Immune-Mediated Control of a Dormant Neurotropic RNA Virus Infection.

Genomic material from many neurotropic RNA viruses (e.g., measles virus [MV], West Nile virus [WNV], Sindbis virus [SV], rabies virus [RV], and influenza A virus [IAV]) remains detectable in the mouse brain parenchyma long after resolution of the acute infection. The presence of these RNAs in the absence of overt central nervous system (CNS) disease has led to the suggestion that they are viral remnants, with little or no potential to reactivate. Here we show that MV RNA remains detectable in permissive mouse neurons long after challenge with MV and, moreover, that immunosuppression can cause RNA and protein synthesis to rebound, triggering neuropathogenesis months after acute viral control. Robust recrudescence of viral transcription and protein synthesis occurs after experimental depletion of cells of the adaptive immune response and is associated with a loss of T resident memory (Trm) lymphocytes within the brain. The disease associated with loss of immune control is distinct from that seen during the acute infection: immune cell-depleted, long-term-infected mice display severe gait and motor problems, in contrast to the wasting and lethal disease that occur during acute infection of immunodeficient hosts. These results illuminate the potential consequences of noncytolytic, immune-mediated viral control in the CNS and demonstrate that what were once considered "resolved" RNA viral infections may, in fact, induce diseases later in life that are distinct from those caused by acute infection.IMPORTANCE Viral infections of neurons are often not cytopathic; thus, once-infected neurons survive, and viral RNAs can be detected long after apparent viral control. These RNAs are generally considered viral fossils, unlikely to contribute to central nervous system (CNS) disease. Using a mouse model of measles virus (MV) neuronal infection, we show that MV RNA is maintained in the CNS of infected mice long after acute control and in the absence of overt disease. Viral replication is suppressed by the adaptive immune response; when these immune cells are depleted, viral protein synthesis recurs, inducing a CNS disease that is distinct from that observed during acute infection. The studies presented here provide the basis for understanding how persistent RNA infections in the CNS are controlled by the host immune response, as well as the pathogenic consequences of noncytolytic viral control.

Tissue and Bronchoalveolar Lavage Biomarkers in Idiopathic Pulmonary Fibrosis Patients on Pirfenidone.

BACKGROUND: Pirfenidone is a novel anti-fibrotic agent in idiopathic pulmonary fibrosis with proven clinical benefit. Better human tissue models to demonstrate the immunomodulatory and anti-fibrotic effect of pirfenidone are required. OBJECTIVES: The purpose of the study was to use transbronchial lung cryobiopsy (TBLC), a novel technique which provides substantial tissue samples, and a large panel of biomarkers to temporally assess disease activity and response to pirfenidone therapy. METHODS: Thirteen patients with confirmed idiopathic pulmonary fibrosis (IPF) underwent full physiological and radiological assessment at diagnosis and after 6-month pirfenidone therapy. They underwent assessment for a wide range of potential serum and bronchoalveolar lavage biomarkers of disease activity. Finally, they underwent TBLC before and after treatment. Tissue samples were assessed for numbers of fibroblast foci, for Ki-67, a marker of tissue proliferation and caspase-3, a marker of tissue apoptosis. RESULTS: All patients completed treatment and investigations without significant incident. There was no significant fall in number of fibroblast foci per unit tissue volume after treatment (pre-treatment: 0.14/mm2 vs. post-treatment 0.08/mm2, p = 0.1). Likewise, there was no significant change in other markers of tissue proliferation, Ki-67 or Caspase-3 with pirfenidone treatment. We found an increase in three bronchoalveolar lavage angiogenesis cytokines, Placental Growth Factor, Vascular Endothelial Growth Factor-A, and basic Fibroblast Growth Factor, two anti-inflammatory cytokines Interleukin-10 and Interleukin-4 and Surfactant Protein-D. CONCLUSIONS: TBLC offers a unique opportunity to potentially assess the course of disease activity and response to novel anti-fibrotic activity in IPF.

Humour production may enhance observational learning of a new tool-use action in 18-month-old infants.

