The worldwide COVID-19 pandemic caused a decline in sonographic examinations - is this a continuing trend?

PURPOSE: Due to the increasing number of COVID-19 infections since spring 2020 the patient care workflow underwent changes in Germany. To minimize face-to-face exposure and reduce infection risk, non-time-critical elective medical procedures were postponed. Since ultrasound examinations include non-time-critical elective examinations and often can be substituted by other imaging modalities not requiring direct patient contact, the number of examinations has declined significantly. The aim of this study is to quantify the baseline number of ultrasound examinations in the years before, during, and in the early post-pandemic period of the COVID-19 pandemic (since January 2015 to September 2023), and to measure the number of examinations at different German university hospitals. MATERIALS AND METHODS: The number of examinations was assessed based on a web-based database at all participating clinics at the indicated time points. RESULTS: N = 288 562 sonographic examinations from four sites were included in the present investigation. From January 2020 to June 2020, a significantly lower number of examinations of n = 591.21 vs. 698.43 (p = 0.01) per month and included center was performed. Also, excluding the initial pandemic period until June 2020, significantly fewer ultrasound examinations were performed compared to pre-pandemic years 648.1 vs. 698.4 (p < 0.05), per month and included center, while here differences between the individual centers were observed. In the late phase of the pandemic (n = 681.96) and in the post-pandemic phase (as defined by the WHO criteria from May 2023; n = 739.95), the number of sonographic examinations returned to pre-pandemic levels. CONCLUSION: The decline in the number of sonographic examinations caused by the COVID-19 pandemic was initially largely intentional and can be illustrated quantitatively. After an initial abrupt decline in sonographic examinations, the pre-pandemic levels could not be reached for a long time, which could be due to restructuring of patient care and follow-up treatment. In the post-pandemic phase, the pre-pandemic level has been achieved again. The reasons for a prolonged reduction in ultrasound examinations are discussed in this article. KEY POINTS: · During the pandemic, significantly fewer ultrasound examinations were performed in the included centers.. · The number of examinations could not be reach the pre-pandemic level for a long time, which could be due to restructuring of patient care and follow-up treatment.. · Identifying causes for sonographic exam reduction is crucial in pandemic preparedness to uphold healthcare quality and continuity for all patients.. · The prolonged decline in sonographic examinations during the pandemic does not represent a lasting trend, as evidenced by the return to pre-pandemic levels..

Preoperative Perforator Mapping in DIEP Flaps for Breast Reconstruction. The Impact of New Contrast-Enhanced Ultrasound Techniques.

Deep inferior epigastric artery flaps (DIEP) represent the gold standard of autologous breast reconstruction. Due to significant variations in vascular anatomy, preoperative perforator mapping (PM) is mandatory in order to ensure the presence of a sufficient perforator within the flap. In this regard, CT angiography (CTA) is currently the method of choice. Therefore, we investigated the value of contrast-enhanced ultrasound (CEUS) techniques for preoperative PM in comparison to CTA. Patients underwent PM, utilizing both CTA and CEUS techniques. Documentation included the course of the vascular pedicle through the rectus muscle (M), fascial penetration (F), the subcutaneous plexus (P) and the skin point (SP) on either side of the abdomen. Thus, contrast-enhanced B-Flow (BCEUS), B-Flow ultrasound (BUS), CEUS, color Doppler ultrasound (CDUS) and CTA were evaluated in terms of the diagnostic consistency and effectiveness of PM. Precision (∆L) was then calculated in relation to the actual intraoperative location. Statistical analysis included Kruskall-Wallis, Levene and Bonferroni tests, as well as Spearman correlations. A total of 39 DIEP flaps were analyzed. Only CTA (∆L = 2.85 mm) and BCEUS (∆L = 4.57 mm) enabled complete PM, also including P and SP, whereas CDUS, CEUS and BUS enabled clear PM throughout M and F only. Regarding the number of detected perforators, PM techniques are ranked from high to low as follows: CTA, BCEUS, BUS, CEUS and CDUS. CTA and BCEUS showed sufficient diagnostic consistency for SP, P and F, while CDUS and CTA had a superior performance for M. BCEUS offers precise image-controlled surface tags and dynamic information for PM without imposing radiation and may, therefore, be considered a feasible add-on or alternative to CTA. However, BCEUS requires an experienced examiner and is more time-consuming.

