Clinical practice consensus for the diagnosis and management of melanoma in Taiwan.

Melanoma is rare in Taiwan. Asian melanoma is distinct from Western melanoma because acral and mucosal melanoma accounts for the majority of melanoma cases, leading to distinct tumor behaviors and genetic profiling. With consideration of the clinical guidelines in Western countries, Taiwanese experts developed a local clinical practice consensus guideline. This consensus includes diagnosis, staging, and surgical and systemic treatment, based only on clinical evidence, local epidemiology, and available resources evaluated by experts in Taiwan. This consensus emphasizes the importance of surgical management, particularly for sentinel lymph node biopsies. In addition, molecular testing for BRAF is mandatory for patients before systemic treatment. Furthermore, immunotherapy and targeted therapy are prioritized for systemic treatment. This consensus aimed to assist clinicians in Taiwan in diagnosing and treating patients according to available evidence.

Cerebral Venous Reflux and Cerebral Amyloid Angiopathy: An Magnetic Resonance Imaging/Positron Emission Tomography Study.

BACKGROUND: Cerebral venous outflow alterations contribute to central nervous system pathology in aging and neurodegenerative disorders and are potentially linked to underlying cerebral microangiopathy. We investigated whether cerebral venous reflux (CVR) is more closely associated with cerebral amyloid angiopathy (CAA) than hypertensive microangiopathy in intracerebral hemorrhage (ICH) survivors. METHODS: This cross-sectional study included 122 patients of spontaneous ICH with magnetic resonance and positron emission tomography imaging studies (2014-2022) in Taiwan. The presence of CVR was defined as abnormal signal intensity in the dural venous sinus or internal jugular vein on magnetic resonance angiography. Cerebral amyloid load was measured using the Pittsburgh compound B standardized uptake value ratio. Clinical and imaging characteristics associated with CVR were evaluated in univariable and multivariable analyses. In the subset of patients with CAA, we applied univariable and multivariable linear regression analyses to evaluate the association between CVR and cerebral amyloid retention. RESULTS: Compared with patients without CVR (n=84, 64.5±12.1 years), patients with CVR (n=38, 69.4±11.5 years) were significantly more likely to have CAA-ICH (53.7% versus 19.8%; P<0.001) and had a higher cerebral amyloid load (standardized uptake value ratio [interquartile range], 1.28 [1.12-1.60] versus 1.06 [1.00-1.14]; P<0.001). In a multivariable model, CVR was independently associated with CAA-ICH (odds ratio, 4.81 [95% CI, 1.74-13.27]; P=0.002) after adjustment for age, sex and conventional small vessel disease markers. In CAA-ICH, higher PiB retention was observed in patients with CVR than patients without CVR (standardized uptake value ratio [interquartile range], 1.34 [1.08-1.56] versus 1.09 [1.01-1.26]; P<0.001). In multivariable analysis after adjustment for potential confounders, the presence of CVR was independently associated with a higher amyloid load (standardized ß=0.40; P=0.001). CONCLUSIONS: In spontaneous ICH, CVR is associated with CAA and a higher amyloid burden. Our results suggest venous drainage dysfunction potentially plays a role in CAA and cerebral amyloid deposition.

Neuroinflammation in Low-Level PM2.5-Exposed Rats Illustrated by PET via an Improved Automated Produced [18F]FEPPA: A Feasibility Study.

Background: [18F]FEPPA is a potent TSPO imaging agent that has been found to be a potential tracer for imaging neuroinflammation. In order to fulfill the demand of this tracer for preclinical and clinical studies, we have developed a one-pot automated synthesis with simplified HPLC purification of this tracer, which was then used for PET imaging of neuroinflammation in fine particulate matter- (PM2.5-) exposed rats. Results: Using this automated synthesis method, the RCY of the [18F]FEPPA was 38 ± 4% (n = 17, EOB) in a synthesis time of 83 ± 8 min from EOB. The radiochemical purity and molar activities were greater than 99% and 209 ± 138 GBq/µmol (EOS, n = 15), respectively. The quality of the [18F]FEPPA synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [18F]FEPPA was stable at 21 ± 2°C for up to 4 hr after the end of synthesis (EOS). Moreover, microPET imaging showed that increased tracer activity of [18F]FEPPA in the brain of PM2.5-exposed rats (n = 6) were higher than that of normal controls (n = 6) and regional-specific. Conclusions: Using the improved semipreparative HPLC purification, [18F]FEPPA has been produced in high quantity, high quality, and high reproducibility and, for the first time, used for PET imaging the effects of PM2.5 in the rat brain. It is ready to be used for imaging inflammation in various clinical or preclinical studies, especially for nearby PET centers without cyclotrons.

