Boiling histotripsy exhibits anti-fibrotic effects in animal models of liver fibrosis.

Liver fibrosis is a hallmark of chronic liver disease which could lead to liver cirrhosis or liver cancer. However, there is currently lack of a direct treatment for liver fibrosis. Boiling histotripsy (BH) is an emerging non-invasive high-intensity focused ultrasound technique that can be employed to mechanically destruct solid tumour at the focus via acoustic cavitation without significant adverse effect on surrounding tissue. Here, we investigated whether BH can mechanically fractionate liver fibrotic tissue thereby exhibiting an anti-fibrotic effect in an animal model of liver fibrosis. BH-treated penumbra and its identical lobe showed reduced liver fibrosis, accompanied by increased hepatocyte specific marker expression, compared to the BH-untreated lobe. Furthermore, BH treatment improved serological liver function markers without notable adverse effects. The ability of BH to reduce fibrosis and promote liver regeneration in liver fibrotic tissue suggests that BH could potentially be an effective and reliable therapeutic approach against liver fibrosis.

Effects of repetitive transcranial magnetic stimulation on improving cerebral blood flow in patients with middle cerebral artery steno-occlusion.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been reported to induce neurogenesis and angiogenesis. As increased neural activity can induce a hemodynamic response, we investigated the effect of rTMS on perfusion in patients with middle cerebral artery steno-occlusion. METHODS: This was a prospective, randomized, open-label, blinded end-point, pilot study. Patients were divided into two groups (rTMS intervention and non-intervention) which were both administered antiplatelet drugs to treat vascular steno-occlusion. In the intervention group, additional rTMS was performed on the area with stenosis and obstruction. Perfusion rates were compared using single-photon emission computed tomography / computed tomography (SPECT/CT). RESULTS: From June 2020 to May 2022, 16 patients were subjected to 1:1 randomization. Using the standardized uptake value ratio (SUVr) to quantify perfusion in the affected brain region, the corresponding SPECT/CT values before and after rTMS were obtained. Imaging analysis was compared between eight and seven patients in the rTMS and control groups, respectively. Based on the comparison between the target and ipsilateral cerebellum SUVmeans, four patients had a ≥ 20% increase in SUVr in the rTMS group and none in the control group. Changes in SUVr were significantly different between the initial and follow-up SPECT/CT in the rTMS group (p = 0.033); no significant difference was observed in the control group (p = 0.481). CONCLUSION: We observed a significant improvement in perfusion in the stimulation group in a perfusion test performed between 6 and 12 months after rTMS stimulation in stroke patients with steno-occlusion of the middle cerebral artery.

Noninvasive mechanical destruction of liver tissue and tissue decellularisation by pressure-modulated shockwave histotripsy.

Introduction: Boiling histotripsy (BH) is a promising High Intensity Focused Ultrasound (HIFU) technique that can be used to mechanically fractionate solid tumours at the HIFU focus noninvasively, promoting tumour immunity. Because of the occurrence of shock scattering phenomenon during BH process, the treatment accuracy of BH is, however, somewhat limited. To induce more localised and selective tissue destruction, the concept of pressure modulation has recently been proposed in our previous in vitro tissue phantom study. The aim of the present study was therefore to investigate whether this newly developed histotripsy approach termed pressure-modulated shockwave histotripsy (PSH) can be used to induce localised mechanical tissue fractionation in in vivo animal model. Methods: In the present study, 8 Sprague Dawley rats underwent the PSH treatment and were sacrificed immediately after the exposure for morphological and histological analyses (paraffin embedded liver tissue sections were stained with H&E and MT). Partially exteriorised rat's left lateral liver lobe in vivo was exposed to a 2.0 MHz HIFU transducer with peak positive (P +) and negative (P -) pressures of 89.1 MPa and -14.6 MPa, a pulse length of 5 to 34 ms, a pressure modulation time at 4 ms where P + and P - decreased to 29.9 MPa and - 9.6 MPa, a pulse repetition frequency of 1 Hz, a duty cycle of 1% and number of pulses of 1 to 20. Three lesions were produced on each animal. For comparison, the same exposure condition but no pressure modulation was also employed to create a number of lesions in the liver. Results and Discussion: Experimental results showed that a partial mechanical destruction of liver tissue in the form of an oval in the absence of thermal damage was clearly observed at the HIFU focus after the PSH exposure. With a single pulse length of 7 ms, a PSH lesion created in the liver was measured to be a length of 1.04 ± 0.04 mm and a width of 0.87 ± 0.21 mm which was 2.37 times in length (p = 0.027) and 1.35 times in width (p = 0.1295) smaller than a lesion produced by no pressure modulation approach (e.g., BH). It was also observed that the length of a PSH lesion gradually grew towards the opposite direction to the HIFU source along the axial direction with the PSH pulse length, eventually leading to the generation of an elongated lesion in the liver. In addition, our experimental results demonstrated the feasibility of inducing partial decellularisation effect where liver tissue was partially destructed with intact extracellular matrix (i.e., intact fibrillar collagen) with the shortest PSH pulse length. Taken together, these results suggest that PSH could be used to induce a highly localised tissue fractionation with a desired degree of mechanical damage from complete tissue fractionation to tissue decellularisation through controlling the dynamics of boiling bubbles without inducing the shock scattering effect.