Multimodal Targeted Nanoparticle-Based Delivery System for Pancreatic Tumor Imaging in Cellular and Animal Models.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), which ranks forth on the cancer-related death statistics still is both a diagnostic and a therapeutic challenge. Adenocarcinoma of the exocrine human pancreas originates in most instances from malignant transformation of ductal epithelial cells, alternatively by Acinar-Ductal Metaplasia (ADM). RA-96 antibody targets to a mucin M1, according to the more recent nomenclature MUC5AC, an extracellular matrix component excreted by PDAC cells. In this study, we tested the usability of multimodal nanoparticle carrying covalently coupled RA-96 Fab fragments for pancreatic tumor imaging. METHODS: In order to make and evaluate a novel, better targeting, theranostic nanoparticle, iron nanoparticles and the optical dye indocyanin green (ICG) were encapsulated into the cationic sphingomyelin (SM) consisting liposomes. RA-96 Fab fragment was conjugated to the liposomal surface of the nanoparticle to increase tumor homing ability. ICG and iron nanoparticle-encapsulated liposomes were studied in vitro with cells and (i) their visibility in magnetic resonance imaging (MRI), (ii) optical, (iii) Magnetic particle spectroscopy (MPS) and (iv) photoacoustic settings was tested in vitro and also in in vivo models. The targeting ability and MRI and photoacoustic visibility of the RA-96-nanoparticles were first tested in vitro cell models where cell binding and internalization were studied. In in vivo experiments liposomal nanoparticles were injected into the tail vain using an orthotopic pancreatic tumor xenograft model and subcutaneous pancreatic cancer cell xenografts bearing mice to determine in vivo targeting abilities of RA-96-conjugated liposomes Results: Multimodal liposomes could be detected by MRI, MPS and by photoacoustic imaging in addition to optical imaging showing a wide range of imaging utility. The fluorescent imaging of ICG in pancreatic tumor cells Panc89 and Capan-2 revealed an increased association of ICG-encapsulated liposomes carrying RA-96 Fab fragments in vitro compared to the control liposomes without covalently linked RA-96. Fluorescent molecular tomography (FMT) studies showed increased accumulation of the RA96-targeted nanoparticles in the tumor area compared to non-targeted controls in vivo. Similar accumulation in the tumor sites could be seen with liposomal ferric particles in MRI. Fluorescent tumor signal was confirmed by using an intraoperative fluorescent imaging system, which showed fluorescent labeling of pancreatic tumors. CONCLUSION: These results suggest that RA-96-targeted liposomes encapsulating ICG and iron nanoparticles can be used to image pancreatic tumors with a variety of optical and magnetic imaging techniques. Additionally, they might be a suitable drug delivery tool to improve treatment of PDAC patients.

[Imaging in the acute abdomen-part 2 : Case examples of frequent organ-specific causes: gastrointestinal tract and urogenital system]. / Bildgebung bei akutem Abdomen ­ Teil 2 : Fallbeispiele häufiger organbezogener Ursachen: Gastrointestinaltrakt und Urogenitalsystem.

The acute abdomen is a potentially life-threatening condition and requires a rapid diagnosis. After clinical inspection and in cases with unclear ultrasound findings or unclear serious symptoms computed tomography (CT) and in pregnant women and children magnetic resonance imaging (MRI) is usually necessary. This second part of "Imaging in the acute abdomen" focuses on frequent organ specific causes of the gastrointestinal tract and the urogenital system.

An Innovative Approach for Preoperative Perforator Flap Planning Using Contrast-enhanced B-flow Imaging.