Plasma soluble TREM2 is associated with white matter lesions independent of amyloid and tau.

Cerebral small vessel disease is one of the most common causes of cognitive decline and stroke. While several lines of evidence have established a relationship between inflammation and cerebrovascular pathology, the mechanistic link has not yet been elucidated. Recent studies suggest activation of immune mediators, including the soluble form of triggering receptor expressed on myeloid cells 2 (TREM2), may be critical regulators. In this study, we compared the plasma levels of soluble TREM2 and its correlations with neuroimaging markers and cerebral amyloid load in 10 patients with Alzheimer's disease and 66 survivors of spontaneous intracerebral haemorrhage with cerebral amyloid angiopathy or hypertensive small vessel disease, two of the most common types of sporadic small vessel disease. We performed brain MRI and 11C-Pittsburgh compound B PET for all participants to evaluate radiological small vessel disease markers and cerebral amyloid burden, and 18F-T807 PET in a subgroup of patients to evaluate cortical tau pathology. Plasma soluble TREM2 levels were comparable between patients with Alzheimer's disease and small vessel disease (P = 0.690). In patients with small vessel disease, plasma soluble TREM2 was significantly associated with white matter hyperintensity volume (P < 0.001), but not with cerebral amyloid load. Among patients with Alzheimer's disease and cerebral amyloid angiopathy, plasma soluble TREM2 was independently associated with a tau-positive scan (P = 0.001) and white matter hyperintensity volume (P = 0.013), but not amyloid load (P = 0.221). Our results indicate plasma soluble TREM2 is associated with white matter hyperintensity independent of amyloid and tau pathology. These findings highlight the potential utility of plasma soluble TREM2 as a strong predictive marker for small vessel disease-related white matter injury and hold clinical implications for targeting the innate immune response when treating this disease.

[Normal and Near Normal Myocardial Perfusion Imaging Data Analysis: Two-Year Major Adverse Cardiac Event].

BACKGROUND: Myocardial perfusion imaging (MPI) is the method most commonly used to assess patients with suspected coronary artery disease for the presence of myocardial ischemia and risk of subsequent adverse cardiac events. Studies are limited on the incidence of major adverse cardiac event (MACE) in patients with normal MPI results. PURPOSE: The aim of this study was to investigate the incidence and risk factors of MACE in patients with normal or near-normal MPI results. METHODS: In this single-center retrospective chart review study, patients who had received MPI tests at a nuclear medicine department of a medical center in 2017 were consecutively enrolled. All of the participants in this study were patients with normal or near-normal MPI results, and were followed for two years to assess the incidence of MACE (death, hospitalized for percutaneous coronary intervention; CABG, heart failure and stroke). Participants with or without MACE were compared to determine whether demographic, comorbidity, and MPI data were significant risk factors. RESULTS: Of the 1,629 participants (age = 70.4 ± 11.3 years, 49.4% male) enrolled, 387 (23.8%) were classified into the normal MPI group and 1,242 (76.2%) were classified into the near-normal MPI group. Notably, 61 participants (15.8%) in the normal MPI group and 206 (16.6%) in the near-normal MPI group experienced MACE events during the two-year follow-up. The risk factors of MACE identified in this study included being older in age, being male, and having poor myocardial perfusion parameters (i.e., ejection fraction) during MPI. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Over the two-year study period, 15.8% of the participants with normal MPI results and 16.6% of those with near-normal MPI results experienced major adverse cardiac events. Thus, it is critical to inform patients regarding the potential risk of MACE risk and to educate them on how to mitigate this risk by actively managing their hyperlipidemia level and left ventricular ejection fraction.

Centrum Semiovale Perivascular Space and Amyloid Deposition in Spontaneous Intracerebral Hemorrhage.

