Retrospective Analysis of the Clinical Characteristics of Patients with Breast Cancer Treated with Telomerase Peptide Immunotherapy Combined with Cytotoxic Chemotherapy.

Purpose: Telomerase activation, a critical step in cancer progression, occurs in approximately 95% of breast cancer cases. Telomerase is an attractive therapeutic target for breast cancer owing to its unique expression pattern. GV1001, a telomerase-derived peptide, is loaded onto human leukocyte antigen (HLA) class II antigen-presenting cells and binds to CD4+ T cell activating immune responses. This study aimed to evaluate the effectiveness and safety of co-administration of GV1001 and cytotoxic chemotherapy in patients with heavily-treated metastatic breast cancer. Patients and methods: We analyzed 63 patients with breast cancer who received both GV1001 and cytotoxic chemotherapy. The GV 1001 administration methods involves 0.56 mg intradermal injection three times during the first week, one time at weeks 2, 3, 4, and 6, and then once every 28 days. The primary endpoint of this study was quality of life according to EORTC QLO-C30 and EQ-5D, while the secondary endpoint was the antitumor response according to RECIST 1.1, progression-free survival, overall survival, and toxicity profile. Results: In 34 patients with HR+ breast cancer evaluable for tumor response, the disease control rate (DCR) and overall response rate (ORR) were 58.8% and 26.4%, respectively. The DCR and ORR were 66.6% and 28.5% in 21 patients with HER-2+ and 50% and 25% in patients with triple-negative breast cancer (TNBC), respectively. The median progression free survival was 10.4, 8.7, and 5.6 months in HR+, HER-2+, TNBC, respectively. The overall survival was 19.7, 13.2, and 9.4 months for patients with HR+, HER-2+, and TNBC, respectively. Most patients had an improved quality of life with statistically significant differences in some variables. The patients in this study experienced no additional toxicities other than the cytotoxic chemotherapy-associated side effects. Conclusion: GV1001 is a relatively safe anticancer vaccine for patients with heavily-treated breast cancer and can to improve the quality of life.

Survival in Korean Patients with Frontotemporal Dementia Syndrome: Association with Behavioral Features and Parkinsonism.

We investigated the survival time of each clinical syndrome of frontotemporal dementia (FTD) and the impacts of behavioral and motor features on survival of FTD. A total of 216 patients with FTD [82 behavioral variant FTD (bvFTD), 78 semantic variant primary progressive aphasia (svPPA), 43 non-fluent/agrammatic variant PPA (nfvPPA), 13 FTD-motor neuron disease (MND)] were enrolled from 16 centers across Korea. Behaviors and parkinsonism were assessed using the Frontal Behavioral Inventory and Unified Parkinson's Disease Rating Scale Part III, respectively. The Kaplan-Meier method was used for the survival analysis and the Cox proportional hazards model was applied for analysis of the effect of behavioral and motor symptoms on survival, after controlling vascular risk factors and cancer. An overall median survival of FTD was 12.1 years. The survival time from onset was shortest for FTD-MND and longest for svPPA. The median survival time of patients with bvFTD was unavailable but likely comparable to that of patients with nfvPPA. In the bvFTD group, negative behavioral symptoms and akinetic rigidity were significantly associated with survival. In the nfvPPA group, the presence of dysarthria had a negative impact on survival. These findings provide useful information to clinicians planning for care.

The Influence of Amyloid Burden on Cognitive Decline over 2 years in Older Adults with Subjective Cognitive Decline: A Prospective Cohort Study.