Many studies have shown that making children laugh enhances certain cognitive capacities such as attention, motivation, perception and/or memory, which in turn enhance learning. However, no study thus far has investigated whether laughing has an effect on learning earlier in infancy. The goal of this study was to see whether using humour with young infants in a demonstration of a complex tool-use task can enhance their learning. Fifty-three 18-month-old infants participated in this study and were included either in a humorous or a control demonstration group. In both groups infants observed an adult using a tool to retrieve an out-of-reach toy. What differed between groups was that in the humorous demonstration group, instead of playing with the toy, the adult threw it on the floor immediately after retrieval. The results show that infants who laughed at the demonstration in the humorous demonstration group reproduced significantly more frequent target actions than infants who did not laugh and those in the control group. This effect is discussed with regard to individual differences in terms of temperament and social capacities as well as positive emotion and dopamine release.

Reduction of guide needle streak artifact in CT-guided biopsy.

PURPOSE: Computed tomography (CT)-guided core needle biopsy (CNB) can be affected by streak artifact obscuring the needle tip. This study investigates factors that influence the occurrence and severity of streak artifact during CNB. MATERIALS AND METHODS: Eight coaxial guide needles of two sizes from two manufacturers with and without stylets were imaged in a CT phantom, with CT reconstructed with adaptive statistical iterative reconstruction and filtered back projection. CNB-related streak artifact was quantified with profile analysis in an image-processing program. Differences between maximum attenuation at the needle tip and minimum attenuation in the streak artifact were compared for each variable. Diagnostic acceptability and streak artifact were subjectively assessed on each phantom image and on 40 clinical CNB procedures by three independent blinded reviewers following training case review. RESULTS: Artifact was significantly less with the central stylet removed versus in situ (median, 1,145 HU vs 3,390 HU; P < .001) for all needles, and less for 19-gauge needles versus 17-gauge needles (median, 1,334 HU vs 2,780 HU, respectively; P = .006). There were no differences based on manufacturer (P = .906) or reconstruction algorithm (P = .524). Independent reviews found that streak artifact was significantly reduced when the central stylet was removed (κ = 0.875-1.0; P < .001), and needle tip position was better in cases in which the stylet was removed (κ = 0.231-0.711; P < .001). CONCLUSIONS: Streak artifact can be reduced and needle tip visualization improved by confirming final biopsy needle position with the central stylet removed on CT and using smaller-gauge guide needles.

CNS recruitment of CD8+ T lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge.

Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with both CNS-restricted measles virus (MV) and peripherally restricted lymphocytic choriomeningitis virus (LCMV). While infection with either virus alone resulted in no illness, infection with both viruses caused disease in all mice, with ∼50% dying following seizures. Co-infection resulted in a 12-fold increase in the number of CD8+ T cells in the brain as compared to MV infection alone. Tetramer analysis revealed that a substantial proportion (>35%) of these infiltrating CD8+ lymphocytes were LCMV-specific, despite no detectable LCMV in CNS tissues. Mechanistically, CNS disease was due to edema, induced in a CD8-dependent but perforin-independent manner, and brain herniation, similar to that observed in mice challenged intracerebrally with LCMV. These results indicate that T cell trafficking can be influenced by other ongoing immune challenges, and that CD8+ T cell recruitment to the brain can trigger CNS disease in the apparent absence of cognate antigen. By extrapolation, human CNS diseases of unknown etiology need not be associated with infection with any particular agent; rather, a condition that compromises and activates the blood-brain barrier and adjacent brain parenchyma can render the CNS susceptible to pathogen-independent immune attack.

Positron emission tomography/computed tomography imaging in Merkel cell carcinoma: a study of 270 scans in 97 patients at the Dana-Farber/Brigham and Women's Cancer Center.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and lethal cutaneous neuroendocrine carcinoma. Imaging is crucial for accurate staging, which remains a strong predictor of survival, as well as earlier detection of recurrence and progression, which are common despite aggressive management. There is no consensus on the role of initial and subsequent imaging for MCC. OBJECTIVE: We sought to evaluate the use of 2-fluoro-[(18)F]-deoxy-2-D-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in the management of MCC. METHODS: In all, 270 FDG-PET/CT studies were performed in 97 patients with pathology-proven MCC at the Dana-Farber/Brigham and Women's Cancer Center, Boston, Mass, from August 2003 to December 2010. RESULTS: FDG-PET/CT scans were obtained as part of the initial (61 scans in 61 patients) and subsequent (209 scans in 79 patients) treatment strategies. MCCs were FDG-avid with a mean maximum standardized uptake value of primary lesions of 6.5 (range 1.3-12.9) and a mean maximum standardized uptake value of regional and distant metastases of 7.2 (range 1.5-9.9). FDG-PET/CT upstaged 16% of patients who underwent baseline scans. FDG-PET/CT studies showed that bone and bone-marrow metastases were more common than previously reported, and were often undetected by CT. LIMITATIONS: Our study is limited by its retrospective design, and potential referral bias associated with a tertiary care center. CONCLUSIONS: FDG-PET/CT performed as part of the initial management strategy tended to upstage patients with more advanced disease. FDG-PET/CT performed as part of the subsequent treatment strategy identified metastatic disease, particularly in bone/bone marrow, which was not seen on CT. FDG-PET/CT imaging is a valuable staging and restaging tool in MCC management.

