Nucl Med Research Articles

Preliminary Data Show Heterogenous Patterns of 18f-FDG PET/CT When Assessing the Inflammatory Component of Primary or Secondary Myelofibrosis

Abstract Background. Recent studies have highlighted the interest of non-invasive procedures to assess extramedullary hematopoiesis in patients with overt myelofibrosis, primary (PMF) or secondary (sMF) to essential thrombocytemia (ET) or to polycythemia vera (PV) (1-4). Several nuclear medicine imaging techniques have been employed without clear consensus about the predominant value of one over other in these mostly preliminary works (2-4). Population and objectives. Because the pathophysiology of PMF or sMF involves some inflammatory pathways we studied the interest of 18F-FDG (18F-fluorodeoxyglucose) PET/CT in patients with PMF (5). The main objective was to know whether the inflammatory component of PMF could be well detected by this technique. Secondly, we looked for some kind of correlation between the FDG uptake on medullary and extramedullary sites of hematopoiesis and the severity of the disease. Five patients with diagnosis of MF (3 PMF and 2 sMF) were assessed (see Table 1 for baseline characteristics and results) Methods.18F-FDG PET/CT imaging was performed following a 60 min. uptake after intravenous injection of a weight-adapted FDG activity (2,5 MBq/kg) on a Siemens Biograph mCT. Images were reviewed by board certified nuclear medicine physicians. Spleen size was measured on axial slices. SUVmax were assessed in a 5 mm diameter spheric volume of interest in homogenous parts of liver and spleen, and in the L2 vertebral body for axial skeleton assessment. Spleen uptake was considered as abnormal in case of a diffuse uptake exceeding hepatic baseline uptake. Skeleton uptake was considered as abnormal in case of diffuse increased uptake. Results. UPN01LP: slight higher metabolic activity in the axial skeleton and diffuse spleen uptake ; UPN02AP: no hypermetabolic activity in the spleen and slightly higher uptake in the axial skeleton ; UPN03AA: diffuse bone hypermetabolic activity and high metabolic activity in the spleen ; UPN05HL: diffuse bone hypermetabolic activity and higher metabolic activity in the spleen ; UPN06DF: no diffuse hypermetabolic activity in the spleen, slight higher uptake in the axial skeleton. In summary, those patients with overt myelofibrosis and constitutional signs tend to show a diffuse higher activity both in the axial skeleton and the spleen whereas those without overt myelofibrosis and without constitutional signs tend to present a normal metabolic activity in the axial skeleton and in the spleen. These patterns are in accordance with the progression and severity of the disease. The higher uptake of 18FDG in the axial skeleton in patients with overt MF contrasts with what is observed with some hybrid imaging techniques that show a lower radionuclide (111In/SPECT/CT) uptake at this level translating a lower hematopoietic activity (3). Conclusions. Based on these preliminary results we consider 18FDG-PET/CT procedures are able to detect the inflammatory component of PMF or sMF and the intensity of FDG uptake appears to be correlated to the severity of the disease. Those patients with a high metabolic activity in the axial skeleton and the spleen might be candidates for specific therapies, although these statements need to be confirmed in a larger series of patients. Bibliography. 1 Derlin T et al. Assessment of bone marrow inflammation in patients with myelofibrosis: an 18F-fluorodeoxyglucose PET/CT study. Eur J. of Nucl Med Mol Imaging 2015 2 Agool A et al. Radionuclide imaging of bone marrow disorders. Eur J Nucl Med Mol Imaging. 2011. 3 Ojeda-Uribe M et al. Assessment of sites of marrow and extramedullary hematopoiesis by hybrid imaging in primary myelofibrosis patients. Cancer Medicine 2016. 4 Vercellino L et al. Assessing bone marrow activity in patients with myelofibrosis: results of a pilot study of 18F-FLT PET. J. of Nucl Med 2017. 5 Desterke C et al. Inflammation as a Keystone of Bone Marrow Stroma Alterations in Primary Myelofibrosis. Mediators Inflamm. 2015 Download : Download high-res image (107KB) Download : Download full-size image Table 1 . Disclosures No relevant conflicts of interest to declare.

26. Radiomics in PET/CT: State-of-the-art and future developments

Introduction Radiomics [ [1] Lambin P. et al. Radiomics: extracting more information from medical images using advanced feature analysis. Eur J Cancer. 2012; Abstract Full Text Full Text PDF Scopus (2855) Google Scholar ] has been a very active field of research during the last five years. There have been very promising results in CT, MRI and PET/CT image modalities. There are, however, also numerous issues and limitations that have been identified. Methods This talk will review the currently available results of radiomics with a focus on PET/CT imaging, and highlights the identified limitations, issues and potential solutions for the future [ 2 Hatt M. et al. Radiomics in PET/CT: more than meets the eye?. J Nucl Med. 2017; Crossref Scopus (72) Google Scholar , 3 Hatt M. et al. Characterization of PET/CT images using texture analysis: the past, the present.. any future?. Eur J Nucl Med Mol Imaging. 2017; Crossref Scopus (330) Google Scholar ]. Results Numerous encouraging results regarding PET/CT radiomics have been published in various types of tumors. However, major limitations include (but are not limited to) statistical power of the studies, lack of methodological standardization, and complexity of the workflow. Conclusions Although radiomics is a fast evolving field of research and encouraging results have been published, caution is required and in order to ensure the future of radiomics, efforts should be focused on methodological standardization, large prospective validation studies, and automatization/simplification of the analysis workflow. Radiomics [ [1] Lambin P. et al. Radiomics: extracting more information from medical images using advanced feature analysis. Eur J Cancer. 2012; Abstract Full Text Full Text PDF Scopus (2855) Google Scholar ] has been a very active field of research during the last five years. There have been very promising results in CT, MRI and PET/CT image modalities. There are, however, also numerous issues and limitations that have been identified. This talk will review the currently available results of radiomics with a focus on PET/CT imaging, and highlights the identified limitations, issues and potential solutions for the future [ 2 Hatt M. et al. Radiomics in PET/CT: more than meets the eye?. J Nucl Med. 2017; Crossref Scopus (72) Google Scholar , 3 Hatt M. et al. Characterization of PET/CT images using texture analysis: the past, the present.. any future?. Eur J Nucl Med Mol Imaging. 2017; Crossref Scopus (330) Google Scholar ]. Numerous encouraging results regarding PET/CT radiomics have been published in various types of tumors. However, major limitations include (but are not limited to) statistical power of the studies, lack of methodological standardization, and complexity of the workflow. Although radiomics is a fast evolving field of research and encouraging results have been published, caution is required and in order to ensure the future of radiomics, efforts should be focused on methodological standardization, large prospective validation studies, and automatization/simplification of the analysis workflow.