Sonothrombolysis with an acoustic net-assisted boiling histotripsy: A proof-of-concept study.

Whilst sonothrombolysis is a promising and noninvasive ultrasound technique for treating blood clots, bleeding caused by thrombolytic agents used for dissolving clots and potential obstruction of blood flow by detached clots (i.e., embolus) are the major limitations of the current approach. In the present study, a new sonothrombolysis method is proposed for treating embolus without the use of thrombolytic drugs. Our proposed method involves (a) generating a spatially localised acoustic radiation force in a blood vessel against the blood flow to trap moving blood clots (i.e., generation of an acoustic net), (b) producing acoustic cavitation to mechanically destroy the trapped embolus, and (c) acoustically monitoring the trapping and mechanical fractionation processes. Three different ultrasound transducers with different purposes were employed in the proposed method: (1) 1-MHz dual focused ultrasound (dFUS) transducers for capturing moving blood clots, (2) a 2-MHz High Intensity Focused Ultrasound (HIFU) source for fractionating blood clots and (3) a passive acoustic emission detector with broad bandwidth (10 kHz to 20 MHz) for receiving and analysing acoustic waves scattered from a trapped embolus and acoustic cavitation. To demonstrate the feasibility of the proposed method, in vitro experiments with an optically transparent blood vessel-mimicking phantom filled with a blood mimicking fluid and a blood clot (1.2 to 5 mm in diameter) were performed with varying the dFUS and HIFU exposure conditions under various flow conditions (from 1.77 to 6.19 cm/s). A high-speed camera was used to observe the production of acoustic fields, acoustic cavitation formation and blood clot fragmentation within a blood vessel by the proposed method. Numerical simulations of acoustic and temperature fields generated under a given exposure condition were also conducted to further interpret experimental results on the proposed sonothrombolysis. Our results clearly showed that fringe pattern-like acoustic pressure fields (fringe width of 1 mm) produced in a blood vessel by the dFUS captured an embolus (1.2 to 5 mm in diameter) at the flow velocity up to 6.19 cm/s. This was likely to be due to the greater magnitude of the dFUS-induced acoustic radiation force exerted on an embolus in the opposite direction to the flow in a blood vessel than that of the drag force produced by the flow. The acoustically trapped embolus was then mechanically destructed into small pieces of debris (18 to 60 µm sized residual fragments) by the HIFU-induced strong cavitation without damaging the blood vessel walls. We also observed that acoustic emissions emitted from a blood clot captured by the dFUS and cavitation produced by the HIFU were clearly distinguished in the frequency domain. Taken together, these results can suggest that our proposed sonothrombolysis method could be used as a promising tool for treating thrombosis and embolism through capturing and destroying blood clots effectively.

Metabolic activity of visceral adipose tissue is associated with age-related macular degeneration: a pilot 18F-FDG PET/CT study.

