[Dynamic activity model of movement disorders: a unified view to understand their pathophysiology].

Malfunction of the basal ganglia leads to movement disorders such as Parkinson's disease, dystonia, Huntington's disease, dyskinesia, and hemiballism, but their underlying pathophysiology is still subject to debate. To understand their pathophysiology in a unified manner, we propose the "dynamic activity model", on the basis of alterations of cortically induced responses in individual nuclei of the basal ganglia. In the normal state, electric stimulation in the motor cortex, mimicking cortical activity during initiation of voluntary movements, evokes a triphasic response consisting of early excitation, inhibition, and late excitation in the output stations of the basal ganglia of monkeys, rodents, and humans. Among three components, cortically induced inhibition, which is mediated by the direct pathway, releases an appropriate movement at an appropriate time by disinhibiting thalamic and cortical activity, whereas early and late excitation, which is mediated by the hyperdirect and indirect pathways, resets on-going cortical activity and stops movements, respectively. Cortically induced triphasic response patterns are systematically altered in various movement disorder models and could well explain the pathophysiology of their motor symptoms. In monkey and mouse models of Parkinson's disease, cortically induced inhibition is reduced and prevents the release of movements, resulting in akinesia/bradykinesia. On the other hand, in a mouse model of dystonia, cortically induced inhibition is enhanced and releases unintended movements, inducing involuntary muscle contractions. Moreover, after blocking the subthalamic nucleus activity in a monkey model of Parkinson's disease, cortically induced inhibition is recovered and enables voluntary movements, explaining the underlying mechanism of stereotactic surgery to ameliorate parkinsonian motor signs. The "dynamic activity model" gives us a more comprehensive view of the pathophysiology underlying motor symptoms of movement disorders and clues for their novel therapies.

[Parkinson's Disease as a Network Disorder].

Network disorders of the basal ganglia may underlie the pathophysiology of movement disorders, such as Parkinson's disease and dystonia. The following models have been proposed to explain network disorders: (1) the firing rate model: an activity imbalance between the direct, indirect, and hyperdirect pathways induces changes in the mean firing rate of the output nuclei of the basal ganglia and causes hypokinetic or hyperkinetic movement disorders, (2) the firing pattern model: oscillatory and/or synchronized activity in the basal ganglia disturbs information processing in this area, resulting in motor symptoms and, (3) the dynamic activity model: abnormal neuronal modulations through the direct, indirect, and hyperdirect pathways disrupt the balance between movement-related inhibition and surrounding excitation in the output nuclei, which leads to motor symptoms. We present a critical analysis of these models in this review. Stereotactic surgery, which involves the application of high-frequency electrical stimulation (deep brain stimulation) or coagulation of a small area in the basal ganglia is an effective therapeutic strategy to treat movement disorders. We have also discussed the mechanism underlying the beneficial effects of stereotactic surgery.

Focal loss of the paranodal domain protein Neurofascin155 in the internal capsule impairs cortically induced muscle activity in vivo.

Paranodal axoglial junctions are essential for rapid nerve conduction and the organization of axonal domains in myelinated axons. Neurofascin155 (Nfasc155) is a glial cell adhesion molecule that is also required for the assembly of these domains. Previous studies have demonstrated that general ablation of Nfasc155 disorganizes these domains, reduces conduction velocity, and disrupts motor behaviors. Multiple sclerosis (MS), a typical disorder of demyelination in the central nervous system, is reported to have autoantibody to Nfasc. However, the impact of focal loss of Nfasc155, which may occur in MS patients, remains unclear. Here, we examined whether restricted focal loss of Nfasc155 affects the electrophysiological properties of the motor system in vivo. Adeno-associated virus type5 (AAV5) harboring EGFP-2A-Cre was injected into the glial-enriched internal capsule of floxed-Neurofascin (NfascFlox/Flox) mice to focally disrupt paranodal junctions in the cortico-fugal fibers from the motor cortex to the spinal cord. Electromyograms (EMGs) of the triceps brachii muscles in response to electrical stimulation of the motor cortex were successively examined in these awake mice. EMG analysis showed significant delay in the onset and peak latencies after AAV injection compared to control (Nfasc+/+) mice. Moreover, EMG half-widths were increased, and EMG amplitudes were gradually decreased by 13 weeks. Similar EMG changes have been reported in MS patients. These findings provide physiological evidence that motor outputs are obstructed by focal ablation of paranodal junctions in myelinated axons. Our findings may open a new path toward development of a novel biomarker for an early phase of human MS, as Nfasc155 detects microstructural changes in the paranodal junction.

