Abstract Background: The EANM Research Ltd. (EARL) guidelines give recommendations for harmonization of [ 18 F]FDG PET-CT image acquisition and reconstruction, aiming to ensure reproducibility of quantitative data between PET scanners. Recent technological advancements in PET-CT imaging resulted in an updated version of the EARL guidelines (EARL2). The aim of this study is to compare quantitative [ 18 F]FDG uptake metrics of the primary tumor and lymph nodes in patients with head and neck squamous cell carcinoma (HNSCC) on EARL2 versus EARL1 reconstructed images and to describe clinical implications for nodal staging and treatment. Methods: Forty-nine consecutive patients with HNSCC were included. For all, both EARL1 and EARL2 images were reconstructed from a singular [ 18 F]FDG PET-CT scan. Primary tumors and non-necrotic lymph nodes ≥ 5mm were delineated on CT-scan. In the quantitative analysis, maximum standardized uptake values (SUV max ) and standardized uptake ratios (SUR max , i.e. SUV max normalized to cervical spinal cord uptake) were calculated for all lesions on EARL1 and EARL2 reconstructions. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were compared between EARL1 and EARL2 using different segmentation methods (adaptive threshold; SUV2.5/3.5/4.5; SUR2.5/3.5/4.5; MAX40%/50%). In the qualitative analysis, each lymph node was scored independently by two nuclear medicine physicians on both EARL1 and EARL2 images on different occasions using a 4-point scale. Results: There was a significant increase of SUV max (19%) and SUR max (11%) of primary tumor and lymph nodes on EARL2 versus EARL1 imaging (p < 0.001). The proportional difference of both SUV max and SUR max between EARL2 and EARL1 decreased with increasing tumor volume (p < 0.001). Absolute differences in MTVs between both reconstructions were small (< 1.0cm 3 ), independent of the segmentation method. Relative differences in MTVs and TLGs were small using the adaptive threshold method and larger using static SUV or SUR thresholds. With visual scoring of lymph nodes 38% (11/29) of nodes with score 2 on EARL1 were upstaged to score 3 on EARL2, which resulted in an alteration of nodal stage in 18% (6/33) of the patients. Conclusions: Using the EARL2 method for PET image reconstruction resulted in higher SUV max and SUR max compared to EARL1, with nodal upstaging in a significant number of patients.
Abstract Lentiviral vectors are attractive tools for liver-directed gene therapy because of their capacity for stable gene expression and the lack of preexisting immunity in most human subjects. However, the use of integrating vectors may raise some concerns about the potential risk of insertional mutagenesis. Here we investigated liver gene transfer by integrase-defective lentiviral vectors (IDLVs) containing an inactivating mutation in the integrase (D64V). Hepatocyte-targeted expression using IDLVs resulted in the sustained and robust induction of immune tolerance to both intracellular and secreted proteins, despite the reduced transgene expression levels in comparison with their integrase-competent vector counterparts. IDLV-mediated and hepatocyte-targeted coagulation factor IX (FIX) expression prevented the induction of neutralizing antibodies to FIX even after antigen rechallenge in hemophilia B mice and accounted for relatively prolonged therapeutic FIX expression levels. Upon the delivery of intracellular model antigens, hepatocyte-targeted IDLVs induced transgene-specific regulatory T cells that contributed to the observed immune tolerance. Deep sequencing of IDLV-transduced livers showed only rare genomic integrations that had no preference for gene coding regions and occurred mostly by a mechanism inconsistent with residual integrase activity. Conclusion: IDLVs provide an attractive platform for the tolerogenic expression of intracellular or secreted proteins in the liver with a substantially reduced risk of insertional mutagenesis. (Hepatology 2011;)
Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis.