Continuation of comprehensive quality control of the itG 68Ge/68Ga generator and production of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for clinical research studies

Performance of a second itG 68Ge/68Ga generator system and production of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC were tested over one year as an accompaniment to a previously published study (J Nucl Med. 2016;57:1402–1405). MethodsPerformance of a 1951MBq 68Ge/68Ga generator was characterized and the eluate used for preparation of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC. Weekly elution profiles of 68Ga elution yield and 68Ge breakthrough were determined. Results68Ga elution yields averaged 82% (61.8–98.4%) and 68Ge breakthrough averaged 0.002% (0.0007% to 0.004%). The radiochemical purities of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC were determined by HPLC analysis to be >98% and specific activity was 12.6 and 42GBq/μmol, respectively. 68Ge contamination in the product was under the detection limit (0.00001%). Final sterile, pyrogen-free formulation of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC in physiologic saline with 5%–7% ethanol was achieved. ConclusionPerformance of a 68Ge/68Ga generator was studied over one year with satisfactory results. The generator eluate was used to synthesize 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC on a routine basis in high purity.

DIAGNOSTIC UTILITY OF FDG-PET IN DIFFERENTIATING BETWEEN LEWY BODY DEMENTIA AND FRONTOTEMPORAL LOBAR DEGENERATION

We performed a systematic review to assess the available evidence for FDG-PET utility in the differential diagnosis between Lewy body dementia (LBD) and fronto-temporal lobar degeneration (FTLD) in difficult to diagnose cases. The search was performed on PubMed, Embase and Cochrane on January 4th, 2016. Critical outcomes were improvement in the sensitivity and specificity of FDG-PET in distinguishing between LBD and FTLD patients as compared to standard clinical/neuropsychological assessment alone. Assessment was required versus gold- (pathology or biomarker) or reference-standard (clinical confirmation at follow-up). No minimum sample size was set a priori. Data were extracted and assessed as to publication bias, heterogeneity, imprecision, risk of bias, indirectness, and applicability. We provide assessment of the quality of evidence, of the target effect, and of strength of recommendation. Out of the 13 papers obtained, only one reported the outcomes of interest. Moreover, sensitivity and specificity were assessed versus baseline clinical diagnosis, in the absence of any gold- or reference-standard. This study* included a total of 98 FTLD and 27 LBD patients, and provides a very low level of evidence for moderate sensitivity and low specificity of FDG-PET in distinguishing between LBD and FTLD patients (Table). Concerns regarding applicability are due to the use of semiquantitative methods of image analysis (increasingly but not routinely adopted in the clinical context). Patterns of hypometabolism associated with the two disorders denote predominantly posterior hypometabolism in LBD and predominantly anterior hypometabolism in FTLD patients, but also a significant overlap (i.e., parietotemporal cortex, posterior cingulate). The available data provide very low evidence for low diagnostic utility of FDG-PET for the differential diagnosis between LBD and FTLD. The available evidence supports a weak recommendation for using FDG-PET to differentiate between LBD and FTLD in doubtful case, and further research is warranted for a proper assessment of its incremental value for this diagnostic question. *Mosconi L. et al., Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias. J Nucl Med. 2008 Mar;49(3):390–8.

Abstract SY02-03: Imaging cancer metabolism in patients: FDG PET and beyond

Abstract The identification of altered energy metabolism as a hallmark of cancer (1) leads to opportunities to exploit cancer metabolism as a target for diagnosis. This has been most widely exploited using the elevated rate of glycolysis observed in most tumors as a target for imaging (2)–in particular, positron emission tomography (PET) imaging of the glucose analog 18F-fluorodeoxyglucose (FDG). FDG PET, now combined with anatomic imaging in the form of PET/CT, has become an important tool for cancer detection, staging, and response assessment, widely used in oncologic clinical practices around the world (3,4). Clinical use of FDG PET has increased our appreciation of aberrant glycolysis as a feature of more aggressive, less differentiated tumors (5,6). At the same time, the variability of tumor FDG uptake seen in clinical imaging has highlighted some of the limitations of imaging tumor glycolysis and has spurred the development of new imaging probes and novel imaging modalities designed to image other facets of cancer energy metabolism. In addition, the use of therapeutics that are targeted to and/or influenced by cancer metabolic phenotype (7) drives applications of cancer metabolic imaging to clinical challenges beyond detection to predicting and and monitoring response to targeted therapy (8). This talk highlights current uses of FDG PET/CT for cancer staging and response evaluation, as well as alternative PET probes targeted to other metabolic substrates such as amino acids, lipids, and TCA intermediates (9). It also highlights other methods for imaging cancer metabolism in patients, including magnetic resonance spectroscopy, optical imaging, chemical exchange saturation transfer (CEST), MR metabolomics, and MR imaging of hyperpolarized 13C-labeled metabolic substrates such as pyruvate (10-14). Unique features and advantages of each modality are highlighted, as are approaches to image analysis common across modalities, including quantitative imaging and kinetic analysis. Finally, the talk emphasizes the benefit of multimodality imaging as an approach to fully characterize cancer metabolism, using glutaminolysis imaging as an example of active investigation. Supported in part by Komen SAC130060, DOE DE-SE0012476, NIH P30-CA016520, and NIH R01-CA211337.