Retrograde gene transfer into neural pathways mediated by adeno-associated virus (AAV)-AAV receptor interaction.

BACKGROUND: Viral vector systems delivering transgenes in the retrograde direction through axons to neural cell bodies are powerful experimental tools for the functional analysis of specific neural pathways. Generally, the efficiency of viral vector-mediated retrograde gene transfer depends on the expression of requisite viral receptors in neural pathways projecting to the viral vector-injected regions. This is known as viral tropism and can limit the utility of retrograde viral vectors. The adeno-associated virus (AAV) vector has become an increasingly popular platform for gene delivery to neural cells in vivo, and it is therefore meaningful to develop a new type of retrograde gene transfer approach based on a tropism-free AAV vector system. NEW METHOD: The wild-type or mutant receptor gene of AAV was expressed to mitigate AAV tropism. RESULTS: Efficient AAV vector-mediated retrograde gene transfer was observed in diverse neural pathways by expression of the AAV receptor (AAVR) gene. Moreover, the expression of a minimal mutant of AAVR (miniAAVR), which maintains binding potential to AAV, demonstrated efficient retrograde gene expression comparable to that of AAVR. COMPARISON WITH EXISTING METHODS: The utility of existing AAV vector-mediated retrograde gene delivery methods is sometimes limited by tropism. Our newly developed AAV-AAVR and AAV-miniAAVR interaction approaches enabled efficient retrograde gene transfer into various neural pathways by mitigating tropism. CONCLUSIONS: AAV-AAVR and AAV-miniAAVR interaction approaches enabled us to induce efficient retrograde gene expression in targeted neural pathways and provide a powerful tool for analyzing specific neural pathways.

Forelimb movements evoked by optogenetic stimulation of the macaque motor cortex.

Optogenetics has become an indispensable tool for investigating brain functions. Although non-human primates are particularly useful models for understanding the functions and dysfunctions of the human brain, application of optogenetics to non-human primates is still limited. In the present study, we generate an effective adeno-associated viral vector serotype DJ to express channelrhodopsin-2 (ChR2) under the control of a strong ubiquitous CAG promoter and inject into the somatotopically identified forelimb region of the primary motor cortex in macaque monkeys. ChR2 is strongly expressed around the injection sites, and optogenetic intracortical microstimulation (oICMS) through a homemade optrode induces prominent cortical activity: Even single-pulse, short-duration oICMS evokes long-lasting repetitive firings of cortical neurons. In addition, oICMS elicits distinct forelimb movements and muscle activity, which are comparable to those elicited by conventional electrical ICMS. The present study removes obstacles to optogenetic manipulation of neuronal activity and behaviors in non-human primates.

Recruitment of calbindin into nigral dopamine neurons protects against MPTP-Induced parkinsonism.

BACKGROUND: Parkinson's disease is caused by dopamine deficiency in the striatum, which is a result of loss of dopamine neurons from the substantia nigra pars compacta. There is a consensus that a subpopulation of nigral dopamine neurons that expresses the calcium-binding protein calbindin is selectively invulnerable to parkinsonian insults. The objective of the present study was to test the hypothesis that dopamine neuron degeneration might be prevented by viral vector-mediated gene delivery of calbindin into the dopamine neurons that do not normally contain it. METHODS: A calbindin-expressing adenoviral vector was injected into the striatum of macaque monkeys to be conveyed to cell bodies of nigral dopamine neurons through retrograde axonal transport, or the calbindin-expressing lentiviral vector was injected into the nigra directly because of its predominant uptake from cell bodies and dendrites. The animals in which calbindin was successfully recruited into nigral dopamine neurons were administered systemically with MPTP. RESULTS: In the monkeys that had received unilateral vector injections, parkinsonian motor deficits, such as muscular rigidity and akinesia/bradykinesia, appeared predominantly in the limbs corresponding to the non-calbindin-recruited hemisphere after MPTP administration. Data obtained from tyrosine hydroxylase immunostaining and PET imaging for the dopamine transporter revealed that the nigrostriatal dopamine system was preserved better on the calbindin-recruited side. Conversely, on the non-calbindin-recruited control side, many more dopamine neurons expressed α-synuclein. CONCLUSIONS: The present results indicate that calbindin recruitment into nigral dopamine neurons protects against the onset of parkinsonian insults, thus providing a novel approach to PD prevention. © 2018 International Parkinson and Movement Disorder Society.