Background and Purpose: We explored whether high-degree magnetic resonance imaging­visible perivascular spaces in centrum semiovale (CSO) are more prevalent in cerebral amyloid angiopathy (CAA) than hypertensive small vessel disease and their relationship to brain amyloid retention in patients with primary intracerebral hemorrhage (ICH). Methods: One hundred and eight spontaneous ICH patients who underwent magnetic resonance imaging and Pittsburgh compound B were enrolled. Topography and severity of enlarged perivascular spaces were compared between CAA-related ICH (CAA-ICH) and hypertensive small vessel disease­related ICH (non-CAA ICH). Clinical and image characteristics associated with high-degree perivascular spaces were evaluated in univariate and multivariable analyses. Univariate and multivariable models were performed to evaluate associations between the severity of perivascular spaces in CSO and amyloid retention in CAA-ICH and non­CAA-ICH cases. Results: Patients with CAA-ICH (n=29) and non­CAA-ICH (n=79) had similar prevalence of high-degree perivascular spaces in CSO (44.8% versus 36.7%; P=0.507) and in basal ganglia (34.5% versus 51.9%; P=0.131). High-degree perivascular spaces in CSO were independently associated with the presence of lobar microbleed (odds ratio, 3.0 [95% CI, 1.1­8.0]; P=0.032). The amyloid retention was higher in those with high-degree than those with low-degree CSO-perivascular spaces in CAA-ICH (global Pittsburgh compound B standardized uptake value ratio, 1.55 [1.33­1.61] versus 1.13 [1.01­1.48]; P=0.003) but not in non­CAA-ICH. In CAA-ICH, the association between cerebral amyloid retention and the degree of perivascular spaces in CSO remained significant after adjustment for age and lobar microbleed number (P=0.004). Conclusions: Although high-degree magnetic resonance imaging­visible perivascular spaces are equally prevalent between CAA-ICH and non­CAA-ICH in the Asian cohort, the severity of magnetic resonance imaging­visible CSO-perivascular spaces may be an indicator of higher brain amyloid deposition in patients with CAA-ICH.

Assessing tumor angiogenesis using dynamic contrast-enhanced integrated magnetic resonance-positron emission tomography in patients with non-small-cell lung cancer.

BACKGROUND: Angiogenesis assessment is important for personalized therapeutic intervention in patients with non-small-cell lung cancer (NSCLC). This study investigated whether radiologic parameters obtained by dynamic contrast-enhanced (DCE)-integrated magnetic resonance-positron emission tomography (MR-PET) could be used to quantitatively assess tumor angiogenesis in NSCLC. METHODS: This prospective cohort study included 75 patients with NSCLC who underwent DCE-integrated MR-PET at diagnosis. The following parameters were analyzed: metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax), reverse reflux rate constant (kep), volume transfer constant (Ktrans), blood plasma volume fraction (vp), extracellular extravascular volume fraction (ve), apparent diffusion coefficient (ADC), and initial area under the time-to-signal intensity curve at 60 s post enhancement (iAUC60). Serum biomarkers of tumor angiogenesis, including vascular endothelial growth factor-A (VEGF-A), angiogenin, and angiopoietin-1, were measured by enzyme-linked immunosorbent assays simultaneously. RESULTS: Serum VEGF-A (p = 0.002), angiogenin (p = 0.023), and Ang-1 (p <  0.001) concentrations were significantly elevated in NSCLC patients compared with healthy individuals. MR-PET parameters, including MTV, Ktrans, and kep, showed strong linear correlations (p <  0.001) with serum angiogenesis-related biomarkers. Serum VEGF-A concentrations (p = 0.004), MTV values (p <  0.001), and kep values (p = 0.029) were significantly higher in patients with advanced-stage disease (stage III or IV) than in those with early-stage disease (stage I or II). Patients with initial higher values of angiogenesis-related MR-PET parameters, including MTV > 30 cm3 (p = 0.046), Ktrans > 200 10- 3/min (p = 0.069), and kep > 900 10- 3/min (p = 0.048), may have benefited from angiogenesis inhibitor therapy, which thus led to significantly longer overall survival. CONCLUSIONS: The present findings suggest that DCE-integrated MR-PET provides a reliable, non-invasive, quantitative assessment of tumor angiogenesis; can guide the use of angiogenesis inhibitors toward longer survival; and will play an important role in the personalized treatment of NSCLC.

A Double-Blind, Randomized, Controlled Trial of Lovastatin in Early-Stage Parkinson's Disease.

