conventional adenovirus. In this pilot study, p53 was targeted by this vector. Our results demonstrate efficient and specific knock‐down of p53 in breast cancer MCF‐7 and lung carcinoma A549 cells and indicate a prospective application of this siRNA expressing recombinant adenovirus system in functional genomics, cancer gene therapy and virus inhibition.

Malignant Melanoma S3-Guideline "Diagnosis, Therapy and Follow-up of Melanoma"

This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma. The diagnosis of primary melanoma based on clinical features and dermoscopic criteria. It is confirmed by histopathologic examination after complete excision with a small margin. For the staging of melanoma, the AJCC classification of 2009 is used. The definitive excision margins are 0.5 cm for in situ melanomas, 1 cm for melanomas with up to 2 mm tumor thickness and 2 cm for thicker melanomas, they are reached in a secondary excision. From 1 mm tumor thickness, sentinel lymph node biopsy is recommended. For stages II and III, adjuvant therapy with interferon-alpha should be considered after careful analysis of the benefits and possible risks. In the stage of locoregional metastasis surgical treatment with complete lymphadenectomy is the treatment of choice. In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations. In the presence of mutations in case of inoperable metastases targeted therapies should be applied. Furthermore, in addition to standard chemotherapies, new immunotherapies such as the CTLA-4 antibody ipilimumab are available. Regular follow-up examinations are recommended for a period of 10 years, with an intensified schedule for the first three years.

Initial results in the assessment of multiple myeloma using 18F-FDG PET.

Abstract. This prospective study was undertaken to investigate the appearance of multiple myeloma on fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET). Furthermore, the accuracy of FDG-PET in detecting myeloma lesions and its influence on patient management were evaluated. Forty-three patients with known multiple myeloma (n=28) or solitary plasmacytoma (n=15) underwent FDG-PET. The results of routinely performed radiographs and of scans obtained using all available imaging modalities (MRI, CT), as well as the clinical course, were used for verification of detected lesions. Focally increased tracer uptake was observed in 38 of 41 known osteolytic bone lesions (sensitivity 92.7%) in 23 patients. In addition, 71 further bone lesions which were negative on radiographs were detected in 14 patients. Twenty-six (36.6%) of these lesions could be confirmed in ten patients. As a result of FDG-PET imaging, clinical management was influenced in five (14.0%) patients. The positive predictive value for active disease was 100% in patients with focal or mixed focal/diffuse skeletal FDG uptake and 75% in patients with diffuse bone marrow uptake. Depending on the interpretation of the PET scans in patients with diffuse bone marrow uptake, the sensitivity ranged from 83.8% to 91.9% and the specificity from 83.3% to 100%. FDG-PET thus proved highly accurate in detecting multiple myeloma, and revealed a greater extent of disease than routine radiographs in 14 of 23 (60.9%) patients who had osteolytic bone lesions. FDG-PET might contribute to the initial staging of solitary plasmacytoma.