Significance of Low-Attenuation Cluster Analysis on Quantitative CT in the Evaluation of Chronic Obstructive Pulmonary Disease.

Objective: To assess clinical feasibility of low-attenuation cluster analysis in evaluation of chronic obstructive pulmonary disease (COPD). Materials and Methods: Subjects were 199 current and former cigarette smokers that underwent CT for quantification of COPD and had physiological measurements. Quantitative CT (QCT) measurements included low-attenuation area percent (LAA%) (voxels ≤ -950 Hounsfield unit [HU]), and two-dimensional (2D) and three-dimensional D values of cluster analysis at three different thresholds of CT value (-856, -910, and -950 HU). Correlation coefficients between QCT measurements and physiological indices were calculated. Multivariable analyses for percentage of predicted forced expiratory volume at one second (%FEV1) was performed including sex, age, body mass index, LAA%, and D value had the highest correlation coefficient with %FEV1 as independent variables. These analyses were conducted in subjects including those with mild COPD (global initiative of chronic obstructive lung disease stage = 0-II). Results: LAA% had a higher correlation coefficient (-0.549, p < 0.001) with %FEV1 than D values in subjects while 2D D-910HU (-0.350, p < 0.001) revealed slightly higher correlation coefficient than LAA% (-0.343, p < 0.001) in subjects with mild COPD. Multivariable analyses revealed that LAA% and 2D D value-910HU were significant independent predictors of %FEV1 in subjects and that only 2D D value-910HU revealed a marginal p value (0.05) among independent variables in subjects with mild COPD. Conclusion: Low-attenuation cluster analysis provides incremental information regarding physiologic severity of COPD, independent of LAA%, especially with mild COPD.

Silencing of FUS in the common marmoset (Callithrix jacchus) brain via stereotaxic injection of an adeno-associated virus encoding shRNA.

Fused in sarcoma (FUS) is an RNA binding protein that is involved in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To establish the common marmoset (Callithrix jacchus) as a model for FTLD, we generated a stereotaxic injection-based marmoset model of FUS-silencing. We designed shRNAs against the marmoset FUS gene and generated an AAV9 virus encoding the most effective shRNA against FUS (shFUS). The AAV encoding shFUS (AAV-shFUS) was introduced into the frontal cortex of young adult marmosets, whereas AAV encoding a control shRNA was injected into the contralateral side. We obtained approximately 70-80% silencing of FUS following AAV-shFUS injection. Interestingly, FUS-silencing provoked a proliferation of astrocytes and microglias. Since FTLD is characterized by various emotional deficits, it would be helpful to establish a marmoset model of FUS-silencing in various brain tissues for investigating the pathomechanism of higher cognitive and behavioral dysfunction.

Pulmonary Apical Opacities on Thin-Section Computed Tomography: Relationship to Primary Spontaneous Pneumothorax in Young Male Patients and Corresponding Histopathologic Findings.

OBJECTIVE: The purpose of this study was to test the hypothesis that apical opacities on computed tomography (CT) are related to occurrence of primary spontaneous pneumothorax (PSP) in young male patients. METHODS: We compared the frequency of apical opacities on thin-section CT between 70 male patients with PSP (PSP group) and 74 male patients without a history of PSP (non-PSP group). We also evaluated histopathologic findings of 39 specimens from 37 surgical cases in the PSP group. RESULTS: Apical opacities were significantly more frequent in the PSP group than in the non-PSP group (right side, P = 0.01; left side, P = 0.005). Histopathologically, subpleural band-like alveolar collapse was seen in 35 specimens (89.7%), which was always accompanied by fibroelastosis and fibroblastic foci. CONCLUSIONS: Apical opacities on CT were significantly associated with PSP in young male patients. These apical opacities histopathologically correspond to fibrotic pleural thickening with subpleural alveolar collapse.

Adeno-Associated Virus-Mediated Gene Transfer into Taste Cells In Vivo.

