Thomas Rodt

Pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for hereditary pulmonary alveolar proteinosis

Macrophage progenitors are an effective and long-lasting therapy of hereditary pulmonary alveolar proteinosis. Macrophages Treat Rare Lung Disease Innate immune cell transplant into the lung could be an effective treatment for a rare lung disease. Happle et al. report that transplanting macrophage progenitors into lungs of a mouse model of hereditary pulmonary alveolar proteinosis (herPAP) improved lung function for up to 9 months after transplant. herPAP is caused by mutations in the granulocyte-macrophage colony-stimulating factor receptor genes, resulting in disturbed alveolar macrophage differentiation and life-threatening respiratory problems. A single transplantation of macrophage progenitors into a mouse model of herPAP resulted in differentiation into functional alveolar macrophages. If these data hold true in humans, this could not only provide a new treatment modality for herPAP but also serve as a proof of principle for other genetic diseases. Hereditary pulmonary alveolar proteinosis (herPAP) is a rare lung disease caused by mutations in the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor genes, resulting in disturbed alveolar macrophage differentiation, massive alveolar proteinosis, and life-threatening respiratory insufficiency. So far, the only effective treatment for herPAP is repetitive whole-lung lavage, a merely symptomatic and highly invasive procedure. We introduce pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for herPAP. In a murine disease model, intrapulmonary transplanted macrophage progenitors displayed selective, long-term pulmonary engraftment and differentiation into functional alveolar macrophages. A single transplantation ameliorated the herPAP phenotype for at least 9 months, resulting in significantly reduced alveolar proteinosis, normalized lung densities in chest computed tomography, and improved lung function. A significant and sustained disease resolution was also observed in a second, humanized herPAP model after intrapulmonary transplantation of human macrophage progenitors. The therapeutic effect was mediated by long-lived, lung-resident macrophages, which displayed functional and phenotypical characteristics of primary human alveolar macrophages. Our findings present the concept of organotopic transplantation of macrophage progenitors as an effective and long-lasting therapy of herPAP and may also serve as a proof of principle for other diseases, expanding current stem cell–based strategies toward potent concepts using the transplantation of differentiated cells.

Virtual endoscopy of the middle ear: experimental and clinical results of a standardised approach using multi-slice helical computed tomography.

Abstract. Virtual endoscopy (VE) enables non-invasive 3D endoluminal imaging of the middle ear by post-processing of CT data. To optimise the clinical application a standardised approach was evaluated in normal and pathologic cases. Data acquisition was performed using multi-slice helical CT in 20 normal patients and 15 patients with malformation or trauma. Virtual endoscopy of the tympanic cavity and 3D images of the ossicles were generated using surface and volume rendering. Qualitative assessment of the representation of anatomical structures was performed in normal patients. In 15 pathological cases the diagnostic benefit was evaluated by comparing the 3D images to the 2D images and intra-operative findings. In all 35 cases 3D imaging was possible using the standardised approach. The ossicular chain as well as the bony and soft tissue structures of the tympanic cavity were visualised in 20 normal patients. In 7 of 8 patients with malformation and 1 of 7 patients with trauma the original diagnosis was changed by 3D imaging. Standardisation and evaluation of the method in normal patients is essential as it enhances the diagnostic reliability. Virtual endoscopy facilitates understanding of the complex anatomy of the middle ear. In cases of suspected malformation and confirmed trauma it is helpful for diagnosis and surgical planning.

Influence of sinogram affirmed iterative reconstruction of CT data on image noise characteristics and low-contrast detectability: an objective approach.

Objectives To utilize a novel objective approach combining a software phantom and an image quality metric to systematically evaluate the influence of sinogram affirmed iterative reconstruction (SAFIRE) of multidetector computed tomography (MDCT) data on image noise characteristics and low-contrast detectability (LCD). Materials and Methods A low-contrast and a high-contrast phantom were examined on a 128-slice scanner at different dose levels. The datasets were reconstructed using filtered back projection (FBP) and SAFIRE and virtual low-contrast lesions (-20HU) were inserted. LCD was evaluated using the multiscale structural similarity index (MS-SIM*). Image noise texture and spatial resolution were objectively evaluated. Results The use of SAFIRE led to an improvement of LCD for all dose levels and lesions sizes. The relative improvement of LCD was inversely related to the dose level, declining from 208%(±37%), 259%(±30%) and 309%(±35%) at 25mAs to 106%(±6%), 119%(±9%) and 123%(±8%) at 200mAs for SAFIRE filter strengths of 1, 3 and 5 (p<0.05). SAFIRE reached at least the LCD of FBP at a relative dose of 50%. There was no statistically significant difference in spatial resolution. The use of SAFIRE led to coarser image noise granularity. Conclusion A novel objective approach combining a software phantom and the MS-SSIM* image quality metric was used to analyze the detectability of virtual low-contrast lesions against the background of image noise as created using SAFIRE in comparison to filtered back-projection. We found, that image noise characteristics using SAFIRE at 50% dose were comparable to the use of FBP at 100% dose with respect to lesion detectability. The unfamiliar imaging appearance of iteratively reconstructed datasets may in part be explained by a different, coarser noise characteristic as demonstrated by a granulometric analysis.