Early response rates and Curie scores at end of induction: An update from a phase II study of an anti-GD2 monoclonal antibody (mAb) with chemotherapy (CT) in newly diagnosed patients (pts) with high-risk (HR) neuroblastoma (NB).

10534 Background: We are conducting a Phase II trial of the anti-GD2 mAb hu14.18K322A given concomitantly with CT in newly diagnosed pts with HR NB. Our primary objective is to compare the response rate (RR; defined as ≥ PR) after two courses of CT with cyclophosphamide (CTX)/topotecan (TPT) and hu14.18K322A with GM-CSF and IL-2 to the RR reported by Park et al. (JCO 29:4351, 2011), using identical CT with GCSF only, in a two-stage group sequential design. Semiquantitative MIBG scoring (Curie; CS) has been shown to be a prognostic indicator of outcome in pts with HR NB (Yanik et al, J Nucl Med, 2013), particularly, those with CS > 2 at end of induction (EoI) CT have inferior outcomes. Here we update the RR and report the CS at EoI CT. Methods: Pts received induction CT (6 cycles) as described by Park et al, with the addition of hu14.18K332A (on d 2-5; 40mg/m2/d x 4d), daily sc GM-CSF and sc IL-2 (1 x 106 IU/m2/dose) qod x 6. 123I-MIBG scans and scoring (CS) were obtained on all pts at diagnosis, after second course of CT and at EoI. Results: 42 evaluable pts completed the first two courses of CT (24 male, median age 2.9 yrs (range 6 m -15.2 yrs), 36 INSS 4, 19 MYCNamplified); 40/42 evaluable pts had measurable reductions in primary tumor volume after two courses of CT (median 79%, average 69%, range +5 – 100%). Responses (≥ PR) after two courses were seen in 32/42 (76.2%; 95% CI 61.3 – 87.9%); No mAb dose-reductions were made but 20/43 (47%) pts had infusion times extended. The development of human anti-human antibody reactivity (HAHA) to hu14.18K322A in the first 22 pts is minimal. Of the 36 INSS 4 pts, 1 withdrew prior to EoI and 2 are too early. The median CS at diagnosis for the 33 stage 4 pts who have completed induction CT was 18 (range 1 – 28). At EoI the median CS was 0 (range 0 -23); 29/33 INSS 4 pts had EoI CS ≤ 2. Conclusions: The addition of hu14.18K322A to two courses of CTX/TPT significantly improves the RR compared to two courses of CTX/TPT alone (32/42 vs 12/30 as reported by Park et al,; P = 0.000004). The improved median CS of the stage 4 patients from 18 at diagnosis to 0 at EoI suggest the improvement in early RR may translate into improved EFS as well. Clinical trial information: NCT01857934.

The Role of PET Scanning in the Evaluation of Patients With Kidney Disease.

Patients with underlying kidney disease are often required to undergo imaging for a variety of purposes including diagnosis and prognosis. A test that is being increasingly used with for this group of patients is the positron emission test (PET) scan. In addition, combining the nuclear medicine technique (PET) with computed tomography scan allows additional imaging advantages over either alone. These imaging modalities are commonly used for a number of extrarenal indications (ie, cancer, coronary artery disease, central nervous system disease, infectious diseases, and others). They have also been used for diagnosis of acute tubulointerstitial nephritis, evaluation and management of retroperitoneal fibrosis, identifying infection within kidney and liver cysts, and distinguishing complex kidney cysts from kidney cancer in patients with underlying CKD. We will review PET scan utility in patients with kidney disease.

68Ga-PSMA-11-PET entdeckt mehr Prostatakarzinom-Metastasen als 11Cholin-PET

Schwenck J, Rempp H. Comparison of 68Ga-labelled PSMA-11 and 11C-choline in the detection of prostate cancer metastases by PET/CT. Eur J Nucl Med Mol Imaging 2017; 44: 92–101

Computer-Assisted Diagnosis System for Breast Cancer in Computed Tomography Laser Mammography (CTLM).

Computed tomography laser mammography (Eid et al. Egyp J Radiol Nucl Med, 37(1): p. 633-643, 1) is a non-invasive imaging modality for breast cancer diagnosis, which is time-consuming and challenging for the radiologist to interpret the images. Some issues have increased the missed diagnosis of radiologists in visual manner assessment in CTLM images, such as technical reasons which are related to imaging quality and human error due to the structural complexity in appearance. The purpose of this study is to develop a computer-aided diagnosis framework to enhance the performance of radiologist in the interpretation of CTLM images. The proposed CAD system contains three main stages including segmentation of volume of interest (VOI), feature extraction and classification. A 3D Fuzzy segmentation technique has been implemented to extract the VOI. The shape and texture of angiogenesis in CTLM images are significant characteristics to differentiate malignancy or benign lesions. The 3D compactness features and 3D Grey Level Co-occurrence matrix (GLCM) have been extracted from VOIs. Multilayer perceptron neural network (MLPNN) pattern recognition has developed for classification of the normal and abnormal lesion in CTLM images. The performance of the proposed CAD system has been measured with different metrics including accuracy, sensitivity, and specificity and area under receiver operative characteristics (AROC), which are 95.2, 92.4, 98.1, and 0.98%, respectively.

