Perspectives on joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards for [18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors.

Response assessment in the context of immunomodulatory treatments represents a major challenge for the medical imaging community and requires a multidisciplinary approach with involvement of oncologists, radiologists, and nuclear medicine specialists. There is evolving evidence that [18F]FDG PET/CT is a useful diagnostic modality for this purpose. The clinical indications for, and the principal aspects of its standardization in this context have been detailed in the recently published "Joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards on recommended use of [18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors version 1.0". These recommendations arose from a fruitful collaboration between international nuclear medicine societies and experts in cancer treatment. In this perspective, the key elements of the initiative are reported, summarizing the core aspects of the guidelines for radiologists and nuclear medicine physicians. Beyond the previous guidelines, this perspective adds further commentary on how this technology can advance development of novel therapeutic approaches and guide management of individual patients.

Joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards on recommended use of [18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors version 1.0.

PURPOSE: The goal of this guideline/procedure standard is to assist nuclear medicine physicians, other nuclear medicine professionals, oncologists or other medical specialists for recommended use of [18F]FDG PET/CT in oncological patients undergoing immunotherapy, with special focus on response assessment in solid tumors. METHODS: In a cooperative effort between the EANM, the SNMMI and the ANZSNM, clinical indications, recommended imaging procedures and reporting standards have been agreed upon and summarized in this joint guideline/procedure standard. CONCLUSIONS: The field of immuno-oncology is rapidly evolving, and this guideline/procedure standard should not be seen as definitive, but rather as a guidance document standardizing the use and interpretation of [18F]FDG PET/CT during immunotherapy. Local variations to this guideline should be taken into consideration. PREAMBLE: The European Association of Nuclear Medicine (EANM) is a professional non-profit medical association founded in 1985 to facilitate worldwide communication among individuals pursuing clinical and academic excellence in nuclear medicine. The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote science, technology and practical application of nuclear medicine. The Australian and New Zealand Society of Nuclear Medicine (ANZSNM), founded in 1969, represents the major professional society fostering the technical and professional development of nuclear medicine practice across Australia and New Zealand. It promotes excellence in the nuclear medicine profession through education, research and a commitment to the highest professional standards. EANM, SNMMI and ANZSNM members are physicians, technologists, physicists and scientists specialized in the research and clinical practice of nuclear medicine. All three societies will periodically put forth new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and improve service to patients. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. Each standard/guideline, representing a policy statement by the EANM/SNMMI/ANZSNM, has undergone a thorough consensus process, entailing extensive review. These societies recognize that the safe and effective use of diagnostic nuclear medicine imaging requires particular training and skills, as described in each document. These standards/guidelines are educational tools designed to assist practitioners in providing appropriate and effective nuclear medicine care for patients. These guidelines are consensus documents based on current knowledge. They are not intended to be inflexible rules or requirements of practice, nor should they be used to establish a legal standard of care. For these reasons and those set forth below, the EANM, SNMMI and ANZSNM caution against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals considering the unique circumstances of each case. Thus, there is no implication that an action differing from what is laid out in the guidelines/procedure standards, standing alone, is below standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources or advances in knowledge or technology subsequent to publication of the guidelines/procedure standards. The practice of medicine involves not only the science, but also the art of dealing with the prevention, diagnosis, alleviation and treatment of disease. The variety and complexity of human conditions make it impossible for general guidelines to consistently allow for an accurate diagnosis to be reached or a particular treatment response to be predicted. Therefore, it should be recognized that adherence to these standards/ guidelines will not ensure a successful outcome. All that should be expected is that practitioners follow a reasonable course of action, based on their level of training, current knowledge, clinical practice guidelines, available resources and the needs/context of the patient being treated. The sole purpose of these guidelines is to assist practitioners in achieving this objective. The present guideline/procedure standard was developed collaboratively by the EANM, the SNMMI and the ANZSNM, with the support of international experts in the field. They summarize also the views of the Oncology and Theranostics and the Inflammation and Infection Committees of the EANM, as well as the procedure standards committee of the SNMMI, and reflect recommendations for which the EANM and SNMMI cannot be held responsible. The recommendations should be taken into the context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions.