BACKGROUND: Subjective cognitive decline (SCD) is a self-perceived cognitive worsening without objective cognitive impairment. Due to its heterogeneity and potential risk of Alzheimer's disease (AD), baseline biomarkers to predict progression are clinically important. In the present study, cognitive trajectories during a 24-month period were compared between amyloid-positive SCD (A+SCD) and amyloid-negative SCD (A-SCD) subjects, and biomarkers associated with memory decline were investigated. METHODS: Data from a prospective cohort study in Korea between 2016 and 2019 were analyzed. SCD subjects ≥50 years of age were eligible. All participants underwent neuropsychological tests, brain magnetic resonance imaging, and florbetaben positron emission tomography scans. Amyloid burden and regional volumes were measured. Cognitive changes corrected for age were compared between A+SCD and A-SCD groups. Biomarkers associated with memory decline were assessed. RESULTS: Forty-seven SCD subjects (69.9 ± 6.7 years, mini-mental state examination (MMSE) score 27.5) were enrolled, and 31 completed at least 1 annual follow-up (mean follow-up: 24.7 months). Baseline characteristics except age, hippocampal atrophy, and white matter hyperintensities were similar between A+SCDs (n = 12, 25.6%) and A-SCDs (n = 35). A+SCD subjects showed greater decline in the verbal memory function compared with the A-SCD subjects after adjustment for age. MMSE scores decreased more in the A+SCD (1.1 in the A+SCD; 0.55 in the A-SCD), although it was not statistically significant. Amyloid burden and baseline memory score were associated with memory decline. CONCLUSIONS: Within SCD, A+SCD subjects showed faster memory decline compared with the A-SCD subjects and amyloid burden might be associated with future memory decline in SCD.

Thalamo-cortical network underlying deep brain stimulation of centromedian thalamic nuclei in intractable epilepsy: a multimodal imaging analysis.

OBJECTIVE: Deep brain stimulation (DBS) of the centromedian thalamic nucleus (CM) can be an alternative treatment option for intractable epilepsy patients. Since CM may be involved in widespread cortico-subcortical networks, identification of the cortical sub-networks specific to the target stimuli may provide further understanding on the underlying mechanisms of CM DBS. Several brain structures have distinguishing brain connections that may be related to the pivotal propagation and subsequent clinical effect of DBS. METHODS: To explore core structures and their connections relevant to CM DBS, we applied electroencephalogram (EEG) and diffusion tensor imaging (DTI) to 10 medically intractable patients - three generalized epilepsy (GE) and seven multifocal epilepsy (MFE) patients unsuitable for resective surgery. Spatiotemporal activation pattern was mapped from scalp EEG by delivering low-frequency stimuli (5 Hz). Structural connections between the CM and the cortical activation spots were assessed using DTI. RESULTS: We confirmed an average 72% seizure reduction after CM DBS and its clinical efficiency remained consistent during the observation period (mean 21 months). EEG data revealed sequential source propagation from the anterior cingulate, followed by the frontotemporal regions bilaterally. In addition, maximal activation was found in the left cingulate gyrus and the right medial frontal cortex during the right and left CM stimulation, respectively. From DTI data, we confirmed concrete structural connections between CM and those maximal activation spots identified from EEG data. CONCLUSION: These results suggest that the anterior cingulate can be a core cortical structure for the bilateral propagation of CM stimulation. Our DTI findings also indicate that the propagation of CM stimulation may rely upon integrity of structural connections between CM and these key cortical regions. Structures and their connections found in this study may be relevant in the interpretation of the clinical outcomes of CM DBS.

Voxel-based analysis of Tc-99m ECD brain perfusion SPECT in patients with normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a reversible dementia characterized by gait disturbance, incontinence and dementia. This study investigates the neuropsychological characteristics and changes of regional cerebral blood flow (rCBF) in patients with iNPH. Ten patients who met the criteria of probable iNPH and 13 normal control subjects were evaluated. The general cognitive function and detailed neuropsychological functions were measured by K-MMSE and comprehensive neuropsychological battery. Tc-99m-ethyl cysteinate dimmer (Tc-99m-ECD) single photon emission computed tomography (SPECT) was performed to measure the rCBF and statistical parametric mapping (SPM) and statistical probabilistic brain anatomic map (SPAM) was applied to the objective analysis of SPECT data. On the neuropsychological examination, all the patients showed abnormality in memory, psychomotor speed and frontal executive function. SPM analysis of SPECT images revealed that rCBF in bilateral thalami, right prefrontal area, bilateral anterior and posterior cingulate gyri, right caudate nucleus, and left parahippocampal gyrus was significantly decreased in patients with iNPH compared to normal controls (uncorrected P<0.005). In SPAM analysis, rCBF reduction was observed in bilateral prefrontal area, anterior, posterior cingulate gyri and caudate nuclei. We have found that rCBF changes occurred predominantly in prefrontal and subcortical areas, the changes were associated with frontal subcortical circuit, and the affected frontal subcortical circuit may contribute to the cognitive decline seen in the iNPH patients. The reduction of rCBF and clinical cognitive impairment are closely connected in patients with iNPH.