The sense of taste is achieved by cooperation of many signaling molecules expressed in taste cells, which code and transmit information on quality and intensity of taste to the nervous system. Viral vector-mediated gene transfer techniques have been proven to be useful to study and control function of a gene product in vivo However, there is no transduction method for taste cells in live animals. Here, we have established a method for inducing foreign gene expression in mouse taste cells in vivo by recombinant adeno-associated virus (AAV) vector. First, using enhanced green fluorescent protein (EGFP) as a reporter, we screened 6 AAV serotypes along with a recombinant lentivirus vector for their ability to transduce taste cells. One week after viral injection into the submucosa of the tongue, EGFP expression in fungiform taste cells was observed only in animals injected with AAV-DJ, a synthetic serotype. Next, time course of AAV-DJ-mediated EGFP expression in fungiform taste cells was evaluated. Intragemmal EGFP signals appeared after a delay, rapidly increased until 7 days postinjection, and gradually decreased over the next few weeks probably because of the cell turnover. Finally, the taste cell types susceptible to AAV-DJ transduction were characterized. EGFP expression was observed in PLCß2-immunoreactive type II and aromatic l-amino acid decarboxylase (AADC)-immunoreactive type III taste cells as well as in cells immunonegative for both PLCß2 and AADC, demonstrating that AAV-DJ does not discriminate functional taste cell types. In conclusion, the method established in this study will be a promising tool to study the mechanism of taste.

Rabies virus-mediated oligodendrocyte labeling reveals a single oligodendrocyte myelinates axons from distinct brain regions.

Oligodendrocytes myelinate neuronal axons during development and increase conduction velocity of neuronal impulses in the central nervous system. Neuronal axons extend from multiple brain regions and pass through the white matter; however, whether oligodendrocytes ensheath a particular set of axons or do so randomly within the mammalian brain remains unclear. We developed a novel method to visualize individual oligodendrocytes and axon derived from a particular brain region in mouse white matter using a combinational injection of attenuated rabies virus and adeno-associated virus. Using this method, we found that some populations of oligodendrocytes in the corpus callosum predominantly ensheathed axons derived from motor cortex or sensory cortex, while others ensheathed axons from both brain regions, suggesting heterogeneity in preference of myelination toward a particular subtype of neurons. Moreover, our newly established method is a versatile tool for analyzing precise morphology of each oligodendrocyte in animal models for demyelinating disorders and addressing the role of oligodendrocyte in higher brain functions. GLIA 2016. GLIA 2017;65:93-105.

Quantitative computed tomography measurements to evaluate airway disease in chronic obstructive pulmonary disease: Relationship to physiological measurements, clinical index and visual assessment of airway disease.

PURPOSE: To correlate currently available quantitative CT measurements for airway disease with physiological indices and the body-mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index in patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: This study was approved by our institutional review board (IRB number 2778). Written informed consent was obtained from all subjects. The subjects included 188 current and former cigarette smokers from the COPDGene cohort who underwent inspiratory and expiratory CT and also had physiological measurements for the evaluation of airflow limitation, including FEF25-75%, airway resistance (Raw), and specific airway conductance (sGaw). The BODE index was used as the index of clinical symptoms. Quantitative CT measures included % low attenuation areas [% voxels≤950 Hounsfield unit (HU) on inspiratory CT, %LAA-950ins], percent gas trapping (% voxels≤-856HU on expiratory CT, %LAA -856exp), relative inspiratory to expiratory volume change of voxels with attenuation values from -856 to -950HU [Relative Volume Change (RVC)-856 to -950], expiratory to inspiratory ratio of mean lung density (E/I-ratio MLD), Pi10, and airway wall thickness (WT), luminal diameter (LD) and airway wall area percent (WA%) in the segmental, subsegmental and subsubsegmental bronchi on inspiratory CT. Correlation coefficients were calculated between the QCT measurements and physiological measurements in all subjects and in the subjects with mild emphysema (%LAA-950ins <10%). Univariate and multiple variable analysis for the BODE index were also performed. Adjustments were made for age, gender, smoking pack years, FEF25-75%, Raw, and sGaw. RESULTS: Quantitative CT measurements had significant correlations with physiological indices. Among them, E/I-ratio MLD had the strongest correlations with FEF25-75% (r=-0.648, <0.001) and sGaw (r=-0.624, <0.001) while in the subjects with mild emphysema subsegmental WA% and segmental WA% had the strongest correlation with FEF25-75% (r=-0.669, <0.001) and sGaw (r=-0.638, <0.001), respectively. The multiple variable analyses showed that RVC-856 to -950 was an independent predictor of the BODE index showing the highest R2 (0.468) as an independent variable among the QCT measurements. CONCLUSION: Quantitative CT measurements of gas trapping such as E/I-ratio MLD, correlate better with physiological indices for airway disease than those of airway such as WA% or LD. In mild emphysema, however, quantitative CT measurements of airway correlate better with the physiological indices. RVC-856 to -950 is a predictor of the BODE index.

