Is local review of positron emission tomography scans sufficient in diffuse large B-cell lymphoma clinical trials? A CALGB 50303 analysis

BACKGROUND: Quantitative methods of Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) interpretation, including the percent change in FDG uptake from baseline (ΔSUV), are under investigation in lymphoma to overcome challenges associated with visual scoring systems (VSS) such as the Deauville 5-point scale (5-PS). METHODS: In CALGB 50303, patients with DLBCL received frontline R-CHOP or DA-EPOCH-R, and although there were no significant associations between interim PET responses assessed centrally after cycle 2 (iPET) using 5-PS with progression-free survival (PFS) or overall survival (OS), there were significant associations between central determinations of iPET ∆SUV with PFS/OS. In this patient cohort, we retrospectively compared local vs central iPET readings and evaluated associations between local imaging data and survival outcomes. RESULTS: Agreement between local and central review was moderate (kappa = 0.53) for VSS and high (kappa = 0.81) for ∆SUV categories (\u3c66% vs. ≥66%). ∆SUV ≥66% at iPET was significantly associated with PFS (p = 0.03) and OS (p = 0.002), but VSS was not. Associations with PFS/OS when applying local review vs central review were comparable. CONCLUSIONS: These data suggest that local PET interpretation for response determination may be acceptable in clinical trials. Our findings also highlight limitations of VSS and call for incorporation of more objective measures of response assessment in clinical trials

Minimal residual disease in Myeloma: Application for clinical care and new drug registration

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow–based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy–based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid–based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes

A new IAEA Technical Report Series Handbook on Radionuclide Transfer to Wildlife

The IAEA Technical Report Series (TRS) handbook on transfer of radionuclides to human foodstuffs from terrestrial and freshwater systems has recently been revised during the EMRAS I programme [1]. The document updates the previous handbook (TRS 364) and constitutes an important source of information for transfer parameters for the human foodchain. Quantification of the rates of transfer of radionuclides through foodchains to humans has long been a key focus of radiation protection. More recently, there has been a move away from radiation protection being solely anthropogenic to one which also considers protection of the environment as recognised by both the IAEA [2] and the ICRP [3] in their Fundamental Safety Principles and revised Recommendations, respectively, both of which now include the need to protect the environment. To address these recommendations and safety principles, the consequences of radiological releases need to be considered in part by estimating an internal dose. To do this, the transfer of radionuclides to wildlife of interest needs to be quantified. In response to the need for a reference source of information on radionuclide transfer to wildlife, the IAEA initiated the development of a TRS handbook, which has been supported by interaction with the EMRAS II Working Group 5, (http://www-ns.iaea.org/projects/emras/emras2/working-groups/working-group-five.asp). The TRS handbook has been finalised and is currently going through the IAEA approval process. The TRS handbook provides equilibrium concentration ratio values for wildlife groups in terrestrial, freshwater, marine and estuarine environments. Wildlife is considered to include all non-domesticated plants, animals and other organisms including feral species (i.e. non-native self-sustaining populations). The TRS handbook provides IAEA Member States with transfer data for use in the radiological assessment of wildlife as a consequence of planned and existing exposure situations [3]. As an equilibrium approach is presented, these data are not directly applicable to emergency situations

Developmental Expression of Adenosine Deaminase in the Upper Alimentary Tract of Mice

The distribution and localization of adenosine deaminase (ADA) was studied during postnatal development of the alimentary tract in mice. There was detectable enzyme activity in all organs examined, but a range of more than 10,000 fold in the relative levels of specific activity was observed among adult tissues. A comprehensive survey of multiple adult tissues revealed that the highest levels of ADA occur in the upper alimentary tract (tongue, esophagus, forestomach, proximal small intestine). Immunohistochemical analysis revealed that ADA was predominantly localized to the epithelial lining of the alimentary mucosa: the keratinized squamous epithelium that lines the forestomach, esophagus, and surface of the tongue; and the simple columnar epithelium of the proximal small intestine (duodenum, proximal jejunum). Biochemical analysis revealed that ADA was one of the most abundant proteins of these mucosal tissue layers, accounting for 5%–20% of the total soluble protein. Tissue-specific differences in ADA activity correlated both with levels of immunoreactive protein and RNA abundance. The level of ADA activity in the upper alimentary tissues was subject to pronounced developmental control, being low at birth and achieving very high levels within the first few weeks of postnatal life. The appearance in development of ADA-immunoreactivity coincided with maturation of the mucosal epithelium. These results suggest that ADA is subject to strong cell-specific developmental regulation during functional differentiation of certain foregut derivatives in mice

The Role of Minimal Residual Disease Testing in Myeloma Treatment Selection and Drug Development: Current Value and Future Applications

Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10(-5)\u201210(-6) cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents, while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions