Disease extent according to baseline [18F]fluorodeoxyglucose PET/CT and molecular subtype: prediction of axillary treatment response after neoadjuvant systemic therapy for breast cancer.

BACKGROUND: Axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT combined with pathological axillary treatment response has been proposed to guide de-escalation of axillary treatment for clinically node-positive breast cancer patients treated with neoadjuvant systemic therapy. The aim of this study was to assess whether axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT and breast cancer molecular subtype are predictors of axillary pCR. METHODS: This study included clinically node-positive patients treated with neoadjuvant systemic therapy in the prospective Radioactive Iodine Seed placement in the Axilla with Sentinel lymph node biopsy ('RISAS') trial (NCT02800317) with baseline [18F]fluorodeoxyglucose PET/CT imaging available. The predictive value of axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT and breast cancer molecular subtype to estimate axillary pCR was evaluated using logistic regression analysis. Discriminative ability is expressed using ORs with 95% confidence intervals. RESULTS: Overall, 185 patients were included, with an axillary pCR rate of 29.7%. The axillary pCR rate for patients with limited versus advanced baseline axillary disease according to [18F]fluorodeoxyglucose PET/CT was 31.9% versus 26.1% respectively. Axillary disease extent was not a significant predictor of axillary pCR (OR 0.75 (95% c.i. 0.38 to 1.46) (P = 0.404)). There were significant differences in axillary pCR rates between breast cancer molecular subtypes. The lowest probability (7%) was found for hormone receptor+/human epidermal growth factor receptor 2- tumours. Using this category as a reference group, significantly increased ORs of 14.82 for hormone receptor+/human epidermal growth factor receptor 2+ tumours, 40 for hormone receptor-/human epidermal growth factor receptor 2+ tumours, and 6.91 for triple-negative tumours were found (P < 0.001). CONCLUSION: Molecular subtype is a significant predictor of axillary pCR after neoadjuvant systemic therapy, whereas axillary disease extent according to baseline [18F]fluorodeoxyglucose PET/CT is not.

Diagnosing necrotizing external otitis on CT and MRI: assessment of pattern of extension.

BACKGROUND AND PURPOSE: Necrotizing external otitis (NEO) is a serious complication of external otitis. NEO can be classified according to-anterior, medial, posterior, intracranial, and contralateral-extension patterns. Currently there is no consensus on the optimal imaging modality for the identification of disease extension. This study compares NEO extension patterns on MR and CT to evaluate diagnostic comparability. METHODS: Patients who received a CT and MR within a 3-month interval were retrospectively examined. Involvement of subsites and subsequent spreading patterns were assessed on both modalities by a radiologist in training and by a senior head and neck radiologist. The prevalence of extension patterns on CT and MR were calculated and compared. RESULTS: All 21 included NEO cases showed an anterior extension pattern on CT and MR. Contrary to MR, medial extension was not recognized on CT in two out of six patients, and intracranial extension in five out of eight patients. The posterior extension pattern was not recognized on MR. Overall, single anterior extension pattern (62%) is more prevalent than multiple extension patterns (38%). CONCLUSION: All anterior NEO extension pattern were identified on CT as well as MR. However, the medial and intracranial spreading patterns as seen on MR could only be identified on CT in a small number of patients. The posterior spreading pattern can be overlooked on MR. Thus, CT and MR are complimentary for the initial diagnosis and work-up of NEO as to correctly delineate disease extent through the skull base.

Dual-Energy Computed Tomography Compared to Lung Perfusion Scintigraphy to Assess Pulmonary Perfusion in Patients Screened for Endoscopic Lung Volume Reduction.

BACKGROUND: Endoscopic lung volume reduction (ELVR) using one-way endobronchial valves is a technique to reduce hyperinflation in patients with severe emphysema by inducing collapse of a severely destroyed pulmonary lobe. Patient selection is mainly based on evaluation of emphysema severity on high-resolution computed tomography and evaluation of lung perfusion with perfusion scintigraphy. Dual-energy contrast-enhanced CT scans may be useful for perfusion assessment in emphysema but has not been compared against perfusion scintigraphy. AIMS: The aim of the study was to compare perfusion distribution assessed with dual-energy contrast-enhanced computed tomography and perfusion scintigraphy. MATERIAL AND METHODS: Forty consecutive patients with severe emphysema, who were screened for ELVR, were included. Perfusion was assessed with 99mTc perfusion scintigraphy and using the iodine map calculated from the dual-energy contrast-enhanced CT scans. Perfusion distribution was calculated as usually for the upper, middle, and lower thirds of both lungs with the planar technique and the iodine overlay. RESULTS: Perfusion distribution between the right and left lung showed good correlation (r = 0.8). The limits of agreement of the mean absolute difference in percentage perfusion per region of interest were 0.75-5.6%. The upper lobes showed more severe perfusion reduction than the lower lobes. Mean difference in measured pulmonary perfusion ranged from -2.8% to 2.3%. Lower limit of agreement ranged from -8.9% to 4.6% and upper limit was 3.3-10.0%. CONCLUSION: Quantification of perfusion distribution using planar 99mTc perfusion scintigraphy and iodine overlays calculated from dual-energy contrast-enhanced CTs correlates well with acceptable variability.

Hypoxia and hypoxia response-associated molecular markers in esophageal cancer: A systematic review.

PURPOSE: In this systematic review, the existing evidence of available hypoxia-associated molecular response biomarkers in esophageal cancer (EC) patients is summarized and set into the context of the role of hypoxia in the prediction of esophageal cancer, treatment response and treatment outcome. METHODS: A systematic literature search was performed in Web of Science, MEDLINE, and PubMed databases using the keywords: hypoxia, esophagus, cancer, treatment outcome and treatment response. Eligible publications were independently evaluated by two reviewers. In total, 22 out of 419 records were included for systematic review. The described search strategy was applied weekly, with the last update being performed on April 3rd, 2017. RESULTS: In esophageal cancer, several (non-)invasive biomarkers for hypoxia could be identified. Independent prognostic factors for treatment response include HIF-1α, CA IX, GLUT-1 overexpression and elevated uptake of the PET-tracer 18F-fluoroerythronitroimidazole (18F-FETNIM). Hypoxia-associated molecular responses represents a clinically relevant phenomenon in esophageal cancer and detection of elevated levels of hypoxia-associated biomarkers and tends to be associated with poor treatment outcome (i.e., overall survival, disease-free survival, complete response and local control). CONCLUSION: Evaluation of tumor micro-environmental conditions, such as intratumoral hypoxia, is important to predict treatment outcome and efficacy. Promising non-invasive imaging-techniques have been suggested to assess tumor hypoxia and hypoxia-associated molecular responses. However, extensive validation in EC is lacking. Hypoxia-associated markers that are independent prognostic factors could potentially provide targets for novel treatment strategies to improve treatment outcome. For personalized hypoxia-guided treatment, safe and reliable makers for tumor hypoxia are needed to select suitable patients.

[18F]FDG whole-body PET-MR including an integrated breast MR protocol for locoregional and distant staging in breast cancer patients-a feasibility study.

PURPOSE: To investigate in a feasibility study the combination of [18F]FDG whole-body (WB) positron emission tomography-magnetic resonance (PET-MR), including an integrated breast MR within a single protocol for locoregional and distant staging in breast cancer patients. METHODS: Consecutive patients with breast cancer diagnoses according to conventional imaging modalities (full-field digital mammography (FFDM) and ultrasound (US)) were prospectively included. All patients underwent [18F]FDG WB PET-MR, including an integrated dedicated breast MR (prone position) and WB PET-MR (supine position) protocol. Results of [18F]FDG WB PET-MR, including integrated breast MR, versus conventional imaging modalities were compared. RESULTS: From April 2021-April 2022, 28 patients were included. On conventional imaging, cT1-2 breast cancer was present in 22 (FFDM) and 23 (US) out of 28 patients. With regard to clinical nodal status, eight patients were considered cN0, eighteen cN1 (1-3 suspicious lymph nodes), and two patients were cN2 (four suspicious axillary lymph nodes/internal mammary lymph node metastasis). [18F]FDG WB PET-MR, including an integrated breast MR protocol, upstaged clinical tumor status in two patients and clinical nodal status in nine patients according to both [18F]FDG WB PET-MR and breast MR findings. In addition, distant metastases were detected in three patients (liver/bone), and another patient was diagnosed with a synchronous primary tumor (lung cancer). CONCLUSION: [18F]FDG WB PET-MR, including an integrated breast MR within a single protocol in breast cancer patients, is feasible and provides a promising new approach in breast cancer patients with regard to locoregional and distant staging. CRITICAL RELEVANCE STATEMENT: [18F]FDG whole-body PET-MR, including an integrated breast MR protocol, is feasible and allows locoregional and distant staging within a single imaging exam in breast cancer patients. KEY POINTS: [18F]FDG PET-MR allows the combination of breast MR and whole-body staging. Therefore, a single protocol of whole-body [18F]FDG PET-MR, including an integrated breast MRI, is investigated. [18F]FDG PET-MR, including an integrated breast MR is feasible and can be considered in daily clinical practice.