5079 Background: In metastatic clear cell renal cell carcinoma (mccRCC), the number of International Metastatic Database Consortium (IMDC) risk factors plus metastatic sites may identify patients with rapid or slow disease progression in a period of watchful waiting (WW) (median WW of 8.4 vs 22.2 months; Rini et al. Lancet Oncol. 2016). We aimed to validate this and prospectively assess the added value of baseline PET with [ 18 F]FDG and [ 89 Zr]Zr-DFO-girentuximab to predict the WW-period in the multicenter IMaging PAtients for Cancer drug selecTion (IMPACT)-RCC cohort study. (NCT02228954). Methods: Between February 2015 and March 2018, 40 treatment-naïve mccRCC patients with a good (n=13) or intermediate prognosis (n=25) according to IMDC, were enrolled. Following baseline CT, [ 18 F]FDG and [ 89 Zr]Zr-DFO-girentuximab-PET, CT scans (RECIST1.1) were acquired at 2, 4, 6, 9, 12 months and thereafter every 4 months. Primary endpoint was time to radiological and/or clinical disease progression, requiring systemic treatment. Patients were assigned to a favorable (<2 IMDC risk factors and <3 metastatic sites) or unfavorable for WW-group (all others; Rini et al). Maximum standardized uptake values (SUV max ) were measured in PET-positive lesions measuring ≥10mm, or 15mm in lymph nodes. High and low-uptake groups were defined based on median geometric mean (gm) SUV max across patients. A one-sided test was used to validate observations by Rini et al; other tests were two-sided. Results: The median WW-period was 9.3 months in the unfavorable WW-group (n=19) vs 20.4 months in the favorable WW-group (n=21) (HR 1.89 95%CI 0.94-3.89; p=0.037), confirming observations of Rini et al. Patients with high [ 18 F]FDG uptake had a median WW-period of 8.5 months compared to 25.2 months in the low-uptake group (HR 4.08 95%CI 1.89-9.28; p=0.0002). Patients with high [ 89 Zr]Zr-DFO-girentuximab uptake had a median WW-period of 10.7 versus 16.4 months in the low-uptake group (HR 1.37; 95%CI 0.69-2.76; p=0.37). [ 18 F]FDG uptake groups improved a Cox-model for WW based on the prognostic groups of Rini et al (p=0.0015); [ 89 Zr]Zr-DFO-girentuximab did not (p=0.98). Conclusions: The IMPACT-RCC study validated the observations by Rini et al. and shows that adding baseline [ 18 F]FDG PET further improves the prediction of the duration of the WW-period in mccRCC patients. Clinical trial information: NCT02228954 .
Advances in the field of radiation oncology in the last decade resulted in an increasing number of opportunities to optimize therapy. Increased accuracy to deliver the dose to tumors while sparing normal tissues demands more precise delineation of the tumors. When considering to deliver a boost to more aggressive parts of tumors, intratumoral heterogeneity needs to be assessed accurately. Adaptive radiotherapy demands evaluation of response during the course of radiotherapy, in terms of both volumetric and functional changes. Molecular imaging with fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has found its way into clinical practice for various indications in head and neck cancer and new applications are under investigation. In this review, an overview is provided of the current status and developments of the use of FDG-PET/CT in radiation oncology, describing the current status in radiation treatment planning, adaptation of therapy and the position compared to other imaging techniques.
Achieving a metabolic complete response (mCR) before high-dose chemotherapy (HDC) and autologous peripheral blood stem-cell transplant (auto-PBSCT) predicts progression free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL). We added brentuximab vedotin (BV) to DHAP to improve the mCR rate. In a Phase I dose-escalation part in 12 patients, we showed that BV-DHAP is feasible. This Phase II study included 55 R/R cHL patients (23 primary refractory). Treatment consisted of three 21-day cycles of BV 1.8 mg/kg on day 1, and DHAP (dexamethasone 40mg days 1-4, cisplatin 100mg/m2; day 1 and cytarabine 2x2g/m2; day 2). Patients with a metabolic partial response (mPR) or mCR proceeded to HDC/auto-PBSCT. Based on independent central FDG-PET-CT review, 42 of 52 evaluable patients (81% [95% CI: 67-90]) achieved an mCR before HDC/auto-PBSCT, five had an mPR and five had progressive disease (three were not evaluable). After HDC/auto-PBSCT, four patients with an mPR converted to an mCR. The 2-year PFS was 74% [95% CI: 63-86], and the overall survival 95% [95% CI: 90-100]. Toxicity was manageable and mainly consisted of grade 3/4 hematological toxicity, fever, nephrotoxicity, ototoxicity (grade 1/2) and transiently elevated liver enzymes during BV-DHAP. Eighteen patients developed new onset peripheral neuropathy (maximum grade 1/2) and all recovered. In conclusion, BV-DHAP is a very effective salvage regimen in R/R cHL patients, but patients should be monitored closely for toxicity. ClinicalTrials.gov identifier: NCT02280993.
Patients with MYC-rearrangement positive large B-cell lymphoma (MYC+ LBCL) have an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) as compared to patients without MYC rearrangement. Although intensive chemotherapy regimens yield higher remission rates, toxicity remains a concern. Lenalidomide is an oral immunomodulatory drug which downregulates MYC and its target genes thereby providing support using lenalidomide as additional therapeutic option for MYC+ LBCL. A phase II trial was conducted evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients identified through a nationwide MYC-FISH screening program. The primary endpoint was complete metabolic response (CMR) on centrally reviewed 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computer tomography (CT)-scan at end-of-treatment. Secondary endpoints were overall survival (OS), disease-free survival (DFS) and event-free survival (EFS). Eighty-two patients with stage II-IV MYC+ LBCL were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 25.4 months, 2-year estimates (95% CI) for OS, DFS, EFS were 73% (62-82%), 75% (63-84%) and 63% (52-73%) respectively. In this prospective trial for newly diagnosed MYC+ LBCL patients, we found that administering R2CHOP was safe, and yields comparable CMR and survival rates as in studies applying more intensive chemotherapy regimens. Hence, these findings offer new prospects for MYC+ LBCL patients and warrant comparison in prospective randomized clinical trials. This trial was registered at www.clinicaltrialsregister.eu (#2014-002654-39).