BACKGROUND: Recent evidence indicates that lipophilic statins have a neuroprotective benefit in animal models of Parkinson's disease (PD). The objective of this study was to evaluate whether lovastatin has the potential to slow motor symptom progression in patients with early-stage PD. METHODS: This double-blind, randomized, placebo-controlled trial enrolled 77 patients with early-stage PD between May 23, 2017, and July 12, 2018, with follow-up ending September 1, 2019. Lovastatin 80 mg/day or placebo with 1:1 randomization was administered for 48 weeks. Mean change in the parts I-III scores of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), changes in the striatal dopamine uptake ratio measured by 18 F-dopa PET scan, and changes in PD medications between baseline and the week 48 visit were measured. RESULTS: Of the 77 randomized patients, 70 (90.9%) completed the study. There was a slightly beneficial trend of the MDS-UPDRS motor score in the lovastatin group (-3.18 ± 5.50) compared with the placebo group (-0.50 ± 6.11); P = 0.14 adjusted for age, sex, disease duration, and baseline LEDD. Mean percentage change in the striatal 18 F-dopa uptake ratio deteriorated less in the lovastatin group than in the placebo group on the dominant side of caudate (1.2% ± 7.3% vs -7.1% ± 8.2%, P < 0.01) and putamen (2.3% ± 7.1% vs -6.4% ± 8.1%, P < 0.01). We found no between-group differences in the change in part I or part II MDS-UPDRS scores. Lovastatin was generally well tolerated. CONCLUSIONS: Lovastatin treatment in patients with early-stage PD was associated with a trend of less motor symptom worsening and was well tolerated. A future larger long-term follow-up study is needed to confirm our findings. © 2021 International Parkinson and Movement Disorder Society.

Preoperative 2-[18F]FDG PET-CT aids in the prognostic stratification for patients with primary ampullary carcinoma.

OBJECTIVES: We sought to investigate whether preoperative dual-phase 2-[18F]FDG PET-CT identify predictors for poor survival in patients with ampullary carcinoma receiving pancreaticoduodenectomy. METHODS: The preoperative PET-CT images of patients with resected ampullary carcinoma from June 2007 to July 2017 were analyzed. Survival curves were analyzed using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard model was used to identify potential prognostic factors associated with disease-free survival (DFS) and overall survival (OS). RESULTS: Fifty-four subjects (26 men, 28 women) were enrolled with a median tumor size of 20 mm. All patients were followed for a median period of 36.9 months with 3- and 5-year DFS of 50.3% and 44.2%, and OS of 77.0% and 68.2%, respectively. Parameters associated with DFS in multivariate analysis were lymphovascular invasion (hazard ratio [HR]: 9.45, p < 0.001), involved margin in pathology (HR: 7.67, p < 0.001), and tumor retention index (RI) from the dual-phase PET (HR: 2.41, p = 0.03), whereas involved margin (HR: 13.14, p < 0.001), post-recurrence chemotherapy (HR: 0.10, p < 0.001), and metabolic tumor volume (MTV) (HR: 4.62, p = 0.009) emerged as independent prognostic factors for OS. CONCLUSIONS: Preoperative 2-[18F]FDG PET-CT offered independent prognostic biomarkers in patients with ampullary carcinoma receiving standard surgical resection. KEY POINTS: • 2-[18F]FDG PET-CT offers good survival prediction before operation in primary malignant neoplasms at ampulla of Vater. • Dual-phase PET scan with bowel distention can better delineate Ampulla of Vater and characterize tumor physiology. • Preoperative risk stratification might aid in better treatment planning.

Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy.

Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease.

Endoscopic ultrasound ablation in a patient with multiple metastatic pancreatic tumors from adrenocorticotropic hormone-producing thymic neuroendocrine neoplasm.

Adrenocorticotropic hormone (ACTH)-producing neuroendocrine neoplasm (NEN) of the thymus is rare. Lymph nodes and bones are the most common metastatic sites. Most cases present with florid Cushing's syndrome (CS). Here, we reported a 58-year-old woman, who presented with intermittent flush and weight loss. Imaging studies revealed tumors in the mediastinum, pancreas, and bones. Contrast-enhanced harmonic endoscopic ultrasound (EUS) of the pancreatic tumors showed heterogeneous and hyperenhancing characteristics. EUS elastography revealed a heterogeneous stiff pattern. EUS-fine needle biopsy to the pancreatic lesion confirmed the NEN nature. Serum ACTH and cortisol levels were abnormally high. Immunohistochemical staining of the thymic and pancreatic specimens was positive for ACTH. However, the patient did not have obvious CS appearance. The patient underwent surgery, radiation, EUS-guided ethanol injection, and anti-cancer medications, but the disease still progressed. The patient died from infection 16 months after NEN was diagnosed. In conclusion, the pancreas can be a metastatic site for ACTH-producing thymic NEN. EUS-associated procedures can help in the diagnosis and treatment of pancreatic metastatic NEN.

