68Ga-DOTATOC PET/CT of neuroendocrine tumors: spotlight on the CT phases of a triple-phase protocol.

UNLABELLED: The diagnostic value of neuroendocrine tumor (NET) imaging using PET with integrated CT is dependent on both components. This retrospective study assessed the value of the single CT phases of a triple-phase (early arterial, portal-venous inflow, and venous) CT protocol in comparison to (68)Ga-DOTATOC PET in a masked reading. METHODS: (68)Ga-DOTATOC PET/CT examinations from 51 patients with known or suspected NET were included. Two readers assessed the data of PET and each of the 3 CT phases for NET lesions independently (using a 3-point score: 1 = benign, 2 = indeterminate, and 3 = malignant) and by consensus (using binary benign/malignant interpretation only). Only lesions within the field of the abdominal scan were evaluated. Clinical and imaging follow-up, histopathology (if available), and the decision of an interdisciplinary truth-panel served as a standard of reference. In addition to the calculation of standard statistical parameters (including general linear mixed models), interobserver reliability was estimated (Cohen's κ). RESULTS: Of 510 abdominal lesions observed, 354 were classified as malignant. Sensitivity was 77.1% for combined triple-phase CT, 53.4% for arterial CT, 66.1% for portal-venous CT, 66.9% for venous CT, and 72.8% for PET. The respective specificities were 85.3%, 92.9%, 92.3%, 89.7%, and 97.4%, and the respective accuracies were 79.6%, 65.5%, 74.1%, 73.9%, and 80.4%. Although arterial CT was found to be inferior to PET, portal-venous CT, and venous CT (P < 0.001), the differences between the other scans were not significant. Detection was exclusively by PET for 16.1% of lesions, by triple-phase CT for 20.3%, by arterial CT for 0.5%, by portal-venous CT for 3.9%, and by venous CT for 3.9%. Regarding interobserver reliability, the κ-value was 0.768 for PET, 0.391 for triple-phase CT, 0.577 for arterial CT, 0.583 for portal-venous CT, and 0.482 for venous CT. CONCLUSION: No CT phase can be omitted in NET imaging, and the triple-phase protocol continues to be strongly recommended also for PET/CT.

Impact of Multiphase 68Ga-DOTATOC-PET/CT on therapy management in patients with neuroendocrine tumors.

AIM: Retrospective evaluation of the impact of integrated positron emission tomography/computed tomography (PET/CT) using (68)Ga-DOTA(0)-Phe(1)-Tyr(3)-octreotide ((68)Ga-DOTATOC) on the therapeutic management of patients with neuroendocrine tumors (NET). METHODS: The (68)Ga-DOTATOC-PET/CT data of 66 patients (31 male, 35 female; age: 29-79, mean age: 56 years) with known or suspected NET were included. Imaging data (PET and triple-phase contrast-enhanced CT) were evaluated in consensus by two readers for the visualization of NET manifestations. Combined PET/CT, clinical and imaging follow-up as well as histopathology (if available) served as the reference standard. In order to assess the impact of the respective submodalities on the therapeutic strategy chosen, the results were compared to the treatment decision made by the interdisciplinary NET tumor board of our institution. RESULTS: Two of the initial 66 patients included did not suffer from NET according to further immunohistopathological examination. In 50 of the remaining 64 (78%) NET patients, a total of 181 NET manifestations were detected by PET/CT. 59/181 (32.6%) were detected by one submodality only (CT 17.1%, PET 15.5%, p for comparison of both = 0.459). Combined PET/CT reading had an impact on the therapeutic management in 24 of 64 (38%) NET patients: primary resection (n = 5), curative lymph node resection (n = 1), initiation/switch of chemotherapy (CTx) due to progressive disease (n = 10), no surgery due to systemic disease (n = 2), radiopeptide receptor therapy instead of CTx (n = 1), additional bisphosphonate therapy (n = 4), and hepatic brachytherapy (n = 1). In 12 of 24 (50%) of these patients, relevant findings were detected by a single submodality only: CT (n = 5), PET (n = 7); p for comparison = 0.774). CONCLUSION: (68)Ga-DOTATOC-PET/CT influences therapeutic management in about one third of patients examined. CT and PET are comparably sensitive, deliver complementary information and equally contribute to therapeutic decision-making. Thus, despite the merits of the PET modality, the CT component must not be neglected and an optimized multiphase CT protocol is recommended.

Attenuation correction of somatostatin receptor SPECT by integrated low-dose CT: is there an impact on sensitivity?