Survival of corticostriatal neurons by Rho/Rho-kinase signaling pathway.

Developing cortical neurons undergo a number of sequential developmental events including neuronal survival/apoptosis, and the molecular mechanism underlying each characteristic process has been studied in detail. However, the survival pathway of cortical neurons at mature stages remains largely uninvestigated. We herein focused on mature corticostriatal neurons because of their important roles in various higher brain functions and the spectrum of neurological and neuropsychiatric disorders. The small GTPase Rho is known to control diverse and essential cellular functions through some effector molecules, including Rho-kinase, during neural development. In the present study, we investigated the role of Rho signaling through Rho-kinase in the survival of corticostriatal neurons. We performed the conditional expression of Clostridium botulinum C3 ADP-ribosyltransferase (C3 transferase) or dominant-negative form for Rho-kinase (Rho-K DN), a well-known inhibitor of Rho or Rho-kinase, respectively, in corticostriatal neurons using a dual viral vector approach combining a neuron-specific retrograde gene transfer lentiviral vector and an adeno-associated virus vector. C3 transferase markedly decreased the number of corticostriatal neurons, which was attributed to caspase-3-dependent enhanced apoptosis. In addition, Rho-K DN produced phenotypic defects similar to those caused by C3 transferase. These results indicate that the Rho/Rho-kinase signaling pathway plays a crucial role in the survival of corticostriatal neurons.

Solitary synovial chondromatosis arising in the gluteus maximus bursa: computed tomography and magnetic resonance imaging findings.

Chondral tumors in soft tissue are referred to as soft-tissue chondromas or extraskeletal chondromas, or as synovial chondromatosis if they arise in synovial tissue. We report the case of a 29-year-old man with synovial chondromatosis, also called synovial osteochondromatosis, which appeared in a solitary and extra-articular form. On magnetic resonance imaging (MRI) and computed tomography, the central portion of the tumor showed similar characteristics to bone marrow, despite the absence of any connection to adjacent bone. T2-weighted imaging displayed marked peripheral hyperintensity consistent with a cartilaginous area. These findings suggested the presence of enchondral ossification and were similar to those of skeletal osteochondroma, with the exception of the absence of attachment to bone. MRI is useful for distinguishing solitary synovial chondromatosis from other lesions, such as myositis ossificans, extraskeletal chondrosarcoma, and parosteal osteosarcoma.

Prognostic Value of Semiautomatic CT Volumetry in Patients With Stage I Non-Small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy.

OBJECTIVE: The aim of this study was to examine the prognostic value of semiautomated 3-dimensional image analysis-based parameters from pretreatment computed tomography (CT) in patients with non-small cell lung cancer treated with stereotactic body radiation therapy. METHODS: We evaluated 91 patients. We defined 2 parameters: (1) VOL, extracted tumor volume with a threshold ≥ -400 HU; and (2) ATN, the mean CT attenuation value. The maximum standardized uptake value (SUVmax) was recorded as F-fluorodeoxyglucose positron emission tomography/CT parameter. The prognostic values were assessed using the Kaplan-Meier and a Cox proportional hazards analysis. RESULTS: Overall survival and progression-free survival were significantly worse in patients with larger VOL, higher ATN, and higher SUVmax. VOL was an independent indicator of overall survival, whereas ATN was an indicator of progression-free survival, lymph node recurrence, and distant metastasis. However, SUVmax was not an independent prognostic factor for either outcome. CONCLUSIONS: VOL and ATN from 3-dimensional image analysis of CT scans have prognostic values for non-small cell lung cancer patients treated with stereotactic body radiation therapy.

Mechanism of Deep Brain Stimulation: Inhibition, Excitation, or Disruption?

Deep brain stimulation (DBS), applying high-frequency electrical stimulation to deep brain structures, has now provided an effective therapeutic option for treatment of various neurological and psychiatric disorders. DBS targeting the internal segment of the globus pallidus, subthalamic nucleus, and thalamus is used to treat symptoms of movement disorders, such as Parkinson's disease, dystonia, and tremor. However, the mechanism underlying the beneficial effects of DBS remains poorly understood and is still under debate: Does DBS inhibit or excite local neuronal elements? In this short review, we would like to introduce our recent work on the physiological mechanism of DBS and propose an alternative explanation: DBS dissociates input and output signals, resulting in the disruption of abnormal information flow through the stimulation site.

