Loss of hepatic Sirt7 accelerates diethylnitrosamine (DEN)-induced formation of hepatocellular carcinoma by impairing DNA damage repair.

The mammalian sirtuin family (SIRT1-SIRT7) has shown diverse biological roles in the regulation and maintenance of genome stability under genotoxic stress. SIRT7, one of the least studied sirtuin, has been demonstrated to be a key factor for DNA damage response (DDR). However, conflicting results have proposed that Sirt7 is an oncogenic factor to promote transformation in cancer cells. To address this inconsistency, we investigated properties of SIRT7 in hepatocellular carcinoma (HCC) regulation under DNA damage and found that loss of hepatic Sirt7 accelerated HCC progression. Specifically, the number, size, and volume of hepatic tumor colonies in diethylnitrosamine (DEN) injected Sirt7-deficient liver were markedly enhanced. Further, levels of HCC progression markers and pro-inflammatory cytokines were significantly elevated in the absence of hepatic Sirt7, unlike those in the control. In chromatin, SIRT7 was stabilized and colocalized to damage site by inhibiting the induction of γH2AX under DNA damage. Together, our findings suggest that SIRT7 is a crucial factor for DNA damage repair and that hepatic loss-of-Sirt7 can promote genomic instability and accelerate HCC development, unlike early studies describing that Sirt7 is an oncogenic factor [BMB Reports 2024; 57(2): 98-103].

Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma.

AIMS: Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance. METHODS: Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib. RESULTS: SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1ß inhibition. CONCLUSIONS: SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.

X-Ray Versus Magnetic Resonance Imaging in Diabetic Foot Osteomyelitis: A Clinical Comparison.

OBJECTIVE: Radiographic imaging is an important diagnostic tool in diabetic foot osteomyelitis (DFO). It is unknown whether DFO cases diagnosed with conventional X-ray versus positive Magnetic Resonance Imaging (MRI) differ regarding epidemiology and treatment outcome. Theoretically, signs of inflammation on MRI without bone lesions might be easier to treat. METHODS: Our clinical pathway for diabetic foot infections discourages the use of MRI for the diagnosis of DFO. We compared the epidemiology and therapy of non-amputated DFO with positive features on conventional X-ray, MRI, or both. Radiology specialists interpreted the images. The intraoperative aspect of bone during amputation and the results of bone cultures were considered the gold standard for DFO diagnosis. RESULTS: We prospectively followed 390 DFO episodes in 186 adult patients for a median of 2.9 years and performed 318 conventional X-rays (median costs 100 Swiss Francs; 100 US$) and 47 (47/390; 12%) MRI scans (median 800 Swiss Francs; 800 US $). Among them, 18 episodes were associated with positive MRI findings but lacked bone lesions on X-ray. After debridement, the median duration of systemic antibiotics was 28 days for MRI-only episodes and 30 days for X-ray-positive cases (Wilcoxonranksum- test; p=0.26). The corresponding median numbers of surgical debridements were 1 and 1; and recurrence was witnessed in 25% and 28%, respectively. In multivariate logistic regression analysis, MRI-only episodes did not alter the remission rate (odds ratio 0.5, 95%CI 0.1-5.2). CONCLUSION: According to our clinical pathway, DFO episodes with positive MRI findings only did not differ epidemiologically from the remaining DFO cases and did not influence the choice of therapy nor remission rate.

Is Response Assessment of Breast Cancer Bone Metastases Better with Measurement of 18F-Fluoride Metabolic Flux Than with Measurement of 18F-Fluoride PET/CT SUV?

Our purpose was to establish whether noninvasive measurement of changes in 18F-fluoride metabolic flux to bone mineral (Ki) by PET/CT can provide incremental value in response assessment of bone metastases in breast cancer compared with SUVmax and SUVmeanMethods: Twelve breast cancer patients starting endocrine treatment for de novo or progressive bone metastases were included. Static 18F-fluoride PET/CT scans were acquired 60 min after injection, before and 8 wk after commencing treatment. Venous blood samples were taken at 55 and 85 min after injection to measure plasma 18F-fluoride activity concentrations, and Ki in individual bone metastases was calculated using a previously validated method. Percentage changes in Ki, SUVmax, and SUVmean were calculated from the same index lesions (≤5 lesions) from each patient. Clinical response up to 24 wk, assessed in consensus by 2 experienced oncologists masked to PET imaging findings, was used as a reference standard. Results: Of the 4 patients with clinically progressive disease (PD), mean Ki significantly increased (>25%) in all, SUVmax in 3, and SUVmean in 2. Of the 8 non-PD patients, Ki decreased or remained stable in 7, SUVmax in 5, and SUVmean in 6. A significant mean percentage increase from baseline for Ki, compared with SUVmax and SUVmean, occurred in the 4 patients with PD (89.7% vs. 41.8% and 43.5%, respectively; P < 0.001). Conclusion: After 8 wk of endocrine treatment for bone-predominant metastatic breast cancer, Ki more reliably differentiated PD from non-PD than did SUVmax and SUVmean, probably because measurement of SUV underestimates fluoride clearance by not considering changes in input function.