68 Ga-DOTANOC PET/CT for the detection of a mesenchymal tumor causing oncogenic osteomalacia

A 54-year-old female patient had presented with clinical features of hyperphosphaturia, hypophosphatemia and osteomalacia. These findings were suggestive of oncogenic osteomalacia, a rare paraneoplastic disorder that is usually associated with a phosphaturic mesenchymal tumor [1]. Conventional morphologic imaging including whole-body computed tomography (CT) failed to localise the primary tumor. The patient underwent additional positron emission tomography (PET)/CT using Ga-DOTANOC, a highly sensitive and specific tracer for imaging of somatostatin receptor overexpression, which has recently proven potential in oncogenic osteomalacia [2, 3]. Abnormal focal tracer uptake was seen in the right distal femur (A). Using image fusion and three-dimensional volume-rendering techniques, the localisation of the suspected primary tumor was clearly visualised (B). Notably, no morphologic correlative was observed in the corresponding low-dose CT (C). Based on the PET/CT findings, the patient underwent segmental resection and compound osteosynthesis of the distal femur. The hematoxylin and eosin-stained section (D) demonstrated randomly organised spindle cells with slight cellular and nuclear atypia and a sparse intercellular matrix. Immunohistochemistry was negative for myogenic, neural, vascular and epithelial markers. These histopathologic findings were consistent with the diagnosis of a benign phosphaturic, mesenchymal tumor.

Placement of Intraventricular Catheters Using Flexible Electromagnetic Navigation and a Dynamic Reference Frame: A New Technique

Background: Catheterization of narrow ventricles may prove difficult resulting in misplacement or inefficient trials with potential damage to brain tissue. Material and Methods: The application of a new module for navigated ventricular catheterization using flexible electromagnetic navigation and a dynamic reference frame is presented. Results: Navigated catheter placement was successful and accurate in a pilot study. Electromagnetic interferences had to be taken into consideration. Conclusion: Flexible electromagnetic navigation with a dynamic reference frame is a useful tool for catheter placement as it reduces the risk of misplacement or repeated catheterization trials.

Increase of Accuracy in Intraoperative Navigation Through High-resolution Flat-panel Volume Computed Tomography: Experimental Comparison With Multislice Computed Tomography-based Navigation

Hypothesis: High-resolution imaging, as provided by flat-panel-based volume computed tomography (fpVCT), could increase navigation accuracy and could therefore improve image-guided procedures or make novel navigated surgery concepts possible. Background: Intraoperative navigation is an accepted tool in head and neck surgery. However, its use is limited in the lateral cranial base because of its low surgical accuracy. Surgical accuracy is substantially influenced by the resolution of the underlying data set. The fpVCT offers a resolution of nearly two times higher than multislice computed tomography (MSCT). Target registration error (TRE), as a measurement for surgical navigation accuracy, should decrease when navigation is based on fpVCT data sets. Methods: An acrylic glass phantom with 37 fiducial points was scanned in a current MSCT and in an experimental fpVCT. Both data sets were imported in an optical navigation system. Five fiducial points were used for registration, and seven points were used for measuring TRE. The distance between the indicated pointer tip and the corresponding fiducial point in data set was measured as TRE. Registration and TRE measurement were repeated five times for each computed tomographic data set. Average TREs were calculated, and results were compared using t-test. Results: The average TRE using MSCT (0.82 mm [standard deviation, 0.35 mm]) was significantly higher than that using fpVCT (0.46 mm [standard deviation, 0.22 mm]) (p < 0.01). Conclusion: Submillimeter surgical navigation accuracy is possible using high-resolution fpVCT. This could be highly beneficial in cranial base surgery navigation.

F-18 2-fluoro-2-deoxy-glucose positron emission tomography/computed tomography for the detection of radicular and peripheral neurolymphomatosis: correlation with magnetic resonance imaging and ultrasound.

Neurolymphomatosis is an uncommon extranodal manifestation of non-Hodgkin lymphoma. It may mimic a broad variety of neurologic conditions which renders clinical diagnosis challenging. As blind nerve biopsy is invasive and may be false negative, surrogate criteria for the diagnosis of neurolymphomatosis have been proposed based on magnetic resonance imaging/computed tomography findings. However, these morphologic modalities may suffer from limited sensitivity. Recently, a few reports have been published that discuss a possible advantage of F-18 2-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (F-18 FDG PET/CT) in these patients. We report the case of a 41-year-old man who presented with progressive tetraparesis and dysaesthesia, in which F-18 FDG PET/CT aided to the diagnosis of neurolymphomatosis due to a large B-cell lymphoma. The patient received chemotherapy (R-CHOP) and the neurologic symptoms were clearly regressive. Three months after the end of systemic chemotherapy the patient presented again with progressive neurologic symptoms. A second PET/CT was performed and demonstrated disease recurrence in the right testis as well as widespread neurolymphomatosis. Additional ultrasound and magnetic resonance imaging examinations were performed and confirmed infiltration of the left brachial plexus, the right femoral, and the right sciatic nerve. We present this case to support the hypothesis that F-18 FDG PET/CT is a valuable imaging modality in patients with suspected neurolymphomatosis. It allows one to accurately determine the extent of the disease in a single whole-body examination.