Limited Additional Value of a Chest CT in Whole-Body Staging with PET-MRI: A Retrospective Cohort Study.

Hybrid PET-MRI systems are being used more frequently. One of the drawbacks of PET-MRI imaging is its inferiority in detecting lung nodules, so it is often combined with a computed tomography (CT) of the chest. However, chest CT often detects additional, indeterminate lung nodules. The objective of this study was to assess the sensitivity of detecting metastatic versus indeterminate nodules with PET-MRI compared to chest CT. A total of 328 patients were included. All patients had a PET/MRI whole-body scan for (re)staging of cancer combined with an unenhanced chest CT performed at our center between 2014 and 2020. Patients had at least a two-year follow-up. Six percent of the patients had lung metastases at initial staging. The sensitivity and specificity of PET-MRI for detecting lung metastases were 85% and 100%, respectively. The incidence of indeterminate lung nodules on chest CT was 30%. The sensitivity of PET-MRI to detect indeterminate lung nodules was poor (23.0%). The average size of the indeterminate lung nodules detected on PET-MRI was 7 ± 4 mm, and the missed indeterminate nodules on PET-MRI were 4 ± 1 mm (p < 0.001). The detection of metastatic lung nodules is fairly good with PET-MRI, whereas the sensitivity of PET-MRI for detecting indeterminate lung nodules is size-dependent. This may be an advantage, limiting unnecessary follow-up of small, indeterminate lung nodules while adequately detecting metastases.

Metabolic tumor volume assessed by 18F FDG - PET CT scan as a predictive biomarker for immune checkpoint blockers in advanced NSCLC and its biological correlates.

PURPOSE: This study aimed to explore metabolic tumor volume (tMTV) as assessed 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT), and understand its biological meaning in patients with NSCLC exposed to immune checkpoint blockers(ICBs). EXPERIMENTAL DESIGN: In this study, patients with advanced NSCLC and a positive PET scan within 42 days of first line treatment were enrolled in 11 institutions across 4 countries. Total MTV (tMTV) was analyzed, with a 42% SUVmax threshold. Survival was analyzed according to high tMTV (≥ median). Plasma proteomic profile, whole exome, transcriptome and other analysis were performed on monocentric cohorts to explore its biological correlates. RESULTS: Of the 518 patients included, 167 received ICBs, 257 had chemotherapy plus ICBs, and 94 had chemotherapy. Median tMTV was 99 cm3. Median overall survival (OS) for patients with high tMTV treated with ICBs was 11.4 months vs 29.6 months (P<0.0012) for those with low tMTV. In patients receiving chemotherapy-ICB tMTV did not correlate with OS (P=0.099). In patients with PD-L1≥1% and high tMTV, chemotherapy-ICB combination was associated with longer OS compared with ICBs alone (20 vs 11.4 months,p=0.026), while no survival differences observed in low tMTV group. High tMTV correlated (and its detrimental effect seems to be driven by) a specific proteomic profile and increase in genomic instability. CONCLUSION: Our analysis indicates high tTMV is linked to an increase in systemic inflammation, specific cytokines production and chromosomal instability. tTMV may serve as one of the biomarker to select the best upfront strategy in patients with PD-L1 positive advanced NSCLC.

Diagnostic value of hybrid FDG-PET/MR imaging of chronic osteomyelitis.