Effects of Focal Radiation on [18 F]-Fluoro-D-Glucose Positron Emission Tomography in the Brains of Miniature Pigs: Preliminary Findings on Local Metabolism.

OBJECTIVES: It would be a medically important advance if durable and focal neuromodulation of the brain could be delivered noninvasively and without ablation. This ongoing study seeks to elucidate the effects of precisely delivered ionizing radiation upon focal brain metabolism and the corresponding cellular integrity at that target. We hypothesize that focally delivered ionizing radiation to the brain can yield focal metabolic changes without lesioning the brain in the process. MATERIALS AND METHODS: We used stereotactic radiosurgery to deliver doses from 10 Gy to 120 Gy to the left primary motor cortex (M1) of Lee Sung miniature pigs (n = 8). One additional animal served as a nonirradiated control. We used positron emission tomography-computed tomography (PET-CT) to quantify radiation dose-dependent effects by calculating the ratio of standard uptake values (SUV) of 2-deoxy-2-[18 F]-fluoro-D-glucose (18 F-FDG) between the radiated (left) and irradiated (right) hemispheres across nine months. RESULTS: We found that the FDG-PET SUV ratio at the targeted M1 was significantly lowered from the pre-radiation baseline measurements for animals receiving 60 Gy or higher, with the effect persisting at nine months after radiosurgery. Only at 120 Gy was a lesion suggesting ablation visible at the M1 target. Animals treated at 60-100 Gy showed a reduced signal in the absence of an identifiable lesion, a result consistent with the occurrence of neuromodulation. CONCLUSION: Focal, noninvasive, and durable changes in brain activity can be induced without a magnetic resonance imaging (MRI)-visible lesion, a result that may be consistent with the occurrence of neuromodulation. This approach may provide new venues for the investigation of neuromodulatory treatments for disorders involving dysfunctional brain circuits. Postmortem pathological analysis is needed to elucidate whether there have been morphological changes not detected by MRI.

2021 Advocacy Statements for the Role of 99mTc-Pyrophosphate Scintigraphy in the Diagnosis of Transthyretin Cardiac Amyloidosis: A Report of the Taiwan Society of Cardiology and the Society of Nuclear Medicine of the Republic of China.

Transthyretin cardiac amyloidosis (ATTR-CM) is an increasingly recognized cause of heart failure with preserved ejection fraction. Favorable prognosis depends on early diagnosis and correct treatment strategy. Among patients for whom there is a high clinical suspicion of cardiac amyloidosis, 99mTc-labeled bone avid scintigraphy including 99mTc-pyrophosphate (PYP) scintigraphy may be of diagnostic and prognostic importance. Various international guidelines support the non-biopsy diagnosis of ATTR-CM using 99mTc-PYP scintigraphy, yet emphasize the gap in standardization of acquisition and imaging analysis protocols, as well as the appropriateness of its clinical use. Therefore, a joint expert consensus has been reached by the Taiwan Society of Cardiology and the Society of Nuclear Medicine of the Republic of China, to advocate for the application of 99mTc-PYP scintigraphy in the diagnosis of ATTR-CM. This article aims to highlight the recommendations on image acquisition, qualitative and quantitative assessments of cardiac 99mTc-PYP uptake, and diagnostic algorithms. We hope the implementation of these recommendations in Taiwan will facilitate the process and enhance the diagnostic rate of ATTR-CM.

Superficial Cerebellar Microbleeds and Cerebral Amyloid Angiopathy: A Magnetic Resonance Imaging/Positron Emission Tomography Study.