Iterative Algorithms Applied to Treated Intracranial Aneurysms.

PURPOSE: To investigate the impact of iterative metal artifact reduction (iMAR) on artifacts related to neurosurgical clips or endovascular coils when combined to filtered back projection (FBP) or advanced modelled iterative reconstruction (ADMIRE). MATERIAL AND METHODS: In this study 21 unenhanced brain computed tomography (CT) examinations were reconstructed with FBP and level 2 of ADMIRE, both techniques with and without iMAR algorithm, resulting in 4 series per acquisition. Subjective assessment of artifact reduction was performed as a double-blinded evaluation with a 5-point-scale. Objective analysis was performed by comparing central tendencies and distributions of voxel densities. The central tendency was assessed as the mean voxel density in Hounsfield units. The distribution was assessed by evaluating the shape and asymmetry of the histograms of voxels densities with measures of kurtosis and skewness, respectively. RESULTS: Inter-reader agreement was excellent (>0.8). FBP and ADMIRE without iMAR were scored 4 and with iMAR 5. Unusual artifacts were noted in all of the series reconstructed with iMAR, especially when combined with ADMIRE. Kurtosis revealed statistical differences for all reconstruction techniques (p ≤ 0.0007) except for the association of FBP with iMAR (p = 0.2211) for the coiling population and skewness demonstrated no statistical difference in any population (p ≥ 0.0558), confirming the subjective analysis results, except for the ADMIRE algorithm with or without iMAR (p ≤ 0.0342) in the coiling population. CONCLUSION: iMAR led to the reduction in artifacts due to intracranial metallic devices. However, it created a new artifact in the form of a halo of photon-starvation, especially when combined with ADMIRE. The combination of FBP and iMAR seems more suitable, combining the beneficial metal artifact reduction without the emergence of a halo of photon starvation just around the point of interest.

Radiological findings of complications after lung transplantation.

Complications following lung transplantation may impede allograft function and threaten patient survival. The five main complications after lung transplantation are primary graft dysfunction, post-surgical complications, alloimmune responses, infections, and malignancy. Primary graft dysfunction, a transient ischemic/reperfusion injury, appears as a pulmonary edema in almost every patient during the first three days post-surgery. Post-surgical dysfunction could be depicted on computed tomography (CT), such as bronchial anastomosis dehiscence, bronchial stenosis and bronchomalacia, pulmonary artery stenosis, and size mismatch. Alloimmune responses represent acute rejection or chronic lung allograft dysfunction (CLAD). CLAD has three different forms (bronchiolitis obliterans syndrome, restrictive allograft syndrome, acute fibrinoid organizing pneumonia) that could be differentiated on CT. Infections are different depending on their time of occurrence. The first post-operative month is mostly associated with bacterial and fungal pathogens. From the second to sixth months, viral pneumonias and fungal and parasitic opportunistic infections are more frequent. Different patterns according to the type of infection exist on CT. Malignancy should be depicted and corresponded principally to post-transplantation lymphoproliferative disease (PTLD). In this review, we describe specific CT signs of these five main lung transplantation complications and their time of occurrence to improve diagnosis, follow-up, medical management, and to correlate these findings with pathology results. KEY POINTS: • The five main complications are primary graft dysfunction, surgical, alloimmune, infectious, and malignancy complications. • CT identifies anomalies in the setting of unspecific symptoms of lung transplantation complications. • Knowledge of the specific CT signs can allow a prompt diagnosis. • CT signs maximize the yield of bronchoscopy, transbronchial biopsy, and bronchoalveolar lavage. • Radiopathological correlation helps to understand CT signs after lung transplantation complications.