Diagnostic value of [18F]FDG-PET/CT for treatment monitoring in large vessel vasculitis: a systematic review and meta-analysis.

PURPOSE: Monitoring disease activity in patients with large vessel vasculitis (LVV) can be challenging. [18F]FDG-PET/CT is increasingly used to evaluate treatment response in LVV. In this systematic review and meta-analysis, we aimed to summarize the current evidence on the value of [18F]FDG-PET/CT for treatment monitoring in LVV. METHODS: PubMed/MEDLINE and the Cochrane library database were searched from inception through October 21, 2020. Studies containing patients with LVV (i.e. giant cell arteritis, Takayasu arteritis and isolated aortitis) that received treatment and underwent [18F]FDG-PET/CT were included. Screening, full-text review and data extraction were performed by 2 investigators. The risk of bias was examined with the QUADAS-2 tool. Meta-analysis of proportions and diagnostic test accuracy was performed by a random-effects model and bivariate model, respectively. RESULTS: Twenty-one studies were included in the systematic review, of which 8 studies were eligible for meta-analysis. Arterial [18F]FDG uptake decreased upon clinical remission in longitudinal studies. High heterogeneity (I2 statistic 94%) precluded meta-analysis of the proportion of patients in which the scan normalized during clinical remission. Meta-analysis of cross-sectional studies indicated that [18F]FDG-PET/CT may detect relapsing/refractory disease with a sensitivity of 77% (95%CI 57-90%) and specificity of 71% (95%CI 47-87%). Substantial heterogeneity was observed among the cross-sectional studies. Both variation in clinical aspects and imaging procedures contributed to the heterogeneity. CONCLUSION: Treatment of LVV leads to reduction of arterial [18F]FDG uptake during clinical remission. [18F]FDG-PET/CT has moderate diagnostic accuracy for detecting active LVV. [18F]FDG-PET/CT may aid treatment monitoring in LVV, but its findings should be interpreted in the context of the clinical suspicion of disease activity. This study underlines the relevance of published procedural recommendations for the use of [18F]FDG-PET/CT in LVV.

Prognostic superiority of International Prognostic Index over [18F]FDG PET/CT volumetric parameters in post-transplant lymphoproliferative disorder.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLDs) are a spectrum of hematological malignancies occurring after solid organ and hematopoietic stem cell transplantation. [18F]FDG PET/CT is routinely performed at PTLD diagnosis, allowing for both staging of the disease and quantification of volumetric parameters, such as whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG). In this retrospective study, we aimed to determine the prognostic value of MTV and TLG in PTLD patients, together with other variables of interest, such as the International Prognostic Index (IPI), organ transplant type, EBV tumor status, time after transplant, albumin levels and PTLD morphology. RESULTS: A total of 88 patients were included. The 1-, 3-, 5- year overall survival rates were 67%, 58% and 43% respectively. Multivariable analysis indicated that a high IPI (HR: 1.56, 95% CI: 1.13-2.16) and an EBV-negative tumor (HR: 2.71, 95% CI: 1.38-5.32) were associated with poor overall survival. Patients with a kidney transplant had a longer overall survival than any other organ recipients (HR: 0.38 95% CI: 0.16-0.89). IPI was found to be the best predicting parameter of overall survival in our cohort. Whole-body MTV, TLG, time after transplant, hypoalbuminemia and PTLD morphology were not associated with overall survival. CONCLUSION: [18F]FDG PET/CT whole-body volumetric quantitative parameters were not predictive of overall survival in PTLD. In our cohort, high IPI and an EBV-negative tumor were found to predictors of worse overall survival while kidney transplant patients had a longer overall survival compared to other organ transplant recipients.

Semi-Quantitative Characterization of Post-Transplant Lymphoproliferative Disorder Morphological Subtypes with [18F]FDG PET/CT.