PET/CT and renal pathology: a blind spot for radiologists? Part 1, primary pathology.

OBJECTIVE: PET/CT with (18)F-FDG shows metabolically active disease and is widely used for the diagnosis and follow-up of patients with cancer. Nonmetabolically active renal pathology may be missed without close attention to the CT portion of the study, whereas metabolically active pathology may be missed on PET because of physiologic tracer excretion in the kidneys. This article illustrates primary lesions of the kidney on FDG PET/CT with emphasis on key anatomic features and the appearance of tracer uptake. CONCLUSION: Close attention to both the FDG PET and CT portions of the study is essential to interpret renal pathology correctly on FDG PET/CT examinations.

PET/CT and renal pathology: a blind spot for radiologists? Part 2--lymphoma, leukemia, and metastatic disease.

OBJECTIVE: PET/CT with (18)F-FDG is a powerful tool to evaluate patients with hematologic malignancy or to assess the burden of metastatic disease from solid tumors. Metabolically active renal pathology associated with lymphoma, leukemia, or metastatic disease can be missed without close attention to both the PET and CT portions of the study because of physiologic FDG excretion in the kidneys. This article illustrates the appearance of tracer uptake and the key anatomic features of lymphoma, leukemia, and metastatic disease involving the kidney on FDG PET/CT. CONCLUSION: Close attention to both the FDG PET and CT portions of an FDG PET/CT study is essential to evaluate the kidneys in oncology patients.

Extraskeletal osteosarcoma: spectrum of imaging findings.

OBJECTIVE: The purpose of this article is to present the spectrum of imaging findings of primary and metastatic extraskeletal osteosarcoma and highlight the differences from primary osteogenic osteosarcoma in bone. CONCLUSION: Extraskeletal osteosarcoma is a rare mesenchymal malignancy of soft tissue, histologically indistinguishable from primary osteosarcoma of bone. However, there are distinct differences in demographics, imaging features, prognosis, and management compared with osteogenic osteosarcoma. Imaging characteristics reflect tumor morphology, with only 50% of primary tumors showing mineralization. Metastases may or may not show mineralization, even if present in the primary tumor. The overall prognosis is poor.

Personalized tumor response assessment in the era of molecular medicine: cancer-specific and therapy-specific response criteria to complement pitfalls of RECIST.

OBJECTIVE: The purpose of this article is to review cancer- and therapy-specific tumor response assessment criteria used in clinical trials and in practice, with illustrative case examples, and to discuss future directions toward "personalized" tumor response assessment. CONCLUSION: Although Response Evaluation Criteria in Solid Tumors will remain as the primary generalized criteria for response assessment, newer cancer- and therapy-specific criteria will play an important role in providing state-of-the-art response assessment of tumor following molecular targeted therapy and will contribute to personalized cancer care in the era of molecular medicine.

Decade of molecular targeted therapy: abdominal manifestations of drug toxicities--what radiologists should know.

OBJECTIVE: Novel drugs targeting molecular pathways involved in tumor development have revolutionized cancer treatment. Radiologists often focus on therapeutic response when evaluating cancer patients and may miss important signs of drug toxicity. This article familiarizes radiologists with the complications of molecular targeted agents in abdominal solid organs, enabling early identification and appropriate intervention and thus reducing patient morbidity and mortality. CONCLUSION: Knowledge of the common abdominal toxicities--including hepatitis, cholecystitis, pancreatitis, fluid retention, and infection--is crucial for early diagnosis, which may spare patients devastating complications or the need for surgery.

Uterine sarcomas: then and now.

