Marius Horger

Immunologic and Clinical Responses after Vaccinations with Peptide-Pulsed Dendritic Cells in Metastatic Renal Cancer Patients

A phase I trial was conducted to evaluate the feasibility, safety, and efficacy of a dendritic cell-based vaccination in patients with metastatic renal cell carcinoma (RCC). Autologous mature dendritic cells derived from peripheral blood monocytes were pulsed with the HLA-A2-binding MUC1 peptides (M1.1 and M1.2). For the activation of CD4(+) T-helper lymphocytes, dendritic cells were further incubated with the PAN-DR-binding peptide PADRE. Dendritic cell vaccinations were done s.c. every 2 weeks for four times and repeated monthly until tumor progression. After five dendritic cell injections, patients additionally received three injections weekly of low-dose interleukin-2 (1 million IE/m(2)). The induction of vaccine-induced T-cell responses was monitored using enzyme-linked immunospot and Cr release assays. Twenty patients were included. The treatment was well tolerated with no severe side effects. In six patients, regression of the metastatic sites was induced after vaccinations with three patients achieving an objective response (one complete response, two partial responses, two mixed responses, and one stable disease). Additional four patients were stable during the treatment for up to 14 months. MUC1 peptide-specific T-cell responses in vivo were detected in the peripheral blood mononuclear cells of the six patients with objective responses. Interestingly, in patients responding to the treatment, T-cell responses to antigens not used for vaccinations, such as adipophilin, telomerase, or oncofetal antigen, could be detected, indicating that epitope spreading might occur. This study shows that MUC1 peptide-pulsed dendritic cells can induce clinical and immunologic responses in patients with metastatic RCC.

Intradermal Vaccinations With RNA Coding for TAA Generate CD8+ and CD4+ Immune Responses and Induce Clinical Benefit in Vaccinated Patients

The aim of this phase I/II nonrandomized trial was to assess feasibility, safety as well as immunological and clinical responses of a mRNA-based vaccination in patients with stage IV renal cell cancer using granulocyte-macrophage colony stimulating factor (GM-CSF) as adjuvant. Intradermal injections of in vitro transcribed naked mRNA, which was generated using plasmids coding for the tumor-associated antigens mucin 1(MUC1), carcinoembryonic (CEA), human epidermal growth factor receptor 2 (Her-2/neu), telomerase, survivin, and melanoma-associated antigen 1 (MAGE-A1) were performed in 30 enrolled patients. In the first 14 patients (cohort A) vaccinations were administered on days 0, 14, 28, and 42 (20 µg/antigen) while in the consecutive 16 patients (cohort B) an intensified protocol consisting of injections at days 0-3, 7-10, 28, and 42 (50 µg/antigen) was used. In both cohorts, after this induction period, vaccinations were repeated monthly until tumor progression analyzed by Response Evaluation Criteria In Solid Tumors criteria (RECIST). Vaccinations were well tolerated with no severe side effects and induced clinical responses [six stable diseases (SD) and one partial response in cohort A and nine SD in cohort B]. In cohort A, 35.7% survived 4 years (median survival 24 months) compared to 31.25% in cohort B (median survival 29 months). Induction of CD4(+) and CD8(+) T cell responses was shown for several tumor-associated antigens (TAA) using interferon-γ (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and Cr-release assays.

Chronic recurrent multifocal osteomyelitis: comparison of whole-body MR imaging with radiography and correlation with clinical and laboratory data.

PURPOSE To describe whole-body magnetic resonance (MR) imaging appearance of chronic recurrent multifocal osteomyelitis (CRMO) and assess the role of MR imaging versus radiography in diagnosis of disease and correlation with clinical findings and laboratory data. MATERIALS AND METHODS Institutional review board approved this retrospective HIPAA-compliant study; informed consent was waived. T1-weighted, short inversion time inversion-recovery, and contrast material-enhanced T1-weighted whole-body MR imaging was performed and two-plane radiographs, clinical findings, and laboratory data were reviewed in 13 children (median age, 13 years) with CRMO. Lesion depiction, location, and characterization and extraskeletal abnormalities were evaluated. MR imaging findings were compared with clinical and laboratory data and radiographic results. Data analysis was performed, and diagnostic performance statistics of radiography, physical examination results, and serum inflammatory markers were calculated. General multilevel linear modeling framework was used. Odds ratios were calculated to estimate effect of age, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level on reliabilities. Associations of ESR and CRP level with total number of lesions were assessed (chi(2) test). RESULTS MR imaging depicted 101 ill-defined edemalike osseous lesions. Most frequent anatomic sites were distal femur (21%, 21 of 101), proximal tibia (17%, 17 of 101), and distal tibia and fibula (14% each, 14 of 101). In tubular bones (70 anatomic sites), metaphysis (86%, 60 of 70) and epiphysis (67%, 47 of 70) were involved. Contiguous physeal relationship (89%, 66 of 74), periosteal reaction (48%, 48 of 101), and symmetric involvement (85%, 11 of 13) were present. MR imaging demonstrated multifocality in all patients. There were no extraskeletal abnormalities and no relationship between serum inflammatory markers and number of symptomatic anatomic sites (P = .472). Sensitivity for radiography was 0.13 (70 of 119); physical examination, 0.31 (52 of 299); and serum inflammatory markers, 0.15 (two of 13). CONCLUSION Whole-body MR imaging is useful for detection of CRMO, particularly in indeterminate cases, because it is more likely to show abnormalities.