Background: Post-transplant lymphoproliferative disorder (PTLD) is a complication of organ transplantation classified according to the WHO as nondestructive, polymorphic, monomorphic, and classic Hodgkin Lymphoma subtypes. In this retrospective study, we investigated the potential of semi-quantitative 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) PET/computed tomography (CT)-based parameters to differentiate between the PTLD morphological subtypes. Methods: 96 patients with histopathologically confirmed PTLD and baseline [18F]FDG PET/CT between 2009 and 2019 were included. Extracted semi-quantitative measurements included: Maximum, peak, and mean standardized uptake value (SUVmax, SUVpeak, and SUVmean). Results: Median SUVs were highest for monomorphic PTLD followed by polymorphic and nondestructive subtypes. The median SUVpeak at the biopsy site was significantly higher in monomorphic PTLD (17.8, interquartile range (IQR):16) than in polymorphic subtypes (9.8, IQR:13.4) and nondestructive (4.1, IQR:6.1) (p = 0.04 and p ≤ 0.01, respectively). An SUVpeak ≥ 24.8 was always indicative of a monomorphic PTLD in our dataset. Nevertheless, there was a considerable overlap in SUV across the different morphologies. Conclusion: The median SUVpeak at the biopsy site was significantly higher in monomorphic PTLD than polymorphic and nondestructive subtypes. However, due to significant SUV overlap across the different subtypes, these values may only serve as an indication of PTLD morphology, and SUV-based parameters cannot replace histopathological classification.

The value of 18F-FDG PET/CT for the diagnosis of device-related infections in patients with a left ventricular assist device: a systematic review and meta-analysis.

BACKGROUND: Left ventricular assist devices (LVADs) are increasingly used for the treatment of advanced heart failure. LVADs improve quality of life and decrease mortality, but the driveline carries substantial risk for major infections. These device-related LVAD and driveline infections are difficult to diagnose with conventional imaging. We reviewed and analysed the current literature on the additive value of 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) imaging for the diagnosis of LVAD-related infections." MATERIALS/METHODS: We performed a systematic literature review using several databases from their inception until the 31st of December, 2019. Studies investigating the diagnostic performance of FDG-PET/CT in patients with suspected LVAD infection were retrieved. After a bias risk assessment using QUADAS-2, a study-aggregate meta-analysis was performed on a per examination-based analysis. RESULTS: A total of 10 studies were included in the systematic review, eight of which were also eligible for study-aggregate meta-analysis. For the meta-analysis, a total of 256 FDG-PET/CT scans, examining pump/pocket and/or driveline infection, were acquired in 230 patients. Pooled sensitivity of FDG-PET/CT was 0.95 (95% confidence interval (CI) 0.89-0.97) and pooled specificity was 0.91 (95% CI 0.54-0.99) for the diagnosis of device-related infection. For pump/pocket infection, sensitivity and specificity of FDG-PET/CT were 0.97 (95%CI 0.69-1.00) and 0.93 (95%CI 0.64-0.99), respectively. For driveline infection, sensitivity and specificity were 0.96 (95%CI 0.88-0.99) and 0.99 (95%CI 0.13-1.00) respectively. Significant heterogeneity existed across studies for specificity, mostly caused by differences in scan procedures. Predefined criteria for suspicion of LVAD and/or driveline infection were lacking in all included studies. CONCLUSIONS: FDG-PET/CT is a valuable tool for assessment of device-related infection in LVAD patients, with high sensitivity and high, albeit variable, specificity. Standardization of FDG-PET/CT procedures and criteria for suspected device-related LVAD infections are needed for consistent reporting of FDG-PET/CT scans.

The relation between cardiac 123I-mIBG scintigraphy and functional response 1 year after CRT implantation.