Abstract B44: Optimization and IND enabling investigations of MVT-2163 (89Zr-DFO-5B1) leading to First-in-Human readiness

Abstract Rationale: MVT-2163 (89Zr-DFO-5B1) — an anti-CA19.9 human monoclonal antibody formed via conjugation of the chelator desferoxamine (DFO) and radiolabeling with zirconium-89 (89Zr) — was recently reported to have excellent ability to delineate CA19-9 positive malignancies via PET imaging, including pancreatic cancer.(1) Additionally, preclinical studies have shown the antibody has antitumor properties alone(2) and, more recently, in combination with frontline chemotherapies such as nab-Paclitaxel and gemcitabine. Herein, we report the preclinical optimization and characterization of MVT-2163 that led to the recent approval of an IND application for first-in-human trials in patients with metastatic pancreatic cancer. Methods: The conditions for appending the chelator DFO to MVT-5873 (5B1) were optimized by screening various combinations of reaction pH, stoichiometric ratios of chelate to antibody, buffer type, and incubation times. The optimized conjugation strategy was used to prepare clinical grade DFO-5B1 that was subsequently radiolabeled with 89Zr to yield MVT-2163 for use in human subjects. The biodistribution was determined in healthy female, athymic nude mice at 1, 24, 48, 72, and 120h via gamma counting of resected tissues and comparison to standards. The normal-organ radiation doses were estimated for the 70-kg Standard Adult anatomic model using the time-dependent organ activity concentrations and total-body activities, and the Standard Adult mean organ dose and effective dose were calculated using OLINDA. The stability of MVT-2163 in formulation buffer and in human serum at 37°C was assessed (24, 48, 96, 120, and 168h) via thin layer chromatography and size exclusion chromatography. Additionally, the remaining immunoreactive fraction was determined at the same time points using an in vitro cellular binding assay with BxPC3 cells. Results: We found that the optimal conjugation strategy was to buffer exchange MVT-5873 into 100mM sodium bicarbonate buffer (pH9) prior to letting the DFO react at 32.5°C for 90m. Unincorporated DFO was removed by buffer exchanging the reaction mixture into 1M ammonium acetate (pH7) buffer. The final MVT-7686 (DFO-5B1) product was stored in long term storage at -80°C. Biodistribution of the MVT-2163 indicated tissue retentions that were within expected norms for a 89Zr-labeled antibody. The highest uptake at 120h in terms of percent injected dose per gram of tissue (%ID/g) was found in the bone, which is common for osteophilic radiometals such as 89Zr. Dosimetry calculations based on the biodistribution results predicted a total absorbed dose of 8.1 rem when accounting for the proposed accompanying low-dose CT scan. The absorbed doses to all organs were within acceptable limits at the proposed human study dose (5 mCi), and the absorbed dose in red marrow — which is often the dose-limiting factor — was within ranges predicted and observed with other 89Zr-radiolabeled antibodies in humans. The radiochemical purity data indicate that the tracer remains intact in formulation buffer up to 120 hours. Cell binding assays performed with multiple lots of the same material showed that the immunoreactivity remains above 75% when stored up to 120h at room temperature, indicating exemplary stability. The stability and immunoreactivity were slightly lower when incubated in human serum at 37°C. However, the data shows that the immunoreactivity is maintained in human serum for more than up to 168h. Conclusions: The stability studies in both formulation buffer and human serum indicate that MVT-2163 maintains sufficient radiochemical purity and immunoreactivity. The results of the reported studies support the proposed specifications and the excellent performance has resulted in MVT-2163 being accepted for first in human trials at MSKCC, which are set to begin in Q2 2016. 1. Viola-Villegas NT, et al. J Nucl Med. 2013;54(11):1876-82. 2. Sawada R, et al. Clin Cancer Res. 2011;17(5):1024-32. Citation Format: Jacob L. Houghton, Serge K. Lyashchenko, Ritsuko Sawada, Pat Zanzonico, Scott Rudge, Wolfgang W. Scholz, Paul Maffuid, Jason S. Lewis.{Authors}. Optimization and IND enabling investigations of MVT-2163 (89Zr-DFO-5B1) leading to First-in-Human readiness. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B44.

Positron Emission Tomography (PET) Guided Therapy of Aggressive Lymphomas - Interim PET-Based Outcome Prediction and Treatment Changes in Patients with B Cell Lymphomas Participating in the PETAL Trial