Whole-body diffusion-weighted MRI with apparent diffusion coefficient mapping for early response monitoring in multiple myeloma: preliminary results.

OBJECTIVE The purpose of our study was to prospectively assess the feasibility of whole-body diffusion-weighted imaging (DWI) for short-term evaluation of response to treatment in multiple myeloma patients using a single-shot echo-planar imaging DWI sequence with a Stejskal-Tanner diffusion encoding scheme and spectral fat suppression. SUBJECTS AND METHODS Twelve consecutive patients (nine men and three women; mean age, 61.4 years; age range, 54-79 years) underwent whole-body DWI (b = 50, 400, and 800 s/mm(2)) both at baseline and 3 weeks (mean, 23 days) after onset of therapy. Bone marrow and extramedullary manifestations were evaluated by quantitative image analysis using measurements of the mean apparent diffusion coefficient (ADC). These parameters were correlated with myeloma response according to standard criteria and were evaluated parallel to MRI and continuously for more than 6 months afterward. RESULTS Fifty-three myeloma lesions, 50 medullary (28 axial and 22 appendicular skeleton) and three extramedullary, were analyzed. Eleven patients were classified as responders and one as a nonresponder. DWI results accurately (100%) correlated with disease course according to standard clinical and laboratory criteria. All involved lesions showed restricted diffusion at baseline. ADC quantification yielded an increase of 63.9% (range, 8.7-211.3%) in responders and a decrease of 7.8% in the sole nonresponding patient during therapy. In parallel, M-gradient measurement showed a mean decrease of 45.1% (range, 19.6-88.8%) in responders and an increase of 21.8% in the nonresponder. Amplitude of response measured by the course of ADC values proved higher in the appendicular skeleton (99.8%) compared with the axial skeleton (54.3%) (p = 0.037). CONCLUSION Whole-body DWI with ADC analysis represents a feasible diagnostic tool for assessment of short-term treatment response in myeloma patients.

Long-term CT follow-up in 40 non-HIV immunocompromised patients with invasive pulmonary aspergillosis: kinetics of CT morphology and correlation with clinical findings and outcome

OBJECTIVE The aim of this study was to assess CT signs of invasive pulmonary aspergillosis (IPA) and their long-term kinetics in correlation with clinical findings and outcome. MATERIALS AND METHODS Three hundred ten serial CT scans (mean, 7.7) in 40 consecutive patients were reviewed retrospectively over a median follow-up of 112 days (range, 5-841 days). Along with underlying disease, hematopoietic stem cell transplantation, neutropenia, graft-versus-host disease or antifungal treatment, signs of IPA, and number or size of lesions were evaluated regarding outcome and radiologic dynamics. RESULTS On the day of IPA diagnosis, median lesion number and size were 3 or 3.1 cm(2), respectively. Irrespective of antifungal therapy, 90% of patients showed an increase in lesion size and number until day 9 (median and mean). Lesion size subsequently showed a median plateau phase of 3.5 days (mean, 7), during which median lesion numbers dropped by 17%. Consequently, 42.5% of patients showed a complete radiologic remission within a median 80 days. Of all parameters, formation of cavitation most strongly predicted time until radiologic remission, which was 2.5 times as long in patients with cavitary lesions. Likewise, cavitations were strong precursors of beneficial outcome (odds ratio, 8.4; confidence interval [CI], 1.07-176). CONCLUSION The kinetics of radiologic signs of IPA adheres to a distinctive pattern with initial rise in number and size, followed by a plateau phase of size and gradual reduction. Both time until complete radiologic remission and outcome are independent of initial or maximum lesion size and number yet strongly influenced by cavitation.

Diffusion-Weighted MRI of Advanced Hepatocellular Carcinoma During Sorafenib Treatment: Initial Results

OBJECTIVE The objective of our study was to evaluate signal changes of advanced hepatocellular carcinoma in diffusion-weighted MRI in the early-response monitoring of oral therapy with the multikinase inhibitor sorafenib. CONCLUSION Hepatocellular carcinoma lesions exhibit characteristic but unusual apparent diffusion coefficient (ADC) changes during sorafenib therapy, consisting of early decrease in ADC after therapy onset followed by a reincrease. The ADC changes seem to reflect the underlying pathophysiologic mechanisms in tumor necrosis (most probably hemorrhagic) induced by this novel targeted agent early after therapy onset and may indicate tumor reactivation in the later follow-up period.