OBJECTIVE: The purpose of this article is to provide an updated review of uterine sarcomas. The traditionally described neoplasms are reviewed as well as several recently characterized entities in terms of their imaging and clinical aspects. We attempt to provide a longitudinal imaging overview, from initial presentation to follow-up. Imaging features are also described of response to traditional therapeutic agents and newer targeted agents. CONCLUSION: A greater understanding of the pathogenesis has improved our ability to image and treat uterine sarcomas, both at initial staging and on follow-up. Targeted therapy is assuming an increasingly important role in the management of these lesions. It is imperative for radiologists to be aware of response characteristics and potential complications of these agents as well as conventional chemotherapeutic agents.

Selection of symptomatic patients with Crohn's disease for abdominopelvic computed tomography: role of serum C-reactive protein.

BACKGROUND: Results of previous studies have shown that repeated abdominopelvic computed tomography (CT) examinations can lead to substantial cumulative diagnostic radiation exposure in patients with Crohn's disease (CD). Improved selection of patients referred for CT will reduce unnecessary radiation exposure. This study examines if serum C-reactive protein (CRP) concentration predicts which symptomatic patients with CD are likely to have significant disease activity or disease complications (such as abscess) detected on abdominopelvic CT. METHODS: All abdominopelvic CTs performed on patients with CD at a tertiary referral centre during the period June 2003 to June 2008 were identified. CT findings were coded by a pair of independent blinded senior radiologists for (i) small bowel luminal disease, (ii) large bowel luminal disease, (iii) mesenteric inflammatory changes, (iv) penetrating disease (fistulas, abscess, or phlegmon), (v) acute disease complications (obstruction or perforation), and (vi) acute non-CD findings. Imaging findings were correlated with serum CRP checked within 14 days before imaging. The reference range for CRP was defined as 0-5 mg/L. RESULTS: A total of 147 patients with symptomatic CD had a CRP assay performed within 14 days before undergoing abdominopelvic CT. The median time from CRP assay to imaging was 2 days (interquartile range, 0-6 days). Median CRP before imaging was 24 mg/L (interquartile range, 6-88 mg/L). CT was normal in 34 of 147 case (23.1%). Patients with normal CRP (n = 36) were significantly less likely to have penetrating disease (odds ratio [OR], 0.04 [95% confidence interval {CI}, 0.01-0.7]; P < .001) or large bowel luminal disease (OR, 0.3 [95% CI, 0.1-0.8]; P < .05). Normal CRP excluded penetrating disease with a sensitivity of 1.0 (95% CI, 0.87-1.0). CRP levels did not correlate with the presence of small bowel luminal disease (n = 82), mesenteric inflammatory changes (n = 68), or acute disease complications (n = 10). CONCLUSION: Symptomatic patients with CD and normal serum CRP are unlikely to have evidence of abscess, fistulating disease, or large bowel luminal disease detected on abdominopelvic CT. However, abdominopelvic CT may demonstrate evidence of clinically significant non-penetrating CD or complications, including perforation and acute obstruction, regardless of serum CRP concentration.

Lymphocytic choriomeningitis virus-induced mortality in mice is triggered by edema and brain herniation.

Although much is known about lymphocytic choriomeningitis virus (LCMV) infection and the subsequent immune response in its natural murine host, some crucial aspects of LCMV-mediated pathogenesis remain undefined, including the underlying basis of the characteristic central nervous system disease that occurs following intracerebral (i.c.) challenge. We show that the classic seizures and paresis that occur following i.c. infection of adult, immunocompetent mice with LCMV are accompanied by anatomical and histological changes that are consistent with brain herniation, likely of the uncal subtype, as a causative basis for disease and precipitous death. Both by water weight determinations and by magnetic resonance imaging of infected brain tissues, edema was detected only at the terminal stages of disease, likely caused by the leakage of cerebrospinal fluid from the ventricles into the parenchyma. Furthermore, death was accompanied by unilateral pupillary dilation, which is indicative of uncal herniation. While immunohistochemical analysis revealed periventricular inflammation and a loss of integrity of the blood-brain barrier (BBB), these events preceded seizures by 2 to 3 days. Moreover, surviving perforin knockout mice showed barrier permeability equivalent to that of moribund, immunocompetent mice; thus, BBB damage does not appear to be the basis of LCMV-induced neuropathogenesis. Importantly, brain herniation can occur in humans as a consequence of injuries that would be predicted to increase intracranial pressure, including inflammation, head trauma, and brain tumors. Thus, a mechanistic dissection of the basis of LCMV neuropathogenesis may be informative for the development of interventive therapies to prevent this typically fatal human condition.

Unexpected late radiation neurotoxicity following bevacizumab use: a case series.