Precise perforator mapping of the epifascial and subcutaneous course of the perforator flaps, including the precise detection of the skin point, is mandatory for successful preoperative flap design and planning of supramicrosurgery. We investigated the effectiveness of contrast-enhanced B-flow (BCEUS) imaging for perforator mapping and preoperative perforator flap planning and compared it with B-flow ultrasound, contrast-enhanced ultrasound, and color Doppler ultrasound. Sixteen patients who received an individualized perforator flap reconstruction were included in the study. Preoperative perforator mapping includes the following structures: subfascial course of the pedicle, fascial penetration point, subcutaneous course (epifascial and subcutaneous), and perforator skin point. The precision of the preoperative perforator mapping was analyzed for color Doppler ultrasound, contrast-enhanced ultrasound, B-flow ultrasound, and BCEUS. Each technique was able to precisely display the subfascial course of the vascular pedicle, including the fascial penetration point. However, only BCEUS enabled precise mapping of the epifascial and subcutaneous (suprafascial) course, including the skin point of the perforators with a clear delineation. Precise knowledge of the suprafascial course of the perforators is mandatory for successful supermicrosurgery and perforator flap planning. BCEUS imaging facilitates full perforator mapping, which improves the safety of flap harvesting. However, BCEUS is technically demanding and requires an experienced sonographer.

[Imaging in the acute abdomen - part 1 : Case examples of frequent organ-specific causes: liver, gallbladder, pancreas, spleen and vessels]. / Bildgebung bei akutem Abdomen ­ Teil 1 : Fallbeispiele häufiger organbezogener Ursachen: Leber, Gallenblase, Pankreas, Milz und Gefäße.

The acute abdomen is characterized by acute abdominal pain with defensive muscular tension, can be triggered by a variety of diseases and sometimes represents a life-threatening condition. After clinical inspection, in most cases dedicated imaging should be performed immediately. The frequently causal appendicitis and cholecystitis can mostly be diagnosed with ultrasound. In other cases with unclear ultrasound findings or unclear severe symptoms, computer tomography (CT) is usually necessary without delay. In contrast, magnetic resonance imaging (MRI) is predominantly indicated in pregnant women and children with unclear ultrasound findings. Thus, the radiologist is an important gatekeeper in the diagnostics of acute abdomen. The radiologist should therefore be familiar with the correct imaging indications, the frequent and rare causes as well as the corresponding morphological imaging characteristics.

Acid-Sphingomyelinase Triggered Fluorescently Labeled Sphingomyelin Containing Liposomes in Tumor Diagnosis after Radiation-Induced Stress.

In liposomal delivery, a big question is how to release the loaded material into the correct place. Here, we will test the targeting and release abilities of our sphingomyelin-consisting liposome. A change in release parameters can be observed when sphingomyelin-containing liposome is treated with sphingomyelinase enzyme. Sphingomyelinase is known to be endogenously released from the different cells in stress situations. We assume the effective enzyme treatment will weaken the liposome making it also leakier. To test the release abilities of the SM-liposome, we developed several fluorescence-based experiments. In in vitro studies, we used molecular quenching to study the sphingomyelinase enzyme-based release from the liposomes. We could show that the enzyme treatment releases loaded fluorescent markers from sphingomyelin-containing liposomes. Moreover, the release correlated with used enzymatic activities. We studied whether the stress-related enzyme expression is increased if the cells are treated with radiation as a stress inducer. It appeared that the radiation caused increased enzymatic activity. We studied our liposomes' biodistribution in the animal tumor model when the tumor was under radiation stress. Increased targeting of the fluorescent marker loaded to our liposomes could be found on the site of cancer. The liposomal targeting in vivo could be improved by radiation. Based on our studies, we propose sphingomyelin-containing liposomes can be used as a controlled release system sensitive to cell stress.

Quantitative accuracy of virtual non-contrast images derived from spectral detector computed tomography: an abdominal phantom study.