AIMS: Cardiac resynchronization therapy (CRT) is a disease-modifying therapy in patients with chronic heart failure (CHF). Current guidelines ascribe CRT eligibility on three parameters only: left ventricular ejection fraction (LVEF), QRS duration, and New York Heart Association (NYHA) functional class. However, one-third of CHF patients does not benefit from CRT. This study evaluated whether 123I-meta-iodobenzylguanidine (123I-mIBG) assessed cardiac sympathetic activity could optimize CRT patient selection. METHODS AND RESULTS: A total of 78 stable CHF subjects (age 66.8 ± 9.6 years, 73% male, LVEF 25.2 ± 6.7%, QRS duration 153 ± 23 ms, NYHA 2.2 ± 0.7) referred for CRT implantation were enrolled. Subjects underwent 123I-mIBG scintigraphy prior to implantation. Early and late heart-to-mediastinum (H/M) ratio and 123I-mIBG washout were calculated. CRT response was defined as either an increase of LVEF to >35%, any improvement in LVEF of >10%, QRS shortening to <150 ms, or improvement in NYHA class of >1 class. In 33 patients LVEF increased to >35%, QRS decreased <150 ms in 36 patients, and NYHA class decreased in 33 patients. Late H/M ratio and hypertension were independent predictors of LVEF improvement to >35% (P = 0.0014 and P = 0.0149, respectively). In addition, early H/M ratio, LVEF, and absence of diabetes mellitus (DM) were independent predictors for LVEF improvement by >10%. No independent predictors were found for QRS shortening to <150 ms or improvement in NYHA class. CONCLUSION: Early and late H/M ratio were independent predictors of CRT response when improvement of LVEF was used as measure of response. Therefore, cardiac 123I-mIBG scintigraphy may be used as a tool to optimize selection of subjects that might benefit from CRT.

Diagnostic value of [18F]FDG-PET/CT in polymyalgia rheumatica: a systematic review and meta-analysis.

PURPOSE: Polymyalgia rheumatica (PMR) can be difficult to diagnose. Whole-body [18F]FDG-PET/CT allows for a comprehensive evaluation of all relevant articular and extra-articular structures affected by PMR. We aimed to summarize current evidence on the diagnostic value of [18F]FDG-PET/CT for a diagnosis of PMR. METHODS: PubMed/MEDLINE and the Cochrane Library database were searched from inception through May 31, 2020. Studies containing patients with PMR who underwent [18F]FDG-PET/CT were included. Screening and full-text review were performed by 3 investigators and data extraction by 2 investigators. Risk of bias was examined with the QUADAS-2 tool. Diagnostic test meta-analysis was performed with a bivariate model. RESULTS: Twenty studies were included in the systematic review, of which 9 studies (n = 636 patients) were eligible for meta-analysis. [18F]FDG positivity at the following sites was associated with a diagnosis of PMR: interspinous bursae (positive likelihood ratio (LR+) 4.00; 95% CI 1.84-8.71), hips (LR+ 2.91; 95% CI 2.09-4.05), ischial tuberosities (LR+ 2.86; 95% CI 1.91-4.28), shoulders (LR+ 2.57; 95% CI 1.24-5.32) and sternoclavicular joints (LR+ 2.31; 95% CI 1.33-4.02). Negative likelihood ratios (LR-) for these sites, as well as the greater trochanters, were all less than 0.50. Composite [18F]FDG-PET/CT scores, as reported in 3 studies, provided a pooled LR+ of 3.91 (95% CI 2.42-6.32) and LR- of 0.19 (95% CI 0.10-0.36). Moderate to high heterogeneity was observed across the studies, mainly due to differences in patient selection, scanning procedures and/or interpretation criteria. CONCLUSION: Significant [18F]FDG uptake at a combination of anatomic sites is informative for a diagnosis of PMR. [18F]FDG-PET/CT might be an important diagnostic tool in patients with suspected PMR. This study also highlights the need for adherence to published procedural recommendations and standardized interpretation criteria for the use of [18F]FDG-PET/CT in PMR.

Analysis of partial volume correction on quantification and regional heterogeneity in cardiac PET.