BACKGROUND: Magnetic resonance imaging (MRI) and 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) Positron Emission Tomography, paired with Computed Tomography (PET/CT) are commonly used modalities in the complicated diagnostic work-up of osteomyelitis. PET/MRI is a relatively novel hybrid modality with suggested applications in bone infection imaging, based on expert opinion and previous qualitative research. 18F-FDG PET/MRI has the advantages of reduced radiation dose, more soft tissue information, and is deemed more valuable for surgical planning compared to 18F-FDG PET/CT. The goal of this study is to quantitatively assess the diagnostic value of hybrid 18F-FDG PET/MRI for chronic osteomyelitis. METHODS: A retrospective analysis was performed by a nuclear medicine physician and radiologist on 36 patients with 18F-FDG PET/MRI scans for suspected osteomyelitis. Sensitivity, specificity, and accuracy were determined with the clinical assessment by the orthopaedic surgeon (based on subsequent intraoperative microbiology or long-term follow-up) as the ground truth. Standardized uptake values (SUV) were measured and analysed by means of receiver operating characteristics (ROC). RESULTS: This first study to quantitatively report the diagnostic value of 18F-FDG PET/MRI yielded a sensitivity, specificity, and accuracy of 78%, 100%, and 86% respectively. Area under the ROC curve was .736, .755, and .769 for the SUVmax, target to background ratio, and SUVmax_ratio respectively. These results are in the same range and not statistically different compared to diagnostic value for 18F-FDG PET/CT imaging of osteomyelitis in literature. CONCLUSIONS: Based on the aforementioned advantages of 18F-FDG PET/MRI and the diagnostic value reported here, the authors propose 18F-FDG PET/MRI as an alternative to 18F-FDG PET/CT in osteomyelitis diagnosis, if available.

The Use of 18F-FET-PET-MRI in Neuro-Oncology: The Best of Both Worlds-A Narrative Review.

Gliomas are the most frequent primary tumors of the brain. They can be divided into grade II-IV astrocytomas and grade II-III oligodendrogliomas, based on their histomolecular profile. The prognosis and treatment is highly dependent on grade and well-identified prognostic and/or predictive molecular markers. Multi-parametric MRI, including diffusion weighted imaging, perfusion, and MR spectroscopy, showed increasing value in the non-invasive characterization of specific molecular subsets of gliomas. Radiolabeled amino-acid analogues, such as 18F-FET, have also been proven valuable in glioma imaging. These tracers not only contribute in the diagnostic process by detecting areas of dedifferentiation in diffuse gliomas, but this technique is also valuable in the follow-up of gliomas, as it can differentiate pseudo-progression from real tumor progression. Since multi-parametric MRI and 18F-FET PET are complementary imaging techniques, there may be a synergistic role for PET-MRI imaging in the neuro-oncological imaging of primary brain tumors. This could be of value for both primary staging, as well as during treatment and follow-up.

Value of 18F-FDG PET/CT for predicting axillary pathologic complete response following neoadjuvant systemic therapy in breast cancer patients: emphasis on breast cancer subtype.

BACKGROUND: Neoadjuvant systemic therapy (NST) is a widely accepted initial treatment modality that can lead to pathologic downstaging of the axillary disease burden in breast cancer patients. Axillary response as well as baseline 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography with computed tomography (PET/CT) differ between breast cancer subtypes. The value of baseline 18F-FDG PET/CT in predicting axillary response to NST is not yet established, possibly since breast cancer subtype was not taken into account. The purpose of this study was to investigate the value of baseline 18F-FDG PET/CT in predicting axillary response to NST with a specific emphasis on subtype. METHODS: PET-parameters derived from the primary tumor as well as the most FDG-avid axillary lymph node were measured on baseline 18F-FDG PET/CT. Overall imaging findings were compared with the gold standard of histopathology of the axillary surgery specimen. Analyses for ER-positive/HER2-negative were performed separately from HER2-positive and TN patients. In addition, separate analyses for clinically node-positive patients were performed. RESULTS: Sixty-six patients with 69 primary tumors were included in this study. Thirty-three axillae contained ER-positive/HER2-negative, 16 HER2-positive, and 20 TN breast cancer. No significant difference in PET-parameters between patients with axillary residual disease and axillary pathologic complete response were found for ER-positive/HER2-negative breast cancer. In the combined HER2-positive/TN subgroup, the SUVmax was significantly lower in patients without residual axillary disease in both the entire cohort and in patients with clinically node-positive disease. In this combined subgroup, a cut-off of 4.89 SUVmax measured on the most FDG-avid axillary lymph node could predict residual axillary disease with a sensitivity, specificity, PPV, and NPV of 90%, 69%, 53%, and 95%, respectively. CONCLUSIONS: Predicting axillary response following NST with baseline 18F-FDG PET/CT can be performed when focusing on breast cancer subtypes. The easily computed PET-parameter SUVmax can predict axillary response in HER2-positive and TN breast cancer. This study adds to the accumulating evidence that studies investigating the value of 18F-FDG PET/CT in breast cancer should always take subtypes into account.