A Case of Massive Bone Metastases From Lung Cancer Detected Only by 18F-FDG PET/CT.

A 74-year-old man was diagnosed with small cell lung carcinoma in the left upper lobe. (18)F-FDG PET/CT showed multifocal strong abnormal uptakes in the axial skeleton and those of the primary lung tumor. CT failed to demonstrate the bony abnormalities. A subsequent (99m)Tc-MDP bone scintigraphy was also almost negative. It is important to note that bone metastasis may be undetectable by both CT and bone scintigraphy even if it is massive.

Relationships between diffusing capacity for carbon monoxide (DLCO), and quantitative computed tomography measurements and visual assessment for chronic obstructive pulmonary disease.

PURPOSE: To evaluate the relationships between DLCO, and Quantitative CT (QCT) measurements and visual assessment of pulmonary emphysema and to test the relative roles of visual and quantitative assessment of emphysema. MATERIALS AND METHODS: The subjects included 199 current and former cigarette smokers from the COPDGene cohort who underwent inspiratory and expiratory CT and also had diffusing capacity for carbon monoxide corrected for alveolar volume (DLCO/VA). Quantitative CT measurements included % low attenuation areas (%LAA-950ins=voxels ≤-950 Hounsfield unit (HU), %LAA-910ins, and %LAA-856ins), mean CT attenuation and 15th percentile HU value on inspiratory CT, and %LAA-856exp (voxels ≤-856 HU on expiratory CT). The extent of emphysema was visually assessed using a 5-point grading system. Univariate and multiple variable linear regression analyses were employed to evaluate the correlations between DLCO/VA and QCT parameters and visual extent of emphysema. RESULTS: The DLCO/VA correlated most strongly with 15th percentile HU (R(2)=0.440, p<0.001) closely followed by %LAA-950ins (R(2)=0.417, p<0.001) and visual extent of emphysema (R(2)=0.411, p<0.001). Multiple variable analysis showed that visual extent of emphysema and 15th percentile HU were independent significant predictors of DLCO/VA at an R(2) of 0.599. CONCLUSIONS: 15th percentile HU seems the best parameter to represent the respiratory condition of COPD. Visual and Quantitative CT assessment of emphysema provide complementary information to QCT analysis.

Whole-body total lesion glycolysis measured on fluorodeoxyglucose positron emission tomography/computed tomography as a prognostic variable in metastatic breast cancer.

BACKGROUND: In this retrospective study, the authors evaluated the prognostic value of whole-body total lesion glycolysis (WTLG) on FDG/PET images in metastatic breast cancer (MBC) patients. METHODS: We retrospectively evaluated 54 MBC patients who were diagnosed as having one or more metastatic lesions between June 2005 and March 2013. Twenty-four patients were diagnosed at the initial presentation (group A) and 30 patients were diagnosed for the first time at some point after a surgery (group B). Patients were excluded if they had received chemotherapy within 30 days before PET/CT. SUVmax and total TLG were calculated for all lesions in each patient and the highest SUVmax and the whole-body TLG (WTLG) values were used as independent variables for the analyses. Mean ages and the proportions of histopathological subtypes were compared between two groups using Mann-Whitney U test and Fisher's exact test, respectively. The prognostic significance of PET parameters was assessed using Cox proportional hazards regression analysis. RESULTS: For groups A and B, the median follow-up period was 26 months (range, 3-58 months) and 40.5 months (range, 3-69 months), and the median age was 61 years (range, 42-81 years) and 59 years (range, 24-74 years), respectively. There were no significant differences between two groups in age (p = 0.294) or histopathological subtype (p = 0.384). In the univariate analyses, WTLG was found to be significantly associated with overall survival (OS) for patients of group A (p = 0.012). In the multivariate analysis, WTLG was also significantly associated with OS (p = 0.015). Only hormonal receptor level was a significant indicator of longer OS in patients with recurrent MBC (group B). CONCLUSIONS: This study demonstrated that WTLG on PET/CT is an independent prognostic factor for survival in breast cancer patients with metastases at the initial presentation.