BACKGROUND: The partial volume correction (PVC) of cardiac PET datasets using anatomical side information during reconstruction is appealing but not straightforward. Other techniques, which do not make use of additional anatomical information, could be equally effective in improving the reconstructed myocardial activity. METHODS: Resolution modeling in combination with different noise suppressing priors was evaluated as a means to perform PVC. Anatomical priors based on a high-resolution CT are compared to non-anatomical, edge-preserving priors (relative difference and total variation prior). The study is conducted on ex vivo datasets from ovine hearts. A simulation study additionally clarifies the relationship between prior effectiveness and myocardial wall thickness. RESULTS: Simple resolution modeling during data reconstruction resulted in over- and underestimation of activity, which hampers the absolute left ventricular quantification when compared to the ground truth. Both the edge-preserving and the anatomy-based PVC techniques improve the absolute quantification, with comparable results (Student t-test, P = .17). The relative tracer distribution was preserved with any reconstruction technique (repeated ANOVA, P = .98). CONCLUSIONS: The use of edge-preserving priors emerged as optimal choice for quantification of tracer uptake in the left ventricular wall of the available datasets. Anatomical priors visually outperformed edge-preserving priors when the thinnest structures were of interest.

Partial volume and motion correction in cardiac PET: First results from an in vs ex vivo comparison using animal datasets.

BACKGROUND: In a previous study on ex vivo, static cardiac datasets, we investigated the benefits of performing partial volume correction (PVC) in cardiac 18F-Fluorodeoxyglucose(FDG) PET datasets. In the present study, we extend the analysis to in vivo cardiac datasets, with the aim of defining which reconstruction technique maximizes quantitative accuracy and, ultimately, makes PET a better diagnostic tool for cardiac pathologies. METHODS: In vivo sheep datasets were acquired and reconstructed with/without motion correction and using several reconstruction algorithms (with/without resolution modeling, with/without non-anatomical priors). Corresponding ex vivo scans of the excised sheep hearts were performed on a small-animal PET scanner (Siemens Focus 220, microPET) to provide high-resolution reference data unaffected by respiratory and cardiac motion. A comparison between the in vivo cardiac reconstructions and the corresponding ex vivo ground truth was performed. RESULTS: The use of an edge-preserving prior (Total Variation (TV) prior in this work) in combination with motion correction reduces the bias in absolute quantification when compared to the standard clinical reconstructions (- 0.83 vs - 3.74 SUV units), when the end-systolic gate is considered. At end-diastole, motion correction improves absolute quantification but the PVC with priors does not improve the similarity to the ground truth more than a regular iterative reconstruction with motion correction and without priors. Relative quantification was not influenced much by the chosen reconstruction algorithm. CONCLUSIONS: The relative ranking of the algorithms suggests superiority of the PVC reconstructions with dual gating in terms of overall absolute quantification and noise properties. A well-tuned edge-preserving prior, such as TV, enhances the noise properties of the resulting images of the heart. The end-systolic gate yields the most accurate quantification of cardiac datasets.

Performance of advanced imaging modalities at diagnosis and treatment response evaluation of patients with post-transplant lymphoproliferative disorder: A systematic review and meta-analysis.