A Tc-99m SPECT study of regional cerebral blood flow in patients with transient global amnesia.

OBJECTIVES: This study aimed to determine whether regional cerebral blood flow (rCBF) is abnormal in patients who have Transient Global Amnesia (TGA). METHODS: We obtained noninvasive rCBF measurements using Tc-99m-ethyl cysteinate diamer Single Photon Emission Computed Tomography (SPECT) in 7 patients diagnosed with TGA within 4 days of onset of the amnestic episode while the patients were still symptomatic and in 17 age-matched healthy control subjects. We assessed memory functioning using the Hopkins's Verbal Learning Test (HVLT) and Statistical Parametric Mapping to compare rCBF across diagnostic groups. RESULTS: The patients with TGA were significantly impaired in their performance on the 20-minute delayed recall of the HVLT. They also exhibited significantly decreased rCBF on their SPECT scans in the inferior and middle frontal gyrus bilaterally, with more prominent left-sided reductions in the superior temporal, precentral, and postcentral gyri, as well as increased rCBF primarily in the right hemisphere within the middle temporal, superior temporal, and inferior frontal gyri, cerebellum, and thalamus, compared with the normal control group. CONCLUSION: These findings suggest that lateralized abnormalities in brain functioning are an important component of the pathophysiology of TGA. Lateralized abnormalities may disrupt functions that are relatively specific to the left hemisphere, including receptive language, symbolic representation, and the processing of local features in the environment, while preserving anterograde memory processes. Increased flow to the right hemisphere centered on regions that subserve the functions of expressive language and visuospatial processing, and may represent processes that compensate for flow reductions to the left hemisphere.

Incidental unruptured intracranial aneurysms in patients with acute ischemic stroke.

BACKGROUND: The management and clinical prognosis of incidental intracranial aneurysms in acute ischemic stroke patients have been understudied. We investigated the clinical outcome of acute ischemic stroke subjects with incidentally found intracranial aneurysms. METHODS: We consecutively included acute ischemic stroke patients within 7 days of onset. Their demographics, risk factors, stroke subtypes, antithrombotics use and modified Rankin scale (mRS) at 3 months after stroke were obtained. CT or MR angiography was used to diagnose the intracranial aneurysms. The development of an aneurysmal rupture was checked during the following 3 months. RESULTS: Incidental intracranial aneurysms were found in 17 (6.6%) of the 258 patients. The female sex and old age were associated with the presence of incidental intracranial aneurysms (p = 0.001, 0.032). The most common site of aneurysm was at the distal internal carotid artery (n = 9), followed by the middle cerebral artery (n = 6). The diameters of the aneurysms ranged from 2.09 to 8.06 mm. All the participants except 1 who had cancer were taking antiplatelet agents. No aneurysmal rupture or subarachnoid hemorrhage happened until 3 months after stroke.There was no significant difference in excellent outcome (3-month mRS = 0, 1) between the patients with an aneurysm and those without (28.6 vs. 53.4%, p = 0.097). CONCLUSION: There was no rupture of the incidentally found aneurysms in the patients with acute ischemic stroke during their first 3 months. The 3-month mRS was not affected by the presence of incidental intracranial aneurysm. A large cohort study and long-term follow-up are required.

Effect of chronic deep brain stimulation of the subthalamic nucleus for frontal lobe epilepsy: subtraction SPECT analysis.