Dual-energy CT allows for the reconstruction of virtual non-contrast (VNC) images. VNC images have the potential to replace true non-contrast scans in various clinical applications. This study investigated the quantitative accuracy of VNC attenuation images considering different parameters for acquisition and reconstruction. An abdomen phantom with 7 different tissue types (different combinations of 3 base materials and 5 iodine concentrations) was scanned using a spectral detector CT (SDCT). Different phantom sizes (S, M, L), volume computed tomography dose indices (CTDIvol 10, 15, 20 mGy), kernel settings (soft, standard, sharp), and denoising levels (low, medium, high) were tested. Conventional and VNC images were reconstructed and analyzed based on regions of interest (ROI). Mean and standard deviation were recorded and differences in attenuation between corresponding base materials and VNC was calculated (VNCerror). Statistic analysis included ANOVA, Wilcoxon test and multivariate regression analysis. Overall, the VNCerror was - 1.4 ± 6.1 HU. While radiation dose, kernel setting, and denoising level did not influence VNCerror significantly, phantom size, iodine content and base material had a significant effect (e.g. S vs. M: - 1.2 ± 4.9 HU vs. - 2.1 ± 6.0 HU; 0.0 mg/ml vs. 5.0 mg/ml: - 4.0 ± 3.5 HU vs. 5.1 ± 5.0 HU and 35-HU-base vs. 54-HU-base: - 3.5 ± 4.4 HU vs. 0.7 ± 6.5; all p ≤ 0.05). The overall accuracy of VNC images from SDCT is high and independent from dose, kernel, and denoising settings; however, shows a dependency on patient size, base material, and iodine content; particularly the latter results in small, yet, noticeable differences in VNC attenuation.

Maternal high-fat diet induces long-term obesity with sex-dependent metabolic programming of adipocyte differentiation, hypertrophy and dysfunction in the offspring.

Maternal obesity determines obesity and metabolic diseases in the offspring. The white adipose tissue (WAT) orchestrates metabolic pathways, and its dysfunction contributes to metabolic disorders in a sex-dependent manner. Here, we tested if sex differences influence the molecular mechanisms of metabolic programming of WAT in offspring of obese dams. To this end, maternal obesity was induced with high-fat diet (HFD) and the offspring were studied at an early phase [postnatal day 21 (P21)], a late phase (P70) and finally P120. In the early phase we found a sex-independent increase in WAT in offspring of obese dams using magnetic resonance imaging (MRI), which was more pronounced in females than males. While the adipocyte size increased in both sexes, the distribution of WAT differed in males and females. As mechanistic hints, we identified an inflammatory response in females and a senescence-associated reduction in the preadipocyte factor DLK in males. In the late phase, the obese body composition persisted in both sexes, with a partial reversal in females. Moreover, female offspring recovered completely from both the adipocyte hypertrophy and the inflammatory response. These findings were linked to a dysregulation of lipolytic, adipogenic and stemness-related markers as well as AMPKα and Akt signaling. Finally, the sex-dependent metabolic programming persisted with sex-specific differences in adipocyte size until P120. In conclusion, we do not only provide new insights into the molecular mechanisms of sex-dependent metabolic programming of WAT dysfunction, but also highlight the sex-dependent development of low- and high-grade pathogenic obesity.

ATM activity in T cells is critical for immune surveillance of lymphoma in vivo.

The proximal DNA damage response kinase ATM is frequently inactivated in human malignancies. Germline mutations in the ATM gene cause Ataxia-telangiectasia (A-T), characterized by cerebellar ataxia and cancer predisposition. Whether ATM deficiency impacts on tumor initiation or also on the maintenance of the malignant state is unclear. Here, we show that Atm reactivation in initially Atm-deficient B- and T cell lymphomas induces tumor regression. We further find a reduced T cell abundance in B cell lymphomas from Atm-defective mice and A-T patients. Using T cell-specific Atm-knockout models, as well as allogeneic transplantation experiments, we pinpoint impaired immune surveillance as a contributor to cancer predisposition and development. Moreover, we demonstrate that Atm-deficient T cells display impaired proliferation capacity upon stimulation, due to replication stress. Altogether, our data indicate that T cell-specific restoration of ATM activity or allogeneic hematopoietic stem cell transplantation may prevent lymphomagenesis in A-T patients.

Volumetric analysis of MRONJ lesions by semiautomatic segmentation of CBCT images.