Introduction: The PETAL trial is a multicenter randomized controlled study for patients with aggressive lymphomas of diverse histologies (EudraCT 2006-001641-33, NCT00554164). In the study population as a whole interim PET (iPET) reliably predicted time to treatment failure (TTTF) and overall survival (OS). Interim PET-based treatment changes, however, had no impact on outcome (ASH 2014, abstract 391). Here we report the exploratory analysis for aggressive B cell lymphomas.Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) followed by iPET. The conditions of iPET were strictly defined: 3-week interval between the 2nd R-CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve reproducibility (favorable iPET response: reduction of maximum SUV by > 66 % compared to baseline; J Nucl Med 48:1626, 2007). Pts. with CD20+ lymphomas and a favorable iPET were randomized to receive 4 more cycles of R-CHOP or the same treatment plus 2 extra doses of R (part A of the trial). Pts. with an unfavorable iPET were randomized to continue R-CHOP for 6 additional cycles or receive 6 blocks of a more complex methotrexate-, cytarabine- and etoposide-based regimen originally designed for Burkitt lymphoma (Blood 124: 3870, 2014; part B). R was omitted in pts. with CD20- lymphomas. Sample size of the entire study population was based on the empirically derived assumption that treatment failure after 2 yrs. (TF: progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 80 % to 90 % in part A and from 30 % to 45 % in part B (alpha=0.05, power=0.8). Secondary endpoints included OS and toxicity.Results: Fifty-seven oncological centers and 23 nuclear medicine institutions participated in the trial. Between 2007 and 2012 1072 pts. were registered, and 862 (80.4 %) had a positive baseline PET, received 2 cycles R-CHOP, underwent iPET and were allocated to one of the post-iPET treatment arms detailed above. Reference pathology was available in 98 %, and median follow-up is 52 months. All in all, there were 779 patients with CD20+ aggressive B-cell lymphomas (90.4 % of all treated pts.) of whom 606 had diffuse large B-cell lymphoma (DLBCL), 42 primary mediastinal B-cell lymphoma (PMBCL) and 42 follicular lymphoma grade 3 (FL3). Interim PET was favorable in 691 pts. (88.7 %) and unfavorable in 88 pts. with CD20+ lymphomas (11.3 %). It was highly predictive of TTTF for CD20+ lymphomas in general and for each of the DLBCL, PMBCL and FL3 subgroups (Table). In CD20+ lymphomas and DLBCL, the iPET response predicted TF independently of the International Prognostic Index, and it was also predictive of OS. The groups of PMBCL and FL3 were too small for multivariate analyses.In part A, adding 2 extra doses of R failed to improve TTTF and OS in all histological entities. Separate analyses for subgroups defined by sex, age (< vs. > 60 yrs.) or a combination of the two showed no statistically significant benefit of extra doses of R in any of the subgroups. In pts. with an unfavorable iPET response, a switch from R-CHOP to the Burkitt regimen failed to improve TTTF or OS in CD20+ lymphomas in general (Figure) and in the DLBCL, PMBCL and FL3 subgroups. In part B, the Burkitt protocol was associated with more grade 3/4 leukopenia (82 % vs. 57 %, p=0.02), thrombocytopenia (59 % vs. 18 %, p=0.0001), infection (41 % vs. 16 %, p=0.017) and mucositis (39 % vs. 7 %, p=0.0007) than R-CHOP, but treatment-related mortality was similar in both arms (1 death each).Conclusion: In this large multicenter trial iPET proved highly predictive of outcome in pts. with CD20+ aggressive B-cell lymphomas, DLBCL, PMBCL or FL3 treated with R-CHOP. In pts. with a favorable iPET response, addition of 2 extra doses of R to 6 cycles R-CHOP failed to improve outcome in CD20+ lymphomas in general and in subgroups defined by histology, sex or age. In pts. with an unfavorable iPET response, switching to a more aggressive protocol also failed to improve outcome in any of the entities. Novel strategies are required for aggressive B-cell lymphomas failing to respond to the first 2 cycles of R-CHOP. [Display omitted] [Display omitted] DisclosuresDuehrsen:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Giagounidis:Celgene Corporation: Consultancy. Grube:BMS, Sanofi: Consultancy. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding. Hüttmann:Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria; Gilead, Amgen: Other: Travel cost.

Positron Emission Tomography (PET) Guided Therapy of Aggressive Lymphomas - Interim PET-Based Outcome Prediction and Treatment Changes in Patients with T Cell Lymphomas Participating in the PETAL Trial

Introduction: The PETAL trial is a multicenter randomized controlled study for patients with aggressive lymphomas of diverse histologies (EudraCT 2006-001641-33, NCT00554164). In the study population as a whole interim PET (iPET) reliably predicted time to treatment failure (TTTF) and overall survival (OS). Interim PET-based treatment changes, however, had no impact on outcome (ASH 2014, abstract 391). Here we report the exploratory analysis for peripheral T cell lymphomas (PTCL).Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) followed by iPET. R was omitted in pts. with CD20-negative lymphomas. The conditions of iPET were strictly defined: 3-week interval between the 2nd (R-)CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve reproducibility (favorable iPET response: reduction of maximum SUV by > 66 % compared to baseline; J Nucl Med 48:1626, 2007). PTCL pts. with CD20-negative lymphomas and a favorable iPET uniformly received 4 additional cycles of CHOP (part A of the trial). Pts. with an unfavorable iPET were randomized to continue CHOP for 6 additional cycles or receive 6 blocks of a more complex methotrexate-, cytarabine- and etoposide-based regimen originally designed for Burkitt lymphoma (Blood 124: 3870, 2014; part B). Sample size of the entire study population was based on the empirically derived assumption that treatment failure after 2 yrs. (progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 30 % to 45 % in part B (alpha=0.05, power=0.8). Secondary endpoints included OS and toxicity.Results: Fifty-seven oncological centers and 23 nuclear medicine institutions participated in the trial. Between 2007 and 2012 1072 pts. were registered, and 862 (80.4 %) had a positive baseline PET, received 2 cycles (R-)CHOP, underwent iPET and were allocated to one of the post-iPET treatment arms detailed above. Reference pathology was available in 98 %, and median follow-up is 52 months. All in all, there were 76 pts. (8.8 % of all treated pts.) with T-cell lymphomas of whom 21 had ALK+ anaplastic large cell lymphoma (ALCL), 13 ALK- ALCL, 18 angioimmunoblastic T-cell lymphoma (AITL) and 20 PTCL not otherwise specified (NOS). Interim PET was favorable in 57 pts. (75 %) and unfavorable in 19 pts. with T-cell lymphomas (25 %). It was highly predictive of outcome, TTTF and OS being significantly higher in part A than B (2-year probability for TTTF: 63 % vs. 21 %; univariate hazard ratio (HR) for B 3.4, 95 % confidence interval (CI) 1.8 - 6.4, p<0.0001; OS: 79 % vs. 25 %; univariate hazard ratio (HR) for B 5.0, 95 % CI 2.4 - 10.3, p<0.0001; Figure). Interestingly, the proportion of T-cell lymphoma pts. with an unfavorable iPET response was more than twice as high as the corresponding proportion of B-cell lymphoma pts., and the difference in survival between pts. with a favorable vs. unfavorable iPET response was more pronounced in T-cell lymphomas than in B-cell lymphomas.TTTF (2-year probability: 81 % vs. 46 % vs. 49 % vs. 35 %; p=0.0110) and OS (90 % vs. 69 % vs. 52 % vs. 50 %; p=0.0026) were better in ALK+ ALCL than in ALK- ALCL, AITL or PTCL NOS. In pts. with an unfavorable iPET response, a switch from CHOP to the alternative regimen failed to improve TTTF or OS. The latter was associated with more frequent grade 3/4 neutropenia (40 % vs. 0 % vs. 11 %, p=0.0279), thrombocytopenia (70 % vs. 33 % vs. 23 %; p=0.0106), infection (60 % vs. 44 % vs. 18 %, p=0.0057) and mucositis (40 % vs. 33 % vs. 4 %, p=0.0025) as compared to 6 or 4 post-iPET cycles of CHOP, respectively, but treatment-related mortality was similar in all treatment arms (2 vs. 1 vs. 2 deaths).Conclusion: In this large multicenter trial iPET proved highly predictive of outcome in PTCL. A favorable iPET was found in 75 % of pts., and this was associated with long-term survival in about 70 %. In pts. with an unfavorable iPET response, outcome was dismal and could not be improved by switching to a more aggressive regimen. Novel strategies are required for PTCL pts. failing to respond to the first 2 cycles of CHOP. [Display omitted] DisclosuresHüttmann:Gilead, Amgen: Other: Travel cost; Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria. Giagounidis:Celgene Corporation: Consultancy. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding. Duehrsen:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding.