Background: Obesity is known to increase the risk and severity of age-related macular degeneration (AMD). Increased inflamed metabolic activity of visceral adipose tissue (VAT) is considered as a crucial underlying mechanism for the harmful effects of obesity. In this study, we aimed to investigate the inflamed metabolic activity of VAT with 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and their association with AMD. Materials and methods: A total of 57 elderly participants (aged ≥ 50 years) who underwent 18F-FDG PET/CT for health screening and subsequent fundoscopic exam for complaint of recently impaired vision were enrolled. The metabolic activity of VAT was measured from the maximum standardized uptake value (SUVmax) of VAT. The early AMD participant was defined as the participant with either eye satisfying AMD and without any sign of advanced AMD (neovascular AMD or geographic atrophy). The late AMD participant was defined as the participant with either eye satisfying advanced AMD. Results: VAT SUVmax was highest in participants with late AMD, intermediate in early AMD, and lowest in non-AMD participants. The levels of systemic inflammation surrogate markers were also highest in late AMD group. Furthermore, VAT SUVmax was positively correlated with systemic inflammation surrogate markers and independently associated with the late AMD. Conclusions: The metabolic activity of VAT evaluated by 18F-FDG PET/CT was associated with the severity of AMD and synchronized with the level of systemic inflammation. Thus, VAT SUVmax could be potentially employed as a surrogate marker of obesity-driven VAT inflammation associated with AMD.

Investigation of the long-term healing response of the liver to boiling histotripsy treatment in vivo.

Boiling histotripsy (BH) is a promising High-Intensity Focused Ultrasound technique that can be employed to mechanically fractionate solid tumours. Whilst studies have shown the feasibility of BH to destroy liver cancer, no study has reported on the healing process of BH-treated liver tissue. We therefore extensively investigated the evolution of the healing response of liver to BH in order to provide an insight into the healing mechanisms. In the present study, 14 Sprague Dawley rats underwent the BH treatment and were sacrificed on days 0, 3, 7, 14, and 28 for morphological, histological, serological and qPCR analyses. The area of the treated region was 1.44 cm2 (1.2 cm × 1.2 cm). A well-defined BH lesion filled with coagulated blood formed on day 0. A week after the treatment, fibroblast activation was induced at the treatment site, leading to the formation of extracellular matrix structure (ECM). The ECM was then disrupted for 7 to 28 days. Regenerated normal hepatocytes and newly formed blood vessels were found within the BH region with the absence of hepatic fibrosis. No significant morphological, histological and genetic changes around the BH lesion occurred. These results suggest that BH could be a safe and promising therapeutic tool for treating solid tumours without inducing any significant adverse effect such as the formation of liver fibrosis.

The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia.

Acute ischemic stroke is the leading cause of morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only agent clinically approved by FDA for patients with acute ischemic stroke. However, delayed treatment of rtPA (e.g., more than 3 h after stroke onset) exacerbates ischemic brain damage by causing intracerebral hemorrhage and increasing neurotoxicity. In the present study, we investigated whether the neuroprotant otaplimastat reduced delayed rtPA treatment-evoked neurotoxicity in male Sprague Dawley rats subjected to embolic middle cerebral artery occlusion (eMCAO). Otaplimastat reduced cerebral infarct size and edema and improved neurobehavioral deficits. In particular, otaplimastat markedly reduced intracerebral hemorrhagic transformation and mortality triggered by delayed rtPA treatment, consequently extending the therapeutic time window of rtPA. We further found that ischemia-evoked extracellular matrix metalloproteases (MMPs) expression was closely correlated with cerebral hemorrhagic transformation and brain damage. In ischemic conditions, delayed rtPA treatment further increased brain injury via synergistic expression of MMPs in vascular endothelial cells. In oxygen-glucose-deprived endothelial cells, otaplimastat suppressed the activity rather than protein expression of MMPs by restoring the level of tissue inhibitor of metalloproteinase (TIMP) suppressed in ischemia, and consequently reduced vascular permeation. This paper shows that otaplimastat under clinical trials is a new drug which can inhibit stroke on its own and extend the therapeutic time window of rtPA, especially when administered in combination with rtPA.

SP-1154, a novel synthetic TGF-ß inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice.