Background and Purpose- The differentiation between cerebral amyloid angiopathy (CAA) and hypertensive small vessel disease in primary intracerebral hemorrhage is mainly based on hemorrhagic neuroimaging markers in the supratentorial regions, and the cause for cerebellar microbleeds remains unknown. Our aim was to investigate whether superficial cerebellar microbleeds are more likely to be related to CAA rather than hypertensive small vessel disease. Methods- Two hundred seventy-five consecutive patients with intracerebral hemorrhage were retrospectively reviewed from a prospectively maintained hospital-based stroke registry. Eighty-five (33.1%) patients had cerebellar microbleeds and were categorized into superficial (gray matter, vermis), deep (white matter, deep nucleus, cerebellar peduncle), or mixed type based on the location of cerebellar hemorrhagic lesions. Amyloid imaging was obtained using 11C-Pittsburgh Compound B-positron emission tomography in a subgroup of patients. The associations between cerebellar microbleed locations and the type of small vessel disease (CAA versus hypertensive small vessel disease) based on distribution of supratentorial hemorrhagic lesions as well as other magnetic resonance imaging and positron emission tomography markers were analyzed. Results- The presence of cerebellar microbleed was independently associated with supratentorial microbleed and lacunar infarcts (both P<0.01). Strictly superficial cerebellar microbleeds were significantly related to CAA-intracerebral hemorrhage, cortical superficial siderosis and high-grade enlarged perivascular space in centrum semiovale (all P<0.05); deep or mixed cerebellar microbleeds were related to hypertension and deep microbleed (all P<0.05). In multivariable models, superficial cerebellar microbleeds were independently associated with CAA-intracerebral hemorrhage (P=0.03). Of 33 patients assessed by amyloid positron emission tomography, cerebral and cerebellar amyloid load (standardized uptake value ratio) was higher in patients with superficial cerebellar microbleeds compared with deep/mixed cerebellar microbleeds (cerebrum standardized uptake value ratio [reference: cerebellum] 1.33±0.24 versus 1.05±0.09, P<0.001; cerebellum standardized uptake value ratio [reference: pons] 0.58±0.08 versus 0.51±0.09, P=0.03). Conclusions- Patients with strictly superficial cerebellar microbleeds are associated with a clinicoradiological diagnosis of CAA as well as increased cerebral and cerebellar amyloid deposition on Pittsburgh Compound B-positron emission tomography, suggesting underlying CAA pathology.

Clinical significance of quantitative assessment of glucose utilization in patients with ischemic cardiomyopathy.

BACKGROUND: The aim of this study was to prospectively quantify the rate of myocardial glucose uptake (MRGlu) in myocardium with different perfusion-metabolism patterns and determine its prognostic value in patients with ischemic cardiomyopathy. METHODS AND RESULTS: 79 patients with ischemic cardiomyopathy were prospectively enrolled for dynamic cardiac FDG PET, and then followed for at least 6 months. Perfusion-metabolism patterns were determined based on visual score analysis of 201Tl SPECT and FDG PET. MRGlu was analyzed using the Patlak kinetic model. The primary end-point was cardiovascular mortality. Significantly higher MRGlu was observed in viable compared with non-viable areas. Negative correlations were found between MRGlu in transmural match and a history of hyperlipidemia, statin usage, and triglyceride levels. Diabetic patients receiving dipeptidyl peptidase-4 inhibitors (DPP4i) had a significantly lower MRGlu in transmural match, mismatch, and reverse mismatch. Patients with MRGlu in transmural match ≥ 23.40 or reverse mismatch ≥ 36.90 had a worse outcome. CONCLUSIONS: Myocardial glucose utilization was influenced by substrates and medications, including statins and DPP4i. MRGlu could discriminate between viable and non-viable myocardium, and MRGlu in transmural match and reverse mismatch may be prognostic predictors of cardiovascular death in patients with ischemic cardiomyopathy.

Targeting histone deacetylase 4/ubiquitin-conjugating enzyme 9 impairs DNA repair for radiosensitization of hepatocellular carcinoma cells in mice.