Idiopathic pulmonary fibrosis: Current knowledge, future perspectives and its importance in radiation oncology.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease with an unknown cause. Uncertainties still remain regarding the pathogenesis of IPF, and the prognosis of this disease is poor despite some recent improvements in treatment. Radiation induced lung injury (RILI) is a common complication and a dose-limiting toxicity of thoracic radiotherapy. Importantly, IPF is a crucial risk factor for pulmonary toxicity after thoracic radiotherapy. Although IPF is not universally accepted as a definite contraindication for thoracic radiotherapy at present, it has been shown that IPF can increase the risk of severe and fatal complications after thoracic radiotherapy. Proton beam therapy has shown promising results in reducing the incidence of thoracic radiotherapy related life-threatening complications in IPF patients, but the current evidence is not sufficient to recommend the standard use of it. Many similarities are noticeable between IPF and RILI in terms of pathogenesis and underlying mechanisms. Better understanding of the mechanisms of IPF and RILI may enable clinicians to provide safer and more effective thoracic radiotherapy treatments in cancer patients with IPF. In this review, we summarize the current knowledge of IPF, present the importance of IPF in radiation oncology practice, and highlight the similarities and relationship between IPF and RILI.

Diagnostic performance of PET/computed tomography versus PET/MRI and diffusion-weighted imaging in the N- and M-staging of breast cancer patients.

OBJECTIVE: To provide a systematic review regarding the diagnostic performance of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) and diffusion-weighted imaging (DWI) compared to 18F-FDG PET/computed tomography (CT) focused on nodal and distant staging in breast cancer patients. METHODS: The PubMed and Embase databases were searched for relevant publications until April 2020. Two independent reviewers searched for eligible articles based on predefined in- and exclusion criteria, assessed quality and extracted data. RESULTS: Eleven eligible studies were selected from 561 publications identified by the search. In seven studies, PET/CT was compared with PET/MRI, and in five, PET/CT with DWI. Significantly higher sensitivity for PET/MRI compared to PET/CT in a lesion-based analysis was reported for all lesions together (77% versus 89%) in one study, osseous metastases (69-99% versus 92-98%) in two studies and hepatic metastases (70-75% versus 80-100%) in one study. Moreover, PET/MRI revealed a significantly higher amount of osseous metastases (90 versus 141) than PET/CT. PET/CT is associated with a statistically higher specificity than PET/MRI in the lesion detection of all lesions together (98% versus 96%) and of osseous metastases (100% versus 95%), both in one study. None of the reviewed studies reported significant differences between PET/CT and DWI for any of the evaluated sites. There is a trend toward higher specificity for PET/CT. CONCLUSION: In general, there is a trend toward higher sensitivity and lower specificity of PET/MRI when compared to PET/CT. Results on the diagnostic performance of DWI are conflicting. Rather than evaluating it separate, it seems to have complementary value when combined with other MR sequences.

Hybrid FDG-PET/MR imaging of chronic osteomyelitis: a prospective case series.