OBJECTIVE: Obesity-induced inflamed visceral adipose tissue (VAT) secretes pro-inflammatory cytokines thereby promoting systemic inflammation and insulin resistance which further exacerbate obesity-associated nonalcoholic fatty liver disease (NAFLD). Transforming growth factor (TGF)-ß /Smad3 signaling plays a crucial role in the inflammatory events within the VAT. Here, we investigate whether SP-1154, a novel synthetic verbenone derivative, can inhibit TGF-ß/Smad3 signaling thereby exhibiting a therapeutic effect against obesity-induced inflamed VAT and subsequent NAFLD in high-fat diet-induced mice. METHODS: NAFLD was induced by a high-fat diet (60% fat) for 20 weeks using the male C57BL/6 mice. SP-1154 (50 mg/kg) was orally given daily for 20 weeks. In vivo VAT- and systemic inflammation were measured by using 18F-fluorodeoxyglucose positron emission tomography and C-reactive protein levels. Both insulin tolerance- and glucose tolerance test were performed to assess the status of insulin resistance and glucose intolerance. Histological and molecular analyses were performed on harvested liver and VAT. KEY FINDINGS: SP-1154 inhibited TGF-ß/Smad3 signaling pathway and remarkably suppressed high-fat diet-induced VAT inflammation and its related systemic inflammation. Furthermore, SP-1154 significantly improved insulin sensitivity with glucose homeostasis and reduced hepatic steatosis. SP-1154 significantly improves VAT inflammation and obesity-related NAFLD. CONCLUSION: Our novel findings support the potential use of SP-1154 as a therapeutic drug for obesity and its related NAFLD by targeting the inflamed VAT.

Chronic physical exercise alleviates stress-associated amygdala metabolic activity in obese women: A prospective serial 18F-FDG PET/CT study.

Background: Psychological stress is considered as a major risk factor for cardiovascular disease (CVD). Chronic exercise is known to reduce CVD risk partly through attenuating psychological stress. Obesity has been linked with increased levels of psychological stress. We aimed to prospectively evaluate whether physical exercise could alleviate stress-associated amygdala metabolic activity, assessed by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in women with obesity. Material and methods: A total of 43 participants were enrolled in this study. Twenty-three obese women were participated in a physical exercise program 5 days per week for 3 months. The exercise program consisted of aerobic exercise and resistance training. Serial 18F-FDG PET/CT was taken before the start of physical exercise program (baseline) and after finishing the program (post-exercise). A total of 20 participants who underwent 18F-FDG PET/CT for general health check-up were enrolled as non-obese control group. Brain amygdala activity (AmygA) was calculated as maximum standardized uptake value (SUVmax) of amygdala normalized to mean SUV of temporal lobe. Results: Chronic physical exercise significantly reduced AmygA and improved body adiposity and systemic inflammation. AmygA was highest in baseline, intermediate in post-exercise, and lowest in non-obese control group (0.76 ± 0.17, 0.61 ± 0.1, 0.52 ± 0.09, p < 0.001). Furthermore, physical exercise also abrogated the association of AmygA with systemic inflammation. Conclusions: Chronic physical exercise reduced stress-associated amygdala metabolic activity and broke its association with systemic inflammation in obese women. This study could explain the putative mechanism underlying the health beneficial effect of exercise on CVD via attenuation of stress neurobiology.

Changes in treatment intent and target definition for preoperative radiotherapy after 18F-Fluorodeoxyglucose positron emission tomography in rectal cancer: A Meta-analysis.

PURPOSE: To evaluate the impact of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on changes in treatment plan and target definition for preoperative radiotherapy in patients with rectal cancer. METHODS: Embase, PubMed, and Cochrane Library were searched up to November 2020 for all studies investigating the role of preoperative FDG PET in patients who underwent neoadjuvant radiotherapy before curative-intent surgery. The proportion of patients whose treatment plan (curative vs. palliative intent) or target definition was changed after FDG PET was analyzed. A random-effects model was used for pooled analysis. The change in target definition was compared between conventional radiological imaging-based target volume [gross tumor volume (GTV) or planning target volume (PTV)] and PET-based target volume (GTV or PTV) using the standardized mean difference (SMD) and 95% confidence interval (CI). RESULTS: A total of 336 patients from twelve studies were included. In eight studies, PET changed either the treatment intent or target definition in 24.8% of patients (95% CI 15.1% to 37.9%, I2 = 69%). In ten studies, the PET-based GTV was lower than the conventional imaging-based target volume (SMD -7.0, 95% CI -1.39 to -0.01). However, there was no significant difference between conventional imaging-based and PET-based PTV (SMD -0.07, 95% CI -0.75 to 0.62). In six studies evaluating the initial staging based on PET, the initial staging (nodal or metastasis status) was changed in 53 of 229 patients (23.1%). Newly detected or additional distant metastases were identified in 22 patients (9.6%) after FDG PET. CONCLUSION: The use of FDG PET influences radiotherapy planning in a fourth of patients with rectal cancer. FDG PET can provide additive information for accurate tumor delineation, although PET-based PTV did not significantly change. These findings suggest that FDG PET may be beneficial to patients with rectal cancer before establishing a radiotherapy plan.