INTRODUCTION AND AIM: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ and hematopoietic stem cell transplantation, associated with significant morbidity and mortality. In this systematic review we evaluated the clinical performance of advanced imaging modalities at diagnosis and treatment response evaluation of PTLD patients after solid organ and hematopoietic stem cell transplantation. METHODS: We have carried out a literature search until December 15, 2017 using PubMed/Medline, Embase, "Web of Science" and Cochrane Library databases concerning the performance of computed tomography (CT), magnetic resonance imaging (MRI) and 18F-flurodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) at diagnosis or treatment response evaluation of PTLD patients. RESULTS: A total of 11 studies were included comprising 368 patients, from which FDG-PET(/CT) was the primary imaging modality investigated. The methodological quality according to QUADAS-2 of the reviewed studies was moderate-poor. Subgroup analysis of imaging results for detection and staging in patients with PTLD indicated that FDG-PET/(CT) identified additional lesions not detected by CT and/or MRI in 27.8%, (95% confidence interval [95%CI]) 17.0%-42.0% (I2 = 51.1%), from which extra-nodal sites in 23.6% (95%CI: 7.9%-52.4%) (I2 = 76.6%). False negative results occurred in 11.5% (95%CI: 4.9%-24.5%) (I2 = 73.4%), predominantly in physiological high background activity regions and in early PTLD lesions. False positive results occurred in 4.8% (95%CI: 2.6%-8.6%) (I2 = 0%) predominantly due to inflammatory conditions. Subgroup analysis of imaging results at treatment response evaluation indicated that FDG-PET(/CT) findings altered or guided treatment in 29.0% (95%CI: 14.0%-50.5%) (I2 = 40.1%). False positive results during treatment response evaluation were reported in 20.0% (95%CI: 10.7%-34.2%) (I2 = 0%), predominantly due to inflammatory conditions. CONCLUSION: FDG-PET(/CT) is currently the most frequently investigated imaging modality in PTLD patients. Available studies report promising results in detection, staging and therapy evaluation but suffer from methodological shortcomings. Concerns remain with regard to occurrence of false negatives due to physiological high background activity and early PTLD lesions as well as false positives due to inflammatory conditions.

Axillary staging for breast cancer during pregnancy: feasibility and safety of sentinel lymph node biopsy.

BACKGROUND: Safety of sentinel lymph node (SLN) biopsy for breast cancer during pregnancy is insufficiently explored. We investigated efficacy and local recurrence rate in a large series of pregnant patients. PATIENTS AND METHODS: Women diagnosed with breast cancer who underwent SLN biopsy during pregnancy were identified from the International Network on Cancer, Infertility and Pregnancy, the German Breast Group, and the Cancer and Pregnancy Registry. Chart review was performed to record technique and outcome of SLN biopsy, locoregional and distant recurrence, and survival. RESULTS: We identified 145 women with clinically N0 disease who underwent SLN during pregnancy. The SLN detection techniques were as follows: 99mTc-labeled albumin nanocolloid only (n = 96; 66.2%), blue dye only (n = 14; 9.7%), combined technique (n = 15; 10.3%), or unknown (n = 20; 13.8%). Mapping was unsuccessful in one patient (0.7%) and she underwent an axillary lymph node dissection (ALND). Mean number of SLNs was 3.2 (interquartile range 1-3; missing n = 15). Positive SLNs were found in 43 (29.7%) patients and 34 subsequently underwent ALND. After a median follow-up of 48 months (range 1-177), 123 (84.8%) patients were alive and free of disease. Eleven patients experienced a locoregional relapse, including 1 isolated ipsilateral axillary recurrence (0.7%). Eleven (7.6%) patients developed distant metastases, of whom 9 (6.2%) died of breast cancer. No neonatal adverse events related to SLN procedure during pregnancy were reported. CONCLUSIONS: SLN biopsy during pregnancy has a comparably low axillary recurrence rate as in nonpregnant women. Therefore, this method can be considered during pregnancy instead of standard ALND for early-stage, clinically node-negative breast cancer.

EBV-Positive and EBV-Negative Posttransplant Diffuse Large B Cell Lymphomas Have Distinct Genomic and Transcriptomic Features.

