On May 3, 2008, a National Cancer Institute (NCI)-sponsored open consensus conference was held in Toronto, Ontario, Canada, during the 2008 International Society for Magnetic Resonance in Medicine Meeting. Approximately 100 experts and stakeholders summarized the current understanding of diffusion-weighted magnetic resonance imaging (DW-MRI) and reached consensus on the use of DW-MRI as a cancer imaging biomarker. DW-MRI should be tested as an imaging biomarker in the context of well-defined clinical trials, by adding DW-MRI to existing NCI-sponsored trials, particularly those with tissue sampling or survival indicators. Where possible, DW-MRI measurements should be compared with histologic indices including cellularity and tissue response. There is a need for tissue equivalent diffusivity phantoms; meanwhile, simple fluid-filled phantoms should be used. Monoexponential assessments of apparent diffusion coefficient values should use two b values (>100 and between 500 and 1000 mm2/sec depending on the application). Free breathing with multiple acquisitions is superior to complex gating techniques. Baseline patient reproducibility studies should be part of study designs. Both region of interest and histogram analysis of apparent diffusion coefficient measurements should be obtained. Standards for measurement, analysis, and display are needed. Annotated data from validation studies (along with outcome measures) should be made publicly available. Magnetic resonance imaging vendors should be engaged in this process. The NCI should establish a task force of experts (physicists, radiologists, and oncologists) to plan, organize technical aspects, and conduct pilot trials. The American College of Radiology Imaging Network infrastructure may be suitable for these purposes. There is an extraordinary opportunity for DW-MRI to evolve into a clinically valuable imaging tool, potentially important for drug development.

To retrospectively evaluate the distribution of fluorine 18 fluorodeoxyglucose (FDG) in the head and neck region with combined positron emission tomography-computed tomography (PET/CT) in patients with no known abnormality in this region. The institutional review board allowed a retrospective review of PET/CT images obtained in 78 patients with non-head and neck cancer and waived the requirement for informed consent. The accumulation of FDG in 11 normal head and neck structures was visually and quantitatively assessed retrospectively. Positive rate percentage (PRP) was defined as the sum of the percentages of patients with grade 2 and grade 3 tracer uptake intensity. Standardized uptake values (SUVs) were calculated for quantitative analysis. Mean SUVs were compared between the male and female patients by using the unpaired t test, and the correlation between FDG uptake and patient age was assessed by using the Pearson correlation coefficient test. Intense tracer uptake was usually seen in the palatine tonsils (PRP, 98%; mean SUV, 3.48), soft palate (PRP, 96%; mean SUV, 3.13), and lingual tonsils (PRP, 96%; mean SUV, 3.11). In the inferior concha (PRP, 4%; mean SUV, 1.56), thyroid gland (PRP, 3%; mean SUV, 1.31), and tongue (PRP, 1%; mean SUV, 1.39), uptake was typically minimal. FDG accumulation was variable in the sublingual glands (PRP, 72%; mean SUV, 2.93), spinal cord (PRP, 64%; mean SUV, 2.12), submandibular glands (PRP, 53%; mean SUV, 2.11), parotid glands (PRP, 51%; mean SUV, 1.90), and vocal cords (PRP, 19%; mean SUV, 1.77). The mean normal-tissue SUV in the soft palate was higher in male than in female patients (P <.01). A negative correlation between age and physiologic FDG uptake was seen in the palatine tonsils (r=-0.51, P <.001) and sublingual glands (r=-0.70, P <.001). Intense FDG uptake was usually observed in the palatine tonsils, lingual tonsils, and soft palate, whereas uptake in the major salivary glands was variable.