PURPOSE: The purpose of this study was to evaluate potential differences in volumes of areas of osteolysis caused by medication-related osteonecrosis of the jaw (MRONJ) between the upper and lower jaw. We aim to analyze the clinical relevance of volumetric measurement of osteolytic lesions for surgical planning of MRONJ patients. METHODS: Sixty-seven patients who were clinically and histopathologically diagnosed with MRONJ were retrospectively included in this study. Cone beam computed tomography (CBCT) images were evaluated according to localization, affected anatomical structures, and volumetric measurement of osteolytic lesions caused by MRONJ in appliance of CBCT datasets by using ITK-SNAP. RESULTS: The most frequently affected localization is the mandible, whereas female patients show significantly more often lesions of the maxilla. The cortical bone was predominantly affected. Furthermore, the affection of teeth, sinus floor, inferior alveolar nerve canal, or even a pathological fracture of the mandible are infrequently existing. The volumetric measurements revealed a statistically significant greater absolute osteolysis volume in males. CONCLUSIONS: Image analysis and volumetric measurements of osteolytic lesions of MRONJ patients is a helpful tool to further understand the clinical appearance and identify compromised anatomic landmarks. Volumetric analysis aids in pre-surgical planning and visualizes the individual extent of the disease for each patient.

Value of spectral detector computed tomography for assessment of pancreatic lesions.

PURPOSE: Dual energy CT (DECT) can contribute to the diagnosis of benign and malignant pancreatic lesions. This study examined whether a novel, detector-based spectral CT scanner (SDCT) may improve subjective assessment of different types of pancreatic lesions and if various quantitative maps may improve lesion contrast and differentiation. MATERIALS AND METHODS: 61 consecutive patients who underwent clinical, contrast-agent enhanced, abdominal SDCT scans and showed pancreatic lesions of different origins were included. Subjective image analysis was performed by two readers who assessed image quality, lesion conspicuity and diagnostic confidence on 5-point Likert scales for conventional polyenergetic reconstructions (polyE), virtual monoenergetic images (monoE), virtual non-contrast images, iodine density, iodine overlay, and Z effective (Zeff) maps. Two readers acquired quantitative values from these maps ROI-based from which contrast-to-noise and lesion-to-parenchyma ratios were calculated. RESULTS: MonoE images at low keV levels yielded highest Likert scores regarding lesion conspicuity and reader confidence; iodine overlays facilitated lesion delineation. Inter-observer agreement ranged between substantial and excellent (kappa values 0.73-0.81). Contrast-to-noise-ratios for low keV monoE images were significantly higher, compared to polyE images (e.g. monoE 40 keV p < 0.0001). Marked overlap between PDAC and miscellaneous non-PDAC lesions was present in various spectral reconstructions. CONCLUSIONS: In line with previous studies, monoE images at low keV levels and iodine overlay maps facilitated subjective lesion delineation which was substantiated by the quantitative analysis. Hence, spectral detector CT improves pancreatic lesion conspicuity, while its value for lesion differentiation needs to be further evaluated in larger study cohorts.

Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU): Overview of Emerging Applications (Part 2).

BACKGROUND: High-intensity focused ultrasound (HIFU) allows noninvasive heating of deep-seated tissues. Guidance under magnetic resonance imaging (MR-HIFU) offers spatial targeting based on anatomical MR images as well as MR-based near-real-time temperature maps. Temperature feedback allows delivery of a well-defined thermal dose enabling new applications such as the ablation of malignant tissue. METHODS: Peer-reviewed publications on MR-HIFU were studied and are summarized in this review. Literature was restricted to applications in oncology. RESULTS: Several MR-HIFU-based applications for the treatment of malignant diseases are currently part of clinical trials or translational research. Recent trials regarding the treatment of prostate cancer with MR-HIFU have already shown this to be a safe and patient-friendly method. For the treatment of breast cancer and malignancies within abdominal organs, MR-HIFU has been applied so far only in proof of concept studies. CONCLUSION: MR-HIFU is currently being investigated for the ablative treatment of malignant tissue in a variety of oncological applications. For example, the transrectal as well as transurethral ablation of prostate cancer using MR-HIFU was shown to be a patient-friendly, safe alternative to other local treatment options with low side effects. KEY POINTS: · MR guidance offers high soft tissue contrast for treatment planning, near-real-time temperature monitoring, and post-interventional therapy evaluation.. · Special HIFU transducers and technological solutions are available for the treatment of e. g. prostate cancer, breast cancer or abdominal malignancies.. CITATION FORMAT: · Siedek F, Yeo SY, Heijman E et al. MR-Guided High-Intensity Focused Ultrasound (MR-HIFU): Overview of Emerging Applications (Part 2). Fortschr Röntgenstr 2019; 191: 531 - 539.

Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU): Technical Background and Overview of Current Clinical Applications (Part 1).

BACKGROUND: Extracorporeal high-intensity focused ultrasound (HIFU) is a promising method for the noninvasive thermal ablation of benign and malignant tissue. Current HIFU treatments are performed under ultrasound (US-HIFU) or magnetic resonance (MR-HIFU) image guidance offering integrated therapy planning, real-time control (spatial and temperature guidance) and evaluation. METHODS: This review is based on publications in peer-reviewed journals addressing thermal ablation using HIFU and includes our own clinical results as well. The technical background of HIFU is explained with an emphasis on MR-HIFU applications. A brief overview of the most commonly performed CE-approved clinical applications for MR-HIFU is given. RESULTS: Over the last decade, several HIFU-based applications have received clinical approval in various countries. In particular, MR-HIFU is now approved for the clinical treatment of uterine fibroids, palliation of bone pain, ablation of the prostate and treatment of essential tremor as a first neurological application. CONCLUSION: MR-HIFU is a patient-friendly noninvasive method for thermal ablation which has received clinical approval for several applications. Overall, clinical data demonstrate treatment efficacy, safety and cost efficiency. KEY POINTS: · HIFU is a promising technique for noninvasive thermal ablation of tissue.. · HIFU is typically performed under image guidance using either diagnostic ultrasound (US-HIFU) or MRI (MR-HIFU).. · The preferred image guidance modality depends on the application.. · MR guidance offers improved soft-tissue contrast for treatment planning, near real-time and noninvasive temperature monitoring and post-interventional therapy evaluation.. · MR-HIFU is CE-approved for treatment of uterine fibroids, alleviation of bone pain, prostate tissue ablation and treatment of essential tremor.. CITATION FORMAT: · Siedek F, Yeo S, Heijman E et al. Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU): Technical Background and Overview of Current Clinical Applications (Part 1). Fortschr Röntgenstr 2019; 191: 522 - 530.

The novel TRAIL-receptor agonist APG350 exerts superior therapeutic activity in pancreatic cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has raised attention as a novel anticancer therapeutic as it induces apoptosis preferentially in tumor cells. However, first-generation TRAIL-receptor agonists (TRAs), comprising recombinant TRAIL and agonistic receptor-specific antibodies, have not demonstrated anticancer activity in clinical studies. In fact, cancer cells are often resistant to conventional TRAs. Therefore, in addition to TRAIL-sensitizing strategies, next-generation TRAs with superior apoptotic activity are warranted. APG350 is a novel, highly potent TRAIL-receptor agonist with a hexavalent binding mode allowing the clustering of six TRAIL-receptors per drug molecule. Here we report on preclinical in vitro and in vivo studies testing the activity of APG350 on pancreatic ductal adenocarcinoma (PDAC) cells. We found that APG350 potently induced apoptosis of Colo357, PancTuI and Panc89 cells in vitro. In addition, APG350 treatment activated non-canonical TRAIL signaling pathways (MAPK, p38, JNK, ERK1/ERK2 and NF-κB) and induced the secretion of IL-8. Stable overexpression of Bcl-xL inhibited APG350-induced cell death and augmented activation of non-canonical pathways. Intriguingly, pre-treatment of Bcl-xL-overexpressing cells with the BH3-mimic Navitoclax restored their sensitivity to APG350. To study the effects of APG350 on PDAC cells in vivo, we applied two different orthotopic xenotransplantation mouse models, with and without primary tumor resection, representing adjuvant and palliative treatment regimes, respectively. APG350 treatment of established tumors (palliative treatment) significantly reduced tumor burden. These effects, however, were not seen in tumors with enforced overexpression of Bcl-xL. Upon primary tumor resection and subsequent APG350 treatment (adjuvant therapy), APG350 limited recurrent tumor growth and metastases. Importantly, therapeutic efficacy of APG350 treatment was more effective compared with treatment with soluble TRAIL in both models. In conclusion, APG350 represents a promising next-generation TRA for the treatment of PDAC. Moreover, our results suggest that combining APG350 with Navitoclax might be a succesfull strategy for cancers harboring mitochondrial apoptosis resistance.