The molecular pathogenesis of posttransplant diffuse large B cell lymphoma (PT-DLBCL) is largely unknown. We have recently shown that Epstein-Barr virus-positive (EBV(+)) and -negative (EBV(-)) PT-DLBCL have distinct gene expression profiles, and the transcriptomic profile of EBV(-) PT-DLBCL is similar to that of DLBCL in immunocompetent individuals (IC-DLBCL). To validate these observations at the genomic level, we performed array-comparative genome hybridization (aCGH) analysis of 21 EBV(+) PT-DLBCL, 6 EBV(-) PT-DLBCL, and 11 control IC-DLBCL, and subsequently combined genomic and transcriptomic data. The analysis showed that EBV(+) and EBV(-) PT-DLBCL have distinct aCGH profiles and shared only one recurrent imbalance. EBV(-) PT-DLBCL, however, displayed at least 10 aberrations recurrent in IC-DLBCL, among which characteristic gain of 3/3q and 18q, and loss of 6q23/TNFAIP3 as well as 9p21/CDKN2A. The most prevalent aberration in EBV(+) PT-DLBCL was gain/amplification of 9p24.1 targeting PDCD1LG2/PDL2. Our data indicate that the FOXP1 oncogene and the tumor suppressor CDKNA2 implicated in EBV(-) DLBCL, do not play a critical role in the pathogenesis of EBV(+) PT-DLBCL. Altogether, genomic profiling of PT-/IC-DLBCL confirms that EBV(-) and EBV(+) PT-DLBCL are distinct entities, while EBV(-) PT-DLBCL has features in common with IC-DLBCL. These findings support the hypothesis that EBV(-) PT-DLBCL are de novo lymphomas in transplant recipients.

Mycobacterium genavense infection in a solid organ recipient: a diagnostic and therapeutic challenge.

Renal transplant recipients are highly susceptible to infections caused by uncommon pathogens because of their immunocompromised state. We report a case of disseminated Mycobacterium genavense infection in a patient with a combined renal and cardiac transplant. Diagnosing M. genavense infections remains a challenge because of the absence of specific clinical symptoms in combination with the difficulties of culturing the organism using standard mycobacterial culture procedures. This clinical case demonstrates the importance of molecular techniques as part of the initial work-up in order to rapidly establish the diagnosis.

Pirfenidone: a potential new therapy for restrictive allograft syndrome?

This case report describes the evolution of pulmonary function findings (FVC, FEV1 and TLC) and CT features with pirfenidone treatment for restrictive allograft syndrome following lung transplantation. Furthermore, we herein report hypermetabolic activity on (18) F-FDG PET imaging in this setting, which could indicate active fibroproliferation and pleuroparenchymal remodeling. These findings may warrant further investigation.

Indirect imaging of cardiac-specific transgene expression using a bidirectional two-step transcriptional amplification strategy.

Transcriptional targeting for cardiac gene therapy is limited by the relatively weak activity of most cardiac-specific promoters. We have developed a bidirectional plasmid vector, which uses a two-step transcriptional amplification (TSTA) strategy to enhance the expression of two optical reporter genes, firefly luciferase (fluc) and Renilla luciferase (hrluc), driven by the cardiac troponin T (cTnT) promoter. The vector was characterized in vitro and in living mice using luminometry and bioluminescence imaging to assess its ability to mediate strong, correlated reporter gene expression in a cardiac cell line and the myocardium, while minimizing expression in non-cardiac cell lines and the liver. In vitro, the TSTA system significantly enhanced cTnT-mediated reporter gene expression with moderate preservation of cardiac specificity. After intramyocardial and hydrodynamic tail vein delivery of an hrluc-enhanced variant of the vector, long-term fluc expression was observed in the heart, but not in the liver. In both the cardiac cell line and the myocardium, fluc expression correlated well with hrluc expression. These results show the vector's ability to effectively amplify and couple transgene expression in a cardiac-specific manner. Further replacement of either reporter gene with a therapeutic gene should allow non-invasive imaging of targeted gene therapy in living subjects.

Noninvasive molecular imaging of small living subjects using Raman spectroscopy.

Molecular imaging of living subjects continues to rapidly evolve with bioluminescence and fluorescence strategies, in particular being frequently used for small-animal models. This article presents noninvasive deep-tissue molecular images in a living subject with the use of Raman spectroscopy. We describe a strategy for small-animal optical imaging based on Raman spectroscopy and Raman nanoparticles. Surface-enhanced Raman scattering nanoparticles and single-wall carbon nanotubes were used to demonstrate whole-body Raman imaging, nanoparticle pharmacokinetics, multiplexing, and in vivo tumor targeting, using an imaging system adapted for small-animal Raman imaging. The imaging modality reported here holds significant potential as a strategy for biomedical imaging of living subjects.