Definitive clinical trials of new chemotherapies for treating tuberculosis (TB) require following subjects until at least 6 months after treatment discontinuation to assess for durable cure, making these trials expensive and lengthy. Surrogate endpoints relating to treatment failure and relapse are currently limited to sputum microbiology, which has limited sensitivity and specificity. We prospectively assessed radiographic changes using 2-deoxy-2-[¹⁸F]-fluoro-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) at 2 and 6 months (CT only) in a cohort of subjects with multidrug-resistant TB, who were treated with second-line TB therapy for 2 years and then followed for an additional 6 months. CT scans were read semiquantitatively by radiologists and were computationally evaluated using custom software to provide volumetric assessment of TB-associated abnormalities. CT scans at 6 months (but not 2 months) assessed by radiologist readers were predictive of outcomes, and changes in computed abnormal volumes were predictive of drug response at both time points. Quantitative changes in FDG uptake 2 months after starting treatment were associated with long-term outcomes. In this cohort, some radiologic markers were more sensitive than conventional sputum microbiology in distinguishing successful from unsuccessful treatment. These results support the potential of imaging scans as possible surrogate endpoints in clinical trials of new TB drug regimens. Larger cohorts confirming these results are needed.

Molecular imaging could fulfill unmet clinical needs for diagnosing and monitoring bacterial infections, if translational barriers are addressed.

The fungus Cryptococcus is a major cause of meningoencephalitis in HIV-infected as well as HIV-uninfected individuals with mortalities in developed countries of 20% and 30%, respectively. In HIV-related disease, defects in T-cell immunity are paramount, whereas there is little understanding of mechanisms of susceptibility in non-HIV related disease, especially that occurring in previously healthy adults. The present description is the first detailed immunological study of non-HIV-infected patients including those with severe central nervous system (s-CNS) disease to 1) identify mechanisms of susceptibility as well as 2) understand mechanisms underlying severe disease. Despite the expectation that, as in HIV, T-cell immunity would be deficient in such patients, cerebrospinal fluid (CSF) immunophenotyping, T-cell activation studies, soluble cytokine mapping and tissue cellular phenotyping demonstrated that patients with s-CNS disease had effective microbiological control, but displayed strong intrathecal expansion and activation of cells of both the innate and adaptive immunity including HLA-DR+ CD4+ and CD8+ cells and NK cells. These expanded CSF T cells were enriched for cryptococcal-antigen specific CD4+ cells and expressed high levels of IFN-γ as well as a lack of elevated CSF levels of typical T-cell specific Th2 cytokines -- IL-4 and IL-13. This inflammatory response was accompanied by elevated levels of CSF NFL, a marker of axonal damage, consistent with ongoing neurological damage. However, while tissue macrophage recruitment to the site of infection was intact, polarization studies of brain biopsy and autopsy specimens demonstrated an M2 macrophage polarization and poor phagocytosis of fungal cells. These studies thus expand the paradigm for cryptococcal disease susceptibility to include a prominent role for macrophage activation defects and suggest a spectrum of disease whereby severe neurological disease is characterized by immune-mediated host cell damage. Cryptococcus is an important cause of fungal meningitis with significant mortality globally. Susceptibility to the fungus in humans has been related to T-lymphocyte defects in HIV-infected individuals, but little is known about possible immune defects in non HIV-infected patients including previously healthy individuals. This latter group also has some of the worst response rates to therapy with almost a third dying in the United States, despite available therapy. Here we conducted the first detailed immunological analysis of non-HIV apparently immunocompetent individuals with active cryptococcal disease. In contrast to HIV-infected individuals, these studies identified a highly activated antigen-presenting dendritic cell population within CSF, accompanied by a highly active T-lymphocyte population with potentially damaging inflammatory cytokine responses. Furthermore, elevated levels of CSF neurofilament light chains (NFL), a marker of axonal damage in severe central nervous system infections suggest a dysfunctional role to this acute inflammatory state. Paradoxically, CSF macrophage proportions were reduced in patients with severe disease and biopsy and autopsy samples identified alternatively activated tissue macrophage populations that failed to appropriately phagocytose fungal cells. Our study thus provides new insights into the susceptibility to human cryptococcal disease and identifies a paradoxically active T-lymphocyte response that may be amenable to adjunctive immunomodulation to improve treatment outcomes in this high-mortality disease.