The purpose of this case series is to report the unexpected occurrence of four cases of late radiation-induced neurotoxicity with bevacizumab use following radiotherapy to the CNS. We retrospectively reviewed the case records of four patients, three with glioblastoma and one with bone metastases secondary to metastatic breast cancer, who were treated with radiotherapy and developed late radiation-induced neurotoxicity following bevacizumab use. Three cases of optic neuropathy in glioblastoma patients and a single case of Brown-Séquard syndrome in the thoracic spine of a patient with metastatic breast cancer are reported. We hypothesize that bevacizumab use following radiotherapy to the CNS may inhibit vascular endothelial growth factor-dependent repair of normal neural tissue, and thus may increase the risk of late radiation neurotoxicity. Phase III data on the safety and efficacy of bevacizumab use with radiation in the setting of glioblastoma is awaited.

The role of 18F-FDG PET/CT imaging in Waldenstrom macroglobulinemia.

Disease assessment in WM is dependent on the quantification of the IgM monoclonal protein and percent involvement of the bone marrow. There is a need for imaging studies that objectively measure tumor load in these patients. In this study, we sought to examine the role of combined FDG-PET/CT imaging in the detection of tumor load and in the assessment of response to therapy. Thirty-five patients were enrolled on a prospective study using bortezomib and rituximab therapy and were included in this study because they completed a pre- and post-treatment FDG-PET/CT imaging at one facility (12 newly diagnosed and 23 relapsed/refractory). The use of combined FDG-PET/CT imaging showed positive findings in 83% of patients with WM, unlike prior studies using conventional imaging that indicate that only 20% of patients have lymphadenopathy or hepatosplenomegaly. Moreover, 43% of patients had abnormal bone marrow uptake on FDG-PET imaging that can potentially help in the assessment of their tumor load, especially with heterogenous sampling of the bone marrow. There was no statistical correlation between EORTC response criteria for FDG-PET/CT and response by monoclonal protein. This is the first study to examine the role of FDG-PET/CT imaging in WM. Future studies should examine the role of FDG-PET/CT in conjunction with monoclonal protein response in the assessment of progression-free survival in patients with WM.

Radiologic aspects of immune-related tumor response criteria and patterns of immune-related adverse events in patients undergoing ipilimumab therapy.

OBJECTIVE: The objective of this article is to illustrate examples of radiologic immune-related response criteria and toxicity in patients with advanced melanoma treated with the immunotherapeutic agent ipilimumab. CONCLUSION: Novel immune-related tumor response criteria should be applied to patients undergoing therapy with ipilimumab for advanced melanoma. Ipilimumab also produces a spectrum of immune-related adverse effects that can be recognized radiologically.

Extrapulmonary small cell carcinoma: a pictorial review.

OBJECTIVE: Extrapulmonary small cell carcinoma (EPSCC) is a rare, aggressive neoplasm arising from virtually any organ. Numerous oncologic studies have addressed prognostic indicators and survival rates in EPSCC, however relatively little has been published regarding the imaging features and metastatic patterns of these uncommon tumors. This article provides a pictorial review of EPSCC in multiple organs, emphasizing the imaging appearance at presentation and the radiologic patterns of recurrence/metastasis. CONCLUSION: Although the appearance of EPSCC is often nonspecific, the typical presentation is large aggressive tumors that, similar to small cell carcinoma in the lung, often respond well to local therapy but tend to recur relentlessly at distant sites.

Imaging of radiation-associated sarcoma.

OBJECTIVE: The objective of this article is to show the imaging features of radiation-associated sarcoma arising after radiation therapy using multiple imaging modalities. CONCLUSION: A multimodality imaging strategy and collaboration between multidisciplinary teams are important for the management of radiation-associated sarcoma. Because radiation-associated sarcoma often displays locally aggressive behavior and may metastasize, resulting in a poor prognosis, it is important to consider this diagnosis in any patient previously treated with radiation therapy and to recognize the imaging findings.

Imaging of liposarcoma: classification, patterns of tumor recurrence, and response to treatment.

OBJECTIVE: The purpose of this study was to illustrate the subtypes of liposarcoma (LPS) and the significance of the nonlipomatous tumor components using multiple imaging modalities. CONCLUSION: The subtypes of LPS with greater nonlipomatous soft-tissue components on imaging studies tend to show less differentiation and are usually more aggressive both histologically and clinically. Imaging plays an important role in the diagnosis, surveillance, and response assessment of LPS.