A Rare Case of PET Scan Positive Amyloidosis in Sjögren Syndrome

SESSION TITLE: Fellow Case Report Poster - Procedures SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 25, 2016 at 01:30 PM - 02:30 PM INTRODUCTION: Sjogren syndrome(SS), is a chronic inflammatory disorder characterized by lymphocytic infiltration of exocrine glands. Pulmonary amyloidosis secondary to Sjogren Syndrome is rare with a paucity of data on its clinical and radiological manifestations. CASE PRESENTATION: A 65 year old female with past medical history of COPD and Sjogren’s syndrome was found to have 1.6 cm right lower lobe and 1.4 cm left upper lobe irregular nodules as an incidental CT scan finding after a traumatic injury to her chest.Her review of systems was significant for dry mouth and non productive cough. A PET scan obtained as a follow up showed moderate FDG uptake with SUV of 4.0 and 2.3 respectively. Due to intermediate risks with a history of smoking and family history of breast cancer , tissue specimen via transbronchial biopsy were obtained to rule out cancer . Histology showed amorphous tissue material that stained positive for Congo red consistent with diagnosis of amyloidosis. She subsequently opted to have the right lower lobe nodule resected via a VATS procedure that conformed the diagnosis of amyloidosis. DISCUSSION: Sjogren syndrome is an autoimmune disease associated with a multitude of pulmonary lympho proliferative disorders. The extracellular deposition of its insoluble amyloid proteins can present with an interstitial and nodular pattern. The most common manifestation is the bilateral pulmonary nodules.The nodules have a peripheral lower lobe distribution and tend to have no FDG activity on PET scan . The transthoracic resection is the recommended approach for diagnosis, however advanced bronchoscopic techniques including electromagnetic navigation bronchoscopy could be utilized to biopsy and diagnose the condition. Bleeding remains a significant risk secondary to pulmonary vascular involvement. We report a rare case of bilateral pulmonary nodules in a patient with Sjogren syndrome that had significant FDG uptake and was diagnosed as amyloidosis. CONCLUSIONS: Amyloidosis should be considered in the differential diagnosis of bilateral pulmonary nodule in patients with Sjogren’s syndrome. Tissue samples sould be obtained from nodules with increased FDG activity or intermediate risks to rule out active malignancy Reference #1: FDG PET Scanning in Pulmonary Amyloidosis; Baqir et al ; J Nucl Med 2014; 55:565-568 Reference #2: Pulmonary amyloidosis in Sjogren Syndrome: A case report and systemic review of the literature; Rajagopala et al; Respirology 2010; 15:860-868 DISCLOSURE: The following authors have nothing to disclose: Hammad Arshad, Meilin Young, Rajashekar Adurty No Product/Research Disclosure Information

An overview of PET/MR, focused on clinical applications.

Hybrid PET/MR scanners are innovative imaging devices that simultaneously or sequentially acquire and fuse anatomical and functional data from magnetic resonance (MR) with metabolic information from positron emission tomography (PET) (Delso et al. in J Nucl Med 52:1914-1922, 2011; Zaidi et al. in Phys Med Biol 56:3091-3106, 2011). Hybrid PET/MR scanners have the potential to greatly impact not only on medical research but also, and more importantly, on patient management. Although their clinical applications are still under investigation, the increased worldwide availability of PET/MR scanners, and the growing published literature are important determinants in their rising utilization for primarily clinical applications. In this manuscript, we provide a summary of the physical features of PET/MR, including its limitations, which are most relevant to clinical PET/MR implementation and to interpretation. Thereafter, we discuss the most important current and emergent clinical applications of such hybrid technology in the abdomen and pelvis, both in the field of oncologic and non-oncologic imaging, and we provide, when possible, a comparison with clinically consolidated imaging techniques, like for example PET/CT.

Abstract 4208: Development of 18F-IL2: a PET radiotracer for imaging activated T-cells