AIM: Somatostatin receptor scintigraphy (SRS) is an established imaging modality for neuroendocrine tumors (NET). Additional single photon emission computed tomography (SPECT-CT) not only permits image fusion but also attenuation correction (AC) of SPECT data. This study evaluated whether attenuation corrected SPECT-images (SPECT[AC]) are more sensitive than nonattenuation corrected SPECT-reconstructions (SPECT[NAC]) for the detection of NET lesions. METHODS: The imaging data (planar In-111-octreotide scintigraphy and SPECT-CT) of 50 consecutive patients (28 male; 22 female; age, 34-80; mean, 65 years) with NET were included in this retrospective analysis. SPECT data were reconstructed with and without integrated CT-based AC and then analyzed by 2 experienced readers for the presence of pathologic uptake in a blinded consensus reading. Fused SPECT-CT, contemporary CT/MRI, and clinical as well as imaging follow-up served as a reference standard. All foci were rated in both the SPECT(NAC)- and SPECT(AC)-reconstructions for intensity and contrast using a 6-point-score ("0 = no uptake/no delineation from surrounding tissue" to "5 = very high uptake/very strong delineation from surrounding tissue"). The scores were analyzed in a 6 x 6 contingency table using the McNemar Bowker test. RESULTS: A total of 222 pathologic foci were detected by SPECT(NAC) and 227 foci by SPECT(AC), respectively. In 67 of 227 foci (29.5%), focus intensity/contrast increased after AC, whereas only 5 foci showed a decrease (P < 0.001). Sensitivity increased by 2.2% (P = 0.025; 95% CI: 0.02%-4.1%) as 5 foci were detected only by SPECT(AC). However, as these 3 patients were already diagnosed with systemic disease, there was no influence on the therapeutic strategy chosen. CONCLUSION: Attenuation correction of somatostatin receptor scintigraphy-SPECT significantly improves focus visualization and, albeit slightly, also significantly increases sensitivity.

The fully human anti-CD30 antibody 5F11 activates NF-{kappa}B and sensitizes lymphoma cells to bortezomib-induced apoptosis.

5F11, a fully human monoclonal antibody directed against CD30, effectively induces killing of CD30-expressing lymphoma cell lines in vitro and in animal models. A recently conducted phase 1/2 study shows that 5F11 is well tolerated in heavily pretreated patients with relapsed and refractory CD30(+) lymphoma and has some clinical activity. In the present study, we demonstrate that 5F11 activates nuclear factor kappaB (NF-kappaB) and the anti-apoptotic protein cellular FLICE (Fas-associating protein with death domain-like interleukin-1beta-converting enzyme) inhibitory protein (c-flip) in Hodgkin lymphoma (HD)-derived cell lines, which might cause apoptosis resistance, thus limiting the clinical use of 5F11. To overcome this resistance, we combined 5F11 with the proteasome inhibitor bortezomib, which has been shown to suppress NF-kappaB activity. This combination revealed a synergistic cytotoxic effect in vitro and in a human HD xenograft model provided that 5F11 precedes bortezomib treatment. We conclude that initial 5F11-mediated NF-kappaB signaling sensitizes the tumor cells to bortezomib-induced cell death. These data suggest a therapeutic value of this combination for HD patients.

Combination of the human anti-CD30 antibody 5F11 with cytostatic drugs enhances its antitumor activity against Hodgkin and anaplastic large cell lymphoma cell lines.

Due to its selective overexpression on the malignant cells of Hodgkin's lymphoma (HL) and large cell anaplastic lymphoma (ALCL), CD30 is an excellent target for immunotherapy of these diseases. The fully human monoclonal anti-CD30-antibody 5F11 has been shown to be effective against CD30-expressing cell lines both in vitro and in vivo. In addition, 5F11 shows promising antitumor activity in phase 1/2 clinical trials. To extend these promising results, the authors evaluated combinations of 5F11 with conventional cytostatic drugs against a variety of lymphoma cell lines in vitro. Most combinations tested showed at least additive cytotoxic effects on the HL-derived cell lines L428, L540, and L1236 and the ALCL-derived cell line Karpas 299 as measured by proliferation assays (XTT) and the induction of apoptosis (annexin-V FACS analysis). The most impressive results were detected with the combination of 5F11 and gemcitabine or etoposide. The data suggest that the combination of the human antibody 5F11 with conventional chemotherapy might be beneficial in the combined chemo-immunotherapy of CD30-positive lymphomas.