Noninvasive pulmonary nodule characterization using transcutaneous bioconductance: Preliminary results of an observational study.

We sought to assess the use of an electro pulmonary nodule (EPN) scanner (FreshMedx, Salt Lake City, UT) in the noninvasive characterization of pulmonary nodules using transcutaneous bioconductance.Monocentric prospective study including patients with a pulmonary nodule identified on a chest computed tomography scan. Study protocol approved by the institutional review board and written consent was obtained for every patient. 32 patients (12 females and 20 males), average age 65 years, and average lesion size 33.1 mm (range: 9-123 mm). Data collection by a trained physician, 62 skin surface measurements on the chest, arms, and hands bilaterally. Results were anonymized and mailed to a central data center for analysis and compared to histopathology.Pathology results obtained by percutaneous biopsy (n = 14), surgical biopsy (n = 1), or surgical resection (n = 17) showed 29 malignant lesions (adenocarcinoma n = 21, squamous cell carcinoma n = 5, typical carcinoid n = 1, metastasis n = 2), and 3 benign lesions (necrotic granuloma n = 1, no malignant cells on biopsy n = 2). EPN scanner results had a specificity of 66.67% (95% confidence interval [CI] 0.09-0.99), sensitivity 72.41% (95% CI 0.53-0.87), positive predictive value 95.45% (95% CI 0.81-0.99), and a negative predictive value 20.00% (95% CI 0.08-0.40).This pilot study showed a high positive predictive value of the EPN scanner, allowing aggressive management of lung nodules characterized as malignant. The low negative predictive value warrants further investigation of nodules that are characterized as benign.

Comparison of whole body magnetic resonance imaging (WBMRI) to whole body computed tomography (WBCT) or 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) in patients with myeloma: Systematic review of diagnostic performance.

OBJECTIVES: To undertake a systematic review to determine the diagnostic performance of whole body MRI (WBMRI) including diffusion weighted sequences (DWI) compared to whole body computed tomography (WBCT) or 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) in patients with myeloma. METHODS: Two researchers searched the primary literature independently for WBMRI studies of myeloma. Data were extracted focusing on the diagnostic ability of WBMRI versus WBCT and 18F-FDG PET/CT. Meta-analysis was intended. RESULTS: 6 of 2857 articles were eligible that included 147 patients, published from 2008 to 2016. Studies were heterogeneous including both newly diagnosed & relapsed patients. All were single centre studies. Four of the six studies (66.7%) accrued prospectively and 5/6 (83.3%, 3 prospective) included WBMRI and 18F-FDG PET/CT. Three of seven (42.9%) included DWI. The lack of an independent reference standard for individual lesions was noted in 5/6 (83.3%) studies. Studies reported that WBMRI detected more lesions than 18F-FDG PET/CT (sensitivity 68-100% versus 47-100%) but was less specific (specificity 37-83% versus 62-85.7%). No paper assessed impact on management. CONCLUSIONS: Studies were heterogeneous, the majority lacking an independent reference standard. Future prospective trials should address these limitations and assess the impact of WBMRI on management.

Unusual Presentation of Elastofibroma Dorsi on 18F-FDG-PET/CT: A Case Report.

A 70-year-old male patient underwent an Fluorodeoxyglucose-positron emission tomography-computed tomography for staging of a left parahilar lung neoplasm found during work-up for fatigue and asthenia. The scan demonstrated a hypermetabolic lung tumor, a hypermetabolic pleural effusion and 4 hypermetabolic bilateral soft tissue lesions of the chest wall corresponding to 4 elastofibroma dorsi. Initially, the oncologic disease was classified as stage IV because of the hypermetabolic pleural effusion. A transbronchial biopsy showed squamous cell carcinoma and the cytology of the pleural effusion revealed no malignant cells. As the other 4 hypermetabolic thoracic wall lesions were correctly diagnosed as benign despite their unusual presentation, the patient underwent surgery by left pneumonectomy and mediastinal lymphadenectomy. The lymph node involvement required adjuvant chemotherapy. Diagnostic confidence of the benignity of the hypermetabolic chest wall lesions allowed a more aggressive treatment with a better outcome after a malignant pleural effusion was excluded.

Diagnosis of acute ischemia using dual energy CT after mechanical thrombectomy.