Clustering subtypes of breast cancer by combining immunohistochemistry profiles and metabolism characteristics measured using FDG PET/CT.

BACKGROUND: The aim of this study was to investigate the effect of combining immunohistochemical profiles and metabolic information to characterize breast cancer subtypes. METHODS: This retrospective study included 289 breast tumors from 284 patients who underwent preoperative 18 F-fluorodeoxyglucose (FDG) positron emission tomography/ computed tomography (PET/CT). Molecular subtypes of breast cancer were classified as Hormonal, HER2, Dual (a combination of both Hormonal and HER2 features), and triple-negative (TN). Histopathologic findings and immunohistochemical results for Ki-67, EGFR, CK 5/6, and p53 were also analyzed. The maximum standardized uptake value (SUV) measured from FDG PET/CT was used to evaluate tumoral glucose metabolism. RESULTS: Overall, 182, 24, 47, and 36 tumors were classified as Hormonal, HER2, Dual, and TN subtypes, respectively. Molecular profiles of tumor aggressiveness and the tumor SUV revealed a gradual increase from the Hormonal to the TN type. The tumor SUV was significantly correlated with tumor size, expression levels of p53, Ki-67, and EGFR, and nuclear grade (all p < 0.001). In contrast, the tumor SUV was negatively correlated with the expression of estrogen receptors (r = - 0.234, p < 0.001) and progesterone receptors (r = - 0.220, p < 0.001). Multiple linear regression analysis revealed that histopathologic markers explained tumor glucose metabolism (adjusted R-squared value 0.238, p < 0.001). Tumor metabolism can thus help define breast cancer subtypes with aggressive/adverse prognostic features. CONCLUSIONS: Metabolic activity measured using FDG PET/CT was significantly correlated with the molecular alteration profiles of breast cancer assessed using immunohistochemical analysis. Combining molecular markers and metabolic information may aid in the recognition and understanding of tumor aggressiveness in breast cancer and be helpful as a prognostic marker.

Stress-Related Amygdala Metabolic Activity Is Associated With Low Bone Mineral Density in Postmenopausal Women: A Pilot 18F-FDG PET/CT Study.

Background: Psychological stress is associated with postmenopausal osteoporosis. However, the underlying mechanism of stress-related brain neural activity with osteoporosis is not fully elucidated. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is an established method to evaluate the metabolic activity of brain amygdala, a region involved in stress. We aimed to evaluate the relationship between metabolic activity of amygdala (AmygA) and osteoporosis in postmenopausal women. Materials and Methods: A total of 115 postmenopausal women who underwent 18F-FDG PET/CT and dual-energy X-ray absorptiometry for routine health screening were enrolled in this study. AmygA was defined as the maximum standardized uptake value (SUVmax) of amygdala divided by the mean SUV of temporal lobe. The levels of psychological stress were measured using the Psychosocial Well-being Index-Short Form (PWI-SF). Results: The participants with osteoporosis exhibited significantly higher AmygA than without osteoporosis (0.81 ± 0.16 vs. 0.61 ± 0.13, p < 0.001). The AmygA value of 0.69 was suggested as an optimal cut-off value to identify participant with osteoporosis (sensitivity; 79.1%, specificity; 83.3%, area under the curve; 0.841, p < 0.001). Furthermore, AmygA showed significant association with osteoporosis in postmenopausal woman by multivariate analysis. Psychological stress scale (PWI-SF) was well correlated with AmygA and AmygA was highest in high stress risk-, intermediate in moderate stress risk-, and lowest in healthy group. Conclusions: AmygA measured by 18F-FDG PET/CT is associated with osteoporosis in postmenopausal women. Our results provide the possibility that stress-related neurobiological activity involving amygdala is linked with postmenopausal osteoporosis.