Abstract Introduction: Activation of T-cells is accompanied by a strong up-regulation of interleukin-2 (IL2) receptor (CD25). Therefore PET imaging of IL2 receptors might be a suitable imaging biomarker for T-cell activation. 18F-IL2 PET could detect CD25-positive T-cells and the migration of these T-cells to distant sites of inflammation in SCID mice subcutaneously injected with human peripheral blood mononuclear cells1 and NOD mice with insulitis. Also a strong correlation was found between the accumulation of 18F-IL2 and the number of injected activated T-cells in immune-competent rats.2 In tumor bearing mice, 18F-IL2 PET could detect treatment-induced accumulation of activated T-cells in the tumor following local radiotherapy and/or vaccination. Cancer immunotherapy is increasingly obtaining a place in clinical practice. However not all patients benefit. A biomarker for upfront or early response prediction for these immunotherapies might support patient selection before and during therapy. Potentially 18F-IL2 PET might serve this purpose. Therefore we aimed to accommodate the production of 18F-IL2 for use in clinical imaging studies. Material and methods: In order to produce a GMP-compliant tracer the production is being implemented on the Eckert &amp; Ziegler PharmTracer synthesis module. In this synthesis module, disposable cassettes, reactors and vials are used to avoid cross-contamination between productions. First the prosthetic group N-succinimidyl 4-fluorobenzoate (18F-SFB) is produced in 3 steps from cyclotron-produced 18F-fluoride. Subsequently, 18F-SFB is conjugated to human recombinant IL2 (Proleukin®). Various methods for synthesis and purification of 18F-SFB have been evaluated. Also purification of 18F-IL2 has been optimized. Quality control has been performed using ultra performance liquid chromatography (UPLC) and Thin Layer Chromatography (TLC). Results: 18F-SFB was successfully synthesized with the Eckert &amp; Ziegler PharmTracer synthesis module with decay-corrected radiochemical yields comparable to literature (range 28-64%). Major challenges have been encountered, most importantly regarding the purification of the 18F-SFB and 18F-IL2, stability of the IL2 and specific activity. The activated ester 18F-SFB was purified by high performance liquid chromatography (HPLC) to remove any impurities that could interfere with the conjugation. 18F-IL2 has been purified using PD-10 columns with PBS containing 0.05% SDS as mobile phase. Conclusions: Several challenges for the GMP-compliant production of 18F-IL2 have been overcome. In the near future this tracer will be used in preclinical and clinical studies to non-invasively image activated T-cells before and during cancer immunotherapy. This can provide insight in the effects of cancer immunotherapy on the immune response.

What Imaging for Cerebral Complications of Infective Endocarditis?

Infective endocarditis (IE) is a serious condition with in-hospital mortality rates of 15-20% and one-year mortality approaching 40%. [ [1] Murdoch D.R. et al. Clinical Presentation, Etiology and Outcome of Infective Endocarditis in the 21st Century: The International Collaboration on Endocarditis-Prospective Cohort Study. Archives of Internal Medicine. 2009; 169.5 (PMC. Web. 23 Aug. 2015): 463-473 Crossref Scopus (1482) Google Scholar ] Early diagnosis and treatment reduces the incidence of septic embolism and mortality. [ [2] Erba P.A. Conti U. Lazzeri E. et al. Added value of 99mTc-HMPAO–labeled leukocyte SPECT/CT in the characterization and management of patients with infectious endocarditis. J Nucl Med. 2012; 53: 1235-1243 Crossref PubMed Scopus (147) Google Scholar ] We reviewed cerebral imaging studies performed for IE and the rate of clinical findings over a 10-year period to determine if there was a significant difference in complications found when using MR over CT. Cerebral imaging requests and reports at our institution from 2003-2013 were searched for IE related complications. Clinical cerebral complications were identified in 62 of the 161 patients scanned (38.5%). Using CT or CTA cerebral complications were found in 42 of 132 patients (31.8%), and 36 of 61 patients (59%) using MRI or MRA. Over a 10-year period, cerebral MR imaging identified significantly more complications of IE than CT (63.5% v 39.6%, p<0.01), with a greater proportion of infarcts being discovered (75% v 46%). Early detection of asymptomatic cerebrovascular complications through the use of systematic cerebral MR in suspected IE cases may be the prompt for more aggressive surgical management.

Efficacy of cabozantinib (C) vs everolimus (E) in patients (pts) with advanced renal cell carcinoma (RCC) and bone metastases (mets) from the phase III METEOR study.

4558Background: In pts with metastatic RCC, bone mets are prognostic for poor outcomes and represent an unmet medical need. The Phase 3 METEOR trial (NCT01865747) assessed the efficacy and safety of C vs E in pts with RCC and ≥1 prior VEGFR TKI. The trial met its primary endpoint of improving progression-free survival (PFS; HR 0.58, 95% CI 0.45–0.75; P<0.001) (Choueiri NEJM 2015). As C has shown clinical activity in bone mets in prostate cancer pts (Smith JCO 33 2015 abs 139), we evaluated clinical outcomes in RCC pts with bone mets in METEOR. Methods: 658 pts were randomized (stratified by MSKCC risk group and number of prior VEGFR TKIs) 1:1 to receive C (60 mg qd) or E (10 mg qd). Clinical outcome measures included PFS, ORR, overall survival (OS), and safety. Exploratory endpoints included bone scan response (BSR) in pts with bone scan lesions at baseline (Brown Nucl Med Commun 2012 33:384), incidence of skeletal-related events (SRE), and changes in bone turnover markers. Results: 142 pts had bone mets ...

A New Proposal for Management of Severe Frostbite in the Austere Environment

Despite advances in outdoor clothing and medical management of frostbite, individuals still experience catastrophic amputations. This is a particular risk for those in austere environments, due to resource limitations and delayed definitive treatment. The emerging best therapies for severe frostbite are thrombolytics and iloprost. However, they must be started within 24 hours after rewarming for recombinant tissue plasminogen activator (rt-PA) and within 48 hours for iloprost. Evacuation of individuals experiencing frostbite from remote environments within 24 to 48 hours is often impossible. To date, use of these agents has been confined to hospitals, thus depriving most individuals in the austere environment of the best treatment. We propose that thrombolytics and iloprost be considered for field treatment to maximize chances for recovery and reduce amputations. Given the small but potentially serious risk of complications, rt-PA should only be used for grade 4 frostbite where amputation is inevitable, and within 24 hours of rewarming. Prostacyclin has less risk and can be used for grades 2 to 4 frostbite within 48 hours of rewarming. Until more field experience is reported with these agents, their use should probably be restricted to experienced physicians. Other modalities, such as local nerve blocks and improving oxygenation at high altitude may also be considered. We submit that it remains possible to improve frostbite outcomes despite delayed evacuation using resource-limited treatment strategies. We present 2 cases of frostbite treated with rt-PA at K2 basecamp to illustrate feasibility and important considerations.