Intra-individual comparison between abdominal virtual mono-energetic spectral and conventional images using a novel spectral detector CT.

OBJECTIVES: To quantitatively and qualitatively assess abdominal arterial and venous phase contrast-enhanced spectral detector computed tomography (SDCT) virtual mono-energetic (MonoE) datasets in comparison to conventional CT reconstructions provided by the same system. MATERIALS AND METHODS: Conventional and MonoE images at 40-120 kilo-electron volt (keV) levels with a 10 keV increment as well as 160 and 200 keV were reconstructed in abdominal SDCT datasets of 55 patients. Attenuation, image noise, and contrast- / signal-to-noise ratios (CNR, SNR) of vessels and solid organs were compared between MonoE and conventional reconstructions. Two readers assessed contrast conditions, detail visualization, overall image quality and subjective image noise with both, fixed and adjustable window settings. RESULTS: Attenuation, CNR and SNR of vessels and solid organs showed a stepwise increase from high to low keV reconstructions in both contrast phases while image noise stayed stable at low keV MonoE reconstruction levels. Highest levels were found at 40 keV MonoE reconstruction (p<0.001), respectively. Solid abdominal organs showed a stepwise decrease from low to high energy levels in regard to attenuation, CNR and SNR with significantly higher values at 40 and 50 keV, compared to conventional images. The 70 keV MonoE was comparable to conventional poly-energetic reconstruction (p≥0.99). Subjective analysis displayed best image quality for the 70 keV MonoE reconstruction level in both phases at fixed standard window presets and at 40 keV if window settings could be adjusted. CONCLUSION: SDCT derived low keV MonoE showed markedly increased CNR and SNR values due to constantly low image noise values over the whole energy spectrum from 40 to 200 keV.

IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin-6 (IL-6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL-6 classic and the IL-6 trans-signaling pathway. Whereas IL-6 classic signaling is important for innate and acquired immunity, IL-6 trans-signaling has been linked to accelerated liver regeneration and several chronic inflammatory pathologies. However, its implication in liver tumorigenesis has not been addressed yet. Here, we show that IL-6 trans-signaling, but not IL-6 classic signaling, is essential to promote hepatocellular carcinogenesis by two mechanisms: First, it prevents DNA-damage-induced hepatocyte apoptosis through suppression of p53 and enhances ß-catenin activation and tumor proliferation. Second, IL-6 trans-signaling directly induces endothelial cell proliferation to promote tumor angiogenesis. Consequently, soluble gp130 fused to Fc transgenic mice lacking IL-6 trans-signaling are largely protected from tumor formation in a diethylnitrosamine/3,3',5,5'-tetrachloro-1,4-bis(pyridyloxy)benzene model of HCC. CONCLUSION: IL-6 trans-signaling, and not IL-6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL-6 classic signaling-driven protective immune responses. (Hepatology 2017;65:89-103).

Increased survival rate by local release of diclofenac in a murine model of recurrent oral carcinoma.

Despite aggressive treatment with radiation and combination chemotherapy following tumor resection, the 5-year survival rate for patients with head and neck cancer is at best only 50%. In this study, we examined the therapeutic potential of localized release of diclofenac from electrospun nanofibers generated from poly(D,L-lactide-co-glycolide) polymer. Diclofenac was chosen since anti-inflammatory agents that inhibit cyclooxygenase have shown great potential in their ability to directly inhibit tumor growth as well as suppress inflammation-mediated tumor growth. A mouse resection model of oral carcinoma was developed by establishing tumor growth in the oral cavity by ultrasound-guided injection of 1 million SCC-9 cells in the floor of the mouth. Following resection, mice were allocated into four groups with the following treatment: 1) no treatment, 2) implanted scaffolds without diclofenac, 3) implanted scaffolds loaded with diclofenac, and 4) diclofenac given orally. Small animal ultrasound and magnetic resonance imaging were utilized for longitudinal determination of tumor recurrence. At the end of 7 weeks following tumor resection, 33% of mice with diclofenac-loaded scaffolds had a recurrent tumor, in comparison to 90%-100% of the mice in the other three groups. At this time point, mice with diclofenac-releasing scaffolds showed 89% survival rate, while the other groups showed survival rates of 10%-25%. Immunohistochemical staining of recurrent tumors revealed a near 10-fold decrease in the proliferation marker Ki-67 in the tumors derived from mice with diclofenac-releasing scaffolds. In summary, the local application of diclofenac in an orthotopic mouse tumor resection model of oral cancer reduced tumor recurrence with significant improvement in survival over a 7-week study period following tumor resection. Local drug release of anti-inflammatory agents should be investigated as a therapeutic option in the prevention of tumor recurrence in oral squamous carcinoma.