Association of Inflammatory Metabolic Activity of Psoas Muscle and Acute Myocardial Infarction: A Preliminary Observational Study with 18F-FDG PET/CT.

Inflamed skeletal muscle promotes chronic inflammation in atherosclerotic plaques, thereby contributing to the increased risk of coronary artery disease (CAD). In this study, we evaluated the metabolic activity of psoas muscle, using 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), and its association with carotid artery inflammation and acute myocardial infarction (AMI). In total, 90 participants (32 AMI, 33 chronic stable angina (CSA), and 25 control) were enrolled in this prospective study. Metabolic activity of skeletal muscle (SM) was measured by using maximum standardized uptake value (SUVmax) of psoas muscle, and corresponding psoas muscle area (SM area) was also measured. Carotid artery inflammation was evaluated by using the target-to background ratio (TBR) of carotid artery. SM SUVmax was highest in AMI, intermediate in CSA, and lowest in control group. SM SUVmax was significantly correlated with carotid artery TBR and systemic inflammatory surrogate markers. Furthermore, SM SUVmax was independently associated with carotid artery TBR and showed better predictability than SM area for the prediction of AMI. Metabolic activity of psoas muscle assessed by 18F-FDG PET/CT was associated with coronary plaque vulnerability and synchronized with the carotid artery inflammation in the participants with CAD. Furthermore, it may also be useful to predict AMI.

Effect of Exercise on Inflamed Psoas Muscle in Women with Obesity: A Pilot Prospective 18F-FDG PET/CT Study.

Obesity increases inflammation in skeletal muscle thereby promoting systemic inflammation which leads to increased risk of cardiometabolic disease. This prospective study aimed to evaluate whether the metabolic activity of psoas muscle (PM) was associated with systemic inflammation, and whether physical exercise could reduce the PM metabolic activity evaluated by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in women with obesity. A total of 23 women with obesity who participated in a 3-month physical exercise program were enrolled. 18F-FDG PET/CT was performed before the start of the program (baseline) and after completion of the program. The maximum standardized uptake value of psoas muscle (PM SUVmax) was used for the PM metabolic activity. The SUVmax of spleen and bone marrow, and the high-sensitivity C-reactive protein were used to evaluate the systemic inflammation. At baseline, PM SUVmax was strongly correlated with the systemic inflammation. The exercise program significantly reduced the PM SUVmax, in addition to adiposity and systemic inflammation. Furthermore, we found that the association between PM SUVmax and the systemic inflammation disappeared after completion of the exercise program. In women with obesity, PM SUVmax, assessed by 18F-FDG PET/CT, was associated with obesity-induced systemic inflammation and exercise reduced the PM SUVmax and eliminated its association with systemic inflammation.

Metabolic Activity of Visceral Adipose Tissue Is Associated with Metastatic Status of Lymph Nodes in Endometrial Cancer: A 18F-FDG PET/CT Study.

Obesity contributes to increased cancer incidence and aggressiveness in patients with endometrial cancer. Inflamed metabolic activity of visceral adipose tissue (VAT) is regarded as a key underlying mechanism of adverse consequences of obesity. The aim of this study was to investigate the association between inflammatory metabolic activity of VAT evaluated by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and metastatic status of lymph nodes (LN) in patients with endometrial cancer. In total, 161 women with newly diagnosed endometrial cancer, who received preoperative 18F-FDG PET/CT, were enrolled. VAT inflammatory metabolic activity was defined as V/S ratio and measured from the maximum standardized uptake value (SUVmax) of VAT normalized to the SUVmax of subcutaneous adipose tissue (SAT). The positive LN metastasis group exhibited a significantly higher V/S ratio than the negative LN metastasis group. Systemic inflammatory surrogate markers including high sensitivity C-reactive protein, spleen SUVmax, and bone marrow SUVmax were also higher in the LN metastasis group than in the negative LN metastasis group, showing significant correlations with V/S ratio. In multivariate logistic regression analysis, V/S ratio was independently associated with LN metastasis. V/S ratio is independently associated with the LN metastasis status in patients with endometrial cancer. This finding could be useful as a potential surrogate marker of obesity-induced VAT inflammation associated with tumor aggressiveness.