BACKGROUND AND PURPOSE: To assess the performance of dual energy unenhanced CT in the detection of acute ischemia after mechanical thrombectomy. METHODS: Retrospective study, approved by the local institutional review board, including all patients that underwent intra-arterial thrombectomy in our institution over a period of 2 years. The presence of acute ischemia and hemorrhage was evaluated by three readers. Sensitivity and specificity of the non-contrast CT weighted sum image (NCCT) and the virtual non-contrast reconstructed image (VNC) were estimated and compared using generalized estimating equations to account for the non-independence of regions in each patient. RESULTS: 58 patients (27 women and 31 men; mean age 70.4 years) were included in the study, yielding 580 regions of interest. Sensitivity and specificity in detecting acute ischemia were higher for all readers when using VNC, with a significant increase in sensitivity for two readers (p<0.001 and 0.01) and a significant increase in specificity in one reader (p<0.001). Specificity in detecting hemorrhage was excellent for all readers. CONCLUSIONS: Dual energy unenhanced CT VNC images were superior in the identification of acute ischemia in comparison with NCCT.

Hybrid PET/MRI as a tool to detect brown adipose tissue: Proof of principle.

OBJECTIVE: The purpose of this study was to assess the performance of (18)F-FDG hybrid PET/MRI to detect and localise the presence of metabolically active brown adipose tissue (BAT). METHODS: We retrospectively analyzed 197 consecutive (18)F-flurodeoxyglucose ((18)F-FDG) positron-emission tomographic (PET) and magnetic resonance imaging (MRI) images performed with a hybrid whole-body PET-MRI tomography in 192 patients. These patients were originally investigated mainly for oncological staging, in the absence of a cooling protocol. The presence of BAT was defined as a soft tissue structure that was larger than 4mm in diameter, had the characteristics of fat tissue on MRI and had a maximal standardised uptake value (SUV) of (18)F-FDG of at least 2.0. No specific MRI sequences for BAT detection were acquired. RESULTS: PET/MRI identified the presence of metabolically active BAT in 5 out of 192 patients (2.6%). BAT positive subjects were all female, significantly younger and with significantly lower body weight than BAT negative subjects. CONCLUSIONS: Whole body hybrid PET/MRI allowed for the identification of BAT, with a low prevalence, comparable to previous retrospective PET/CT studies realised in the absence of a cooling protocol. The main advantages of the PET/MRI hybrid technique, as compared with PET/CT, includes a lower radiation burden, and the possibility to combine a multiparameter fat characterization by dedicated MRI sequences. Hybrid PET/MRI might represent the ideal tool for BAT evaluation.

Three-dimensional MR imaging of the brachial plexus.

Pathologic conditions of the brachial plexus often result in serious and disabling complications. With the increasing availability and use of new and powerful MRI sequences and coils, understanding and assessment of the complex anatomy and pathology of the brachial plexus have been greatly facilitated. These new technical developments have led to an improved assessment of brachial plexus lesions, thereby improving patient care. In this article we describe various MRI techniques for the evaluation of the brachial plexus obtained at 1.5 T and 3 T, and we explain differences and similarities between sequences and protocols performed on MRI equipment from different vendors. The main characteristics of pathologic conditions affecting the brachial plexus are discussed and illustrated, as well as their differential diagnoses, with an emphasis on key imaging findings and relevance for patient management. Pitfalls related to suboptimal technique and image interpretation are also addressed.

Approaches for the optimization of MR protocols in clinical hybrid PET/MRI studies.

Magnetic resonance imaging (MRI) is the examination method of choice for the diagnosis of a variety of diseases. MRI allows us to obtain not only anatomical information but also identification of physiological and functional parameters such as networks in the brain and tumor cellularity, which plays an increasing role in oncologic imaging, as well as blood flow and tissue perfusion. However, in many cases such as in epilepsy, degenerative neurological diseases and oncological processes, additional metabolic and molecular information obtained by PET can provide essential complementary information for better diagnosis. The combined information obtained from MRI and PET acquired in a single imaging session allows a more accurate localization of pathological findings and better assessment of the underlying physiopathology, thus providing a more powerful diagnostic tool. Two hundred and twenty-one patients were scanned from April 2011 to January 2012 on a Philips Ingenuity TF PET/MRI system. The purpose of this review article is to provide an overview of the techniques used for the optimization of different protocols performed in our hospital by specialists in the following fields: neuroradiology, head and neck, breast, and prostate imaging. This paper also discusses the different problems encountered, such as the length of studies, motion artifacts, and accuracy of image fusion including physical and technical aspects, and the proposed solutions.