Several strategies to improve the efficacy of radiation therapy against hepatocellular carcinoma (HCC) have been investigated. One approach is to develop radiosensitizing compounds. Because histone deacetylase 4 (HDAC4) is highly expressed in liver cancer and known to regulate oncogenesis through chromatin structure remodeling and controlling protein access to DNA, we postulated that HDAC4 inhibition might enhance radiation's effect on HCC cells. HCC cell lines (Huh7 and PLC5) and an ectopic xenograft were pretreated with HDAC inhibitor or short hairpin RNA to knock down expression of HDAC4 and then irradiated (2.5-10.0 Gy). We evaluated cell survival by a clonogenic assay; apoptosis by Annexin V immunofluorescence; γH2AX, Rad51, and HDAC4 by immunofluorescence staining; HDAC4, Rad51, and ubiquitin-conjugating enzyme 9 (Ubc9) in HCC cell nuclei by cell fractionation and confocal microscopy; physical interaction between HDAC4/Rad51/Ubc9 by immunoprecipitation; and the downstream targets of HDAC4 knockdown by immunoblotting. Both HDAC4 knockdown and HDAC inhibitor enhanced radiation-induced cell death and reduced homologous recombination repair of DNA double-strand breaks and protein kinase B activation, leading to increased apoptosis. HDAC4 knockdown with or without an HDAC inhibitor significantly delayed tumor growth in a radiation-treated xenograft model. Radiation stimulated nuclear translocation of Rad51 in an HDAC4-dependent manner and the binding of Ubc9 directly to HDAC4, which led to Ubc9 acetylation. Moreover, these effects were accompanied by HDAC4/Ubc9/Rad51 complex dissociation through inhibiting nuclear translocation. Conclusion: HDAC4 signaling blockade enhances radiation-induced lethality in HCC cells and xenografts. These findings raise the possibility that HDAC4/Ubc9/Rad51 complex in DNA repair may be a target for radiosensitization of HCC. (Hepatology 2018;67:586-599).

Predicting tumor responses and patient survival in chemoradiotherapy-treated patients with non-small-cell lung cancer using dynamic contrast-enhanced integrated magnetic resonance-positron-emission tomography.

PURPOSE: We investigated whether radiologic parameters by dynamic contrast-enhanced (DCE) integrated magnetic resonance-positron-emission tomography (MR-PET) predicts tumor response to treatment and survival in non-metastatic non-small-cell lung cancer (NSCLC) patients receiving chemoradiotherapy (CRT). METHODS: Patients underwent DCE integrated MR-PET imaging 1 week before CRT. The following parameters were analyzed: primary tumor size, gross tumor volume, maximal standardized uptake value (SUVmax), total lesion glycolysis (TLG), apparent diffusion coefficient (ADC), volume transfer constant (Ktrans), reverse reflux rate constant (kep), extracellular extravascular volume fraction (ve), blood plasma volume fraction (vp), and initial area under the time-concentration curve defined over the first 60 s post-enhancement (iAUC60). CRT responses were defined using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). RESULTS: Thirty patients were included. Non-responders demonstrated higher baseline TLG (p = 0.012), and lower baseline Ktrans (p = 0.020) and iAUC60 (p = 0.016) compared to responders, indicating the usefulness of DCE integrated MR-PET to predict treatment responses. Receiver operating characteristic curve indicated that TLG has the best differentiation capability to predict responders. By setting the threshold of TLG to 277, the sensitivity, specificity, and accuracy were 66.7%, 83.3%, and 75.0%, respectively, with an area under the curve of 0.776. The median follow-up time was 19.6 (range 7.8-32.0) months. In univariate analyses, baseline TLG >277 (p = 0.005) and baseline Ktrans <254 (10-3 min-1; p = 0.015) correlated with poor survival after CRT. In multivariate analysis, baseline TLG >277 remained the significant factor in predicting progression (p = 0.012) and death (p = 0.031). CONCLUSIONS: The radiologic parameters derived from DCE integrated MR-PET scans are useful for predicting treatment response in NSCLC patients treated with CRT; furthermore, these parameters are correlated with clinical and survival outcomes including tumor progression and death.

Improved diagnostic accuracy of thallium-201 myocardial perfusion single-photon emission computed tomography with CT attenuation correction.

BACKGROUND: The benefits of attenuation correction (AC) in technetium-99m myocardial perfusion imaging (MPI) have been well established. However, the value of thallium (Tl-201) AC and routine computed tomography AC (CTAC) were less well established. The aims of this study were to evaluate the diagnostic performance of thallium (Tl-201) MPI with additional CTAC and to determine which participants would benefit most. METHODS AND RESULTS: A total of 108 consecutive patients who underwent Tl-201 MPI and received coronary angiography within 3 months were enrolled. Diagnostic performance was determined by sensitivity, specificity, and receiver operating characteristic curve analysis. Subgroup analyses were performed using gender and obesity. CTAC improved the area under the curve (0.84 vs. 0.77, P = 0.037 at patient level), primarily due to a significant improvement in specificity (0.78 vs. 0.57, P = 0.013) and no significant difference in sensitivity (0.79 vs. 0.82, P = 0.75). In subgroup analysis, CTAC was most helpful in obese subjects, men, and especially right coronary artery lesions. CONCLUSIONS: CTAC significantly improved diagnostic performance primarily by increasing the specificity, and the improvements were significantly greater in obese patients and male patients. These findings suggest that CTAC should be applied to Tl-201 MPI as routine clinical practice.