BACKGROUND: Magnetic resonance imaging (MRI) and 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography paired with computed tomography (PET/CT) are two commonly used imaging modalities in the complicated diagnostic workup of osteomyelitis. Diagnosis using these modalities relies on, respectively, anatomical (MRI) and metabolic (PET) signs. With hybrid PET/MRI being recently available, our goal is to qualitatively compare hybrid FDG PET/MRI to FDG PET/CT in the diagnosis and operative planning of chronic osteomyelitis. METHODS: Five patients with suspected chronic osteomyelitis in an extremity underwent an 18F-FDG single-injection/dual-imaging protocol with hybrid PET/CT and hybrid PET/MR. Images and clinical features were evaluated using a standardized assessment method. Standardized uptake value (SUV) measurements were performed on all images. Concordant and discordant findings between PET/MRI and PET/CT were analysed. RESULTS: The consensus diagnoses based on PET/MRI and PET/CT images were identical for all five patients. One discrepancy between PET/MRI and PET/CT was found in the assessment of the features in one patient. PET signal intensities and target-to-background ratios were on average highest for PET/MRI. On PET/MRI, the location of infection based on FDG uptake could clearly be correlated with certain soft tissue structures (oedema, fluid collection, or muscle), which is paramount for surgical planning. CONCLUSIONS: In the presented cases, FDG PET/MRI led to the same diagnosis and provided at least the same diagnostic information as PET/CT. PET/MRI was able to provide additional soft-tissue information for the physician planning treatment. Because of this, we suggest that PET/MRI could be used for osteomyelitis diagnosis and treatment planning.

Performing clinical 18F-FDG-PET/MRI of the mediastinum optimising a dedicated, patient-friendly protocol.

OBJECTIVE: To construct a mediastinal-specific fluorine-18-fluorodeoxyglucose (F-FDG)-PET/MR protocol with high-quality MRI of minimal acquisition-time and comparable diagnostic value to F-FDG-PET/computed tomography (CT). MATERIALS AND METHODS: Fifteen healthy participants received PET/MRI and 10 patients with mediastinal tumours (eight non-small-cell lung, two oesophageal cancer) received F-FDG-PET/MRI immediately after F-FDG-PET/CT. Sequences volume interpolated breath-hold examination (T1-VIBE) and Half-Fourier acquisition single-shot turbo spin echo (T2-HASTE) were optimised by varying the parameters: breath-hold (BH, end-expiration), fat suppression (spectral adiabatic inversion recovery), and ECG-triggering (ECG, end-diastole). Image quality (IQ) of each sequence-variation was qualitatively scored by medical experts and quantitatively assessed by calculating signal-to-noise ratios, contrast relative to muscle, standardized-uptake-value, and tumour-to-blood ratios. Patient comfort was evaluated on patients' experience. Diagnostic accuracy of F-FDG-PET/MRI was compared to F-FDG-PET/CT, in reference to histopathology/cytopathology. RESULTS: ECG-triggered T1-VIBE images showed the highest signal-to-noise ratio (P < 0.01) and the largest contrast between mediastinal soft-tissues, regardless of BH or free-breathing acquisition. IQ of ECG-triggered T1-VIBE scans in BH were scored qualitatively highest with good reader agreement (κ = 0.62). IQ of T2-HASTE was not significantly affected by BH acquisition (P > 0.9). Qualitative IQ of T1-VIBE and T2-HASTE declined after spectral adiabatic inversion recovery fat-suppression. All patients could maintain BH at end-expiration and reported no discomfort. Diagnostic performance of F-FDG-PET/MR was not significantly different from F-FDG-PET/CT with comparable staging, standardized-uptake-values, and tumour-to-blood ratios. However, T-status was more often over-staged on F-FDG-PET/CT, while N-status was more frequently under-staged on F-FDG-PET/MR. CONCLUSION: ECG-triggered T1-VIBE sequences acquired during short, multiple BHs are recommended for mediastinal imaging using F-FDG-PET/MR. With dedicated protocols, F-FDG-PET/MRI will be useful in thoracic oncology and aid in diagnostic evaluation and tailored treatment decision-making.

Uncomplicated 90Y Selective Internal Radio Therapy in a Patient With Hepatocellular Carcinoma After Arterial and Portal Vein Embolizations.

Selective internal radio therapy (SIRT) with Y-glass microspheres was performed in a cirrhotic patient with hepatocellular carcinoma (Barcelona Clinic Liver Cancer stage C) after arterial coil embolization for treatment of intratumoral hemorrhage and planned preoperative right portal vein embolization. Three technetium Tc macro-albumin-aggregate injections were needed to optimize intralesional uptake without extrahepatic deposition. The consecutive SIRT treatment was uncomplicated with a remarkable result.

A universal approach to eliminate antigenic properties of alpha-gliadin peptides in celiac disease.