OBJECTIVES: Experimental data and case reports of patients with intractable epilepsy treated with deep brain stimulation (DBS) of the subthalamic nucleus (STN) suggest a considerable anticonvulsant effect. However, no satisfactory mechanisms of action have yet been elucidated. We investigated the putative therapeutic mechanisms of DBS from cerebral perfusion changes as measured by subtracting the SPECT image of the pre-DBS period from that of the chronic post-DBS state. METHODS: Two patients who had previous resective surgery on their right frontal cortices with or without anterior callosotomy were selected for DBS of the STN. Both of them showed frequent bilateral asymmetric tonic seizures (left > right) with rare drop attacks, and 1 patient's seizure frequency was more than 15/month during the pre-DBS period. They had both taken more than four antiepileptic agents for more than 10 years. After video-EEG monitoring, the irritative zones of the brain were delineated. The regional cerebral blood flow (rCBF) changes between the two SPECT images (pre-DBS and post-DBS after at least 6 months) were analyzed by SPECT subtraction with the volumetric MRI coregistration method using Analyze 5.0 software. RESULTS: After chronic STN DBS (18 months, case 1; 6 months, case 2), both patients experienced markedly reduced seizure frequencies (86.7% reduction in patient 1, 88.6% in patient 2). In patient 1, the increased rCBF was observed in the right frontal areas (dorsolateral and inferior frontal area), which corresponded to the irritative zones as confirmed by previous EEG recording. Unexpectedly, there was definite hyperperfusion in the right superior and inferior temporal areas as well as rCBF increase in the right superior frontal area (SMA) in patient 2. CONCLUSIONS: We demonstrated that the cerebral perfusion increase in the irritative zones of epilepsy patients is associated with favorable seizure reduction after STN DBS in 2 cases of frontal lobe epilepsy. Although the exact mechanism remains unknown, our findings suggest that the perfusion changes after STN DBS in frontal lobe epilepsy patients are quite different from those in subjects with Parkinson's disease. Our preliminary data suggest the clinical relevance of subtraction SPECT imaging in assessing the postprocedural outcome as well as the characteristics of SPECT perfusion patterns in other epilepsy syndromes.

Analysis of cerebral blood flow of subcortical vascular dementia with single photon emission computed tomography: adaptation of statistical parametric mapping.

BACKGROUND AND OBJECTIVES: Subcortical vascular dementia (VaD) is a relatively homogeneous subtype of VaD, but the mechanisms of cognitive dysfunction of subcortical VaD are not fully understood. This study investigates the changes of cerebral blood flow (CBF) in patients with subcortical VaD and the contribution of the white matter hyperintensity (WMHI) and clinical severity to CBF changes. METHODS: 99mTc-ethyl cysteinate dimer single photon emission computed tomography (SPECT) was performed to measure the regional CBF and statistical parametric mapping SPM99 software was applied to automated and objective analysis of the SPECT image data. Twenty-three patients (12 male, 11 female) with mild to moderate dementia who met both the criteria of the DSM-IV and probable and possible NINDS-AIREN for VaD and had subcortical white matter changes and lacunar infarctions in brain MRI were evaluated against 17 normal control subjects (7 male, 10 female). The severity of the WMHI was measured by the semi-quantitative scale method proposed by Mäntyla. The Clinical Dementia Rating scale measured the severity of dementia. RESULTS: SPM analysis of the SPECT image reveals significantly reduced regional CBF in the right thalamus, left caudate nucleus, cingulate, bilateral superior temporal, and left ventral subcallosal gyri in subcortical VaD patients compared to the normal controls (corrected P<0.001). Of four WMHIs, only the deep WMHI was associated with the small CBF reduction in the left superior temporal gyrus (uncorrected P<0.01). The reduction of the CBF according to the severity of dementia was noted in the anterior and posterior association areas (uncorrected P<0.01). CONCLUSIONS: Our study suggests that cognitive dysfunction of subcortical VaD may be related to the reduction of the CBF in the brain areas mentioned, which are probably not associated with the severity of periventricular WMHI and dementia.