Fractal Dimension of Tumor Microvasculature by DCE-US: Preliminary Study in Mice.

Neoangiogenesis, which results in the formation of an irregular network of microvessels, plays a fundamental role in the growth of several types of cancer. Characterization of microvascular architecture has therefore gained increasing attention for cancer diagnosis, treatment monitoring and evaluation of new drugs. However, this characterization requires immunohistologic analysis of the resected tumors. Currently, dynamic contrast-enhanced ultrasound imaging (DCE-US) provides new options for minimally invasive investigation of the microvasculature by analysis of ultrasound contrast agent (UCA) transport kinetics. In this article, we propose a different method of analyzing UCA concentration that is based on the spatial distribution of blood flow. The well-known concept of Mandelbrot allows vascular networks to be interpreted as fractal objects related to the regional blood flow distribution and characterized by their fractal dimension (FD). To test this hypothesis, the fractal dimension of parametric maps reflecting blood flow, such as UCA wash-in rate and peak enhancement, was derived for areas representing different microvascular architectures. To this end, subcutaneous xenograft models of DU-145 and PC-3 prostate-cancer lines in mice, which show marked differences in microvessel density spatial distribution inside the tumor, were employed to test the ability of DCE-US FD analysis to differentiate between the two models. For validation purposes, the method was compared with immunohistologic results and UCA dispersion maps, which reflect the geometric properties of microvascular architecture. The results showed good agreement with the immunohistologic analysis, and the FD analysis of UCA wash-in rate and peak enhancement maps was able to differentiate between the two xenograft models (p < 0.05).

Periodontal regeneration employing gingival margin-derived stem/progenitor cells in conjunction with IL-1ra-hydrogel synthetic extracellular matrix.

AIM: This study investigated the periodontal regenerative potential of gingival margin-derived stem/progenitor cells (G-MSCs) in conjunction with IL-1ra-releasing hyaluronic acid synthetic extracellular matrix (HA-sECM). MATERIALS AND METHODS: Periodontal defects were induced at four sites in eight miniature pigs in the premolar/molar area (-4 weeks). Autologus G-MSCs were isolated from the free gingival margin and magnetically sorted, using anti-STRO-1 antibodies. Colony formation and multilineage differentiation potential were tested. The G-MSCs were expanded and incorporated into IL-1ra-loaded/unloaded HA-sECM. Within every miniature pig, four periodontal defects were randomly treated with IL-1ra/G-MSCs/HA-sECM (test group), G-MSCs/HA-sECM (positive-control), scaling and root planing (SRP; negative control-1) or left untreated (no-treatment group; negative control 2). Differences in clinical attachment level (ΔCAL), probing depth (ΔPD), gingival recession (ΔGR), radiographic defect volume (ΔRDV), and changes in bleeding on probing (BOP) between baseline and 16 weeks post-transplantation, as well as periodontal attachment level (PAL), junctional epithelium length (JE), connective tissue adhesion (CTA), cementum regeneration (CR) and bone regeneration (BR) at 16 weeks post-transplantation were evaluated. RESULTS: Isolated G-MSCs showed stem/progenitor cell characteristics. IL-1ra loaded and unloaded G-MSCs/HA-sECM showed higher ΔCAL, ΔPD, ΔGR, PAL, CR and BR as well as a lower JE compared to their negative controls and improved BOP. CONCLUSION: G-MSCs in conjunction with IL-1ra-loaded/unloaded HA-sECM show a significant periodontal regenerative potential.