Distribution of Lacunar Infarcts in Asians With Intracerebral Hemorrhage: A Magnetic Resonance Imaging and Amyloid Positron Emission Tomography Study.

BACKGROUND AND PURPOSE: We evaluated whether lacunes in centrum semiovale (lobar lacunes) were associated with cerebral amyloid angiopathy (CAA) markers in an Asian intracerebral hemorrhage (ICH) population. METHODS: One hundred ten patients with primary ICH were classified as CAA-ICH (n=24; mean age, 70.9±13.9) or hypertensive ICH (n=86; mean age, 59.3±13.0) according to the presence of strictly lobar (per modified Boston criteria) or strictly deep bleeds (both ICH and cerebral microbleeds), respectively. Lacunes were evaluated in the supratentorial area and classified as lobar or classical deep based on the location. A subgroup of 36 patients also underwent Pittsburgh Compound B positron emission tomography to measure cerebral amyloid deposition and global standardized uptake value ratio were calculated. RESULTS: Lobar lacunes were more frequent in CAA-ICH than hypertensive ICH (29.2 versus 11.6%; P=0.036). In multivariable models, lobar lacunes were associated with lobar cerebral microbleed (odds ratio, 6.8; 95% confidence interval, 1.6-29.9; P=0.011) after adjustment for age, sex, hypertension, and white matter hyperintensity. In 15 CAA-ICH and 21 hypertensive ICH patients with Pittsburgh Compound B positron emission tomography, correlation analyses between lobar lacune counts and global standardized uptake value ratio showed positive association (ρ=0.40; P=0.02) and remained significant after adjustment for age (r=0.34; P=0.04). CONCLUSIONS: Our findings expand on recent work showing that lobar lacunes are more frequent in CAA-ICH than hypertensive ICH. Their independent association with lobar cerebral microbleeds and brain amyloid deposition suggests a relationship with CAA even in an Asian cohort with overall higher hypertensive load.

Impact of initial myocardial perfusion imaging versus invasive coronary angiography on outcomes in coronary artery disease: a nationwide cohort study.

PURPOSE: In patients with stable coronary artery disease (CAD), two main options exist to guide management: initial invasive coronary angiography (CAG), or selective CAG after risk stratification using myocardial perfusion imaging (MPI). This study compared clinical outcomes between these two strategies in a large, real-world population. METHODS: The initial cohort comprised 1,000,000 randomly selected patients who had been entered in the National Health Insurance Research Database of Taiwan between 2000 and 2011. Patients with acute coronary syndromes, prior myocardial infarction (MI) or coronary revascularization, and prior treadmill testing or stress echocardiography were excluded. The remaining patients with suspected or known CAD were divided into those in whom initial CAG had been performed and those in whom initial MPI had been performed, and were followed until the end of 2011 for all-cause mortality, MI, and revascularization. A Cox proportional hazards model was used to estimate the risk of events after adjusting for covariates. RESULTS: The MPI and CAG groups each comprised 4,495 patients after frequency matching, with a similar Charlson comorbidity index (CCI). The MPI group had a significantly and dramatically lower incidence of revascularization (729 vs. 2,380, p < 0.001), MI (268 vs. 1,044, p < 0.001), and all-cause mortality (522 vs. 784, p < 0.001) than the CAG group. Multivariable analysis adjusting for age, gender, CCI, and comorbidities showed that in the MPI group fewer patients had revascularization (HR 0.24, 95% CI 0.22-0.26) and MI (HR 0.23, 95% CI 0.20-0.26), and the rate of all-cause mortality was lower (HR 0.58, 95% CI 0.52-0.64). CONCLUSIONS: In patients with suspected stable CAD, compared with initial invasive CAG, a selective strategy guided by MPI was associated with lower rates of revascularization and MI and improved survival.