Celiac disease is caused by an uncontrolled immune response to gluten, a heterogeneous mixture of wheat storage proteins, including the α-gliadins. It has been shown that α-gliadins harbor several major epitopes involved in the disease pathogenesis. A major step towards elimination of gluten toxicity for celiac disease patients would thus be the elimination of such epitopes from α-gliadins. We have analyzed over 3,000 expressed α-gliadin sequences from 11 bread wheat cultivars to determine whether they encode for peptides potentially involved in celiac disease. All identified epitope variants were synthesized as peptides and tested for binding to the disease-associated HLA-DQ2 and HLA-DQ8 molecules and for recognition by patient-derived α-gliadin specific T cell clones. Several specific naturally occurring amino acid substitutions were identified for each of the α-gliadin derived peptides involved in celiac disease that eliminate the antigenic properties of the epitope variants. Finally, we provide proof of principle at the peptide level that through the systematic introduction of such naturally occurring variations α-gliadins genes can be generated that no longer encode antigenic peptides. This forms a crucial step in the development of strategies to modify gluten genes in wheat so that it becomes safe for celiac disease patients. It also provides the information to design and introduce safe gluten genes in other cereals, which would exhibit improved quality while remaining safe for consumption by celiac disease patients.

Fine specificity of monoclonal antibodies against celiac disease-inducing peptides in the gluteome.

BACKGROUND: In celiac disease patients, peptides derived from dietary gluten are recognized by HLA-DQ2-restricted CD4(+) T cells, which results in inflammation. Such immune-stimulatory peptides are found in both gliadins and glutenins. Monoclonal antibodies (mAbs) against these peptides can be used to screen food for the presence of such peptides. OBJECTIVE: We aimed to determine the specificity of 5 mAbs raised against T cell stimulatory peptides found in alpha- and gamma-gliadins and in low- and high-molecular-weight glutenins and to compare it with the specificity of patient-derived T cells. DESIGN: The reactivity of the mAbs with gluten peptides, enzymatic gluten digests, and intact gluten proteins was determined and compared with that of gluten-specific T cells by using a combination of immunologic and biochemical techniques. Furthermore, the reactivity of the mAbs with gluten homologues in barley, rye, and oat was determined. RESULTS: The specificity of the mAbs largely overlaps with that of gluten-specific T cells. Moreover, mAbs detect several homologous peptides present in gluten proteins. All except the LMW-specific mAbs also detect storage proteins present in barley and rye, whereas the gamma-gliadin-specific mAbs also recognize oat proteins. CONCLUSION: The mAbs raised against T cell stimulatory peptides in gliadins and glutenins allow a comprehensive screen for the presence of harmful gluten and gluten-like proteins and peptides in food products. They can thus be used to guarantee the safety of food for celiac disease patients.

Highly efficient gluten degradation with a newly identified prolyl endoprotease: implications for celiac disease.

Celiac disease is a T cell-driven intolerance to wheat gluten. The gluten-derived T cell epitopes are proline-rich and thereby highly resistant to proteolytic degradation within the gastrointestinal tract. Oral supplementation with prolyl oligopeptidases has therefore been proposed as a potential therapeutic approach. The enzymes studied, however, have limitations as they are irreversibly inactivated by pepsin and acidic pH, both present in the stomach. As a consequence, these enzymes will fail to degrade gluten before it reaches the small intestine, the site where gluten induces inflammatory T cell responses that lead to celiac disease. We have now determined the usefulness of a newly identified prolyl endoprotease from Aspergillus niger for this purpose. Gluten and its peptic/tryptic digest were treated with prolyl endoprotease, and the destruction of the T cell epitopes was tested using mass spectrometry, T cell proliferation assays, ELISA, reverse-phase HPLC, SDS-PAGE, and Western blotting. We observed that the A. niger prolyl endoprotease works optimally at 4-5 pH, remains stable at 2 pH, and is completely resistant to digestion with pepsin. Moreover, the A. niger-derived enzyme efficiently degraded all tested T cell stimulatory peptides as well as intact gluten molecules. On average, the endoprotease from A. niger degraded gluten peptides 60 times faster than a prolyl oligopeptidase. Together these results indicate that the enzyme from A. niger efficiently degrades gluten proteins. Future studies are required to determine if the prolyl endoprotease can be used as an oral supplement to reduce gluten intake in patients.