Association of glucose uptake of visceral fat and acute myocardial infarction: a pilot 18F-FDG PET/CT study.

BACKGROUND: Inflamed visceral adipose tissue (VAT) facilitates chronic inflammation in atherosclerotic lesions thereby leading to increased risk of coronary artery disease (CAD). In this study, we evaluated the glucose uptake of VAT and the carotid artery with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) and their association with CAD, including acute myocardial infarction (AMI). METHODS: A total of 90 participants were enrolled (32 with AMI, 33 with chronic stable angina; CSA, and 25 control participants) and undertook 18F-FDG PET/CT. VAT glucose uptake was measured by using maximum standardized uptake value (SUVmax) of VAT region. The target-to-background ratio (TBR) of carotid artery was defined as the SUVmax of carotid artery divided by the SUVmax of jugular vein. The SUVmax of spleen, bone-marrow (BM), and high-sensitivity C-reactive protein (hsCRP) were used for the assessment of systemic inflammatory activity. RESULTS: VAT SUVmax was highest in participants with AMI, intermediate in participants with CSA, and lowest in control participants. Carotid artery TBR and systemic inflammatory surrogate markers including spleen SUVmax, BM SUVmax, and hsCRP were also higher in the AMI group than in the CSA or control group. Furthermore, VAT SUVmax showed significant positive correlation with carotid artery TBR, spleen SUVmax, BM SUVmax, and hsCRP. In multivariate linear regression and logistic regression analyses, VAT SUVmax was independently associated with carotid artery TBR and AMI. CONCLUSIONS: Glucose uptake of VAT assessed by 18F-FDG PET/CT was associated with the severity of CAD and synchronized with the carotid artery inflammation in participants with CAD.

Visceral fat metabolic activity evaluated by 18F-FDG PET/CT is associated with osteoporosis in healthy postmenopausal Korean women.

BACKGROUND: Traditionally, obesity has been regarded as protective against osteoporosis. However, recent accumulating evidences suggest that visceral obesity can increase the risk of osteoporosis and obesity-driven dysfunctional metabolic activity in visceral adipose tissue (VAT) is considered as a key underlying mechanism. Visceral obesity is known to increase during menopausal transition.18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is an established method to assess the degree of VAT metabolic activity. We aimed to investigate the association between VAT metabolic activity evaluated by 18F-FDG PET/CT and osteoporosis in healthy postmenopausal Korean women. METHODS: A total of 115 postmenopausal women who underwent routine health check-up were enrolled in this study, retrospectively. They all underwent dual-energy X-ray absorptiometry and 18F-FDG PET/CT. Osteoporosis was defined as bone mineral density (BMD) T-score ≤ -2.5 at either lumbar spine or femoral neck. VAT metabolic activity was defined as the maximum standardized uptake value (SUVmax) of VAT divided by the SUVmax of subcutaneous adipose tissue (V/S ratio). RESULTS: The participants with osteoporosis showed significantly higher V/S ratio, age, body mass index, waist circumference, and postmenopausal period than the participants without osteoporosis. V/S ratio of 1.33 was proposed as an optimal cut-off value for identifying osteoporosis. Furthermore, V/S ratio was the most significant predictive factor for osteoporosis in postmenopausal woman by uni-and multivariate analyses. Interestingly, V/S ratio showed significant positive correlation with high sensitivity C-reactive protein, a surrogate marker for systemic inflammation. CONCLUSION: VAT metabolic activity assessed by 18F-FDG PET/CT is associated with osteoporosis in healthy postmenopausal Korean women.

Exercise training reduces inflammatory metabolic activity of visceral fat assessed by 18 F-FDG PET/CT in obese women.