Registration and fusion of CT and MRI of the temporal bone.

Objective: To present and evaluate a registration method to fuse complementary information of CT and MRI of the temporal bone. Methods: CT and MRI of the temporal bone of 26 patients were independently registered 4 times. A manual, iterative, intrinsic, rigid, and retrospective registration method was used. Mean CREm (consistency registration error) was calculated as a reproducibility measurement. Results: CREm was 0.6 mm (95% CI = 0.52-0.68 mm). T-test revealed no difference between pathologic and normal cases (t[102] = −1.71; P = 0.09). Time needed: 13 minutes. In the registered and fused datasets, important bony surgical landmarks (eg, facial nerve canal, inner ear) could be assessed in 3 dimensions relatively to tumor tissue (eg, acoustic schwannoma). Fluid distribution within partially obliterated cochleae could be assigned to either scalae. Conclusion: An accurate, reproducible registration and fusion method that improves tumor surgery and cochlea implantation planning with only minor changes to the clinical workflow was presented and described. We suggest this method in selected cases.

Transarterial chemoembolization (TACE) for colorectal liver metastases—current status and critical review

BackgroundTransarterial liver-directed therapies are currently not recommended as a standard treatment for colorectal liver metastases. Transarterial chemoembolization (TACE), however, is increasingly used for patients with liver-dominant colorectal metastases after failure of surgery or systemic chemotherapy. The limited available data potentially reveals TACE as a valuable option for pre- and post-operative downsizing, minimizing time-to-surgery, and prolongation of overall survival after surgery in patients with colorectal liver only metastases.PurposeIn this overview, the current status of TACE for the treatment of liver-dominant colorectal liver metastases is presented. Critical comments on its rationale, technical success, complications, toxicity, and side effects as well as oncologic outcomes are discussed. The role of TACE as a valuable adjunct to surgery is addressed regarding pre- and post-operative downsizing, conversion to resectability as well as improvement of the recurrence rate after potentially curative liver resection. Additionally, the concept of TACE for liver-dominant metastatic disease with a focus on new embolization technologies is outlined.ConclusionsThere is encouraging data with regard to technical success, safety, and oncologic efficacy of TACE for colorectal liver metastases. The majority of studies are non-randomized single-center series mostly after failure of systemic therapies in the 2nd line and beyond. Emerging techniques including embolization with calibrated microspheres, with or without additional cytotoxic drugs, degradable starch microspheres, and technical innovations, e.g., cone-beam computed tomography (CT) allow a new highly standardized TACE procedure. The real efficacy of TACE for colorectal liver metastases in a neoadjuvant, adjuvant, and palliative setting has now to be evaluated in prospective randomized controlled trials.

Erythropoietin and erythropoietin receptor expression in vestibular schwannoma: potential role in tumor progression.

Hypothesis: Hypoxia-inducible factor (HIF)-1&agr;, erythropoietin (Epo), Epo receptor (EpoR), and bcl-2 are expressed in both sporadic unilateral vestibular schwannomas (VSs) and those associated with neurofibromatosis Type 2, and the expression data correlate with clinicopathological tumor features including microvessel density and Ki-67-labeling index. Background: Erythropoietin expression is regulated by the transcription factor, HIF-1&agr;. Erythropoietin signaling via EpoR results in stimulation of cell proliferation and elevated expression of the antiapoptotic protein, bcl-2, and then inhibition of apoptosis. Erythropoietin has been shown to be associated with Schwann cell proliferation, and a recent report suggested a role in VS growth. Methods: Immunohistochemical analysis of HIF-1&agr;, Epo, EpoR, and bcl-2 was performed on formalin-fixed paraffin-embedded archival surgical specimens. Microvessel density and Ki-67-labeling index of VS were analyzed and correlated with the immunoreactivity pattern of the examined factors. Results: Immunoreactivity data demonstrate robust protein expression for HIF-1&agr;, Epo, EpoR, and bcl-2 in VS. Sixty-six percent of the cases showed Epo expression, and EpoR was found in 85% of tumor samples. A significantly positive correlation of the immunoreactivity scores of Epo/EpoR and bcl-2 expression could be noted. In case of tumor specimens with high levels of HIF-1&agr; expression, a significantly higher Ki-67-labeling index was observed. There was no correlation between the expression of HIF-1&agr;, Epo, EpoR, and bcl-2 and microvessel density, tumor size, sex, and age. Conclusion: Expression of Epo and EpoR might suggest a functional role in VS biology. The observed correlation of Epo/EpoR and bcl-2 expression levels may suggest a proliferative and antiapoptotic role of the Epo/EpoR system in VS.