Early MRI response monitoring of patients with advanced hepatocellular carcinoma under treatment with the multikinase inhibitor sorafenib

BackgroundNew therapeutic principles in clinical oncology require the adjustment of response criteria to govern therapy decisions. For advanced hepatocellular carcinoma (HCC) a new era has recently begun by the approval of the multikinase inhibitor sorafenib. As a unique feature, HCC usually develops in a diseased liver and current imaging technologies employing classical response criteria have not been prospectively evaluated for this new treatment.MethodsMRI signal patterns were assessed in 21 advanced HCC patients receiving sorafenib. MRI was performed at baseline and in short-term intervals thereafter. Signal changes under therapy on T1WI, T2WI and post-gadolinium images including necrosis volume and its ratio to the entire tumor volume were compared to baseline imaging. To assess the association between the categorical variables, Fishers exact tests were applied for a statistical analysis. Survey time ranged from 2–65 weeks, and a total of 39 target lesions were evaluated.ResultsSignal abnormalities during sorafenib therapy were disclosed by T1WI and T2WI in 15/21 patients. The predominant tumor signal change was hyperintensity on both T1WI and T2WI. Interestingly, most patients developed MRI signal changes within 4 weeks of therapy; in contrast, two non-responders did not show any signal alteration at follow-up. Under therapy, 16/21 patients presented with new or progressive necrosis, whereas 7 patients achieved temporarily >75% tumor necrosis under sorafenib. Significantly associated MRI variables were increase in T1WI signal and tumor necrosis (p = 0.017) as well as increase of tumor necrosis with an elevated ratio of necrotic to vital tumor areas (p = 0.002). Remarkably, some (3/13) of the patients developing necrotic tumor areas showed a relevant (>20%) increase in tumor volume, which should be considered in the assessment of imaging studies.ConclusionAs sorafenib induces early intralesional necrosis with profound changes in T1WI/T2WI MRI signal intensities and measurable necrotic tumor areas in most HCC patients, early MRI-based evaluation could pave the way for its rationale and cost-effective application.

The benefit of using whole-body, low-dose, nonenhanced, multidetector computed tomography for follow-up and therapy response monitoring in patients with multiple myeloma.

The objectives of this study were to assess the status and clinical course of patients with multiple myeloma based on the direct visualization of changes in medullary, extramedullary, and focal osteolytic myeloma involvement by using whole‐body, low‐dose, multidetector computed tomography (WBLD‐MDCT) and to compare those results with an assessment based on conventional hematologic parameters.

Mixed response to tocilizumab for ankylosing spondylitis

Since the introduction of tumour necrosis factor (TNF) antagonists for the treatment of ankylosing spondylitis (AS) the majority of patients can be successfully treated. However, individual patients have persistent disease activity. We report on a 36-year-old male patient with HLA-B27-positive AS. No peripheral arthritis or extra-articular manifestation was documented. After insufficient response to standard treatment with non-steroidal anti-inflammatory drugs (NSAIDs), sulfasalazine, methotrexate and all three available TNF antagonists (infliximab, etanercept and adalimumab), the last of these even in an intensified dose of 40 mg weekly, a rescue treatment with the interleukin 6 (IL-6) antagonist tocilizumab (TCZ; Roche Pharma, Roche Pharma, Grenzach-Wyhlen, Germany) was initiated. TCZ was administered intravenously with 8 mg/kg bodyweight every 4 weeks. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) served as clinical response measure. For functional assessment the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI) were applied. For global …

MRI-Guided Injection Procedures of the Temporomandibular Joints in Children and Adults: Technique, Accuracy, and Safety

OBJECTIVE The purpose of our study was to test the hypothesis that real-time MRI-guided, selective injection procedures of the temporomandibular joints are feasible, accurate, and safe when performed on a clinical open-bore 1.5-T MR system. MATERIALS AND METHODS A retrospective analysis of 67 injection procedures of the temporomandibular joints (55% [37/67] were therapeutic injections, 27% [18/67] were diagnostic injections, and 18% [12/67] were arthrocentesis procedures), performed in 31 patients (58% [18/31] female, 42% [13/31] male; mean age, 14 years; age range, 3-34 years), was made. Seven of 38 (18%) subjects had two temporally separate procedures. Determinations of skin entry points, puncture, and injection were performed under real-time MRI. Data were assessed for rate of successful injections, quantitative and qualitative image quality, time requirements, and occurrence of complications. RESULTS Drug delivery was successful in all procedures. The quality of real-time FLASH 2D MR images was sufficient in all cases. Real-time MRI proved to be helpful to achieve high rates of intraarticular injections. Contrast-to-noise ratios were sufficiently high for good delineation of relevant structures. Average length of time was 25 minutes (range, 16-53 minutes). No major complications occurred. CONCLUSION We accept the hypothesis that real-time MRI-guided selective injection procedures of the temporomandibular joints are feasible, accurate, and safe when performed on a clinical open-bore 1.5-T MR system.