Abstract P3-14-07: Intra-cellular dsRNA receptor RIG-I: A ubiquitous novel target for treatment of chemotherapy drug resistant breast cancer

Abstract INTRODUCTION: Toll-like receptor 3 (TLR3), the cell surface receptor for double stranded RNA (dsRNA), expressed in ∼40% of advanced primary breast cancers (T2/T3/N+) has been shown to be an effective therapeutic target for synthetic dsRNA poly A:U in combination with radiation and adjuvant chemotherapy, producing a significant decrease in risk of metastatic relapse (HR 1.85-2.0; 1.03-3.89; Cancer Res;71:1607). AIM: The present pre-clinical study aimed to explore the therapeutic potential of a ubiquitously expressed intracellular dsRNA receptor, retinoic-acid-inducible gene-I (RIG-I) - a cytoplasmic pathogen recognition receptor directed at pathogen-associated molecular pattern (PAMP) motifs to differentiate viral from cellular dsRNAs. We have shown Ampligen, poly I:C12U (a synthetic dsRNA polymer designed to rapidly degrade in vivo to prevent the toxicity of long dsRNA polymers such as poly I:C) is capable of entering cells in its fragmented dsRNA oligomeric form (&amp;lt;1–2 kb) optimal for activation of intra-cellular RIG-I (J Exp Med 2008;205:1601–1610). METHODOLOGY &amp; RESULTS: Preliminary experiments with Ampligen on several human breast cancer cell lines (MCF-7 &amp; MDA-MB 453) and normal human mammary epithelial &amp; fibroblast cell lines (HMEC &amp; HFC) unexpectedly showed it to consistently cause a significant loss of cell viability (CellTiter-Glo Luminescent Cell Viability Assay) in p53-deficient drug resistant (5-FU/doxorubicin) MDA-MB 453 cell line in contrast to cell growth arrest (Guava cell Cycle Assay) in p53 wild type MCF-7 cancer and the two non-neoplastic cells lines. This selective effect was confirmed using syngeneic clones of MCF-7 breast cancer cells stably transfected with a dominant negative p53 construct or vector alone: p53-function blocked (DD1) vs p53-function active (EV1) MCF-7 cell lines, respectively (J Nucl Med 2006; 47:1525–1530), and shown to be associated with RIG-I specific mRNA induction (RT-PCR) and Type I interferon pathway activation both inhibited by BX795 (selective inhibitor of IRF3 activation and IFN-b production). Decitabine (DNA demethylating drug capable of intra-cellular generation of dsRNA through transcriptional activation of Alu retrotransposons - PNAS 2012; December 10: E89–E98 ) was next tested as an alternative source of intra-cellular dsRNA, and found to produce results similar to Ampligen on DD1 and EV1. Work is in progress to examine dose response and time-course relationships of the effects Ampligen or decitabine added singly or in combination with chemotherapeutic drug (e.g. doxorubicin) on DD1 and triple negative breast cancer cell lines such as MDA-MB 453 to explore potential therapeutically most effective protocols. PROVISIONAL CONCLUSIONS: Intra-cellular dsRNA receptor RIG-I constitutively expressed in all cells offers a more ubiquitous target compared to TLR3 for the treatment of breast cancer. Ampligen and decitabine with their selective growth inhibitory effect on drug resistant p53-deficient breast cancer cell lines, merit testing as novel drugs for treatment of p53-deficient drug resistant breast cancer e.g. triple negative breast cancer frequently (∼70%) associated with drug resistance and altered p53 status. Citation Format: Jasani B, Navabi N, Barrett-Lee P, Thompson A, Chester J, Mason M. Intra-cellular dsRNA receptor RIG-I: A ubiquitous novel target for treatment of chemotherapy drug resistant breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-07.

First intravesical α-radioimmunotherapy of human urothelial carcinoma in men as a new therapy for carcinoma in situ after BCG failure.

427 Background: Failure to respond to BCG in patients with carcinoma in situ (CIS) of the urinary bladder is problematic, since those tumours often have the potential to progress to muscle invasion. radical cystectomy remains the mainstay after BCG failure.Because treatment of mice bearing intravesical human bladder cancer xenografts with Bi-213-anti-EGFR-MAb turned out highly efficient (Pfost B et al. 2009, J of Nucl Med 50:1700-1708), the aim of this pilot study was to evaluate tolerability and safety of the α-emitter radioimmunoconjugate in patients after BCG failure. Methods: The alpha-emitter Bi-213 was eluted from a generator system provided by the Institute for Transuranium Elements (European Commission, JRC, Karlsruhe, Germany) and coupled to the anti-EGFR-mAb (Cetuximab, Merck, Germany) via the chelating agent CHX-A”-DTPA. 7 patients suffering from carcinoma in situ of the bladder who had histologically proven residual tumor after BCG induction therapy were included. After emptying the bladder an activity between 9,9 mCi and 22,2 mCi in 40 ml NaCl of Bi-213-anti-EGFR-mAb via a transurethral catheter was instilled. Distribution of Bi-213-anti-EGFR-mAb was monitored by SPECT/CT. Treatment was terminated by emptying of the radioimmunoconjugate from the bladder 120 min after injection. Efficacy was evaluated via endoscopy and histology six weeks after instillation. Results: All patients showed excellent toleration of the treatment without any side effects. SPECT/CT monitoring clearly revealed location of the Bi-213-anti-EGFR-MAb immunoconjugate only in the bladder without extravasation. Treatment resulted in complete eradication of tumor cells in 3 patients and persistent tumor detection in the other 4 patients. Conclusions: Intravesical instillation of Bi-213-anti-EGFR-mAb is a promising therapeutic option for treatment of in situ bladder cancerafterBCG failure for patients who wish to preserve the bladder.