OBJECTIVES: Obesity plays pivotal roles in the increased risk of cardiometabolic disease via induction of the inflammatory reaction from macrophages in visceral adipose tissue (VAT), which may elevate the inflammatory activity of VAT. This prospective study aimed to evaluate whether the inflammatory activity of VAT existed in association with systemic inflammation, and whether exercise could ameliorate the inflammatory activity of VAT assessed by 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in obese women. DESIGN AND PATIENTS: A total of 23 obese women who participated in an exercise program were included. Subjects underwent 18 F-FDG PET/CT before the start of the exercise program (baseline) and after the completion of the 3-month exercise program. For the assessment of VAT metabolic activity, the maximum standardized uptake value (SUVmax) and the mean standardized uptake value (SUVmean) were measured. The SUVmax of spleen, bone marrow (BM) and the high-sensitivity C-reactive protein (hsCRP) were used as a surrogate marker for systemic inflammation. RESULTS: Baseline SUVmax of VAT was positively correlated with the SUVmax of spleen, BM and hsCRP, whereas VAT SUVmean was not correlated. Exercise reduced SUVmax of VAT in addition to adiposity, the SUVmax of spleen, BM and hsCRP. However, VAT SUVmean was not significantly changed. Furthermore, the association of SUVmax of VAT, and the SUVmax of spleen, BM and hsCRP was no longer relevant after exercise. CONCLUSION: In obese women, the SUVmax of VAT assessed by 18 F-FDG PET/CT was associated with systemic inflammation and exercise reduced the SUVmax of VAT and abrogated its association with systemic inflammation.

A Novel CD147 Inhibitor, SP-8356, Attenuates Pathological Fibrosis in Alkali-Burned Rat Cornea.

The corneal fibrotic responses to corneal damage often lead to severe corneal opacification thereby resulting in severe visual impairment or even blindness. The persistence of corneal opacity depends heavily on the activity of corneal myofibroblast. Myofibroblasts are opaque and synthesize a disorganized extracellular matrix (ECM) and thus promoting opacification. Cluster of differentiation 147 (CD147), a member of the immunoglobulin superfamily, is known to play important roles in the differentiation process from fibroblast to myofibroblast in damaged cornea and may therefore be an effective target for treatment of corneal opacity. Here, we examined the therapeutic efficacy of novel CD147 inhibiting verbenone derivative SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) on corneal fibrosis. Topical SP-8356 significantly reduced corneal haze and fibrosis in the alkali-burned cornea. In detail, SP-8356 inhibited both alpha-smooth muscle actin (α-SMA) expressing myofibroblast and its ECM-related products, such as matrix-metalloproteinase-9 and collagen type III and IV. Similar to SP-8356, topical corticosteroid (prednisolone acetate, PA) also reduced the ECM-related products and opacification. However, prednisolone acetate failed to decrease the population of α-SMA-positive corneal myofibroblast. In conclusion, SP-8356 is capable enough to prevent corneal haze by preventing pathological fibrosis after severe corneal damage. Therefore, SP-8356 could be a potentially promising therapeutic drug for corneal fibrosis.

Characterization of glucose uptake metabolism in visceral fat by 18 F-FDG PET/CT reflects inflammatory status in metabolic syndrome.

OBJECTIVE: The inflammatory activity of visceral adipose tissue (VAT) is elevated in metabolic syndrome (MS), and associated with vulnerability to atherosclerosis. Inflammation can be assessed by glucose uptake in atherosclerotic plaques. We investigated whether the glucose uptake of VAT, assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), is associated with systemic inflammatory status, and related to the number of MS components. METHODS: 18F-FDG PET/CT was performed in a total of 203 participants: 59 without MS component; M(0), 92 with one or two MS components; M(1-2), and 52 with MS. Glucose uptake in VAT was evaluated using the mean standardized uptake value (SUVmean) and the maximum SUV (SUVmax). Glucose uptakes of immune-related organs such as the spleen and bone marrow (BM) were evaluated using the SUVmax. RESULTS: VAT SUVmax correlated with high-sensitivity C-reactive protein (hsCRP) and the SUVmax of spleen and BM, which reflect the status of systemic inflammation. Both hsCRP and the SUVmax of the spleen and BM were higher in the MS group than in the M(1-2) or M(0) groups. In VAT, SUVmax increased with increasing number of MS components, while SUVmean decreased. CONCLUSIONS: The SUVmax and SUVmean of VAT assessed by 18F-FDG PET/CT reflected inflammation-driven unique glucose metabolism in the VAT of MS patients, distinct from that of atherosclerotic plaques.